New amines
The invention relates to novel compounds of the formula (I). The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I) and especially their use as renin inhibitors in cardiovascular events and renal insufficiency.
in the renin-angiotensin system (RAS) the bioiogically active angiotensin II (Aug 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 AT| and AT2. Whereas AT| 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 AT] blockers have been accepted to treat hypertension
(Waeber B. el ai, 'The renin-angiotensin system: role in experimental and human hypertension", in Birkenhager W. H., Reid J. L. (eds): Hyperlemion, Amsterdam. Elsevier Science Publishing Co, 1986, 489-519; Weber M. A.,m. J. Hypertem.. 1992. 5. 247S). In addition. ACE inhibitors are used for renal protection (Rosenberg M. E. et a!.. Kidney Intemalional. 1994. 45, 403: Breyer J. A. et aU Kidney Jntevnalional. 1994, 45. SI 56). in the prevention of congestive heart failure (Vaughan D. E. et ciL. Cardiovasc. Res- 1994. 28. 159: Fouad-Tarazi F. el al. Am- J. Med, 1988, 5- (SuppL 3Jj, 83) and myocardial infarction (Pfeffer M. A. el al., N. Engl. J- Med.., 1992, 327. 669).
The rationale to develop renin inhibitors is the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The only substrate known for renin is angiotensinogen. which can only be processed (under physiological conditions) by renin. In contrast, ACE can also cleave bradykinin besides Ang I and can be by-passed by chymase, a serine protease (Husain A.. J. Hyperlens.. 1993, //, 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 2. H. et al, Annah of Interna! 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 AT | receptor {e.g. by iosartan) on the other hand overexposes other AT-receptor subtypes (e.g. AT) to Ang 11. whose concentration is significantly increased by the blockade of ATj 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.er a/.. J, Hvperiens.. 1994. 72, 419; Neutel J. M. e! a!.. Am. Heai-l, 1991, 722. 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 slopped because of this problem together with the high cost of goods. Only one compound containing four chiral centers has entered cUnical trials (Raliuel J.ei o/., Chem. Bio!.. 2000, 7, 493; Mealy M. E.. Drugs of the Fulvre, 2001, 26, 1139). Thus, renin inhibitors with good oral bioavailability and long duration of action are required. Recently, the first non-peptide renin iuhibitors were described which show high in vitro activity' (Oefner C. et al.. Chcm. Bio!., 1999. 6. 127; Patent Application WO 97/0931!; MSrki H. P. et al., II 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 (1) which have a long duration of action and which are active in indications beyond blood pressure regulation where the tissular renin-chymase system mav be activated leading to pathophysiologically altered local functions such as renal, cardiac and vascular remodelling, 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)


W represents a /7ara-substituted phenyl, a /fara-substituted pyridinyi, or a thiazoiyl, such as especialiy/jara-substituted phenyl or

V represents -CH2CH:CH2-, -CH;CH2-A-, -CH2-A-CH2-. -A-CH;CH;-. -CHCHCHCH.-, -A-CH2CH2CH2-. -CH2-A-CH2CH2-, -CH2CH2-A-CH:-, -CH2CH.CH.-A-. -A-CH2CH2-B- (preferred), -CH2CH2CH2CH2CH2-, -A-CHjCH.CH.CH;-, -CH2-A-CH2CH2CH2-. -CH2CH:-A-CH2CH2-. -CH2CH2CH2-A-CH2-. -CH.CHCHCH-A-. -A-CH2CH2CH2-B-. -CH2-A-CH2CH2-B-, -A-CH2CH2-B-CH2-, -A-CH2CH2CH2-B-CH2-, -CH2-A-CH2CH2CH2-B-, or -O-CH2-Q- (also preferred), wherein Q is bound to the group U of formula (I), or (also preferably) V represents a pyrrolidinyl of the formula:


U represenis unsubstituted aryl, especially phenyl; mono-, di-, tri- or tetra-substituted arj'l (especially mono- di-, tri-. or tetra-substituted phenyl), wherein the substituenis are independently selected from the group consisting of C|_7-alkyl (such as especially methyl). -CF3, halogen, and hydroxy-C!_7-alkyi; or five-membered heteroaryl with two heteroatoms independently selected from nitrogen, oxygen and sulphur (preferably pyrazolyl or isoxazolyl), wherein said heteroaryl radical is opTionally mono-, di- or tri-substituted, wherein the substitutents are independently selected from the group consisting of C1-7-alkyl, C|_7-alkoxy, -CF3, -OCF3, and halogen;
0 represenis a five-membered heteroaryl with two or three heteroatoms independently selected from O and N, preferably an isoxazolyl, especially an isoxazolyl that is connected to the rest of the molecule of formula (I) as follows:

L represents -CH2-CH2-, -CH.-CHCRVCHS-. -CH2->J(R')-CH2-. -CHJ-O-CH:-, or -CH3-S-CH2-:
A and B represent independently from each others -O- or -S-:
R' represents C|.7-alkyl or cycioalkyl. preferably cycloalkyl such as especially cyclopropyl:
R represents halogen or Ci-7-alkyl, preferably chloro or methyl;
R represents hydrogen, halogen, Ci-7-alkyl (such as especially methyl), Ci.7-alkoxy, or -CF3;
R represents hydrogen; C,.7-a!kyl-0-(CH2)(i-4-CH3-: CFrOCFbjrM-CH-; R■2>J-(CH2)0-4-CH2-, wherein R' is independently selected from the group consisting of hydrogen. C1.7-

alkyi (optionally but preferably substituted by one Eo three fluorine), cyclopropyi (optionally substituted by one to three fluorine), cyclopropyl-C,_7-alkyi (optionally but preferably substituted by one to three fluorine), and -C(=0)-R"" wherein R" is C|_4-alkyl, C,_4-aikoxy. -CF3, -CH;-CF3, or cyclopropyi; or R'-'-C(=0)-{0)O,|-(CH:;)O-4-, wherein R'- is CM-alkyl, CM-alkoxy, or cyclopropyi; wherein R' and R" preferably do not both simultaneously represent hydrogen;
R represents hydroxy, Ct-7-alkoxy, hydroxy-Ci.7-alkyl, dihydroxy-Ci.y-alkyl. Ci.y-alkoxy-C|.7-alkyl. C,_7-alkoxy-C|_7-alkoxy-Ci.7-alkyl, hydroxy-C|.7-alkoxy-Ci.7-alkyl, carbamoyl-Ci.7-alkoxy. or Ci-7-alkyl-carbonyloxy;
R represents -H. -CHsOR -CHjNRR, -CHSNRCOR', -CH.NRSOR". -COR -CH20C0NR*R -CONRR -CH2NRC0NR'R -CH:S02NRRI -CH2SR -CH.SORI or -CH7S02R;

wherein T represents -CH2-, -NH- or -0-, r is an integer from I to 6 and s is an integer from 1 to 4;
R and R"' independently represent hydrogen, Ci-7-aiky!. C2-7-alkenyL cycloalkyl. or cycloalkyl-Ci.7-a!kyl. wherein Ci-7-alkyl, cycloalkyl, and cycloa!kyl-C].7-alkyl can be substituted by one, two. or three halogens;
R represents hydrogen, C|.7-alkyl, cycioalkyl, or cycloa!kyl-C|.7-alkyl. wherein C|.7-aikyl, cycloalkyl, and cycloalkyl-C|.7-alkyl may be mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, -OCOR'', -C00R'\ C|.7-a!koxy, cyano, SOJR'I -CONR'-R'', morphoiin-4-yl-CO-. ((4-C,.7-alkyl)piperazin-l-yl)-C0-, -NHC(TsiH)NH2, -NR'R'"' and Ci.T-alkyl, with the proviso

that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp-hybridized;
R"' and R'"' independently represent hydrogen, C,,7-a]kyl, cycloaikyi. cycloalkyl-Ci.?-alkyl. hydroxy-C,_7-a[ky]. -COORI or -CONHj:
R' ' represents haiogen, C|_7-alkyl, Ci.7-aikoxy, -CF, or hydrogen;
R'- and R'' independently represent hydrogen. C,.7-alkyl. C:.7-a!kenyl, cycloaikyi. or cycloa!kyl-C|.7-alkyl, wherein Ci.7-alkyl, cycloaikyi, and cycioa!kyi-C].7-alkyl can be substituted by one, two, or three halogens:
n represents the integer 0 or i, especially 0; and
m represents the integer 0 or 1, especially i, with the proviso that m represents the integer 1 if n represents the integer 1;
and salts thereof.
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 salts (especially pharmaceuticaliy acceptable salts) of a compound of formula (1). as appropriate and expedient.
The term Ci-7-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. Ci-alkyl. Examples of Ci-y-alkyl groups are methyl, ethyl, n-propyl, iso-propy!, n-butyl, iso-butyl, sec-butyl, tert-butyl, penty!, hexyl and heptyl. The methyl, ethyl and isopropyl groups are preferred.

The tenn C(_7-alkoxy, alone or in combination witti other groups, refers to an R-0- group, whierein R is a Ci.i-ail-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 liydroxide and the like. For other examples of pharmaceutical ly acceptable salts, reference can be made to "Salt selection for basic drugs". Int. J. Phann. (1986). 33, 201-217.
The compounds of the formula (I) may contain asymmetric carbon atoms. Substiluents at a double bond or a ring may be prtsmt in cis- (= Z-) or trans (- E-) form unless indicated otherwise. The compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known per xe, e.g. by column chromatography, thin layer chromatography. HPLC or crystallization.
Compounds of the invention also include nitrosated compounds of formula (I) that have been nitrosated through one or more sites such as oxygen (hydroxy! condensation), suifur (sullydryl 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 preferred embodiment of the present invention relates to a compound of formula (1). viherein X represents 'H-O' and R'* represents Ci-4-alkoxy-C(=0)-NH-(CH:)o.4-CH2- or R'-C(=0)-(0)(>I-{CH2)(4-, wherein R'"' is Ci-4-alkyl. C|_(-alkoxy. or cyclopropyi.
A preferred embodiment of the present invention relates to a compound of formula (1). wherein X represents CH orN; and
R* represents hydrogen: C,.7-alkyl-0-(CH2)a-!-CH.-: CF:,-0-{CH2)(M-CH2-: or RN-(CH2)o-4-CH2-, wherein R' is independently selected from the group consisting of hydrogen, Ci-7-alkyl (optionally substituted by one to three fluorine), cyclopropyi (optionally substituted by one to three fluorine), cyclopropyl-Ci_7-alkyl (optionally substituted by one to three fluorine), and -C(=0)-R" wherein R'' is CM-alkyI, -CF3, -CHr CF3, or cyclopropyi.

A preferred embodiment of the present invention relates to a compound of formula (I), wherein X represents CH orN-O".
A preferred embodiinent of the present invention relates to a compound of formula (I), wherein R represents -R -COR -COOR", -CONRR". -C(NR)NR'R -CSNRR'*. -S02R".or-S03NRR
A preferred embodiment of the present invention relates to a compound of formula (I), wherein A and B both represent -0-.
A preferred embodiment of the present invention relates to a compound of formula (I), wherein R represents -CO2CH3 or -CO2H.
A preferred embodiment of the present invention relates to a compound of formula (1), wherein R represents -H. -COCH3, -C(NH)NH2. -CONHCH2C(CH.-i)2CONH2. -CONHCH(CH2)2, or -CONHC(CH2}2C>J.
A preferred embodiment of the present invention relates to a compound of formula (1), wherein R represents -H.
A preferred embodiment of the present invention relates to a compound of formula (1). wherein L represents -CH2-CH2- or -CH2-NH-CH2-.
A preferred embodiment of the present invention relates to a compound of formula (1). wherein R' represents cyclopropyl.
A preferred embodiment of the present invention relates to a compound of formula (1), wherein W represents a/Jaro-substituted phenyl, or


A preferred embodiment of the present invention relates to a compound of formula (1), wherein V represents -O-CH2CH2-O-. -0-CH:-Q-, -CH2-CH:-0- wherein the -CH; pan of-CH2-CH:-0- is bound to the group W of formula 0), or

A preferred embodiment of the present invention relates to a compound of formula (i). wherein V represents -O-CH2CH2-O- or -O-CH2-Q-.
A preferred embodiment of the present invention relates to a. compound of formula (1), wherein Q represents an isoxazolyj or an oxadiazolyl.
A preferred embodiment of the present invention relates to a compound of formula {!). wherein Q represents an isoxazolyl, especialiy an isoxazolyl that is connected to the rest of the molecule of formula (1) as follows:

A preferred embodiment of the present invention relates to a compound of formula (1). wherein V-W represents;

A preferred embodiment of the present invention relates to a compound of formula (1), wherein U represents:


A preferred embodiment of the present invention relates to a compound of formula (I), wherein R" represents Ci, and R"* represents hydrogen.
A preferred embodiment of the present invention relates to a compound of formula (I), wherein R' represents CH3-0-(CH2)2-3- or CH3-C(=0)-NH-CH2-CH2-.
A preferred embodiment of the present invention relates to a compound of formula (1), wherein R represents -CH2CH2CH2-O-CH3 or -CH2CH2-O-CH3.
A preferred embodiment of the present invention relates to a compound of formula {!)-wherein R"* represents -CH2CH2-0--CH5.
A preferred embodiment of the present invention relates to a compound of formula (I), wherein R represents hydroxy.
A preferred embodiment of the present invention relates to a compound of formula (I), wherein n represents the integer 0.
A preferred embodiment of the present invention relates to a compound of formula (I), wherein the moiety


An especially preferred embodiment of the present invention relates to a compound of formula (i), wherein
X represents CH, N, orN"'-0";
W represents a /lora-substituted phenyl or a /ora-substituted pyridiny!, wherein the pyridinyl is especially connected to the rest of the molecule of formula (1) as follows:

U represents tri-substituted phenyl, wherein the substituenls are independently selected from the group consisting of Ci_7-alkyl (such as especially methyl) and halogen:

Q represents an isoxazolyl, especially an isoxazolyl that is connected to the rest of the molecule of formula fl) as follows:

A and B both represent -0-;
R* represents cyciopropyl;
R" represents halogen or Ci.7-a(ky!, especially chloro or methyl;
R represents hydrogen or C].7-a!k.yl, especially hydrogen or methyl;
R represents C,.7-aikyl-0-(CH2)o-CH:-, especiaOy CHrO-(CH2)f.2-CH-;
R' represents hydroxy;
n represents the integer 0; and
m represents the integer 1.
A pvefeired embodiment of the present invention relates to a compound of formula (I). wherein the absolute configuration of a compound of formula (I) is as represented for formula (V):


The present invention also relates to compounds of formula (I) wherein the meanings of one or more of tlie substituents and symbols as defined for formula (I), or a preferred embodiment of formula (J), are replaced by their preferred meanings as defined herein, such as those defined for the above-given preferred embodiments.
A preferred embodiment of the present invention relates to a compound of formula (I), which is (3S*\ -/i;*)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-4-hydroxy-pipendme-3-carboxyl(cacidcyc!opropyl-(2,3-dimethyl-benzy!)-amide.
Another preferred embodiment of the present invention relates to a compound of formula (1) selected from:
{3S, -/./)-4-{4-[2-(2,6-dichIoro-4-methyl-phenoxy)-ethoxy]-phenyl}-4-hydroxy-piperidine-3-carboxylicacid [2-chioro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amide,
{3% '/'i;)-6-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-4'-hydroxy-r,2',3',4',5',6'-
hexahydro-[3.4']bipyridinyl-3'-carboxylic acid [2-chloro-5-(2-methoxy-ethyl)-ben2yl]-cyciopropyi-amide,
{3'S, 'i?)-6-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-4'-hydroxy-
r.2',j',4'.5',6'-hexahydro-[3,4']bipyridinyI-3'-carboxylic acid [2-chioro-5-(2-methoxy-ethy O-benzy I ] -cyclopropyl -am ide,
(S'S, 7;)-6-[(i;)-3-(2,6-dichloro-4-methyl-phenoxy)-pyrroiidin-]-yl]-4'-hydroxy-
]',2',3',4'.5',6'-hexahydro-[34']bipyridinyl-3'-carboxylic acid [2-chloro-5-{2-methoxy-ethy I )-benzy I ]-cycl opropy i-ami de,
(3'S. 'ii)-6-[2-(2.6-dichloro-4-methyl-phenoxy)-ethoxy]-4'-hydroxy-i'.2'.3'.4'.5'.6'-
hexahydro-[3.4']bipyridinyl-3'-carboxylic acid [5-chloro-2-(3-methoxy-propyl)-pyridin-4-ylmethyl]-cyciopropyl-amide, and
{3'S, -;'fi)-6-[2-(2,6-dich!oro-4-methyl-phenoxy)-ethoxy]-4'-hydroxy-r.2'.3',4'.5',6'-
hexahydro-[3.4']bipyridinyl-3'-carboxyiic acid [5-chloro-2-(3-methoxy-propyl)-l-oxy-pyridin-4-ylmethyl]-cyclopropyi-amide.
The compounds of formula (1) are useful for the treatment and/or prophylaxis of diseases such as or related to hypertension, congestive heart failure, pulmonary hypertension, renal

nsufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac lypertrophv, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomeriiionepbntis. ■enai colic, compiications resulting from diabetes such as nephropathy, vasculopathy and leuropatliy. glaucoma, elevated intra-ocuiar pressure, atherosclerosis, restenosis post ingiopiasty, complications following vascular or cardiac surgery, erectile dysfunction, lyperafdosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications 5f treatments with immunosuppressive agents, and other diseases related to the renin-mgiotensin system.
The compounds of formula (J) are especiaSl}' usefu] for the treatment and/or prophylaxis of lypertension. congestive heart failure, pulmonar>' hypertension, renal insufficiency, renal schemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac Tibrosis, myocardial ischemia, cardiomyopathy, compiications resulting from diabetes such IS nephropathy, vasculopathy and neuropathy.
In one embodiment, the invention relates to a method for the treatment and/or prophylaxis 3f diseases, which are associated with a dysregulation of the renin-angiotensin system, in particular to a method for the treatment and/or prophylaxis of the above-mentioned diseases, said methods comprising administering to a patient a pharmaceuticaliy active amount of a compound of formtila (I).
A. further aspect of the present invention relates to pharmaceutical compositions :;ompris!ng a compound of formula (I) and a pharmaceuticaliy acceptable carrier material. These pharmaceutical compositions may be used for the treatment and/or prophylaxis of the above-mentioned diseases. The phannaceutical compositions can be used for enteral parenteral, or topical administration. They can be administered, for example, peroralfy, 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 (!) for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above-mentioned diseases.

The production of the pharinaceuticai compositions can be effected in a manner which wit! be familiar to an> person skilled in the art (see for exainple 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, 11 beta-hydroxysteroid dehydrogenase type I inhibitors, soluble guanylate cyclase activators and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases.
The present invention also relates to pro-drugs of a compound of formula (I) that convert in vivo to the compound of formula (I) as such. Any reference to a compound of formula (1) is therefore to be understood as referring also to the corresponding pro-drugs of the compound of formula (1), as appropriate and expedient.
The compounds of formula (!) can be manufactured by the methods outlined below, by the methods described in the examples or by analogous methods.
A compound of type A {see patent applications WO 2003/093267, WO 2004/002957, WO 2004/096769. WO 2004/096803, WO 2004/096799, and WO 2004/096366) as described in Scheme 1 can be transformed into a compound of type B, wherein L" stands for a precursor of the group L as defined for formula (1), and R for a typical ester substituent, like methyl, ethyl, or benzyl. PG stands for a suitable protecting group, typically a carbamate, a benzyl, or a methvl. Scheme 1 represents a compound of formula (I) wherein m is the integer 1: the same scheme can be used if m and n represent the integers 0, but m was omitted in the

Scheme for the purpose of clarity. L' can be modified along the synthesis. The amine has to be prepared separately (vide infra for specific examples). An alkylafion of the ketone of a compound of type B leads to a compound of type C, or. if the U-V-W-segment is already achieved, to a compound of type D. V stands for a precursor of V as defined for formula (i), and can be transformed along the synthesis. Achievement of the U-V-W-segment in a compound of type C leads to a compound of type D. Alkyiation or acyiation of the tertiary alcohol in a compound of type D leads to a compound of type E. Final achievement of the L-substituent leads to a compound of type F. Deprotection will finally yield a compound of formula (I).

The alkyiation of a compound of type B to a compound of type C yields a mixture of diastereoisomers. These diastereoisomers can be separated at this stage, or at any later stage (compounds of type D, E. F, or compound of formula (1)).
The preparation of several U-V-W- or V'-W-substituents is described in the patent applications mentioned earlier. Otherwise a pyrrolidine substituent can be attached to an aromatic ring by a copper- or palladium-catalysed coupling as described in Scheme 2.

Under certain circumstances a transition metal is not necessary to catalyse this reaction. A compound of type G, wherein PG" stands for a suitable protecting group, will be transformed into a compound of type H, wherein X' stands for CH or "N. If W in formula (I) represents a thiazolyl, the same chemistry can be applied as well.

If V represents -O-CHi-Q-, the isoxazoiyi moiety is prepared by cycloaddition. This cycloaddition can be realized on the W-V-fragment in a compound of type C, leading to a compound of type D as described in Scheme J. Otherwise the cycloaddition can be performed separately as, for instance, described in Scheme 3. Cycloaddition on a compound of type J with an often commerciaDy available aldehyde leads to a compound of type K. Of course the aldehyde moiety can be built on the W-V-fragment, and a compound of the form U-CCH can be constructed, to give after cycloaddition another iso\azolyl moiety. The same principles can be used to prepare oxadiazoiyi moieties, using methodologies described in the literature.

Also a hydroxy methyl isoxazole (Scheme 4) can be prepared from the aldehyde mentioned in Scheme 3 and propargyl alcohol. Coupling to a phenyl or heteroaryl derivative, wherein X" typically stands for -OH, -Br, or -I. leads to a compound of type K.


The following examples serve to illustrate the present invention in more details. They are. however, not intended to limit its scope in any manner.
Experimental Part
Abbreviations (as used herein):
AcOH acetic acid
Ang angiotensin
aq. aqueous
Boc ;ert-butyloxycarbony3
BSA bovine serum album ine
Bu butyl
BuLi ?7-buty]lithiLim
Cy cyclohexyi
dba dibenzylidene acetone
DIPEA diisopropylethylamine
DMAP 4-A',A'-dimethytaminopyridine
DMF A'-dimethyiformamide
DMPU L3-dimethy!-3,4,5,6-tetrahydro-2{l//)-pyrimidinone
DMSO dimethy]sulfoxide
dppp 1,3-bis(diphenylphosphino)propane
EDC-HCI ethyl-AHV-dimethylaminopropylcarbodiimide hydrochloride
EIA enzyme immunoassay

ELSD evaporative light scattering detection
eq. equivalent(s)
ES electrospray
ES- electrospray, positive ionization
Et ethyl
EtOAc ethyl acetate
EtOH ethanoi
FC flash chromatography
h hour(s)
HOBt hydroxybenzotriazol
HPLC high performance liquid chromatography
LC-MS liquid chromatography - mass spectroscopy
Me methyl
MeOH methanol
min minute(s)
MS mass spectroscopy
NCS A'-chlorosuccinimide
org. organic
p para
PG protecting group
rt room temperature
sat. saturated
sol. solution
TBAC tetra-77-butj'lammoniura chloride
TBME /ert-butyl-methyl-ether
/Bu /ert-butyl
TFA trifluoroacetic acid
THF letrahydrofuran
TLC thin layer chromatography
tR retention time (in LC-MS or HPLC) given in minutes
UV ultra vioiet
Vis visible
xantphos 4.5-bis(dipheny!phosphino)-9,9-dimethylxanthene

HPLC- or LC-MS-conditions (if not indicated otherwise):
Analytic: Zorbax 59 SB Aqua column, 4.6 x 50 mm from Agilent Technologies. Ekients:
A: acetonilriJe; B; H2O +- 0.5% TFA. Gradient; 90% B - 5% B over 2 min. F]ow: I
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.
Chirai, analytic:
a) Regis Whelk column, 4.6 x 250 mm, 10 jam. Eiuent A: EtOH + 0.05% EtN. Eluent B: hexane. Flow: 1 mL/min.
b) ChiralPak AD, 4.6x250 mm, 5 m. Eluent A: EtOH + 0.05% EtjM. Eluent B: hexane. Flow: 1 mL/min.
c) ChiralCel 00, 4.6x250 mm, 10 m. Eluent A: EtOH + 0.1% EtjN. Eluent B: hexane. Flow: 0.8 mL/min.
Chirai. preparative:
a) Regis Whelk 01 column, 50x250 mm and a flow of 100 mL/min. Eluent A: EtOH + 0.05% Et,iN. Eluent B: hexane.
b) ChiralCel OD, 20 m, 50 mm x 250 mm. flow 100 mL/min. Eluent A: EtOH + 0.1%Et3N. Eluent B: hexane.
5-Bromo-2-chloro-A'-cyclopropytbenzamide
into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under N2 were added 5-bromo-2-chiorobenzoic acid (10.0 g, 42.5 mmol) and DMF (3.9 mL, 51.0 mmo!) in toluene (80 mL). Tiie soi. was cooled to 0 °C. and oxalyl chloride (4.4 mL. 51.0 mmol) was added dropwise over 1 h. The resulting mixture was stirred at 0 °C for 2 h and then the volatiles were removed. The resulting crude reaction mixture was dissolved in CH2CI2 (100 mL) and cooled to 0 °C in an ice bath. Cyclopropylamine (4.5 mL, 63.7 mmol) was added dropwise over 1 h followed fay addition of DIPEA (11.8 mL. 85.0 mmol). The resulting sol. was stirred at rt for 16 h. The reaction mixture was poured into a 1 L separatory funnel containing IM aq. HCl (600 mL). The mixture was extracted with CH2CI2 (6 X 250 mL). The combined org. layers were washed with brine, dried over

MgS04. filtered and concentrated under reduced pressure. The product was crystafiized from hexanes/CH2CI; and isolated by filtration to give the title compound (8.24 g. 7!%).
A'-(5-bromo-2-chiorobeiizyI)cycIopropyiamine
A so!, of 5-bromo-2-chloro-iV-cyclopropylben2amide (12.0 g. 43.7 mmol) in THF (TOO mL) was placed into a 250 mL round-bottom flask, equipped with a magnetic stir bar and
under Ni. The sol. was treated with dropwise addition of BHrMciS (13.1 mL, 13) mmol). and the resulting suspension was stirred at rt for 1 h. The mixture was heated to reflux for 1 h, cooled to rt, and slowly quenched with dropwise addition of 1 M aq. HCI (25 mL). The suspension was again refluxed for 1 h, cooled to rt, and basifled to pH = 10-! 1 with 1 M aq. NaOH. The mixture was poured into a 500 mL separatory funnel containing IM aq. NaOH (350 mL). The mixture was eKtracted with EtOAc (3 x 100 mL). The combined org. layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The crude amine was used directly in the next step.

A soL of substituted benzaldehyde (17.8 mmol, TO eq.), cyclopropylamine (3.13 mL, 44.5 mmol, 2.5 eq.) and sodium cyanoborohydride (1.34 g, 2L4 mmoL 1.2 eq.) in MeOH (100 mL) was treated with dropwise addition of glacial AcOH (3.06 mL. 53.4 mmol, 3.0 eq.). The resulting sol. was stirred at rt for 16 h overnight. The reaction mixture was quenched with dropwise addition of sat. aq. NaHCO, and concentrated under reduced pressure to remove the MeOH. The crude residue was poured into a 250 mL separatory funnel containing sat. aq. NaHC03 (150 mL), and extracted with EtOAc (3 x 50 mL). The combined org. layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. Purification by FC yielded the benzamine product.
General procedure for the Boc-protection ofcyclopropylbenzamims:


A sol. of the cyclopropyibenzamine (43.7 mmol, 1.0 eq.) in a biphssic mmurc of CHCJj (50 mL) and !M aq. NaOH (50 mL) was treated with BociO (15.1 mL, 65.6 mmol. 1.5 eq.). The mixture was stirred at rt vigorousiy for \6 h. The mixture was poured into a 500 mL separatory funnel containing H2O (300 mL), and extracted with CHCK (3 x TOO mL). The combined org. layers were washed with brine, dried over MgS04, filtered and concentrated under rsduced pressure. Purification by FC yielded the Boc-protscted amine.

Into a flame-dried round-bottom flask or Schienk tube, under N; was added Pd[PCy3]2 (0.05 eq.). CsF (2.0 eq.) and the corresponding aryl bromide (1.0 eq.). If the aryl chloride was being used as a starting material, the (Pd[PiBii3]Br)2 dimer (0.025 eq.) was used in place of the Pd[PCy3]2 catalyst. The fJask was evacuated under reduced pressure (0,1 mm Hg) and backfilled with N2 (repeated 3 times). The resulting solids were dissolved in anhydrous THF or dioxane (0.15 M sol.) and tri-n-butyl allyitin (1.5 eq.) was added and the resulting mixture was reftuxed for 8-16 h, until TLC shows complete consumption of starting material. The reaction mixture was cooled to rt, and filtered through a pad of silica gel on a sintered glass funnel, washing with Et20. The tlltrate was concentrated and purified by FC to give the corresponding allylbenzamide derivative.


into a flame-dried round-bottom flask equipped with'a magnetic stir bar was added ihe aliylbenzamine (1.0 eq.) and anhydrous THF (0.3 M soL). The sol. was cooied to 0 °C and BHs-MeSil.l eq.) was added dropwise over 20 min. The sol. was stirred at 0 °C for 1 h. then allowed to warm to rt, and stirred for an additional 2 h. The sol. was cooled to 0 °C and IM aq. NaOH was added dropwise (CAUTION - EXOTHERMIC REACTION), followed by dropwise addition of 30% aq. H2O2. The mixture was allowed to warm to rt. and stirred for 2 h. The mixture was poured into a separator>' funnel containing H:0 and extracted with EtiO (3 times). The combined org. layers were washed with brine, dried over MgS04. filtered and concentrated under reduced pressure. Purification by FC yielded the desired alcohol product.

A sol. of allylbenzamine (1.0 eq.) in CH2CI2 (0.4 M sol.) was cooled to -78 "C and O.. gas was introduced into the sol. using a gas dispersion tube. The ozone gas was introduced until all of the starting material had been consumed, as determined by TLC. and the reaction mixture maintained a slight blue colour. The reaction was stirred at -78 °C for 20 min, then EtOH (0.5 M soi.) and NaBH4 (2.5 eq.) were added. The mixture was allowed to warm to rt overnight (16 h). The reaction mixture was quenched with dropwise addition of sat. aq. NH4CI (5 mL), and poured into a separatory funnel containing sat. aq. ■NH4CI. The mixture was extracted with Et20 (3 times). The combined org. layers were washed with brine, dried over M2SO4, filtered and concentrated under reduced pressure. Purification by FC yielded the desired alcohol.
General procedure for the etherificaiion of aromatic primary alcohob with methyl iodide:


A suspension of the primary alcohol (1.0 eq.) in THF (0.25 M sol.) was cooied to 0 °C and treated witii NaH (60% in oiL 2.0 eq.). The resulting mixture was stirred at 0 °C for 30 min and then at rt for another 30 min. The suspension was re-cooled to 0 "C and then Mei (8.0 eq.) was added in a single portion. The reaction mixture was stirred at 0 °C for 30 min, at rt for 30 min, and then heated to reflux for 4 h until all of the starting material was consumed as determined by TLC. The cooled reaction mixture was quenched with dropwise addition of sat. aq. >JH4C1 and poured into a separatory funnel containing sat. aq. NH4CI. and extracted with EtOAc (3 times). The combined org. layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. Purification by FC yielded the methyl ether.

To a sol. of Boc-protected cyclopropylbenzamine (1.0 eq.) in CHCb (0.1-0.5 M soi.) was added 4 M HCI in dioxane (5.0 eq.). The resulting mixture was stirred at rt for 8-16 h until TLC shows complete conversion of starting material. The reaction was poured into a separatory funnel containing iM aq. NaOH, and extracted with CHCb (3 times). Purification by FC yielded the corresponding free amine.
2-Bronio-5-chloro-pyridine-4-carbaldehyde
To a stirred sol. of diisopropylamine (20.9 mL, 148 mmo!) in dry THF (350 mL) at -5 °C was added dropwise BuLi (1.6M in hexane, 89.5 mL, 143 mmol), and the resulting sol. was

stirred for 30 min at -5 °C. The soi. was allowed to coo! to -70 °C, and a sol. of 2-bromo-5-ciiloropvrjdine (25-0 g, 130 mmol) in THF ( 100 mL) was added dropwise at -70 °C over i 5 min such that the internal temperature did not exceed -65 °C. The mixture was stirred at -70 °C for 30 min. DMF (10.52 mL, 136 mmol) was added dropwise over 20 min such that the internal temperature did not exceed -70 °C. The orange mixture was stirred at -70 °C for 40 min. The mixture was allowed to warm up to rt. and was poured onto a mixture of water (200 mL) and aq. IM NaOH (50 mL). The mixture was extracted with F.tOAc (2x). and the combined org. extracts were washed back with aq. IM NaOH (2K). The org. extracts were dried over MgS04, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/lieptane 1:9—> }-.8—> ]-.6 ' }:4—> l;2 1:1) yielded the title compound (2L55 g, 72 %). LC-MS: tR = 0,74 min; ES+: 295.0!.
2-Bromo-5-chloro-4-dimethoxymethyI-pyridine
To a sol. of 2-bromo-5-chloro-pyridine-4-carbaldehyde (43.9 g. 199 mmol) in MeOH (800 mL) were successively added at rt trimethyl orthoformate (65.3 mL, 597 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10.0 mmol). This reaction mixture was then heated to reflux for 3 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in CH2Cb.and this mixture was washed with aq. 10% KiC03. The org. layer was dried over MgS04. filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the title compound (51.7 g. 97 %). LC-MS: tR = 0.92 min; ES+: 309.06.
5-Chloro-4-dimethoxymethyl-2-(3-methoxy-propyI)-pyridine
To a suspension of Mg (911 mg, 37.5 mmol) and of iodine (one cr\'stal) in dry THF (30 mL) was added dropwise 5% of the total amount of l-bromo-3-methoxypropane (4.59 g, 30,0 mmol). The mixture was heated to reflux with the help of a heat gun until the Grignard formation had started. The rest of the 1-bromo-3-methoxypropane was added slowly, while an exothermic reaction proceeded. After the end of the addition, the reaction mixture was stirred under reflux for 20 min, and was allowed to cool to rt. This Grignard sol. (IM in THF. 23.5 mL, 23.5 mmol) was added dropwise to a mixture of 2-bromo-5-chloro-4-dimethoxymethyl-pyridine (2.50 g, 9.38 mmoi) and Ni(dppp)Cb (495 mg, 0.938 mmol) in THF (50 mL) at 0 X. The reaction mixture was stirred at rt for 30 min, and was
T7

then heated to reflux for 2 h. The mixture was allowed to cool to rt, and was dissolved with EtOAc. This mixture was washed with aq. sat. X'aHCO,,. The org. layer was dried over MgS04. filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane - EtOAc/heptane 1:1) yielded the title compound (1.51 g, 62%). LC-MS: IR = 0.80 mir; ES+: 260.15.
5-Chloro-2-(3-mefhoxy-propyl)-pyridine-4-carbaldehyde
5-Chloro-4-dimethoxymethyl-2-(3-methoxy-propy!)-pyridine (25.5 g. 98.2 mmol) was
dissolved in aq. IM HCl (500 mL), and the mixture was heated to 80 "C for 2 h. The
mixture was allowed to cool to rt. and EtOAc was added. The mixture was cooied to 0 "C,
and was basifled with aq. 2.5M NaOH until a pH = 10 was reached. The layers were
separated, and the org. layer was dried over MgS04, filtered, and concentrated under
reduced pressure. Drying the residue under high vacuum yielded the crude title compound
(98.1 mmol. 99%) that was used further without purification. LC-MS: IR = 0.62 min; ES+:
246.12. ....
[5-ChIoro-2-(3-methoxy-propyl)-pyridin-4-ylmethy I]-cyclopropyl-amine
A mixture of 5-chloro-2-(3-methoxy-propyl)-pyridine-4-carbaidehyde (21.0 g, 98.2 mmol) and cyclopropylamine (13.8 mL, 196 mmol) in MeOH (450 mL) was stirred at rt overnight. NaBH4 (4.83 g. 128 mmol) was added at 0 °C, and the mixture was stirred at rt overnight. Ice was added, and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc, and this mixture was washed with aq. 1M NaOH. The aq. layer was extracted back with EtOAc. The combined org. extracts were dried over MgS04-filtered. and the solvents were removed under reduced pressure. Purification of the crude by FC ( EtOAc/heptane 1:5 -5- 1:4 - 1:3 -> 1:1 - 3:1 - EtOAc) yielded the title compound (11.8 g) and [5-chloro-2-(3-methoxy-propyl)-pyridin-4-ylmethylene]-cyclopropyf-amine (10.7 g). This unreacted imine was dissolved in MeOH (20 mL). and this sol. was cooled to 0 °C. MaBH4 (3.20 g, 84.6 mmol) was added, and the mixture was stirred at rt overnight. NaBH4 (3.20 g, 84.6 mmol) was added again, and the mixture was stirred for 3 days. Ice was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc and the resulting mixture was washed with aq. IM NaOH. The aq. phase was extracted back with EtOAc.

The combined org. extracts were dried over MgS04, filtered, and tiie solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/iieptane 1:3 --> 1:2 - 1:1 - EtOAc) yielded tlie title compound (9.4 g). The fractions of the title compounds were mixed together (21.2 g, 85%). LC-MS: IR = 0.55 min: ES+: 296.16.
2-(4-Brom o-ph enoxy)-ethanol
4-Bromphenol (1003 g, 0.58 mol) was dissolved in in xylenes (220 mL). [l,3]Dioxolan-2-one (53.7 g. 0.61 mol) and imidazole (592 mg, 8.70 mmol) were added. The mixture was healed to 140 °C for 3 days. The mixture was allowed to cooi to rt, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the title compound (13.0 g. quantitative). LC-MS: tR = 0.81 min.
Methanesulfonic acid 2-(4-bromo-pheiioxy)-ethj'l ester
2-(4-Bromo-phenoxy)-ethanol (125 g, 0.576 mo!) was dissolved in CH2Ci2 (650 mL), and the sol. was cooled to 0 °C. EtsN (110 mL, 0.864 mol), then mesyl chloride (67.1 mL, 0.864 mol) were dropped at such a speed that the temperature did not raise above 10 °C (about 60 min). The mixture was stirred at 0 °C for I h. then at ft overnight. The mixture was diluted with CHCb, and washed with brine (2x). The aq. phase was extracted back with CHiCb. The combined org. extracts were dried over MgS04- filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the raw title compound (174 g, quantitative yield) that was used further without purification. LC-MS: IR = 0.92 min.
1 - [2-(4-Brom o-phenoxy)-eth oxy]-2,6-dichloro-4-inethyl-benzene
K2CO3 (29.3 g, 212 mmol) was dissolved in water (162 mL). 1-Propanol (150 mL) ivas added. A sol. of 2,6-dichloro-p-cresoi (25 g, 141 mmol) in l-propanol (150 mL) was added. Methanesulfonic acid 2-(4-bromo-phenoxy)-ethyl ester (41.6 g, 141 mmol) was added. The mixture was stirred at 85 °C for 6 h. The heating oil bath was removed, and water (330 mL) was added dropwise when the internal temperature had reached 78 °C. The beige suspension was allowed to cool to n:. The mixture was filtered, and,the precipitate was washed with water. Drying the precipitate under high vacuum at 30 °C for 48 h yielded the title compound (43 g, 81 %). LC-MS: tR = 1.15 min.

2-(2,6-Dichloro-4-niethyI-phenoxy)-ethanoI
In a three-necked flask equipped with a gas droplet counter and an efficient cooling system. a mixture of 2,6-dichloro-p-creso! (20.0 g, 113 mmolX [1.3]dioxoian-2-one (9.95 g. 113 mmol) and imidazole (115 mg, 1.70 mmol) was heated to 160 °C for 25 h. The mixture was allowed to cool to rt. Purification by FC (EtO/heptane 1:1) yielded the title compound 0 8,7 g, 75%). LC-MS: tR = 0.88 min.
5-Bromo-2-i2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-pyridine
A sol. of 2-(2.6-dichioro-4-methyl-phenoxy)-ethanol (18.6 g, 84 mmol) in THF (360 mL) was cooied to 0 °C. NaH (about 55% in oil, 6.60 g, about 153 mmol) was added in portions, and the mixture was stirred at rt for 30 min. A sol. of 2.5-dibrompyridine (1 8.0 g, 76.3 mmol) in THF (60 mL) was added dropwise, and the mixture was heated to reflux for 90 min. The mixture was allowed to cool to rt, and ice was added carefully. The solvents were partially removed under reduced pressure, and the residue was diluted with EtOAc. This mixture was washed with aq. sat. NH4CI. The aq. layer was extracted back with EtOAc (2x), The combined org. extracts were washed with brine, dried over MgS04, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 3:97) yielded the title compound (22.7 g. 79%). LC-MS; IR = 1.13 min; ES+: 378.08.
2-Chlo ro-3,6-difluoro-benzaIdehyde oxime
2-Chloro-3.6-difluoro-benzaidehyde (25.0 g, 142 mmol) was dissolved in CH3CN (175 mL). To this soi. was added NaHCO (35.7 g, 424 mmol), and the mixture was stirred vigorously for 5 min. Water (350 mL) was added, and the mixture was stirred for 10 min.
NH.OH-HCI (19.7 g. 283 mmol) and TBAC (1.97 g, 7.08 mmol) were added, and the reaction mixture was stirred at rt for ! h. AcOH (20 mL) was added dropwise to pH 6-7. The mixture was extracted with EtiO (3x). The combined org. extracts were washed with brine, dried over NaiSOa, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the title compound (25.0 g. 92%). LC-MS: IR = 0.93 min.

(5)-l-(5-Bromo-pyridin-2-yl>-pyrroIidiD-3-oI
A mixture of 2,5-dibromopyridine (12.2 g, 51.5 mmol) and (.V)-!iydroxypyrrolidine ("2.80 g. 32.1 mmol) in toluene (50 mL) was heated to reflux overnight. The mi-ture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dissolved with EtOAc (150 mL), and the mixture was washed with aq. 10 % K;CO> The org. layer was dried over MgS04, filtered, atid the solvents were removed under reduced pressure. Purification of the residue by FC (heptane -> heptane/EtOAc 1:2) yielded the title compound (3.62 g. 46%). LC-MS: IR = 0.48 min; ES+: 243.15.
(if )-5-Bromo-2-[3-(2,6-dichloro-4-m ethyl-phenoxy)-pyrrolidin-l-yl]-pyi'idine
Azodicarboxylate dipiperidide (11.7 g, 45.4 mmo!) was added to a sol. of (.S)-i-(5-bromo-pyridin-2-yl)-pyrrolidm-3-ol (8.82 g, 36.3 mmol) and 2.6-dichloro-p-cresol (7.37 g. 40.0 mmol) in toluene (200 mL). The mixture was degassed with nitrogen for 5 min. and PBu (85%, 15.8 mL, 46.2 mmol) was added. The mixture was heated rapidly to 100 °C. and stirred at this temperature for 2 h. The mixture was allowed to cool to rt, and was diluted with heptane (200 mL). The mixture was filtered, and the filtrate was evaporated under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:7) yielded a crude title compound that was diluted with CHiCL. This mixture was washed with aq. (M NaOH. The org. layer was dried over MgSOa, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the pure title compound (13.5 g, 93%). LC-MS: ta = 0.92 min; ES+: 402.98.
f>'£:(c.)-3-|Cyclopropyl-(2,3-dimethyI-benz>'l)-carbamoj'l]-4-oxo-piperidine-l-carboxyIic acid terf-buM ester (Bl)
A sol. of 4-hydroxy-5,6-dihydro-2ff-pyridine-l,3-dicarboxylic acid I-/ert-butyl ester 3-methyl ester (WO 2004/105738, 1.00 g, 3.89 mmol), cyc!opropyl-(2,3-dimethyl-benzyl)-amine (681 mg, 3.89 mmol) and p-toktenesulfonic acid monohydrate (92.4 mg, 0.486 mmol) in anhydrous toluene (40 mL) was stirred at reflux overnight in a Dean-Stark trap equipped flask. The reaction mixture was allowed to cool to rt, EtOAc (120 mL) was added, and the resulting mixture was washed successively with aq. sat. NaHCOj (2x), aq. IM HCI (Ix), and finally with aq. sat. "NaHCOj (Ix). The org. layer was dried over MgS04, filtered, and the solvents were removed under reduced pressure. Purification of

the residue by FC (heptane heptane/EtOAc 50:50) yielded the title compound (566 mg, 36%). LC-MS:tR = 1.02 min; ES-r: 401.02.
{rac. )-3- {12-Ch loro-5-(2- raethoxy-ethyl)-benzy 1] -cyclopropyl-car bam oy I }-4-oso-piperidine-1-carboxylic acid teri-hutyl ester (B2)
A sol. of 4-hydroxy-5,6-dihydro-2//-pyi'idine-13-dicarboxylic acid 1-;e;'/-butyl ester 3-methyl ester (WO 2004/105738, 4.83 g, 18.8 mmol). [2-chtoro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amine (3.00 g, 12.5 mmo!) and p-toluenesulfonic acid monohydrate (298 mg. K56 mmol) in anhydrous toluene (188 niL) was stirred at reflux (oil bath at nCC) for 24 h in a Dean-Stark trap equipped flask. The mixture was allowed to cool to rt and left over the week-end. EtOAc (100 mL) was added, and the resulting mixture was washed successively with aq. sat. NaHCOs, aq- IM HCl (2x), and with brine. The org. layer was dried over MgS04, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane -> heptane/EtOAc 40:60) yielded the title compound (2.39 g, 41%). LC-MS: tp = L03 min: ES+: 465.43.
(rac. )-3-{|5-Chloro-2-(3-mefhoxy-propyl)-py ridin-4-ylmethylJ-cy clopropyl-carbanioyl}-4-oxo-piperidine-l-carboxylic acid lert-hutyi ester (B3)
A sol. of 4-hydroxy-5,6-dihydro-2-pyridine-l,3-dicarboxylic acid \-iei-l-buty\ ester 3-methyl ester (WO 2004/105738, 2.00 g, 7.77 mmo!), [5-chloro-2-(3-methoxy-propyl)-pyridin-4-ylmethyl]-cyciopropyl-amine (1.98 g, 7.77 mmol) and /i-toluenesulfonic acid monohydrate (185 mg, 0.972 mmol) in anhydrous toluene (78 mt) was stirred at reflux overnight in a Dean-Stark trap equipped flask. 4-Hydroxy-5.6-dihydro-2i/-pyridine-1.3-dicarboxylic acid 1 -lert-butyi ester 3-methyl ester (500 mg, 1.94 mmol) was added, and the mixture was heated to reflux for 4 h. The mixture was allowed to cool to rt. EtOAc was added, and the mixture was washed with aq. sat. NaHCOs, aq. IM HCl and aq. sat. NaHCOi- The org. layer was dried over MgS04, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 7:3) yielded the title compound (1.70 g. 46%). LC-MS: IR = 0.90 min; ES+: 480.39.

(mc.)-(3S*, '#/f"')-3-[CyelopropyI-(23-(iimethyl-benzyl)-carbamoyI]-4-{4-|2-(2,6-
dichloio-4-methyl-phenoxy)-ethoxy]-pbenyi}-4-hy(lroxy-piperidine-l-carboxylic acid /er/-butyl ester (Dl)
A sol, of l-[2-(4-bromo-phenoxy)-ethoxy]-2,6-dichioro-4-methyi-benzene (537 mg. 1.43 mmol) in dry THF (15 tnL) at-78 °C was treated with BuLi (I.6M in hexane, 0.428 mL. 1.56 mmol). After 30 min this sol. was cannulated on a sol. of compound Bl (520 mti, 1.30 mmoi) in dry THF (15 mL) at-78 °C. After I h. the mixture was poured in aq, sat. NH4CI, extracted with EtOAc (2x), dried over NajSOa, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane -> heptane/EtOAc 70:30) yielded the title compound (89 mg. 10%). LC-MS: IR = 1.23 min: ES+: 697.16.
irac.)-(3R*, •#5'*)-3-{(2-Chloro-5-(2-methoxy-ethyl)-benzylj-cyclopropyl-carbamoyl}-4-{4- [2-(2,6-d ichloro-4-methy l-phenoxy)-ethoxy] -phenyl}-4-hydroxy-piperid ine-1 -carboxyliG acid teri-bnty\ ester (D2)
A so!, of l-[2-(4-bromo-phenoxy)-ethoxy]-2,6-dichloro-4-methyl-benzene (4.04 g, 10.8 mmol) inTHF(I07mL)at-78Xwas treated with BuLi(1.6M in hexane. 7.38 mU 15.8 mmol). .After 30 min, DMPU (2.85 mL, 23.7 mmol) was added, and the mixture was stirred for 5 min. A sol. of compound B2 (2.00 g, 4.30 mmol) in THF (14 mL) was added slowly. The mixture was stirred for 15 min at -78 °C. and aq. sat. NH4CI (lOOmL) was added. The mixture was afiowed to warm up to rt, and the solvents were partia/fy removed under reduced pressure. The aq. residue was diluted with aq. sat. NH4CI (50 mL), and the mixture was extracted with EtOAc (3x). The combined org. e.xtracts were dried over MgS04. filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane -> EtOAc/heptane 40:60) yielded the title compound (380 mg. 12%). LC-MS: tR = 1.27 min; ES+: 763.22.
(rac.}-(3R*, •/5'*)-3'-{[2-Chloro-5-(2-methoxy-ethyl)-benzyI]-cyclopropyi-carbamoyl}-6-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxyl-4'-hydroxy 3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-r-carboxylic acid tett-huty\ ester (D3)
Mg turnings (535 mg, 22.0 mmol) and anhydrous LiCl (848 mg. 20.0 mmol) were placed in a dried flask in an oil bath at 120°C overnight under high vacuum. Once this was cooled

under N,. without opening the flask, THF (10 mL) was added. A sol. of /so-propy) chloride in THF (10 mL) was slowiy added at rt, and the mixture was stirred for 12 h at ri. The resulting grey IM-sol. is ready to be used but should not be kept more than 24 h, 5-Bromo-2-[2-(2.6-dichloro-4-niethyl-phenoxy}-ethoxy]-pyridine (3040 mg. 8.07 mmol) in dry THF (80.6 mL) was treated with the previously prepared Grignard sol. ()M. 8.48 mL. 8.48 mmol). The mixture was stirred for 4 h at rt. The ;.TO-propyI Grignard sol. (! M , 8.00 mL. 8.00 mmol) was added again, and the mixture was stirred for 2 h. A sol. of compoimd B2 (1500 mg. 3.226 mmol) in dry THF (15 mL) was added, and the mixture was stirred at rt for 15 min. The mi.xture was poured onto aq. sat. NH4CI. and extracted with EtOAc, The combined org. extracts were dried over Na2S04. filtered, and the solvents were removed under reduced pressure. Purification of the residue by PC (heptane -heptane/EtOAc 70:30) yielded the titk compound (1.74 g, 71%). LC-MS: IR = L23 min; ES+: 764.49.
(rac.)-(3R*, -/5*)-6-[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-yImethoxy]-3'-{|2-chioro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-carbamoyl}-4'-hydroxy-3',4',5',6'-tetrahydro-2'H-f3,4']bipyridinyl-r-carboxyIicacid tert-butyl ester {D4)
Mg turnings (535 mg, 22.0 mmol) and anhydrous LiCi (848 mg, 20.0 mmol) were placed in a dried flask in an oil bath at 120°C overnight under high vacuum. Once this was cooled under M. without opening the flask. THF (10 mL) was added. A sol. of fso-propyl chloride in THF (10 mL) was slowly added at rt, and the mixture was stirred for 12 h at rt. The resulting grey IM-sol. is ready to be used but should not be kept more than 24 h. A soL of compound KI (1.08 g, 2.69 mmol) in dry THF (27 mL) was treated at n with the previously prepared Grignard sol. (IM, 3.76 mL, 3.76 mmol). The mixture was stirred at rt and the formation of the Grignard was checked every hour. After 5 h, a sol. of compound B2 (500 mg, 1.08 mmol) in dry THF (10 mL) was added, and the reaction was stirred at rt for I h. The mixture was poured onto aq. sat. NH4CI, and the mixture was extracted with EtOAc. The combined org. extracts were dried over Na3S04, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane -> EtOAc/heptane 30:70) afforded the title compound (275 mg. 33%). LC-MS: tR = 1.20 min: ES+: 787.64.

Mixture of {3'R, '5-3'-{12-Cliloro-5-(2-methoxy-ethyl)-benzj'l]-cyclopropyl-carbamoyl}-6-[(ft)-3-{2,6-dich!oro-4-methyl-phenoxy)-pyrrolidin-l-yIj-4'-hydrosy-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyI-r-carboxyIic acid terf-butyl ester and (S'S, 4'R)-y-{ i 2-C hioro-5-(2-methoxy-ethyl)~benzyl ]-cyclopropy I-carbamoy l}-6-|(ft )-3-(2,6-dichloro-4-methyl-phenoxy)-pyrroiidin-l-yll-4'-hydroxy-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-r-carboxylic acid tert-butyl ter (D5)
Mg turnings (535 mg, 22.0 mmol) and anhydrous LiCl (848 mg, 20.0 mmOl) were placed in a dried flask in an oil bath at 120°C overnight under high vacuum. Once this was cooled under Nj, without opening the flask, THF (10 niL) was added. A sol. of /so-propyl chloride in THF (10 mL) was slowly added at n, and the mixture was stirred for 12 h at rt. The resulting grey IM-sol. is ready to be used but should not be kept more than 24 h. (R)-5-Bromo-2-[3-(2,6-dichloro-4-methyl-phenoxy)-pyrrolidin-]-yi]-pyridine (2.16 g, 5.38 mmol) in dry THF (61 mL) was treated at rt with the previousiy prepared Grignard sol. (IM. 8.47 mU.8.47 mmol). The mixture was stirred at rt and the formation of the Grignard was checked every hour. After 8 h, a sol. of compound B2 (1.13 g, 2.42 mmol) in dry THF {11 mL) was added and the reaction was stirred at rt for 1 h. The mixture was poured onto aq. sat. NH4CK and the mixture was extracted with EtOAc. The combined org. extracts were dried over Na2S04, filtered, and the solvents were removed under reduced pressure. Purification of the residue by PC (heptane -> EtOAc/heptane 30:70) afforded the title compounds mixture (1.29 g, 68%). LC-MS; tR = 1.03 min; ES+: 787.77.
(raaHS'R*, .#'5*)-3'-{[5-Chloro-2-(3-methoxy-propyl)-pyridiii-4-ylmethylI-
cyclopropyl-carbamoyl}-6-[2-(2,6-dichloro-4-methyi-phenoxy)-ethoxy]-4'-hydroxy-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-l'-carboxylic acid tert-hut\\ ester (D6)
Mg turnings (535 mg, 22.0 mmol) and anhydrous LiCI (848 mg, 20.0 mmol) were placed in a dried flask in an oil bath at 120X overnight under high vacuum. Once this was cooled under N2, without opening the flask, THF (10 mL) was added. A sol. of /".sopropyl chloride in THF (10 mL) was slowly added at rt, and the mixture was stirred for 12 h at rt. The resulting grey IM-sol. is ready to be used but should not be kept more than 24 h. 5--Bromo-2-[2-(2.6-dichloro-4-methyi-phenoxy)-ethoxy]-pyridine (2.02 g, 5.37 mmol) in dr\' THF (54 mL) was treated at rt with the previously prepared Grignard sol. (iM, 7.5! mL,

7.51 mmol). The mixture was stirred at rt and the formation of the Grignard was checked every hour. After 5 h, a sol. of compound B3 (1.03 g, 2.15 mmoi) in dr\ THF {10 mL] was added and the reaction was stirred at rt for 1 h. The mixture was poured onto aq. sat. NH4CI, and the mixture was extracted with EtOAc. The combined org. extracts were dried over Na2S04, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane —> EtOAc/heptane 2:7) afforded the title compound (921 mg, 55%). LC-MS: IR = 1.19 min; ES+: 779.64.
(rac.)-(i**, ''5*)-3'-{[5-Chloro-2-(3-methoxy-propyl)-l-oxy-pyridin-4-ylmethyl|-
cyclopropyl-car bam oyl}-6-[2-(2,6-dichIoro-4-methyI-phenoxy)-ethoxy 1-4'-hydro xy-3',4',5',6'-tetrahydro-2'H-[3,4'jbipyridinyl-r-carboxylic acid tert-butyl ester (D7)
A sol. of compound D6 (46 mg, 0.603 mmol) in dry CHCK (6.00 mL) was treated at rt with 3-ch!oroperbenzoic acid (70%, 166 mg, 0.675 mmol), and the mixture was stirred at rt for 2 h. The mixture was poured onto aq. sat. NaHCOs, and extracted with EtOAc. The org. extract was washed with aq. sat. NaHCOj (2x), was dried over Na2S04, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane —> heptane/EtOAc 50:50) yielded the title compound (347 mg. 73%).
5-Bromo-2-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazoI-5-ylmethoxy]-pyridine(KI)
2,5-Dibromopyridine (31.4 g, !32 mmo!) and compound LI (25.0 g, 102 mmol) were dissolved in dry toluene (1.00 L) under nitrogen. terl-BuOa (14.7 g. 153 mmol),
xantphos (3.54 g, 6.12 mmol) and Pd;(dba)3-CHCl3 (1-83 g, 2.00 mmol) were added to the mixture. The mixture was heated to reflux, overnight, and was allowed to was coo! to rt. The mixture was washed with aq. sat. NaHCO and brine. The org. layer was dried over MgS04, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 10:90) yielded the title compound (17.4 g, 43%). LC-MS: tR = LOS min.
[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-yl]-inethanol(Ll)
A sol. of2-chloro-3,6-d!fluoro-benzaldehydeoxime(21.3g, 1 i 1 mmoi) in DMF (66.7 mL) was added dropwise to a sol. of NCS (14.9 g, 111 mmol) and pyridine (1.78 mL) in DMF

(222 inL). The mixture was stirred for 1 h at rt, and a sol. of propargyl alcohol (4.99 g. 89.1 mmoi) in DMF (71 inL) was added dropwise. TJie reaction mixture was heated to S5 °C. and a sol. of EhN (15,5 mL. 111 mmo!) in DMF (89.3 mL) was slowly added. The reaction mixture was stirred at 85 °C for 60 min, and was allowed to cool to rt. The mixture was diluted with water (533 mL), and was extracted with EtOAc (2x). The combined org. extracts were washed with water and brine, were dried over Na2S04, filtered, and the solvents were removed under reduced pressure. Purification of the residue by PC (EtOAc/heptane 40:60) yielded the title compound (i 7.0 g. 78%). LC-MS: tR = 0.84 min; ES+: 287.12.
3-(BenzyI-/'er/'-butoxycarbonyI-amino)-propionic acid ethyl ester (MI)
B0C2O (5.53 g, 25.3 mmol) was added to a sol. of iV'-benzyl-|3-alanine ethyl ester (3.40 mL. 16.9 mmol) and DIPEA (11.6 mL, 67.6 mmol) in CHoCb (200 mL) at 0 °C. The mixture was stirred overnight while warming up to rt. The mixture was cooled to 0°C, and was partitioned with aq. IM HCI. The org. layer was washed again with aq. ! M HCI and with aq. sat. NaHC03. The org. layer was dried over MgS04, filtered, and the solvents were removed under reduced pressure. Purification of the crude by PC (EtOAc/heptane 3:20) yielded the title compound (5.16 g, 99%). LC-MS: tR = 1.02 min.
3-(BenzyWert-butoxycarbonyl-amino)-propionic acid (Nl)
A mixture of compound Ml (838 mg, 2.73 mmol) in EtOH (34 mL) and aq. IM MaOH (13.7 mL) was stirred at 70 °C for 2 h. The mixture was allowed to cool to rt. and aq. 1M HCI was added until a pH = 4 was reached. The solvents were partially removed under reduced pressure, and the aq. residue was extracted with EtOAc. The combined org. extracts were washed with brine, dried over MgS04, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the crude title compound (769 mg, quantitative yield) that was used further without purification. LC-MS: tR = 0.89 min; ES+: 280.33.
Benzyl-(2-{[2-chloro-5-(2-methoxy-ethyI)-benzyl]-cyclopropyl-carbamoyl}-etbyl)-carbamic acid tert-batyl ester (01)

A mixture of compound Nl (769 mg, 2.75 mmol). DMAP (84.1 mg, 0.688 mmol). HOBt (446 mg. 3.30 mmol), DIPEA (1,78 g, 2.36 mmol) and EDC-HC! (1.32 g. 6.88 mmol) in CH2CI: (65 mL) was stirred at rt for 45 min. [2-Chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amine (1.14 g. 4.13 mmol) was added, and the mixture was stirred overnighl. CH2CI2 was added, and the mixture was washed with aq. 1M HCI (2x}. The org. layer was dried over MgS04, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CHsCb 1:99) yielded the title compound (I.I2 g. 76%). LC-MS:tR=].n min; ES+: 501.30.
4-|2-(2,6-Diehloro-4-niethyI-phenoxy)-ethoxy}-benzaldehyde(Ql)
BuLi (L6M in hexane, 17.0 mU 26.9 mmol) was added to a sol. l-[2-(4-bromo-phenoxy)-ethoxy]-2,6-dichloro-4-methyl-benzene (8.81 g, 23.4 mmol) in THF (91 mL) at -78 X. The mixture was stirred for 10 min at -78 °C, and DMF (2.72 mL. 35.1 mmol) was added. The mixture was stirred at -78 °C for 2.5 h. and aq. sat. NH4CI was added. The mixture was allowed to warm up to rt, and was extracted with TBME (2x). The combined org. extracts were washed with brine, dried over MgS04, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtO.Ac/heptane i:4) yielded the title compound (3.64 g, 48%). LC-MS: tR = 1.07 min: ES: 325.03.
Examples
Example I
(r«e.)-(i5'% 4if')-4-{4-[2-(2,6-Dichloro-4-methyi-phenoxy)-ethoxy]-phenyl}-4-
hydroxy-piperidine-3-carboxylicacid cyclopropyI-(2,3-dimethyl-benzyl)-amide
A sol. of compound Dl (51 mg, 0.073 mmol) in dioxane (1 mL) at 0 °C was treated with HCI (4M in dioxane, 0.5 mL), and the mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated to dryness. Purification by FC (CH2CI2 -> CHjCb/MeOH 90:10) yielded the titie compound (18 mg, 39%). LC-MS: IR = 0.96 min; ES+: 597.16.
Example 2

(3S, 'ft)-4-{4-[2-(2,6-DichIoro-4-m ethyl-phenoxy)-ethoxy]-phenyl}-4-hydroxy-
piperidine-3-carboxylic acid I2-chloro-5-{2-methoxy-etbyl)-benzyl]-cyclopropyl-amide
HCl (4M in dioxane, 2.40 mL) was added to a sol. of compound D2 (380 mg. 0.499 mmol) in CH2CI2 (2.40 mL) at 0 °C. The mixture was stirred for 2 h wliije warming up to rt, and the solvents were then removed under reduced pressure. Purification of the crude by FC (CHoCI./MeOH 90:10} yielded the racetnic title compound (249 mg, 75%). This mixture was separated by chiral, preparative HPLC (Regis Whelk, isocratic eluent B 85%). The title compound was obtained (42 mg. 19%). LC-MS: tR = 0.96 min; ES+: 663.56. Chiral. analytic HPLC (Regis Whelt isocratic eiuent B 85%): tp = 33.0 min.
Example 3
(S'S, •/'/f)-6-|2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-4'-hydroxy-l',2',3',4',5',6'-
hexahydro-|3,4']bipyridiny|-3'-carboxylic acid [2-chloro-5-(2-niethoxy-ethyl)-benzyl|-
cyclopropyl-amide
Compound D3 (1.132 g, 1.485 mmol) wasdissolved in CH2CI2 (7.40 mL). The sol. was cooled to 0 "C. HCl (4M in dioxane, 7.40 mL) was added dropwise to the mixture. The mixture was stirred for 1 h at rt, and was carefully poured onto a mixture of aq. sal. NaHCOj and EtOAc. The mixture was eiitracted W'ith EtOAc. The combined org. extracts were dried over NaiSO, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2CI2 to CHjCb/MeOH 90:10) yielded the racemic title compound still mixed with little silica gel. This mixture was diluted with CHCL, and filtered over cotton. The solvents were removed under reduced pressure to yield the pure, racemic title compound (904 mg, 92%). This racemate was separated by chiral. analytic HPLC (Chiralpack AD, isocratic eluent S 45%). The title compound was obtained (350 mg, 42%). LC-MS: tR = 0.94 min; ES+: 662.43. Chiral. anahtic HPLC (Chiralpack AD, isocratic eluent B 65%): tR 11.4 min.
Example 4
{3'S, 'fl)-6-[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-4'-hydroxy-
l',2'',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid [2-chloro-S-(2-methoxy-
ethyl)-benz>l]-cyclopropyKamide

Compound D4 (275 mg, 0.349 mmof) was dissolved in CHCIi (1.75 inL). The sol. was cooled to 0 "C. HCS (4M in dtoxane, 1.75 mL) was added dropwise to the mixture. The miwure was stirred for 1 h at rt. and was carefuli> poured onto a mixture of aq. sat. NaHCO.i and EtOAc. The mixture was extracted with EtOAc. The combined org. extracts were dried over Na2S04, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2CI2 -- CHCb/MeOH 90:i0) yielded the racemic title compound (162 mg, 67%). This racemate was separated by chiral. analytic HPLC (Chiralpack AD, isocratic eiuent B 50%). The title compound was obtained (45 mg, 30%). LC-MS: t,; = 0.92 min: ES+: 687.63. Chiral. analytic HPLC (Chiralpack AD, isocratic eiuent B 50%): IR = ] i.5 min.
Example 5
(3% 7;)-6-[(ff)-3-(2,6-Dichioro-4-methyI-phenoxy)-pyrrolidin-l-yl]-4'-hydroxy-
1 ''',4',5',6'-bexahydro-[3,4']bipyridinyl-3'-carboxylic acid [2-chloro-5-(2-methoxy-
ethy!)-benzyl]-cyclopropyl-ainide
Compounds D5 (1.29 g, 1.64 mmol) were dissolved in CH2CI2 (8.2 niL). The sol. was cooled to 0 °C. HCI (4M in dioxane, 8.2 mL) was added dropwise to the mixture. The mixture was stirred for 1 h at rt, and was carefully poured onto a mixture of aq.. sat. NaHC03 and EtOAc. The mixture was extracted with EtOAc. The combined org. extracts were dried over Na2S04. filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2CI2 to CH2C!2/MeOH 90:10) yielded the title compound still mixed with its corresponding stereoisomer and with little silica gel. This mixture was diluted with CH2CI2, and filtered over cotton. The solvents were removed under reduced pressure to yield the pure title compound mixed with its corresponding diastereoisomer (904 mg, 80%). Part of this mixture (150 mg) was separated by chiral, analytic HPLC (Chiralpack AD, isocratic eiuent B 50%). The title compound was obtained (50 mg, 33%). LC-MS: tp = 0.81 min; ES+: 689.66. Chiral, analytic HPLC (Chiralpack AD, isocratic eiuent B 50%):tR= 10.7 min.
Example 6

(S'S, 'ff)-6-[2-(2,6-Dichloro-4-methyl-phenoxyj-efhoxyI-4'-liydroxy-l\2',3',-i',5',6'-hexahydro-[3,4']bipyridinyI-3'-carboxyHc acid |5-chloro-2-(3-methoxy-propyl)-pyndin-4-yJmethy]]-cyclopropy]-amide
Compound D6 (920 mg. I.IS mmo!) was dissolved in CHCI: (5.9 niL). The sol. was cooled to 0 "C. HCt {4V1 in dioxane, 5.9 mL) was added dropwise to the mixture. Tiie mixture was stirred for I ti at rt, and was carefully poured onto a mixture of aq. sat. NaHCO.1 and EtOAc. The mixture was extracted with EtOAc. The combined org. e.xtracts were dried over 32504, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC {CH:Cl2 to CHCb/MeOH 0:10) yielded the title compound still mixed its corresponding stereoisomer and with little silica gel. This mixture was diluted whh CH2CI2, and filtered over cotton. The solvents were removed under reduced pressure to yield the pure title compound mixed with its corresponding diastereoisomer (6S2 mg, 85%). Part of this mixture (SO mgj was separated by chiral. analytic HPLC (Chiralpack AD, isocratic eluent B 50%). The title compound was obtained . (31 mg, 39%). LC-MS: tR = 0.88 min; ES+: 679.23. Chiral analytic HPLC (Chiralpack AD, isocratic eluent B 50%): tR = 16.4 min.
Example 7
(3% V'ff)-6-f2-(2,6-Dichloro-4-niethy!-phenoxy)-ethoxyl-4'-hydroxy-r,2',3',4',5',6'-
hexahydro-|3,4']bipyridinyl-3'-carboxylic acid [5-chloro-2-(3-methoxy-propyl)-l-oxy-
pyridin-4-ylmethyl]-cyclopropyl-amide
Compound W (347 mg. 0.50O mmol) was dissolved in CHCK (2.5 mL), HCI {AM in dioxane. 2.50 mL) was added dropwise to the sol. The mixture was stirred at rt for I h. and was carefully poured onto a mixture of aq. sat. NaHCOj and EtOAc, The mixture was extracted with EtOAc, dried over Na2S04, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CHCL -> CH2Cl2/MeOH 9:1) yielded the title compound still mixed with silica gel. This mixture was taken in CHiCb. and filtered over cotton, which yielded the racemic title compound (266 mg. 77%). Part of this racemate (83 mg) was separated by chiral, analytic HPLC (Chiralpack AD, isocratic eluent B 50%). The title compound was obtained (29 mg, 35%), Chiral, analytic HPLC (Chiralpack AD, isocratic eluent B 50%): tR -31.1 min.

Biological Assays
1. Enzyme immune assay (EIA) to estimate AngJ accumulation and renin inhibition
1.1 Preparation of Angl-BSA conjugate
1.3 mg(l nmoljof AngI [1-10 (Bachem, H-t 680)] and 17mg(0.26 nmol) of BSA (Fluka. 05475) were dissolved in 4 mL of O.iM ptiosphate buffer. pH 7.4. after which 2 mL of a 1:100 dilution of glutaraldehyde in HjO (Sigma G-5882) was added dropwise. The mixture was incubated overnight at 4 °C, then dialyzed against 2 liters of 0.9% NaCl, twice for 4 h a£ It, followed by dialysis against 2 litere of PBS iX overnight at rt. The solution was then filtered with a Syringe filter, 0.45 )xm (Nalgene, Cat. No. 194-2545). The conjugate can be stored in polypropylene tubes in 0.05% sodium azide at 4 °C for at least 12 months.
1.2 Preparation of BSA-AngI coated MTP
Microtiter plates (MPT384, MaxiSorpM Nunc) were incubated overnight at 4 °C with 80 ■ )ii of Angi (1-10)/BSA conjugate, diluted 1:IOO'000 in PBS IX in a teflon beaker (exact dilution dependent on batch of conjugate), emptied, filled with 90 |j.l of blocking solution [0.5% 8SA (Sigma A-2J53) in PBS !X, 0.02% NaN], and incubated for at least 2 h at n. or overnight at 4 "C. 96 well MTP (MaxiSorp™, Nunc) were coated with 200 M-l conjugate and blocked with 250 jxl blocking solution as above, except that the blocking solution contained 3% BSA. The plates can be stored in blocking solution at 4 X for 1 month.
1.3 AngX-EIA in 384 well MTP
The Angl (I -10)/BSA coated MTP were washed 3 times with wash buffer (PBS I X, 0.01 % Tween 20) and filled with 75 |ii of primary antibody solution (anti-Angf antiserum, pre-diluted 1:10 in horse serum), diluted to a final concentration of 1:100'000 in assay buffer (PBS IX, ImM EDTA, 0.1% BSA, pH 7.4). 5 \ 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 "C. 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 n.

The plates were washed 3 times with wash buffer and then incubated for I h at rt with substrate sokition [l,89rnM ABTS (2.2'-azino-di-(3-ethyl-benzth!a2olinsutfonate)] (Rociie Diagnostics. 102 946) and 2.36mM H2O2 [30%. (Fiuka, 95300] in substrate buffer (O.IM 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 AngI during the renin reaction was quantified by comparing the OD of the sample with the ODof a standard curve of Angl(l-10), measured in parallel.
2. Primarj' renin inhibition assay: ICso in buffer, 384 well MTP
The renin assay was adapted from an assay described before (Fischii W. el uL. Hyperlemion. 1991. 38:22-31) 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 (AngI), In the second step, the accumulated -AngJ is measured by an immunological assay (enzyme immuno assay, EIA). The detailed description of this assay is found below. The EIA is very senshive and well suited for renin activity measurements in buffer or in plasma. Due to the low concentration of renin used in this assay (2 fmo! 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/(xl) in assay buifer (PBS \ X. ! mM EDTA. 0.1 % BSA. pH 7.4), human tetradecapeptide (1-14) substrate (Bachem, M-1120) [5 jiM in 10 mM HCI], hydroxyquinoline sulfate (Fiuka, 55100) [30 mM in H2O] and assay buffer were premixed at 4 °C at a ratio of 100:30:10:145. 47.5 [i\ per well of this premix was transferred into polypropylene plates (MTP384, Nunc). Test compounds were dissolved and diluted in 100%DMSOand2.5 |il added to the premix, then incubated at 37 X for 3 h. At the end of the incubation period, 5 |il of the renin reaction (or standards in assay buffer) were transferred into EIA assays (as described above) and AngI produced by renin was quantified. The percentage of renin inhibition (AngI 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 exhibit a very good bioavailability and are metabolically more stable than prior art compounds.

Claims
1. A compound of the formula (1)

wherein
X represents CH, N, or "N+=O:
W represents aparo-substhuted phenyl, a paro-substituted pyridinyl, or a thiazolyl;
V represents -CH2CH1CH2-, -CH2CH2-A-, -CH2-A-CH2-, -A-CH.CH;-. -CH2CH2CH2CH;- -A-CH2CH.CH2-, -CH2-A-CH2CH2-, -CH2CH2-ACH2-. -CH2CH2CH2-A-, -A-CH2CH2-B-. -CH2CH2CH2CH2CH2-. -A-CH2CH2CH2CH2-, -CH.-A-CH2CH.CH.-, -CH2CH2-A-CH2CH2-. -CH2CH2CH2-A-CH2-, -CH2CH2CH2CH2-A-. -A-CH2CH:CH2-B-. -CH2-A-CH.CH2-B-, -A-CH2CH2-B-CH2-, -A-CH2CH2CH2-B-CH2-, -CH2-A-CH2CH2CH;-B-. or -O-CH2-Q-. wherein Q is bound to the group U of formula (I), or V represents a pyrrolidinyl of the formula:

U represents unsubstituted aryl: mono-, di-. tri- or tetra-substituted aryl, wherein the substituents are independently selected from the group consisting of C1-7-alkyl, -CF3,

halogen, and hydroxy-Ct-7-alkyl; or five-membered heteroaryj with two heleroatoms independently selected from nitrogen, oxygen and sulphur, wherein said heteroaryl radical is optionally mono-, di- or tri-substituted. wherein the substitutents are independently selected from the group consisting of C1-7-alkyl. C1-7-aIkoxy. -CF3. -OCF:,. and halogen;
Q represents a five-membered heteroaryl with two or three heteroatoms independently selected from O and N;
L represents -CH2-CH2-, -CH2-CH(R'')-CH2-, -CH2-N(R)-CH2-. -CH2-O-CH2-, or -CH2-S-CH2-;
A and B represent independently from each others -O- or -S-;
R1 represents C1-7-alky! or eye balky I;
R2 represents halogen or C1-7-alkyi;
R3 represents hydrogen, halogen, C1-7-alkyl, Ci-7-alkoxy, or -CF3;
R4 represents hydrogen; Ci-7-alkyl-0-(CH2)2-CH2-; CF3-0-(CH2)o-CH2S R'2N-{CH2)()-4-CH2-, wherein R1 is independently selected from the group consisting of hydrogen. C1.7-alkyl (optionally substituted by one to three fluorine), cyclopropyl (optionally substituted by one to three fluorine), cyclopropyl-C1-7-alkyl (optionally substituted by one to three fluorine), and -C(K))-R"' wherein R'' is CM-alkyi, C1-4-alkoxy. -CF3, -CH2-CF3. or cyclopropyl: or R'-C(=0)-(0)O.I-(CH2)O-4-, wherein R13 is C1-4-alkyL C1-4-alkoxy. or cyclopropyl: wherein R' and R" preferably do not both simultaneously represent hydrogen:
R2 represents hydroxy, C1-7-alkoxy, hydroxy-C1-7-aikyl, dihydroxy-C1-7-alkyl. C1-7-a!koxy-C1-7-alkyL C1-7-alkoxy-C1-7-alkoxy-Ci-7-alkyl, hydroxy-C1-7-alkoxy-C,-7-alkyl, carbamoyl-C1-7-alkoxy. or Ci-7-alkyi-carbonyloxy;
R' represents -H, -CHjOR -CH2NRV, -CH.NRCOR', -CH2NR'S02R'. -CO2R', -CH.OCONR'R'. -CONRR -CH2NR'C0NR''R', -CH2S07NRR', -CH2SR', -CHjSOR or -CH7SO2R';


wherein T represents -CH1-, -NH- or -0-, r is an integer from I to 6 and s is an integer from 1 to 4;
R1 and R2 independently represent hydrogen, C1-7-alkyl. C;.7-alkenyl. cycloalkyl, or cyc(oaiky!-C1-7-alkyl. wherein C1-7-aikyl, cycloalkyl, and cyc]oalkyl-C1-7-alkyl can be substituted by one, two, or three halogens:
R6' represents hydrogen, C1-7-alkyl, cycloaikyl, or cycloa]kyl-C1-7-alkyl. wherein C1-7-ajkyl. cycloalkyi, and cycloalkyl-C1-7-alkyI may be mono-, di- or tri-substituted, wherein the . substituents are independently selected from the group consisting of halogen, hydroxy, -OCOR'l -COOR2 C1-7-a!koxy, cyano, SOIR12 -CONR'-R'-', morpholin-4-yl-CO-. ((4-C1-7-alkyl)piperazin-l-yl)-C0-, -NHC(NH)NH2, -NR'R"*' and C1-7-alkyl, with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp2-hybridized;
R" and R'"' independently represent hydrogen, Ci-7-alkyl, cycloalkyi, cycloalkyl-C1-7-alkyl. hydroxy-C,_7-alkyl, -COOR or -CONH2;
R' ' represents halogen, C|.7-alkyl, C!.7-alkoxy, -CF3, or hydrogen:
R11 and R12' independently represent hydrogen, C1-7-a!kyk C1-7-alkenyl. cycloalk;! or cycloalkyl-C|.7-alkyi, wherein C1-7-alkyl, cycloaikyl, and cyctoaikyl-C1-7-alkyl can be substituted by one, two, or three halogens;
n represents the integer 0 or 1; and
m represents the integer 0 or 1, with the proviso that m represents the integer 1 if n represents the integer 1:
and salts thereof.

2. A compound according to claim 1, wherein X represents W-0~ and R represents C1-4-alkoxy-C(=0)-NH-(CH2)o-4-CH:- or R'-.C(=0)-(0)O.:-(CH:),,.4-. wherein R13 is C,.4-alkyl. C(.4-a!koxy, or cyclopropyl or a salt of such a compound.
3. A compoLind according to claim 1. wherein X represents CH or N: and
R" represents hiydrogen: C,.7-a]kyl-0-(CH3):M-CH2-; CF3-0-fCH2)o-CH2-; or R'N-(CHijfM-CH-. wherein R' is independently selected from the group consistintz of hydrogen. C|_7-alkyi (optionally substituted by one to three fluorine), cyclopropyl (optionally substituted by one to three fluorine), cyclopropyl-Ci-y-alkyI (optionaSly substituted by one to three fluorine), and -C{=0)-R" wherein R" is Ci-4-alkyl, -CFj. -CH;-CF,i, or cyclopropyl; or a salt of such a compound.
4. A compound according to claim 1, wherein X represents CH or N~-0', or a salt of such a compound.
5. A compound according to any one of claims 1 to 4, wherein R represents -R, -COR, -COOR", -CONRR, -CCNRjNR'R -CSNRR, -SOsR or -S02NRR or a salt of such a compound.
6. A compound according to any one of claims 1 to 5, wherein A and B both represent -0-. or a salt of such a compound.
7. .A compound according to any one of claims 1 to 6. wlierein R represents -COCH; or -CO2H. or a salt of such a compound.
8. A compound according to any one of claims 1 to 7. wherein R represents -H, -COCH3. -C(NH)NH2. -CONHCH2C(CH3)2CONH2, -CONHCH(CH2)2. or -C0>;HC(CH2)2CN. or a salt of such a compound.

9. A compound according to claim 8, wherein R represents -H, or a salt of such a compound.
10. A compound according to any one of claims 1 to 6, wherein L represents -CH2-CH2- or -CH2-NH-CH2-, or a salt of such a compound.

11. A compound according to any one of claims I to 10. wherein R' represents cyclopropyl. or a salt of such a compound.
52. A compound according to any one of claims 1 to 11, wherein W represents & para-substituted phenyl, or

14. A compound according to claim 13, wherein V represents -O-CH3CH1-O- or -0-CH:-
Q-, or a salt of such a compound.
15. A compound according to any one of claims 1 to 14. wherein Q represents an
isoxazolyl or an oxadiazolyl, or a salt of such a compound.
16. .A compound according to claim 15, wherein Q represents an isoxazolyl. or a salt of
such a compound.
\ 7. A compound according to any one of claims I to ) 1, wherein V-W represents:


or a salt of such a compound,
20. A compound according to any one of claims 1 to 19. wherein R" represents Ci. and R"' represents hydrogen, or a salt of such a compound,
21. A compound according to any one of claims i and 3 to 20, wherein R* represents CH3-0-{CH2)7.3- or CH3-C(=0}-NH-CH2-CH2-, or a salt of such a compound.
22. A compound according to claim 21, wherein R' represents -CH2CH2CH2-O-CH3 or -CH3CH2-O-CH5, or a salt of such a compound.

23. A compound according to claim 22, wherein R3 represents -CH2CH2-O-CH3, or a sail
of such a compound.
24. A compound according to any one of claims ) to 23, wherein R3 r-eprcsents hydroxy, or a salt of such a compound.
25. A compound according to any one of claims ! to 24, wherein n represents the integer 0, or a salt of such a compound.
26. A compound according to any one of claims I. 5 to 19 and 24 to 25, wherein the
moiety

or a salt of such a compound.
27. A compound according to claim 1, wherein
X represents CH. "N, or N-0";
W represents a para-substituted phenyl ora/Jara-substituted pyridinyl;
V represents -A-CH2CH2-B- or -O-CH2-Q-, wherein Q is bound to the group U of formula ({), or V represents a pyrroiidiny! of the formula:


U represents tri-substituted phenyl, wherein the substituents are independently selected from the group consisting of C1-7-alkyl and halogen;
0 represents an isoxazolyl:
A and B both represent -0-;
R' represents cyclopropyl;
R' represents halogen or C1-7-a]kyl,-
R^ represents hydrogen or C1-7-alk;yl;
R* represents C1--7-alkyl-0-(CH2)(M-CH2-;
R' represents hydroxy;
n represents the integer 0; and
m represents the integer 1.
or a salt of such a compound.
28. A compound according to any one of claims 1 to 27. or a salt thereof, wherein the absolute configuration of a compound of formula (I) is as represented for formula (!'):


29. A compound according to claim 1. which is (JLV*. -/i^*)-4-{4-12-(2.6-dichioro-4-
methy]'pher!oxy}-QthDxy}-pyieny]}-4'hydroxy-piperid'me-^-carboxy\]c acid cyclopropyl-
{2.3-c!imethyl-ben2yl)-amide, or a salt thereof.
30, A compound according to claim 1, selected from:
{3S. -/i?)-4-{4-[2-(2,6-dichioro-4-methyl-phenoxy)-ethoxy]-phenyl}-4-hydroxy-piperidine-3-carboxyiic acid [2-chloro-5-(2-methojcy-ethyl)-benzyl]-cyclopropyl-amide.
{3'S, -;'7;)-6-[2-(2,6-dichloro-4-methyl-phenoxj)-ethoxy]-4'-hydroxy-r.2'-3'.4'.5'.6'-
hexahydro~[3,4']bipyridinyl-3'-carboxyiic acid [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyciopropyl-amide.
{3'S. -(R)-6-[3-(2-chIoro-3,6-difiuoro-phenyl)-isoxazol-5-ylmethoxy]-4'-hydroxy-
!'.2'.3'.4'.5'.6'-hexahydro-f3,4']bipyridinyl-3'-carboxylfC acid [2-ct]loro-5-(2-methoy-eth>l)-benzyl]-cyciopropyl-amide.
(3'S, ni';;)-6-[(i?)-3-(2,6-dichlor.>4-meth;'l-phenox\)-pyrrolidin-l-\-l]-4'-hydroxy-
l'.2',3',4'.5',6'-hexahydro-[3,4']bipyridinyi-3'-carboxyiic acid [2-chioro-5-(2-methoxy-ethyl)-benzyl]-cyclopropy!-amide,
(3'S, -?'/f)-6-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-4'-hydroxy-!'.2'.3'.4'.5'.6'-
hexahydro-[3.4']bipyridinyI-3'-carbox;yiic acid [5-chloro-2-(3-methoxy-propyl)-pyndin-4-yl methyl ]-cyclopropyl-afnide, and

-(R))-6-p-(2,6-dichioro-4-methy(-pheiioxy)-etnoxy]-4'-hydroxy-l'.2'.3'.4'.5'.6'-
hexa!iydro-[3.4']bipyridinyl-3'-carboxy|ic acid [5-chloro-2-{3-methoxy-propyl)-l-ox\' pyridin-4-yli'nethyi]-cyclopropy!-amide,
or salts of such compounds.
31. A pharmaceutical composition comprising a compound according to any one of claims
1 to 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
carrier malerial.
32. A compound according to any one of claims I to 30. or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composhion according to claim 31. for use as a
medicament.
33. Use of a compound according to any one of claims 1 to 30, or a pharmaceutically
acceptable salt thereof, for the preparation of a pharmaceutical composition tor-the
treatment and/or prophylaxis of diseases selected from hypertension, congestive heart
failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal
fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia,
cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes
such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular
pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or
cardiac surgery, erectile dysfunction, hyperaldosteronism. lung fibrosis, scleroderma,
anxiety, cognitive disorders, complications of treatments with immunosuppressive agents,
and other diseases related to the renin-angiotensin system.