Pyrrolidine ether derivatives as NK3 receptor antagonists

The present invention relates to a compounds of formula I

wherein

R ¹ is hydrogen or lower alkyl;

R ² is lower alkyl, lower alkyl substituted by halogen or is halogen or CN, and may be independently from each other if o is 2; Ar is aryl or heteroaryl;

R' is hydrogen, lower alkyl, halogen, cyano or lower alkyl substituted by halogen; R ³ is hydrogen, lower alkyl or hydroxy; X is -CH(R ⁴ )-, -N(R ^4' )- or -O-;

R ⁴ is hydrogen, hydroxy, =0, lower alkyl, lower alkinyl, -S(O) ₂ -lower alkyl, -C(O)-Io wer alkyl, -C(O)CH ₂ O-Io wer alkyl, -CH ₂ CN, -C(O)CH ₂ CN,

-C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, =0 or by amino, or is

-C(O)O-lower alkyl, -NH-lower alkyl, -NRC(O)O-lower alkyl, -NRC(O)-lower alkyl or ■ CH ₂ O-lower alkyl; and R ⁴ is hydrogen, lower alkyl, -S(O) ₂ -lower alkyl, -C(O)-lower alkyl, -C(O)CH ₂ -O-lower alkyl, -CH ₂ CN, -C(O)CN, -C(O)CH ₂ CN,

-C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, =0 or by amino, or is -C(O)O-lower alkyl or -CH ₂ O- lower alkyl; R is hydrogen or lower alkyl; or

R ³ and R ⁴ may form together with the carbon atoms to which they are attach a five or six- membered non aromatic ring or R ³ and R ⁴ may form together with the nitrogen and carbon atoms to which they are attach a five or six-membered non aromatic ring; m is 0, 1 , or 2 when n is 0; or m is 0 or 1 when n is 1 ; n is 0 or 1 ; o is 0, 1, 2 or 3; or pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers or tautomeric forms thereof.

The invention includes all sterio isomeric forms, including individual diastereoisomers and enantiomers of the compound of formula I as well as racemic and non-racemic mixtures thereof.

It has been found that the present compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).

The three main mammalian tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) belong to the family of neuropeptides sharing the common COOH-terminal pentapeptide sequence of Phe-X-Gly-Leu-Met-NH2. As neurotransmitters, these peptides exert their biological activity via three distinct neurokinin (NK) receptors termed as NK-I, NK-2 and NK-3. SP binds preferentially to the NK-I receptor, NKA to the NK-2 and NKB to the NK-3 receptor.

The NK-3 receptor is characterized by a predominant expression in CNS and its involvement in the modulation of the central monoaminergic system has been shown. These properties make the NK-3 receptor a potential target for central nervous system disorders such as anxiety, depression, bipolar disorders, Parkinson's disease, schizophrenia and pain (Neurosci. Letters, 2000, 283, 185 -188; Exp. Opin. Ther. Patents 2000, 10, 939-960; Neuroscience, 1996, 74, 403-414; Neuropeptides, 1998, 32, 481-488).

Schizophrenia is one of the major neuropsychiatric disorders, characterized by severe and chronic mental impairment. This devastating disease affects about 1 % of the world's population. Symptoms begin in early adulthood and are followed by a period of interpersonal and social dysfunction. Schizophrenia manifests as auditory and visual hallucinations, paranoia, delusions

(positive symptoms), blunted affect, depression, anhedonia, poverty of speech, memory and attention deficits as well as social withdrawal (negative symptoms).

For decades scientists and clinicians have made efforts with the aim of discovering an ideal agent for the pharmacological treatment of schizophrenia. However, the complexity of the disorders, due to a wide array of symptoms, has hampered those efforts. There are no specific focal characteristics for the diagnosis of schizophrenia and no single symptom is consistently present in all patients. Consequently, the diagnosis of schizophrenia as a single disorder or as a variety of different disorders has been discussed but not yet resolved. The major difficulty in the development of a new drug for schizophrenia is the lack of knowledge about the cause and nature of this disease. Some neurochemical hypotheses have been proposed on the basis of pharmacological studies to rationalize the development of a corresponding therapy: the dopamine, the serotonin and the glutamate hypotheses. But taking into account the complexity of schizophrenia, an appropriate multireceptor affinity profile might be required for efficacy against positive and negative signs and symptoms. Furthermore, an ideal drug against schizophrenia would preferably have a low dosage allowing once-per-day dosage, due to the low adherence of schizophrenic patients.

In recent years clinical studies with selective NKl and NK2 receptor antagonists appeared in the literature showing results for the treatment of emesis, depression, anxiety, pain and migraine (NKl) and asthma (NK2 and NKl). The most exciting data were produced in the treatment of chemotherapy- induced emesis, nausea and depression with NKl and in asthma with NK2- receptor antagonists. In contrast, no clinical data on NK3 receptor antagonists have appeared in the literature until 2000. Osanetant (SR 142,801) from Sanofϊ-Synthelabo was the first identified potent and selective non-peptide antagonist described for the NK3 tachykinin receptor for the potential treatment of schizophrenia, which was reported in the literature {Current Opinion in Investigational Drugs, 2001,2(7), 950-956 and Psychiatric Disorders Study 4, Schizophrenia, June 2003, Decision Recources, Inc., Waltham, Massachusetts) . The proposed drug SR 142,801 has been shown in a phase II trial as active on positive symptoms of schizophrenia, such as altered behaviour, delusion, hallucinations, extreme emotions, excited motor activity and incoherent speech, but inactive in the treatment of negative symptoms, which are depression, anhedonia, social isolation or memory and attention deficits.

The neurokinin-3 receptor antagonists have been described as useful in pain or inflammation, as well as in schizophrenia, Exp. Opinion. Ther. Patents (2000), 10(6), 939-960 and Current Opinion in Investigational Drugs, 2001, 2(7), 950-956956 and Psychiatric

Disorders Study 4, Schizophrenia, June 2003, Decision Recources, Inc., Waltham, Massachusetts) .

Objects of the present invention are novel compounds of formula I, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as depression, pain, bipolar disorders, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).

The preferred indications using the compounds of the present invention are depression, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).

The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.

As used herein, the term "lower alkyl" denotes a straight- or branched-chain alkyl group containing from 1-8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.

The term "lower alkyl substituted by halogen" denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example -CF ₃ , -CHF ₂ , -CH ₂ F, - CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ CF ₂ CF ₃ and the like. Preferred lower alkyl substituted by halogen groups are groups having 1-4 carbon atoms. The term "lower alkinyl" denotes a straight- or branched-chain alkinyl group containing from 2-8 carbon atoms, for example, ethynyl, propynyl, n-butynyl, i-butynyl, and the like. Preferred lower alkinyl groups are groups with 2-4 carbon atoms.

The term "halogen" denotes chlorine, iodine, fluorine and bromine.

The term "cycloalkyl" denotes a saturated carbon ring containing from 3-7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclpentyl, cyclohexyl, cycloheptyl, and the like.

The term "aryl" denotes a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 6-14 carbon atoms in which at least one ring is aromatic in nature, for example phenyl, benzyl, naphthyl or indanyl. Preferred is the phenyl group.

The term "heteroaryl" denotes a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 5-14 ring atoms, preferably containing 5-10 ring atoms, in which at least one ring is aromatic in nature, and which contains at least one heteroatom, selected from N, O or S, for example quinoxalinyl, dihydroisoquinolinyl, pyrazinyl, pyrazolyl, pyridinyl, pyridyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, furyl, imidazolyl,

or benzofuranyl. Preferred heteroaryl group is pyridinyl.

The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, 5 methanesulfonic acid, p-toluenesulfonic acid and the like.

Preferred compounds of the present invention relates to a compounds of formula I

0 wherein

R ¹ is lower alkyl;

R ² is halogen or CN, and may be independently from each other if o is 2; 5 Ar is heteroaryl;

R' is halogen, cyano or lower alkyl substituted by halogen;

R ³ is hydrogen or hydroxy;

X is -CH(R ⁴ )-, -N(R ^4' )- or -O-;

R ⁴ is hydrogen, hydroxy, =0, lower alkinyl, -S(O) ₂ -lower alkyl, 0 or is -NH-lower alkyl, -NRC(O)O-lower alkyl, -NRC(O)-lower alkyl or -CH ₂ O-lower alkyl; and

R ^4' is hydrogen, lower alkyl, -S(O) ₂ -lower alkyl, -C(O)-lower alkyl, -C(O)CH ₂ -O-lower alkyl, -CH ₂ CN, -C(O)CH ₂ CN, -C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, =0 or by amino,5 or is -C(O)O-lower alkyl;

R is hydrogen or lower alkyl; or m is 0, 1 , or 2 when n is 0; or m is 0 or 1 when n is 1 ; n is 0 or 1 ; O o is 1 or 2;

or pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers or tautomeric forms thereof.

Compounds of formula I, wherein Ar is heteroaryl, are preferred. Especially preferred are compounds of formula I, wherein Ar is pyridinyl.

Compounds of formula I, wherein X is -CH(R ⁴ )-, are preferred. For example the following compounds:

{4-[(3RS,4SR)-3-[(SR)-l-(5-chloro-pyridin-2-yloxy)-ethyl] -4-(3,4-dichloro-phenyl)-pyrrolidine- l-carbonyl]-cycloheyl}-carbamic acid methyl ester

[(3RS,4SR)-3-[(SR)-l-(5-chloro-pyridin-2-yloxy)-ethyl]-4- (3,4-dichloro-phenyl)-pyrrolidin-l- yl]-(4-methoxymethyl-cyclohexyl)-methanone

[(3RS,4SR)-3-[(SR)- 1 -(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-p yrrolidin- 1 - yl]-(4-ethynyl-cyclohexyl)-methanone 4-[(3RS,4SR)-3-[(SR)-l-(5-chloro-pyridin-2-yloxy)-ethyl]-4-( 3,4-dichloro-phenyl)-pyrrolidine-

1 -carbonylj-cyclohexanone

{4-[(3RS,4SR)-3-[(SR)-l-(5-cyano-pyridin-2-yloxy)-ethyl]- 4-(3,4-dichloro-phenyl)-pyrrolidine- l-carbonyl]-cyclohexyl}-methyl-carbamic acid tert-butyl ester

{4-[(3RS,4SR)-3-[(SR)-l-(5-cyano-pyridin-2-yloxy)-ethyl]- 4-(3,4-dichloro-phenyl)-pyrrolidine- l-carbonyl]-cyclohexyl}-carbamic acid tert-butyl ester or

N-{4-[(3RS,4SR)-3-[(SR)-l-(5-cyano-pyridin-2-yloxy)-ethyl ]-4-(3,4-dichloro-phenyl)- pyrrolidine- 1 -carbonylj-cyclohexyl} -N-methyl-acetamide.

Compounds of formula I, wherein X is -N(R ⁴ )-, are preferred. For example the following compounds: l-{4-[(3RS,4SR)-3-[(SR)-l-(5-chloro-pyridin-2-yloxy)-ethyl]- 4-(3,4-dichloro-phenyl)- pyrrolidine- 1 -carbonylj-piperidin- 1 -yl} -ethanone

6-{(SR)-l-[(3RS,4SR)-l-(l-acetyl-piperidine-4-carbonyl)-4 -(3,4-dichloro-phenyl)- [(3RS,4SR)-

3-[(SR)-l-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichlo ro-phenyl)-pyrrolidin-3-yl]-ethoxy}- nicotinonitrile pyrrolidin-l-yl]-(l-cyclobutanecarbonyl-piperidin-4-yl)-meth anone

[(3RS,4SR)-3-[(SR)-l-(5-chloro-pyridin-2-yloxy)-ethyl]-4- (3,4-dichloro-phenyl)-pyrrolidin-l- yl] -( 1 -isobutyl-piperidin-4-yl)-methanone

4-[(3RS,4SR)-3-[(SR)-l-(5-cyano-pyridin-2-yloxy)-ethyl]-4 -(3,4-dichloro-phenyl)-pyrrolidine- l-carbonylj-piperidine-l-carboxylic acid tert-butyl ester

6-{(SR)-l-[(3RS,4SR)-l-(l-cyclopropanecarbonyl-piperidine -4-carbonyl)-4-(3,4-dichloro- phenyl)-pyrro lidin-3 -yl] -ethoxy } -nicotinonitrile 6-((SR)- 1 - {(3RS,4SR)-4-(3 ,4-dichloro-phenyl)- 1 -[ 1 -( 1 -methyl-cyclopropanecarbonyl)- piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethoxy)-nicotinonitr ile

6-{(SR)-l-[(3RS,4SR)-l-[l-(l-amino-cyclopropanecarbonyl)- piperidine-4-carbonyl]-4-(3,4- dichloro-phenyl)-pyrro lidin-3 -yl] -ethoxy } -nicotinonitrile

6-{(SR)-l-[(3RS,4SR)-l-(l-cyclobutanecarbonyl-piperidine- 4-carbonyl)-4-(3,4-dichloro- phenyl)-pyrro lidin-3 -yl] -ethoxy } -nicotinonitrile

6-((SR)- 1 - {(3RS,4SR)-4-(3,4-dichloro-phenyl)- 1 -[ 1 -(3-oxo-cyclobutanecarbonyl)-piperidine-4- carbonyl]-pyrrolidin-3-yl}-ethoxy)-nicotinonitrile

6-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-l-(l-propion yl-piperidine-4-carbonyl)- pyrrolidin-3-yl]-ethoxy} -nicotinonitrile 6-{(SR)-l-[(3RS,4SR)-l-[l-(2-cyano-acetyl)-piperidine-4-carb onyl]-4-(3,4-dichloro-phenyl)- pyrrolidin-3-yl]-ethoxy} -nicotinonitrile

6-((SR)- 1 - {(3RS,4SR)-4-(3,4-dichloro-phenyl)- 1 -[ 1 -(2-methoxy-acetyl)-piperidine-4-carbonyl]- pyrrolidin-3-yl}-ethoxy)-nicotinonitrile l-(4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(SR)-l-(5-trifluo romethyl-pyridin-2-yloxy)-ethyl]- pyrrolidine- 1 -carbonyl} -piperidin- 1 -yl)-ethanone

6-((SR)- 1 - {(3RS,4SR)-4-(3 ,4-dichloro-phenyl)- 1 -[ 1 -( 1 -methyl-cyclopropanecarbonyl)- piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethoxy)-nicotinonitr ile

[(3RS,4SR)-3-[(SR)-l-(5-chloro-pyridin-2-yloxy)-ethyl]-4- (2,4-difluoro-phenyl)-pyrrolidin-l- yl] - [ 1 -( 1 -methyl-cyclopropanecarbonyl)-piperidin-4-yl] -methanone {(3S,4R)-3-(4-chloro-phenyl)-4-[(S)- 1 -(5-chloro-pyridin-2-yloxy)-ethyl]-pyrrolidin- 1 -yl} -[ 1 -(I - methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone or

{(3S,4R)-3-(4-chloro-3-fluoro-phenyl)-4-[(S)-l-(5-chloro- pyridin-2-yloxy)-ethyl]-pyrrolidin-l- yl} - [ 1 -( 1 -methyl-cyclopropanecarbonyl)-piperidin-4-yl] -methanone.

Compounds of formula I, wherein X is -O-, are also preferred, for example the following compound:

{(3SR,4RS)-3-(3,4-Dichloro-phenyl)-4-[(SR)-l-(5-trifluoro methyl-pyridin-2-yloxy)-ethyl]- pyrrolidin- 1 -yl} -(tetrahydro-pyran-4-yl)-methanone.

The preparation of compounds of formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.

The compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in scheme 1, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art. The present compounds of formula I and their pharmaceutically acceptable salts may be prepared by methods, known in the art, for example by the process described below, which process comprises a) coupling a compound of formula

with a suitable acid chloride or carboxylic acid of formula

wherein Y is halogen or hydroxy, to a compound of formula

wherein the substituents R ¹ , R ² , R', R ³ , X and Ar and the definitions o, n and m are described above, b) reacting a compound of formula

with a compound of formula

R ⁴ '-Z wherein Z is halogen, to a compound of formula

wherein the substituents R ¹ , R ² , R ³ , R ⁴ , R', Ar and and the definitions o, n and m are described above, or, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts. The preparation of compounds of formula I is further described in more detail in schemes I - V and in examples 1 -53.

Abbreviations: CH ₂ Cl ₂ : dichloromethane; DMAP: dimethylaminopyridine; HOBt: 1 -hydro xy-benzotriazol hydrat; EDC: l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Et ₃ N: triethylamine; EtOAc: ethyl acetate; H: hexane;

RT: room temperature; PPh ₃ : triphenylphosphine;

DBAD: di-tert-butyl azodicarboxylate

General scheme I

wherein Y is halogen or hydroxy, R ¹ a lower alkyl and the other definitions are as above.

The 3,4-disubstituted pyrrolidines IV are prepared via a stereo specific 1,3-dipolar cycloaddition between substituted (E)-4-phenyl-but-3-en-2-one derivative II and the azomethine ylide generated in situ from the N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyla mine III in the presence of a catalytic amount of acid, such as TFA. Reduction of the acetyl moiety using standard conditions for example LiAlH ₄ yields the two diasteroisomers V-A and V-B which are subsequently separated by column chromatography. Each of the diastereoisomers is then separately converted to the final derivatives I-A and I-B in the same manner. For instance V-B is subjected to a standard Mitsunobu reaction with for example a phenol, pyridin-ol, pyrimidin-ol to give the aryl-ether VI-B. Selective N-debenzylation is then carried out using several known procedures which are compatible with the substitution patterns of the aromatic rings to afford VII-B. Final derivatives I-B are prepared via a coupling with a suitable acid chloride or carboxylic acid using known methods, wherein Y is hydroxy or halogen, R ¹ a methyl moiety and the other definitions are as described above.

General scheme II

wherein Y is hydroxy or halogen, Z is halogen and the other definitions are as described above.

Alternatively the pyrrolidine VII-B can undergo a coupling with a carboxylic acid derivative which after selective Boc deprotection generated the intermediate VIII-B. Final derivatives I-B-l are prepared via a coupling with R ⁴ -Y using well known reactions and procedures. In the same manner, the diastereomer VII-A can be converted to final derivatives I- A.

General scheme III

Alternatively to the Mitsunobu reaction shown scheme I, derivatives V-A and V-B can used in a nucleophilic aromatic substitution reaction when the Ar moiety is a o-pyridinyl or a o- pyrimidinyl to yield respectively VI-B and VI-A.

General Scheme IV

An alternative method for the preparation of intermediates IV (with R ¹ is Me) is highlighted scheme 4. A 1,3-dipolar cycloaddition between the commercially available but-3-yn-2-one IX and the azomethine ylide generated in situ from the N-(methoxymethyl)-N-(phenylmethyl)-N- (trimethylsilyl)methylamine III in the presence of a catalytic amount of acid, such as TFA afforded the dihydropyrrole derivative X. A 1,4-addition of a boronic acid catalysed by a Rh(I) catalyst such as the Rhacetylacetonatbis(ethylene) in a presence of of a chiral phosphine ligand such as the (R) or (S)-BINAP afforded the optically enriched disubstituted pyrrolidine IV.

Similar Rh-catalysed asymmetric 1 ,4-arylation have been reported earlier (Tet. Lett., 2004, 45(16), 3265)

General scheme V

The derivatives of the type I-C with R ¹ equal H where prepared via the following route (scheme 5). The 3,4-disubstituted pyrrolidines XII were prepared via a stereo specific 1,3-dipolar cycloaddition between the (E)-3-substituted phenyl-acrylic acid ethyl ester derivatives XI and the azomethine ylide generated in situ from the N-(methoxymethyl)-N-(phenylmethyl)-N- (trimethylsilyl)methylamine III in the presence of a catalytic amount of acid, such as TFA.

Reduction of the ester moiety using standard conditions for example LiAlH ₄ yielded the primary alcohol V-C. Standard Mitsunobu reaction with for example a phenol, pyridin-ol, pyrimidin-ol gave the aryl-ether VI-C. Selective N-debenzylation was then carried out using several known procedures which are compatible with the substitution patterns of the aromatic rings to afford VII-C. Final derivatives I-C were obtained via a coupling with a suitable acid chloride or carboxylic acide using known methods.

EXPERIMENTAL PROCEDURES

As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of neurokinin 3 (NK-3) receptors. The compounds were investigated in accordance with the tests given hereinafter.

Experimental procedure

The compounds were investigated in accordance with the tests given hereinafter.

[ ³ H]SR142801 competition binding assay hNK3 receptor binding experiment were performed using [ HJSR142801 (Catalog No. TRKl 035, specific activity: 74.0 Ci/mmol, Amersham, GE Healthcare UK limited, Buckinghamshire, UK) and membrane isolated from HEK293 cells transiently expressing recombinant human NK3 receptor. After thawing, the membrane homogenates were centrifuged at 48,000 X g for 10 min at 4 ⁰ C, the pellets were resuspended in the 50 mM Tris-HCl, 4 mM MnCl ₂ , 1 μM phosphoramidon, 0.1 % BSA binding buffer at pH 7.4 to a final assay concentration of 5 μg protein/well. For inhibition experiments, membranes were incubated with [ H] SRl 42801 at a concentration equal to K _D value of radioligand and 10 concentrations of the inhibitory compound (0.0003-10 μM) (in a total reaction volume of 500 μl) for 75 min at room temperature (RT). At the end of the incubation, membranes were filtered onto unitfilter (96-well white microplate with bonded GF/C filter preincubated 1 h in 0.3% PEI + 0.3% BSA, Packard BioScience, Meriden, CT) with a Filtermate 196 harvester (Packard BioScience) and washed 4 times with ice-cold 50 mM Tris-HCl, pH 7.4 buffer. Nonspecific binding was measured in the presence of 10 μM SB222200 for both radioligands. The radioactivity on the filter was counted (5 min) on a

Packard Top-count microplate scintillation counter with quenching correction after addition of 45 μl of microscint 40 (Canberra Packard S. A., Zurich, Switzerland) and shaking for 1 h. Inhibition curves were fitted according to the Hill equation: y = lOO/(l+(x/IC5o) ^nH ), where nπ = slope factor using Excel- fit 4 software (Microsoft). IC50 values were derived from the inhibition curve and the affinity constant (K ₁ ) values were calculated using the Cheng-Prussoff equation K ₁ = IC _5O /(1+[L]/K _D ) where [L] is the concentration of radioligand and K _D is its dissociation constant at the receptor, derived from the saturation isotherm. All experiments were performed in duplicate and the mean ± standard error (SEM) of the individual K ₁ values was calculated.

Some results of preferred compounds with a good hNK-3 receptor affinity were shown in the following table 1.

Table 1 Example Data [μM] Example Data [μM]

1 0.0047 21 0.0021

2 0.0076 22 0.0036

3 0.0012 23 0.0075

5 0.0095 24 0.0036

6 0.0058 42 0.0028

10 0.009 43 0.007

11 0.0061 45 0.004

12 0.0092 46 0.0018

13 0.0044 47 0.0019

14 0.0049 48 0.0074

17 0.0046 52 0.001

19 0.0077 53 0.0008

20 0.0026

The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules.

Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc.

Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc. Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.

Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi- liquid or liquid polyols etc.

Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifϊers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.

Example A Tablets of the following composition are manufactured in the usual manner: mg / tablet Active substance 5

Lactose 45

Corn starch 15

Micro crystalline cellulose 34

Magnesium stearate 1 Tablet weight 100

Example B

Capsules of the following composition are manufactured: mg / capsule

Active substance 10 Lactose 155

Corn starch 30

Talc 5

Capsule fill weight 200

The active substance, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer, the talc is added thereto and mixed thoroughly. The mixture is filled by machine into hard gelantine capsules.

Example C

Suppositories of the following composition are manufactured: mg / supp.

Active substance 15

Suppository mass 1285

Total 1300

The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45 ⁰ C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

The following Examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.

General procedure I: Amid coupling (pyrrolidine VII and carboxylic acid)

To a stirred solution of a carboxylic acid derivative (commercially available or known in the literature) (1 mmol) in 10 mL OfCH ₂ Cl ₂ was added (1.3 mmol) of EDC, (1.3 mmol) of HOBt and Et ₃ N (1.3 mmol). After one hour at RT, was added a pyrrolidine intermediate of general formula (VII). The mixture was stirred at RT over night and then poured onto water and extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo. Flash chromatography or preparative HPLC afforded the title compound.

General procedure II: Coupling between a compound of formula VII or VIII with an acid chloride, chloroformate or sulfonyl chloride

A solution of the pyrrolidine (1 mmol) of formula (VII) in CH ₂ Cl ₂ (10 mL) was treated with Et ₃ N (1.2 mmol) and an acid chloride, chloroformate or sulfonylchlorid (1.2 mmol) and stirred at 5 RT overnight. Purification by preparative HPLC yielded the title compound.

Pyrrolidine intermediates of formula VII-B

Pyrrolidine VII-B-I 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin-3-yl]-ethoxy}-pyridine

a) l-[(3RS.4SR)-l-Benzyl-4-(3.4-dichloro-phenyl)-pyrrolidin-3-y ll-ethanone (IV-I) A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyla mine (32.78 g, 0.138 mol) in CH ₂ Cl ₂ (50 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-4-(3,4-dichloro-phenyl)-but-3-en-2-one (19.80 g, 0.092 mol) and trifluoro acetic 15 acid (1.05 mL, 0.009 mol) in CH ₂ Cl ₂ (100 mL) at 0 ⁰ C. The ice bath was removed, and the solution was stirred at 25 ⁰ C for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO ₂ , CH ₂ Cl ₂ /Me0H 98:2) afforded 28.3 g (88 %) of the title compound as a yellow oil. ES-MS m/e: 348.2 (M+H ⁺ ). 0 b) (SR)-l-[(3RS.4SR)-l-Benzyl-4-(3.4-dichloro-phenyl)-pyrrolidi n-3-yll-ethanol (V-A-I) and (RS)- 1 -[(3RS.4SR)- 1 -Benzyl-4-(3.4-dichloro-phenyl)-pyrrolidin-3-yll-ethanol (V-B-I) To a solution of l-[(3SR,4RS)-l-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y l]-ethanone (IV- 1) (14.90 g, 0.043 mol) in THF (300 mL) at 0 ⁰ C were added portion wise LiAlH ₄ (2.05 g, 0.051 mol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by 5 addition of aq. NH ₄ Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na ₂ SO ₄ and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO ₂ , EtOAc/H, 1 : 1) to yield (RS)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-e thanol (V-B-I) 4.69 g (31 %) as a white solid ES-MS m/e: 350.2 (M+H ⁺ ) and (SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-

30 pyrrolidin-3-yl]-ethanol (V-A-I) 5.30 g (35 %) as a white solid ES-MS m/e: 350.2 (M+H ⁺ ).

c) 2-{(SR)-l-r(3RS.4SR)-l-Benzyl-4-(3.4-dichtoro-phenyl)-pyrroU din-3-yll-ethoxy}-5-chton)- pyridine

To a suspension of PPI1 ₃ (PPI1 ₃ polymer bound, 3 mmol PPh ₃ Zg resin) (3.14 g, 9.4 mmol) in THF (70 mL) at 0 ⁰ C were added 5-chloro-pyridin-2-ol (0.832 g, 6.42 mmol) and then DBAD (1.578 g, 6.85 mmol). After 5 minutes was added (RS)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)- pyrrolidin-3-yl]-ethanol (V-B-I) (1.50 g, 4.28 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH IM, followed by column chromatography (SiO ₂ , EtOAc/H, 1 :6) yielded 1.71 g (87%) of the title compound as a colorless oil. ES-MS m/e: 461.2 (M+H ⁺ ).

d) 5-Chloro-2-((SR)-l-[(3RS.4SR)-4-(3.4-dichloro-phenyl)-pyrrol idin-3-yll-ethoxyl-pyridine

(VII-B-I)

To a solution of 2-{(SR)-l-[(3RS,4SR)-l-benzyl-4-(3,4-dichloro-phenyl)-pyrrol idin-3-yl]- ethoxy}-5-chloro-pyridine (1.71 g (3.71 mmol) dissolved in CH ₃ CN (50 mL) was added 0.75 mL

(5.57 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 4 hours at RT.

Volatiles were removed under vacuo, and the crude was dissolved in AcOH (30 mL) before a total of 1.0 g of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by an extraction with EtOAc/aq. NaHCO ₃ (basic pH). The organic phases were dried on Na ₂ SO ₄ and column chromatography (SiO ₂ , CH ₂ Cl ₂ /Me0H 9:1) yielded 0.74g (54%) of the title compound as a colorless oil. ES-MS m/e: 373.1 (M+H ⁺ ).

Pyrrolidine VII-B-2 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]-ethoxy}-nicotinonitrile

a) 6- ((SR)- 1 -[(3RS.4SR)- 1 -Benzyl-4-(3.4-dichloro-phenyl)-pyrrolidin-3-yll-ethoxyl - nicotinonitrile

To a suspension of PPI1 ₃ (PPI1 ₃ polymer bound, 3 mmol PPh ₃ /g resin) (1.97 g) in THF (300 mL) at 0 ⁰ C were added 6-hydroxy-nicotinonitrile (0.61 g, 5.1 mmol) and then DBAD (1.10 g). After 5 minutes was added (RS)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-e thanol (V-B- 1) (1.20 g, 3.4 mmol, described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH IM, followed by column chromatography (SiO ₂ , EtOAc/H, 1 :4) yielded 1.02 g (66 %) of the title compound as a colorless oil. ES-MS m/e: 452.0 (M+H ⁺ ).

b) 6-((SR)-l-[(3RS.4SR)-4-(3.4-Dichloro-phenyl)-pyrrolidin-3-yl l-ethoxyl-nicotinonitrile (VII- B ₁ Zl

To a solution of 6-{(SR)-l-[(3RS,4SR)-l-benzyl-4-(3,4-dichloro-phenyl)-pyrrol idin-3-yl]- ethoxy}-nicotinonitrile 0.75 g (1.70 mmol) dissolved in CH3CN (50 mL) was added 0.56 mL (4.14 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 4 hours at RT. Volatiles were removed under vacuo, and the crude was dissolved in AcOH (30 mL) before a total of 0.45 g of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by an extraction with EtOAc/aq. NaHCO ₃ (basic pH). The organic phases were dried On Na ₂ SO ₄ and column chromatography (SiO ₂ , CH ₂ Cl ₂ /Me0H 9:1) yielded 0.36 g (60 %) of the title compound as a colorless oil. ES-MS m/e: 362.3 (M+H ⁺ ).

Pyrrolidine VII-B-3

2-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3 -yl]-ethoxy}-5-trifluoromethyl- pyridine

a) 2-((SR)-l-[(3RS.4SR)-l-Benzyl-4-(3.4-dichloro-phenyl)-pyrrol idin-3-yll-ethoxyl-5- trifluoromethyl-pyridine

To a suspension OfPPh ₃ (PPh ₃ polymer bound, 3 mmol PPh ₃ /g resin) (0.77 g) in THF (25 mL) at 0 ⁰ C were added 5-trifiuoromethyl-pyridin-2-ol (0.28 g, 1.75 mmol) and then DBAD (0.43 g).

After 5 minutes was added (RS)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-e thanol (V-B-I) (0.41 g, 1.17 mmol, described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH IM, followed by column chromatography (SiO ₂ , EtOAc/H, 1 :4) yielded 0.45 g (78 %) of the title 5 compound as a colorless oil. ES-MS m/e: 495.8 (M+H ⁺ ).

b) 2-((SR)-l-[(3RS.4SR)-4-(3.4-Dichloro-phenyl)-pyrrolidin-3-yl l-ethoxyl-5-trifiuoromethyl- pyridine (VII-B-3)

To a solution of 2-{(SR)-l-[(3RS,4SR)-l-benzyl-4-(3,4-dichloro-phenyl)-pyrrol idin-3-yl]-0 ethoxy}-5-trifluoromethyl-pyridine 0.45 g (0.91 mmol) dissolved in toluene (5 mL) were added 0.30 mL (2.7 mmol) of 1-chloroethyl chloro formate and 0.46 mL of Hunig's base. The reaction mixture was heated at 100 ⁰ C for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (5 mL). The reaction mixture was heated at 85 ⁰ C for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the5 residue was directly purified on column chromatography (SiO ₂ , CH ₂ Cl ₂ ZMeOH 9:1) yielded 0.32 g (87 %) of the title compound as a light yellow oil. ES-MS m/e: 405.9 (M+H ⁺ ).

Pyrrolidine VII-B-4 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(2,4-difluoro-phenyl)-pyrrol idin-3-yl]-ethoxy}-pyridine

a) (E)-4-(2,4-Difluoro-phenyl)-but-3-en-2-one

A two necked flask was charged with 2,4-difluorobenzaldehyde (4.0 g, 28.1 mmol) and (2-oxo- propyl)-phosphonic acid dimethyl ester (5.78 g, 33.0 mmol) and cooled down at at 0 ⁰ C. K3CO35 (7.62 g, 55.1 mmol) in H ₂ O (14 mL) was added dropwise. Stirring was continued over night at RT. The product was extracted with EtOAc, and the organic phase was dried over Na ₂ SO ₄ . Flash chromatography (SiO ₂ , Heptane/EtOAc 1 :3) afforded 4.0 g (79 %) of the title compound as alight yellow oil. 0 b) 1 -IY3RS.4SRV 1 -Benzyl-4-(2.4-difluoro-phenyl)-pyrrolidin-3-yll-ethanone (IV-4)

A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyla mine (7.82 g, 32.9 mmol) in CH ₂ Cl ₂ (40 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-4-(2,4-difluoro-phenyl)-but-3-en-2-one (4.0 g, 21.9 mmol) and trifluoro acetic acid (0.17 mL, 0.21 mmol) in CH ₂ Cl ₂ (10 mL) at 0 ⁰ C. The ice bath was removed, and the solution was stirred at 25 ⁰ C for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO ₂ , CH ₂ Cl ₂ MeOH 98:2) afforded 6.2 g (89 %) of the title compound as a yellow oil. ES-MS m/e: 316.1 (M+H ⁺ ).

c) (RS)-l-[(3SR.4RS)-4-(2.4-Difiuoro-phenyl)-pyrrolidin-3-yll-e thanol (V-A-4) and (SR)-I- [(3SR.4RS)-4-(2.4-Dichloro-phenyl)-pyrrolidin-3-yll-ethanoUV -B-4)

To a solution of l-[(3RS,4SR)-l-benzyl-4-(2,4-difluoro-phenyl)-pyrrolidin-3-y l]-ethanone (IV- 4) (1.87 g, 5.92mmol) in THF (30 mL) at 0 ⁰ C were added portion wise LiAlH ₄ (0.19 g, 5.21 mol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH ₄ Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na ₂ SO ₄ and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO ₂ , EtOAc/H, 1 : 1) to yield (RS)-l-[(3RS,4SR)-4-(2,4-difiuoro-phenyl)-pyrrolidin-3-yl]-e thanol (V-B-4) 0.72 g (38 %) as a white solid ES-MS m/e: 318.1 (M+H ⁺ ) and (SR)-l-[(3RS,4SR)-4-(2,4-difluoro-phenyl)- pyrrolidin-3-yl]-ethanol (V-A-4) 0.374 g (19 %) as a white solid ES-MS m/e: 318.1 (M+H ⁺ ).

d) 2- ((SR)- 1 -[(3RS.4SR)- 1 -Benzyl-4-(2.4-difluoro-phenyl)-pyrrolidin-3-yll-ethoxyl -5-chloro- pyridine (VI-B-4)

To a suspension OfPPh ₃ (PPh ₃ polymer bound, 3 mmol PPh ₃ /g resin) (1.27 g, 4.85 mmol) in THF (25 mL)at 0 ⁰ C were added 5-chloro-pyridin-2-ol (0.429 g, 3.31 mmol) and then DBAD (0.81 g, 3.51 mmol). After 5 minutes was added (RS)-l-[(3RS,4SR)-4-(2,4-difiuoro-phenyl)- pyrrolidin-3-yl]-ethanol (V-B-4) (0.70 g, 2.20 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH IM, followed by column chromatography (SiO ₂ , EtOAc/H, 1 :6) yielded 0.69 g (73 %) of the title compound as a colorless oil. ES-MS m/e: 429.2 (M+H ⁺ ).

e) 5-Chloro-2- ((SR)- l-[(3RS.4SR)-4-(2.4-difiuoro-phenyl)-pyrrolidin-3-yll-ethoxy l -pyridine (VII-B-4)

To a solution of 2- ((SR)-I -[(3RS,4SR)-1 -benzyl-4-(2,4-difluoro-phenyl)-pyrro lidin-3-yl]- ethoxy}-5-chloro-pyridine 570 mg (1.32 mmol) dissolved in toluene (12 mL) were added 0.43 mL (3.96 mmol) of 1-chloroethyl chloro formate and 0.68 mL (3.96 mmol) of Hunig's base. The reaction mixture was heated at 100 ⁰ C for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85 ⁰ C for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO ₂ , CH ₂ Cl ₂ ZMeOH 9:1) yielded 350 mg (78 %) of the title compound as a light yellow oil. ES-MS m/e: 339.1 (M+H ⁺ ). Pyrrolidine VII-B-5

6-{(SR)-l-[(3RS,4SR)-4-(4-Cyano-phenyl)-pyrrolidin-3-yl]- ethoxy}-nicotinonitrile

a) 4-((E)-3-Oxo-but- 1 -enyl)-benzonitrile A two necked flask was charged with 4-formyl-benzonitrile (20.0 g, 0.152 mol) and (2-oxo- propyl)-phosphonic acid dimethyl ester (30.4 g, 0.18 mol) and cooled down at at 0 ⁰ C. K ₂ Cθ3 (42.16 g, 0.305 mol) in H ₂ O (45 mL) was added dropwise. Stirring was continued over night at RT. The product was extracted with EtOAc, and the organic phase was dried over Na ₂ SO ₄ . Flash chromatography (SiO ₂ , Heptane/EtOAc 1 :1) afforded 18.7 g (72 %) of the title compound as alight yellow solid.

b) 4-((3SR.4RS)-4-Acetyl-l-benzyl-pyrrolidin-3-yl)-benzonitrile αV-5)

A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyla mine (22.46 g,

94.6 mmol) in CH ₂ Cl ₂ (100 mL) was added dropwise, over a 30 minutes period, to a stirred solution of 4-((E)-3-oxo-but-l-enyl)-benzonitrile (10.8 g, 63.1 mmol) and trifluoro acetic acid (0.48 mL, 6.30 mmol) in CH ₂ Cl ₂ (40 mL) at 0 ⁰ C. The ice bath was removed, and the solution was stirred at 25 ⁰ C for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO ₂ , EtOac/Heptane 1 :1) afforded 6.3 g (33 %) of the title compound as a yellow oil. ES-MS m/e: 305.1 (M+H ⁺ ).

c) 4-[(3SR.4RS)-l-Benzyl-4-((SR)-l-hvdroxy-ethyl)-pyrrolidin-3- yll-benzonitrile (V-A-5) and 4-[(3SR.4RS)- 1 -Benzyl-4-((RS)- 1 -hvdroxy-ethyl)-pyrrolidin-3-yll-benzonitrile (V-B-5)

To a solution of 4-((3SR,4RS)-4-acetyl-l-benzyl-pyrrolidin-3-yl)-benzonitrile (IV-5) (IV-5) (6.30 g, 20.7 mmol) in MeOH (300 mL) at RT were added portion wise LiBH ₄ (9.49 g, 0.43 mol). Stirring was continued for overnight, and the reaction mixture was carefully quenched by addition of aq. NH ₄ Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na ₂ SO ₄ and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO ₂ , EtOAc/H, 1 : 1) to yield 4- [(3SR,4RS)-l-benzyl-4-((RS)-l-hydroxy-ethyl)-pyrrolidin-3-yl ]-benzonitrile (V-B-5) 1.35 g (21 %) as a colorless oil ES-MS m/e: 307.2 (M+H ⁺ ) and 4-[(3SR,4RS)-l-benzyl-4-((SR)-l- hydroxy-ethyl)-pyrrolidin-3-yl]-benzonitrile (V- A-5) 1.30 g (20 %) as a colorless oil ES-MS m/e: 307.2 (M+H ⁺ ).

d) 6- ((SR)- 1 -[(3RS.4SR)- 1 -Benzyl-4-(4-cvano-phenyl)-pyrrolidin-3-yll-ethoxy| -nicotinonitrile (VI-B-5)

To a stirred solution of 4-[(3SR,4RS)-l-benzyl-4-((SR)-l-hydroxy-ethyl)-pyrrolidin-3- yl]- benzonitrile (V- A-5) (0.65 g, 2.12 mmol) in DMF (40 mL) at RT was added NaH (55% purity, 0.10 g, 4.1 mmol). After 10 minutes, 6-chloro-nicotinonitrile (0.32 g, 2.33 mmol) was added. The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc / aq.NH ₄ Cl sat, followed by column chromatography (SiO ₂ ,

EtOAc/H, 1 :1) yielded 0.39 g (45 %) of the title compound as a colorless oil. ES-MS m/e: 409.3 (M+H ⁺ ).

e) 6- ((SR)- 1 -[(3RS.4SR)-4-(4-Cvano-phenyl)-pyrrolidin-3-yll-ethoxyl -nicotinonitrile (VII-B-5) To a solution of 6- ((SR)- 1 -[(3RS.4SR)- 1 -benzyl-4-(4-cyano-phenyl)-pyrrolidin-3-yl]-ethoxy} - nicotinonitrile (VI-B-5) 380 mg (0.93 mmol) dissolved in toluene (10 mL) were added 0.30 mL (2.79 mmol) of 1-chloroethyl chloroformate and 0.47 mL (2.79 mmol) of Hunig's base. The reaction mixture was heated at 100 ⁰ C for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85 ⁰ C for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO ₂ , CH ₂ Cl ₂ /Me0H 9:1) yielded 105 mg (35 %) of the title compound as a light yellow oil. ES-MS m/e: 319.2 (M+H ⁺ ).

Pyrrolidine VII-B-6

4-{(3SR,4RS)-4-[l-((SR)-5-Trifluoromethyl-pyridin-2-yloxy )-ethyl]-pyrrolidin-3-yl}- benzonitrile

a) 4-((3SR.4RS)-l-Benzyl-4-[l-((SR)-5-trifluoromethyl-pyridin-2 -yloxy)-ethyl l-pyrrolidin-3-yl| -benzonitrile (VI-B-6)

To a stirred solution of 4-[(3SR,4RS)-l-benzyl-4-((SR)-l-hydroxy-ethyl)-pyrrolidin-3- yl]- benzonitrile (V- A-5) (0.65 g, 2.12 mmol, described herein above) in DMF (40 mL) at RT was added NaH (55% purity, 0.10 g, 4.1 mmol). After 10 minutes, 2-chloro-5-trifluoromethyl- pyridine (0.42 g, 2.33 mmol) was added. The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc / aq.NH ₄ Cl sat, followed by column chromatography (SiO ₂ , EtOAc/H, 1 :1) yielded 0.15 g (15 %) of the title compound as a colorless oil. ES-MS m/e: 452.1 (M+H ⁺ ).

b) 4-((3SR.4RS)-4-[l-((SR)-5-Trifiuoromethyl-pyridin-2-yloxy)-e thyll-pyrrolidin-3-vU- benzonitrile (VII-B-6)

To a solution of 4-{(3SR,4RS)-l-benzyl-4-[l-((SR)-5-trifluoromethyl-pyridin-2 -yloxy)-ethyl]- pyrrolidin-3-yl} -benzonitrile (VI-B-6) 150 mg (0.33 mmol) dissolved in toluene (5 mL) were added 0.11 mL (1.00 mmol) of 1-chloroethyl chloroformate and 0.17 mL (1.00 mmol) of

Hunig's base. The reaction mixture was heated at 100 ⁰ C for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (7.5 mL). The reaction mixture was heated at 85 ⁰ C for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO ₂ , CH ₂ Cl ₂ MeOH 9:1) yielded 60 mg (50 %) of the title compound as a colorless oil. ES-MS m/e: 362.2 (M+H ⁺ ).

Pyrrolidine VII-B-7 4-{(3SR,4RS)-4-[l-((SR)-5-Chloro-pyridin-2-yloxy)-ethyl]-pyr rolidin-3-yl}-benzonitrile

a) 4- {(3SR.4RS)- l-Benzyl-4-r 1 -((SR)-5-chtoro-pyridin-2-yloxy)-ethyl1-pyrrolidin-3-yl> - benzonitrile (VI-B-7) To a stirred solution of 4-[(3SR,4RS)-l-benzyl-4-((SR)-l-hydroxy-ethyl)-pyrrolidin-3- yl]- benzonitrile (V- A-5) (0.65 g, 2.12 mmol, described herein above) in DMF (40 mL) at RT was added NaH (55% purity, 0.10 g, 4.1 mmol). After 10 minutes, 2,5-dichloro-pyridine (0.34 g, 2.33 mmol) was added. The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc / aq.NH ₄ Cl sat, followed by column chromatography (SiO ₂ , EtOAc/H, 1 : 1) yielded 0.75 g (78 %) of the title compound as a colorless oil. ES-MS m/e: 418.3 (M+H ⁺ ).

b) 4-((3SR4RS)-4-[l-((SR)-5-Chloro-pyridin-2-yloxy)-ethyll-pyrr olidin-3-yl|-benzonitrile (VII-B-7) To a solution of 4-{(3SR,4RS)-l-benzyl-4-[l-((SR)-5-chloro-pyridin-2-yloxy)-e thyl]-pyrrolidin- 3 -yl} -benzonitrile (VI-B-7) 700 mg (1.65 mmol) dissolved in toluene (20 mL) were added 0.54 mL (5.03 mmol) of 1-chloroethyl chloro formate and 0.85 mL (5.03 mmol) of Hunig's base. The reaction mixture was heated at 100 ⁰ C for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (30 mL). The reaction mixture was heated at 85 ⁰ C for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO ₂ , CH ₂ Cl ₂ ZMeOH 9:1) yielded 260 mg (47%) of the title compound as a colorless oil. ES-MS m/e: 328.2 (M+H ⁺ ).

Pyrrolidine VII-B-8 5-Chloro-2-{(S)-l-[(3R,4S)-4-(4-chloro-phenyl)-pyrrolidin-3- yl]-ethoxy}-pyridine

a) l-(l-Benzyl-2,5-dihvdro-lH-pyrrol-3-yl)-ethanone

To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyla mine (9.76 g, 0.041 mol) in CH ₂ Cl ₂ (40 mL) at 0 ⁰ C, was added dropwise over a 5 minutes period but-3-yn-2- one (2.0 g, 0.029 mol) followed by trifluoro acetic acid (0.22 mL, 0.003 mol) (very exothermic reaction). The ice bath was removed after 30 minutes, and the solution was stirred at 25 ⁰ C for an additional 2 h. It was then concentrated and purification by flash chromatography (SiO ₂ ,

EtO Ac/Heptane 1 :1) afforded 2.90 g (49 %) of the title compound as a yellow oil. ES-MS m/e: 202.2 (M+H ⁺ ).

b) 1 -IY3R.4SV 1 -Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yll-ethanone (TVS) A two necked flask was charged under argon with rhodium(acac)bis ethylene (45 mg, 0.05 eq.), (R)-BINAP (110 mg, 0.05 eq.) and 4-chloro-phenylboronic acid (1.20 g, 2.2 eq.). 100 mL of MeOH and 10 mL of H ₂ O were added followed by l-(l-benzyl-2,5-dihydro-lH-pyrrol-3-yl)- ethanone (0.70 g). The reaction mixture was heated at 55 ⁰ C for 8 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO ₂ , EtO Ac/Heptane 2/1) afforded 0.36 g (33 %) of the title product as a light yellow oil. ES-MS m/e: 314.0 (M+H ⁺ ).

c) (S)-l-[(3R.4S)-l-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yll -ethanol (V- A-8) and (R)- 1 -IY3R.4SV 1 -Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yll-ethanol (V-B-8)

To a solution of l-[(3R,4S)-l-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-eth anone (0.52 g, 1.65 mmol) in THF (20 mL) at 0 ⁰ C were added portion wise LiAlH ₄ (55 mg, 1.45 mmol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq.

NH ₄ Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na ₂ SO ₄ and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO ₂ , EtOAc/H, 1 :1) to yield (R)-l-[(3R,4S)-l-benzyl-4- (4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol (V-B-8) 0.24 g (46 %) as a white solid ES-MS m/e:

316.1 (M+H ⁺ ) and (S)-l-[(3R,4S)-l-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl] -ethanol (V-A-

8) 0.25 g (47 %) as a white solid ES-MS m/e: 316.1 (M+H ⁺ ).

d) 2- ((S)- 1-IY3R.4SV 1 -Benzyl-4-(4-chloro-phenvπ-pyrrolidin-3-yll-ethoxy| -5-chloro-pyridine (VI-B-8)

To a suspension OfPPh ₃ (PPh ₃ polymer bound, 3 mmol PPh ₃ /g resin) (0.44 g, 1.69 mmol) in THF (50 mL) at 0 ⁰ C were added 5-chloro-pyridin-2-ol (0.15 g, 1.15 mmol) and then DBAD (0.28 g, 1.23 mmol). After 5 minutes was added (R)-l-[(3R,4S)-l-benzyl-4-(4-chloro-phenyl)-

pyrrolidin-3-yl]-ethanol (0.25 g, 0.79 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH IM, followed by column chromatography (SiO ₂ , EtOAc/H, 1 :3) yielded 0.22 g (65 %) of the title compound as a colorless oil. ES-MS m/e: 427.8 (M+H ⁺ ).

e) 5-Chloro-2- ((S)- l-[(3R.4S)-4-(4-chloro-phenyl)-pyrrolidin-3-yll-ethoxyl -pyridine (VII-B-8) To a solution of 2-{(S)-l-[(3R,4S)-l-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3- yl]-ethoxy}-5- chloro -pyridine 220 mg (0.51 mmol) dissolved in toluene (5 mL) were added 0.17 mL (1.53 mmol) of 1-chloroethyl chloroformate and 0.27 mL (1.53 mmol) of Hunig's base. The reaction mixture was heated at 100 ⁰ C for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85 ⁰ C for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO ₂ , CH ₂ Cl ₂ ZMeOH 9:1) yielded 110 mg (62 %) of the title compound as a light yellow oil. ES-MS m/e: 337.1 (M+H ⁺ ).

Pyrrolidine VII-B-9

5-Chloro-2-{(S)-l-[(3R,4S)-4-(4-chloro-3-fluoro-phenyl)-p yrrolidin-3-yl]-ethoxy}-pyridine

a) 1 -IY3R.4SV 1 -Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yll-ethano ne QV-9) A two necked flask was charged under argon with rhodium(acac)bis ethylene (31 mg, 0.05 eq.), (R)-BINAP (74 mg, 0.05 eq.) and 4-chloro-3-fiuoro-phenylboronic acid (825 mg, 2.5 eq.). 30 mL of MeOH and 3 mL of H ₂ O were added followed by l-(l-benzyl-2,5-dihydro-lH-pyrrol-3- yl)-ethanone (480 mg, described herein above). The reaction mixture was heated at 55 ⁰ C for 3 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO ₂ , EtOAc/Heptane 2/1) afforded 261 mg (33 %) of the title product as a light yellow oil. ES- MS m/e: 332.1 (M+H ⁺ ).

b) (S)-l-[(3R.4S)-l-Benzyl-4-(4-chloro-3-fiuoro-phenyl)-pyrroli din-3-yll-ethanol (IV-A-9) and (R)- 1 -IY3R.4S)- 1 -Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yll-ethano l (IV-B-9)

To a solution of l-[(3R,4S)-l-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin- 3-yl]-ethanone (260 mg, 0.78 mmol) in THF (10 mL) at 0 ⁰ C were added portion wise LiAlH ₄ (26 mg, 0.68 mmol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH ₄ Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na ₂ SO ₄ and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO ₂ , EtOAc/H, 1 : 1) to yield (R)- l-[(3R,4S)-l-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin- 3-yl]-ethanol (IV-B-9) 101 mg (38 %) as a white solid ES-MS m/e: 334.2 (M+H ⁺ ) and (S)-l-[(3R,4S)-l-benzyl-4-(4-chloro-3- fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (IV-A-9) 80 mg (30 %) as a white solid ES-MS m/e: 334.2 (M+H ⁺ ).

c) 2-((S)-l-[(3R.4S)-l-Benzyl-4-(4-chloro-3-fiuoro-phenyl)-pyrr olidin-3-yll-ethoxyl-5-chloro- pyridine (VI-B-9)

To a suspension OfPPh ₃ (PPh ₃ polymer bound, 3 mmol PPh ₃ /g resin) (216 mg, 0.65 mmol) in THF (10 mL) at 0 ⁰ C were added 5-chloro-pyridin-2-ol (58 mg, 0.45 mmol) and then DBAD (110 mg, 0.48 mmol). After 5 minutes was added (R)-l-[(3R,4S)-l-benzyl-4-(4-chloro-3-fluoro- phenyl)-pyrrolidin-3-yl]-ethanol (100 mg, 0.30 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH IM, followed by column chromatography (SiO ₂ , EtOAc/H, 1 :3) yielded 100 mg (75 %) of the title compound as a colorless oil. ES-MS m/e: 445.1 (M+H ⁺ ).

d) 5-Chloro-2-((S)-l-[(3R.4S)-4-(4-chloro-3-fiuoro-phenyl)-pyrr olidin-3-yll-ethoxyl-pyridine

(VII-B-9)

To a solution of 2-{(S)-l-[(3R,4S)-l-benzyl-4-(4-chloro-3-fiuoro-phenyl)-pyrr olidin-3-yl]- ethoxy}-5-chloro-pyridine 98 mg (0.22 mmol) dissolved in toluene (5 mL) were added 0.072 mL (0.66 mmol) of 1-chloroethyl chloroformate and 0.11 mL (0.66 mL) of Hunig's base. The reaction mixture was heated at 100 ⁰ C for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (5 mL). The reaction mixture was heated at 85 ⁰ C for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO ₂ , CH ₂ Cl ₂ /Me0H 9:1) yielded 75 mg (95 %) of the title compound as a light yellow oil. ES-MS m/e: 355.1 (M+H ⁺ ).

Pyrrolidine intermediates of formula VIII-B

Pyrrolidine VIII-B-I

6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidin e-4-carbonyl)-pyrrolidin-3-yl]- ethoxy}-nicotinonitrile

a) 4-[(3RS.4SR)-3-[(SR)-l-(5-Cvano-pyridin-2-yloxy)-ethyll-4-(3 .4-dichloro-phenyl)- pyrrolidine-l-carbonylj-piperidine-l-carboxylic acid tert-butyl ester

To a stirred solution of piperidine-l,4-dicarboxylic acid mono -tert-butyl ester (0.165 g, 0.72 mmol) in 20 mL OfCH ₂ Cl ₂ was added (0.14 g, 0.94 mmol) of EDC, (0.10 g, 0.94 mmol) of HOBt and Et ₃ N (0.11 mL, 1.1 mmol). After one hour at RT, was added 6- ((SR)- 1 -[(3RS.4SR)- 4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonit rile (VII-B-2, 0.26g, 0.72 mmol). The mixture was stirred at RT over night and then poured onto water and extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo. Column chromatography (SiO ₂ , EtOAc/H, 1 :1) yielded 0.29 g (91 %) of the title compound as a white foam. ES-MS m/e: 574.8 (M+H ⁺ ).

b) 6- ((SR)- 1 -|Y3RS.4SR)-4-(3.4-Dichloro-phenyl)- 1 -(piperidine-4-carbonyl)-pyrrolidin-3-yll- ethoxy} -nicotinonitrile (VIII-B-I)

To a stirred solution of 4-[(3RS,4SR)-3-[(SR)-l-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3 ,4- dichloro-phenyl)-pyrrolidine- 1 -carbonyl]-piperidine- 1 -carboxylic acid tert-butyl ester (0.28 g, 0.50 mmol) in 24 mL OfCH ₂ Cl ₂ was added 6 mL of TFA. After one hour at RT, the reaction was quenched by addition of aq. NaOH IM (until ph=10) and the product was extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo to yield 0.237 g (99 %) of the title compound as a white foam. ES-MS m/e: 473.0 (M+H ⁺ ).

Pyrrolidine VIII-B-2

6-{(SR)-l-[(3RS,4SR)-l-(Azetidine-3-carbonyl)-4-(3,4-dich loro-phenyl)-pyrrolidin-3-yl]- ethoxy}-nicotinonitrile

a) 3-IY3R.4SV3-IYSV 1 -(5-Cvano-pyridin-2-yloxy)-ethyll-4-(3.4-dichloro-phenyl)-py rrolidine- 1 - carbonylj-azetidine-l-carboxylic acid tert-butyl ester

To a stirred solution of azetidine-l,3-dicarboxylic acid mono-tert-butyl ester (0.072 g, 0.36 mmol) in 15 mL OfCH ₂ Cl ₂ was added (0.069 g, 0.36 mmol) of EDC, (0.048 g, 0.36 mmol) of HOBt and Et ₃ N (0.06 mL, 0.42 mmol). After one hour at RT, was added 6- ((SR)-I -[(3RS.4SR)- 4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonit rile (VII-B-2, O.lOg, 0.27 mmol). The mixture was stirred at RT over night and then poured onto water and extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo. Column chromatography (SiO ₂ , EtOAc/H, 1 : 1) yielded 0.14 g (98 %) of the title compound as a white solid. ES-MS m/e: 545.3 (M+H ⁺ ).

b) 6- ((SR)-I -[(3RS.4SR)-! -(Azetidine-3-carbonvn-4-(3.4-dichloro-phenyl)-pyrrolidin-3- yll- ethoxy} -nicotinonitrile (VIII-B-2) To a stirred solution of 3-[(3R,4S)-3-[(S)-l-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3,4- dichloro- pheny^-pyrrolidine-l-carbonylj-azetidine-l-carboxylic acid tert-butyl ester (0.14 g, 0.25 mmol) in 4 mL OfCH ₂ Cl ₂ was added 1 mL of TFA. After one hour at RT, the reaction was quenched by addition of aq. NaOH IM (until ph=10) and the product was extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo to yield 0.106 g (92 %) of the title compound as a white foam. ES-MS m/e: 445.1 (M+H ⁺ ).

Example 1 l-{4-[(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl]- 4-(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-piperidin-l-yl}-ethanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-I) - Carboxylic acid: l-Acetyl-piperidine-4-carboxylic acid (commercially available), ES-MS m/e: 524.3 (M+H ⁺ ).

Example 2

6-{(SR)-l-[(3RS,4SR)-l-(l-Acetyl-piperidine-4-carbonyl)-4 -(3,4-dichloro-phenyl)- pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -nicotinonitrile (VII-B-2)

- Carboxylic acid: l-Acetyl-piperidine-4-carboxylic acid (commercially available), ES-MS m/e: 515.0 (M+H ⁺ ).

Example 3

[(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl]-4- (3,4-dichloro-phenyl)-pyrrolidin- l-yl]-(l-cyclobutanecarbonyl-piperidin-4-yl)-methanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-I) - Carboxylic acid: l-Cyclobutanecarbonyl-piperidine-4-carboxylic acid (commercially available), ES-MS m/e: 565.7 (M+H ⁺ ).

Example 4

[(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl]-4- (3,4-dichloro-phenyl)-pyrrolidin- l-yl]-(l-methyl-piperidin-4-yl)-methanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-I)

- Carboxylic acid: l-Methyl-piperidine-4-carboxylic acid (commercially available), ES-MS m/e: 496.04 (M+H ⁺ ).

Example 5

{4-[(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl] -4-(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-cyclohexyl}-carbamic acid methyl ester

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-I) - Carboxylic acid: 4-Methoxycarbonylamino-cyclohexanecarboxylic acid, ES-MS m/e: 555.72 (M+H ⁺ ).

4-Methoxycarbonylamino-cyclohexanecarboxylic acid:

To a stirred solution of trans-4-amino-cyclohexanecarboxylic acid methyl ester (commercially available) in CH ₂ Cl ₂ was added Et ₃ N (2 eq.) and methyl-chloroformate (1.05 eq.). Stirring was continued overnight at RT. The reaction was quenched by addition of H ₂ O, the product was extracted with CH ₂ Cl ₂ and the organic phase washed with aq. HCl IM. The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo. The residue was dissolved in MeOH and a 2M KOH aq. solution was added. The reaction was stirred at RT 4 hours, aq. HCl was added until ph=6, and then the product was extracted with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo to afford the title product as a white foam which was used in the next step without further purification.

Example 6 [(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl]-4-(3, 4-dichloro-phenyl)-pyrrolidin- l-yl]-(4-methoxymethyl-cyclohexyl)-methanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-I)

- Carboxylic acid: 4-Methoxymethyl-cyclohexanecarboxylic acid (described in JP60258141), ES-MS m/e: 526.8 (M+H ⁺ ).

Example 7

6- ((SR)- 1- [(3RS,4SR)-4-(3,4-Dichloro-phenyl)- 1 -(piperidine-4-carbonyl)-pyrrolidin-3-yl] - ethoxy}-nicotinonitrile

a) 4-[(3RS.4SR)-3-[(SR)-l-(5-Cvano-pyridin-2-yloxy)-ethyll-4-(3 .4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-piperidine-l -carboxylic acid tert-butyl ester

To a stirred solution of piperidine-l,4-dicarboxylic acid mono -tert-butyl ester (0.165 g, 0.72 mmol) in 20 mL OfCH ₂ Cl ₂ was added (0.14 g, 0.94 mmol) of EDC, (0.10 g, 0.94 mmol) of HOBt and Et ₃ N (0.11 mL, 1.1 mmol). After one hour at RT, was added 6- ((SR)-I -[(3RS.4SR)- 4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonit rile (VII-B-2, 0.26 g, 0.72 mmol). The mixture was stirred at RT over night and then poured onto water and extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo. Column chromatography (SiO ₂ , EtOAc/H, 1 :1) yielded 0.29 g (91 %) of the title compound as a white foam.

b) 6- ((SR)- 1 -[(3RS.4SR)-4-(3.4-Dichloro-phenyl)- 1 -(piperidine-4-carbonyl)-pyrrolidin-3-yll- ethoxy} -nicotinonitrile (VIII-B-I)

To a stirred solution of 4-[(3RS,4SR)-3-[(SR)-l-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3 ,4- dichloro-phenyl)-pyrrolidine-l-carbonyl]-piperidine-l -carboxylic acid tert-butyl ester (0.28 g, 0.50 mmol) in 24 mL OfCH ₂ Cl ₂ was added 6 mL of TFA. After one hour at RT, the reaction was quenched by addition of aq. NaOH IM (until ph=10) and the product was extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo to yield 0.237 g (99 %) of the title compound as a white foam. ES-MS m/e: 473.0 (M+H ⁺ ).

Example 8

[(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl]-4- (3,4-dichloro-phenyl)-pyrrolidin- l-yl]-((2R,4S,5S)-3,4-dihydroxy-cyclohexyl)-methanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-I)

- Carboxylic acid: (lR,3S,4S)-3,4-Dihydroxy-cyclohexanecarboxylic acid (commercially available), ES-MS m/e: 513.3 (M+H ⁺ ).

Example 9

[(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl]-4- (3,4-dichloro-phenyl)-pyrrolidin- l-yl]-((2S,4S,5S)-3,4-dihydroxy-cyclohexyl)-methanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-I)

- Carboxylic acid: (lS,3S,4S)-3,4-Dihydroxy-cyclohexanecarboxylic acid (described in patent WO2006/016167), ES-MS m/e: 513.3 (M+H ⁺ ).

Example 10

[(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl]-4- (3,4-dichloro-phenyl)-pyrrolidin- l-yl]-(4-ethynyl-cyclohexyl)-methanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-I)

- Carboxylic acid: 4-Ethynyl-cyclohexanecarboxylic acid (commercially available), ES-MS m/e: 506.9 (M+H ⁺ ).

Example 11

[(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl]-4- (3,4-dichloro-phenyl)-pyrrolidin- l-yl]-(l-isobutyl-piperidin-4-yl)-methanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-I)

- Carboxylic acid: l-Isobutyl-piperidine-4-carboxylic acid (commercially available), ES-MS m/e: 540.3 (M+H ⁺ ).

Example 12

4-[(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl]- 4-(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-cyclohexanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-I)

- Carboxylic acid: 4-Oxo-cyclohexanecarboxylic acid (commercially available), ES-MS m/e: 497.0 (M+H ⁺ ).

Example 13

4-[(3RS,4SR)-3-[(SR)-l-(5-Cyano-pyridin-2-yloxy)-ethyl]-4 -(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-piperidine-l-carboxylic acid tert-butyl ester

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -nicotinonitrile (VII-B-2)

- Carboxylic acid: Piperidine-l,4-dicarboxylic acid mono -tert-butyl ester (commercially available), ES-MS m/e: 572.7 (M+H ⁺ ). Example 14

6-{(SR)-l-[(3RS,4SR)-l-(l-Cyclopropanecarbonyl-piperidine -4-carbonyl)-4-(3,4-dichloro- phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I: - Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 ) - Carboxylic acid: Cyclopropanecarboxylic acid (commercially available),

ES-MS m/e: 540.9 (M+H ⁺ ).

Example 15

{(3SR,4RS)-3-(3,4-Dichloro-phenyl)-4-[(SR)-l-(5-trifluoro methyl-pyridin-2-yloxy)-ethyl]- pyrrolidin-l-yl}-(tetrahydro-pyran-4-yl)-methanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 2-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -5-trifluoromethyl-pyridine (VII-B-3)

- Carboxylic acid: Tetrahydro-pyran-4-carboxylic acid (commercially available), ES-MS m/e: 517.3 (M+H ⁺ ).

Example 16

6-{(SR)-l-[(3RS,4SR)-l-[l-(l-Cyano-cyclopropanecarbonyl)- piperidine-4-carbonyl]-4-(3,4- dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 )

- Carboxylic acid: 1-Cyano-cyclopropanecarboxylic acid (commercially available), ES-MS m/e: 566.4 (M+H ⁺ ).

Example 17

6-((SR)-l-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-[l-(l-meth yl-cyclopropanecarbonyl)- piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethoxy)-nicotinonitr ile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 )

- Carboxylic acid: 1-Methyl-cyclopropanecarboxylic acid (commercially available), ES-MS m/e: 555.2 (M+H ⁺ ). Example 18

6-((SR)-l-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-[l-(2,2-di fluoro-cyclopropanecarbonyl)- piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethoxy)-nicotinonitr ile

Coupling according to general procedure I: - Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 )

- Carboxylic acid: 2,2-Difluoro-cyclopropanecarboxylic acid (commercially available), ES-MS m/e: 577.3 (M+H ⁺ ).

Example 19 6-{(SR)-l-[(3RS,4SR)-l-[l-(l-Amino-cyclopropanecarbonyl)-pip eridine-4-carbonyl]-4-(3,4- dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 )

- Carboxylic acid: 1-Amino-cyclopropanecarboxylic acid (commercially available), ES-MS m/e: 556.2 (M+H ⁺ ).

Example 20

6-{(SR)-l-[(3RS,4SR)-l-(l-Cyclobutanecarbonyl-piperidine- 4-carbonyl)-4-(3,4-dichloro- phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 )

- Carboxylic acid: Cyclobutanecarboxylic acid (commercially available), ES-MS m/e: 555.2 (M+H ⁺ ).

Example 21

6-((SR)-l-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-[l-(3-oxo- cyclobutanecarbonyl)- piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethoxy)-nicotinonitr ile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 )

- Carboxylic acid: 3-Oxo-cyclobutanecarboxylic acid (commercially available), ES-MS m/e: 569.3 (M+H ⁺ ).

Example 22

6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(l-propion yl-piperidine-4-carbonyl)- pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure II:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 )

- Acid chlorid: Propionyl chloride (commercially available), ES-MS m/e: 529.2 (M+H ⁺ ).

Example 23

6-{(SR)-l-[(3RS,4SR)-l-[l-(2-Cyano-acetyl)-piperidine-4-c arbonyl]-4-(3,4-dichloro- phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 )

- Carboxylic acid: Cyano-acetic acid (commercially available), ES-MS m/e: 540.3 (M+H ⁺ ).

Example 24

6-((SR)-l-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-[l-(2-meth oxy-acetyl)-piperidine-4- carbonyl]-pyrrolidin-3-yl}-ethoxy)-nicotinonitrile

Coupling according to general procedure II:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 )

- Acid chlorid: Methoxy-acetyl chloride (commercially available), ES-MS m/e: 545.2 (M+H ⁺ ).

Example 25

6-{(SR)-l-[(3RS,4SR)-l-(l-Acetyl-azetidine-3-carbonyl)-4- (3,4-dichloro-phenyl)-pyrrolidin-

3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure II:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-l-(Azetidine-3-carbonyl)-4-(3,4-dichlor o- phenyl)-pyrro lidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B-2)

- Acid chlorid: Acetyl chloride (commercially available), ES-MS m/e: 487.3 (M+H ⁺ ).

Example 26

6-{(SR)-l-[(3RS,4SR)-l-(l-Cyclopropanecarbonyl-azetidine- 3-carbonyl)-4-(3,4-dichloro- phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-l-(Azetidine-3-carbonyl)-4-(3,4-dichlor o- phenyl)-pyrro lidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B-2)

- Carboxylic acid: Cyclopropanecarboxylic acid (commercially available), ES-MS m/e: 513.4 (M+H ⁺ ).

Example 27

6-{(SR)-l-[(3RS,4SR)-l-[l-(l-Cyano-cyclopropanecarbonyl)- azetidine-3-carbonyl]-4-(3,4- dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-l-(Azetidine-3-carbonyl)-4-(3,4-dichlor o- phenyl)-pyrro lidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B-2)

- Carboxylic acid: 1-Cyano-cyclopropanecarboxylic acid (commercially available), ES-MS m/e: 538.3 (M+H ⁺ ).

Example 28

6- ((SR)- 1- [(3RS,4SR)- 1- [ l-(2-Cyano-acetyl)-azetidine-3-carbonyl] -4-(3,4-dichloro-phenyl)- pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-l-(Azetidine-3-carbonyl)-4-(3,4-dichlor o- phenyl)-pyrro lidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B-2)

- Carboxylic acid: Cyano-acetic acid (commercially available), ES-MS m/e: 512.4 (M+H ⁺ ).

Example 29

3-[(3RS,4SR)-3-[(SR)-l-(5-Cyano-pyridin-2-yloxy)-ethyl]-4 -(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-azetidine-l-carboxylic acid tert-butyl ester

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -nicotinonitrile (VII-B-2) - Carboxylic acid: Azetidine-l,3-dicarboxylic acid mono-tert-butyl ester (commercially available), ES-MS m/e: 545.3 (M+H ⁺ ).

Example 30

6-{(SR)-l-[(3RS,4SR)-l-(Azetidine-3-carbonyl)-4-(3,4-dich loro-phenyl)-pyrrolidin-3-yl]- ethoxy}-nicotinonitrile

a) 3-|Y3R.4SV3-|YSV 1 -(5-Cvano-pyridin-2-yloxy)-ethyll-4-(3.4-dichloro-phenyl)-py rrolidine- 1 - carbonyl]-azetidine-l -carboxylic acid tert-butyl ester

To a stirred solution of azetidine-l,3-dicarboxylic acid mono-tert-butyl ester (0.072 g, 0.36 mmol) in 15 mL OfCH ₂ Cl ₂ was added (0.069 g, 0.36 mmol) of EDC, (0.048 g, 0.36 mmol) of HOBt and Et ₃ N (0.06 mL, 0.42 mmol). After one hour at RT, was added 6- ((SR)-I -[(3RS,4SR)-

4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotino nitrile (VII-B-2, O.lOg, 0.27 mmol).

The mixture was stirred at RT over night and then poured onto water and extracted with CH ₂ Cl ₂ .

The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo. Column chromatography (SiO ₂ , EtOAc/H, 1 :1) yielded 0.14 g (98 %) of the title compound as a white solid.

b) 6- ((SR)-I -[(3RS.4SR)-! -(Azetidine-3-carbonvn-4-(3.4-dichloro-phenyl)-pyrrolidin-3- yll- ethoxy} -nicotinonitrile (VIII-B-2)

To a stirred solution of 3-[(3R,4S)-3-[(S)-l-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3,4- dichloro- pheny^-pyrrolidine-l-carbonylj-azetidine-l-carboxylic acid tert-butyl ester (0.14g, 0.25 mmol) in 4 mL OfCH ₂ Cl ₂ was added 1 mL of TFA. After one hour at RT, the reaction was quenched by addition of aq. NaOH IM (until ph=10) and the product was extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo to yield 0.106 g (92 %) of the title compound as a white foam. ES-MS m/e: 445.1 (M+H ⁺ ).

Example 31

{(3SR,4RS)-3-(3,4-Dichloro-phenyl)-4-[(SR)-l-(5-trifluoro methyl-pyridin-2-yloxy)-ethyl]- pyrrolidin-l-yl}-(l-methyl-piperidin-4-yl)-methanone

Coupling according to general procedure I: - Pyrrolidine intermediate: 2-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -5-trifluoromethyl-pyridine (VII-B-3)

- Carboxylic acid: l-Methyl-piperidine-4-carboxylic acid (commercially available), ES-MS m/e: 529.9 (M+H ⁺ ).

Example 32 3-[(3RS,4SR)-3-[(SR)-l-((S)-5-Cyano-pyridin-2-yloxy)-ethyl]- 4-(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-pyrrolidine-l-carboxylic acid tert-butyl ester

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -nicotinonitrile (VII-B-2)

- Carboxylic acid: (S)-Pyrrolidine-l,3-dicarboxylic acid 1-tert-butyl ester (commercially available), ES-MS m/e: 558.7 (M+H ⁺ ).

Example 33

3-[(3RS,4SR)-3-[(SR)-l-((R)-5-Cyano-pyridin-2-yloxy)-ethy l]-4-(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-pyrrolidine-l-carboxylic acid tert-butyl ester

Coupling according to general procedure I: - Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -nicotinonitrile (VII-B-2)

- Carboxylic acid: (R)-Pyrrolidine-l,3-dicarboxylic acid 1-tert-butyl ester (commercially available), ES-MS m/e: 558.7 (M+H ⁺ ).

Example 34 6-{(SR)-l-[(3RS,4SR)-l-(l-Cyanomethyl-piperidine-4-carbonyl) -4-(3,4-dichloro-phenyl)- pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

To a stirred solution of 6-{(SR)-l-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (VIII-B-I) (25 mg, 0.053 mmol) in THF (2 mL) was added NaH (2.4 mg, 55 % purity, 0.056 mmol). After 10 min. 2-iodo acetonitrile (13 mg, 0.079 mmol) was added and stirring was continued at RT overnight. The reaction was quenched with H ₂ O, and the product extracted with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ , concentrated under vacuo and the residue was purified

by column chromatography (SiO ₂ , CH ₂ Cl ₂ /Me0H 9/1) to yield 20 mg (74 %) of the title compound as a light brown foam. ES-MS m/e: 512.0 (M+H ⁺ ).

Example 35 4-[(3RS,4SR)-3-[(SR)-l-(5-Cyano-pyridin-2-yloxy)-ethyl]-4-(3 ,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-piperidine-l-carboxylic acid methyl ester

Coupling according to general procedure II:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy}-nicotinonitrile (VII-B-2)

- Chloro formate: Methyl chloroformate (commercially available), ES-MS m/e: 531.6 (M+H ⁺ ).

Example 36

6- ((SR)- 1- [(3RS,4SR)-4-(3,4-Dichloro-phenyl)- 1 -(pyrrolidine-3-carbonyl)-pyrrolidin-3-yl] - ethoxy}-nicotinonitrile

To a stirred solution of 3-[(3RS,4SR)-3-[(SR)-l-((S)-5-cyano-pyridin-2-yloxy)-ethyl]- 4-(3,4- dichloro-phenyl)-pyrrolidine-l-carbonyl]-pyrrolidine-l-carbo xylic acid tert-butyl ester (described herein above) (80 mg, 0.140 mmol) in CH ₂ Cl ₂ (4 mL) was added TFA (1 mL). Stirring was continued at RT for 1 hour, and an aqueous solution of NaHCOs was added (until ph =8). The product was extracted with CH ₂ Cl ₂ and the combined organic phase dried over Na ₂ SO ₄ . Concentration under vacuo afforded 64 mg (97 %) of the title compound as a white solid. ES-MS m/e: 459.1 (M+H ⁺ ).

Example 37

6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(pyrrolidi ne-3-carbonyl)-pyrrolidin-3-yl]- ethoxy}-nicotinonitrile

To a stirred solution of 3-[(3RS,4SR)-3-[(SR)-l-((R)-5-Cyano-pyridin-2-yloxy)-ethyl]- 4-(3,4- dichloro-phenyl)-pyrrolidine-l-carbonyl]-pyrrolidine-l-carbo xylic acid tert-butyl ester (described herein above) (80 mg, 0.140 mmol) in CH ₂ Cl ₂ (4 mL) was added TFA (1 mL). Stirring was continued at RT for 1 hour, and an aqueous solution of NaHCOs was added (until ph =8). The product was extracted with CH ₂ Cl ₂ and the combined organic phase dried over Na ₂ SO ₄ . Concentration under vacuo afforded 62 mg (94 %) of the title compound as a white solid. ES-MS m/e: 459.1 (M+H ⁺ ).

Example 38 6-{(SR)-l-[(3RS,4SR)-l-(l-Acetyl-pyrrolidine-3-carbonyl)-4-( 3,4-dichloro-phenyl)- pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure II:

- Intermediate: 6- ((SR)- 1 -[(3RS,4SR)-4-(3,4-dichloro-phenyl)- 1 -(pyrrolidine-3-carbonyl)- pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (described hereinabove)

- Acid chlorid: Acetyl chloride (commercially available), ES-MS m/e: 500.9 (M+H ⁺ ).

Example 39

6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(l-methane sulfonyl-piperidine-4- carbonyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure II:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-(piperidine-4 - carbonyl)-pyrrolidin-3 -yl] -ethoxy } -nicotinonitrile (VIII-B- 1 )

- Sulfonyl chlorid: Methanesulfonyl chloride (commercially available), ES-MS m/e: 551.6 (M+H ⁺ ). Example 40

6-{(SR)-l-[(3RS,4SR)-l-(l-Acetyl-piperidine-3-carbonyl)-4 -(3,4-dichloro-phenyl)- pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I: - Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -nicotinonitrile (VII-B-2)

- Carboxylic acid: l-Acetyl-piperidine-S-carboxylic acid (commercially available), ES-MS m/e: 515.2 (M+H ⁺ ).

Example 41

3-[(3RS,4SR)-3-[(SR)-l-(5-Cyano-pyridin-2-yloxy)-ethyl]-4 -(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-piperidine-l-carboxylic acid tert-butyl ester

Coupling according to general procedure I:

- Pyrrolidine intermediate: β-KS^-l-CCSRS^S^^^S^-Dichloro-pheny^-pyrrolidin-S-yl]- ethoxy} -nicotinonitrile (VII-B-2) - Carboxylic acid: Piperidine-l,3-dicarboxylic acid 1-tert-butyl ester (commercially available), ES-MS m/e: 573.2 (M+H ⁺ ).

Example 42

{4-[(3RS,4SR)-3-[(SR)-l-(5-Cyano-pyridin-2-yloxy)-ethyl]- 4-(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-cyclohexyl}-methyl-carbamic acid tert-butyl ester

Coupling according to general procedure I:

- Pyrrolidine intermediate: ό-ICS^-l-KSRS^S^^-CS^-Dichbro-phenyO-pyrrolidin-S-yl]- ethoxy} -nicotinonitrile (VII-B-2)

- Carboxylic acid: trans-4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexanecarbox ylic acid (described in US20050065210), ES-MS m/e: 601.3 (M+H ⁺ ).

Example 43

{4-[(3RS,4SR)-3-[(SR)-l-(5-Cyano-pyridin-2-yloxy)-ethyl]- 4-(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-cyclohexyl}-carbamic acid tert-butyl ester

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -nicotinonitrile (VII-B-2) - Carboxylic acid: trans- 4-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid (commercially available), ES-MS m/e: 587.2 (M+H ⁺ ).

Example 44

6- ((SR)- 1- [(3RS,4SR)-4-(3,4-Dichloro-phenyl)- 1 -(4-methylamino-cyclohexanecarbonyl)- pyrrolidin-3-yl]-ethoxy}-nicotinonitrile

To a stirred solution of (4-[(3RS,4SR)-3-[(SR)-l-(5-cyano-pyridin-2-yloxy)-ethyl]-4-( 3,4- dichloro-phenyl)-pyrrolidine-l-carbonyl]-cyclohexyl}-methyl- carbamic acid tert-butyl ester described herein above (30 mg, 0.050 mmol) in CH ₂ Cl ₂ (4 mL) was added TFA (1 mL). After 1 hour, aqueous NaHCOs was added until ph = 8, the product was extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ to give the title product as a colorless oil (25 mg, 98 %). ES-MS m/e: 500.9 (M+H ⁺ ).

Example 45 N-{4-[(3RS,4SR)-3-[(SR)-l-(5-Cyano-pyridin-2-yloxy)-ethyl]-4 -(3,4-dichloro-phenyl)- pyrrolidine-l-carbonyl]-cyclohexyl}-N-methyl-acetamide

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -nicotinonitrile (VII-B-2) - Carboxylic acid: 4-(Acetyl-methyl-amino)-cyclohexane carboxylic acid (described in JP2006298909), ES-MS m/e: 542.9 (M+H ⁺ ).

Example 46 l-(4-{(3SR,4RS)-3-(3,4-Dichloro-phenyl)-4-[(SR)-l-(5-trifluo romethyl-pyridin-2-yloxy)- ethyl]-pyrrolidine-l-carbonyl}-piperidin-l-yl)-ethanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 2-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -5-trifluoromethyl-pyridine (VII-B-3) - Carboxylic acid: l-Acetyl-piperidine-4-carboxylic acid (commercially available), ES-MS m/e: 558.1 (M+H ⁺ ).

Example 47

6-((SR)-l-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-l-[l-(l-meth yl-cyclopropanecarbonyl)- piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethoxy)-nicotinonitr ile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl ]- ethoxy} -nicotinonitrile (VII-B-2) - Carboxylic acid: l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (described herein after), ES-MS m/e: 592.0 (M+H ⁺ ).

l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid: a) l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester To a stirred solution of 1-methyl-cyclopropanecarboxylic acid (14.4 g, 0.144 mol) in 200 mL of CH ₂ Cl ₂ was added (27.10 g, 0.141 mol) of EDC, (19.10 g, 0.141 g) of HOBt and Et ₃ N (35.93 mL, 0.259 mol). After one hour at RT, was added piperidine-4-carboxylic acid ethyl ester (18.90 g, 0.120 mol). The mixture was stirred at RT over night and then poured onto water and extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo. Column chromatography (SiO ₂ , EtOAc/H, 1 : 1) yielded 26.1 g (92 %) of the title compound as a light yellow oil.

b) 1 -( 1 -Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid

To a stirred solution of l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (26.09 g, 0.109 mol) in 500 mL of a mixture of THF, EtOH and H ₂ O) (1/1/1) was added LiOH. H ₂ O) (6.86 g, 0.163 mol). After one hour at RT, the solvent were evaporated and the residue taken up in CH2C12 and the organic phase was washed with aqueous HCl IM. The organic phases were dried over Na ₂ SO ₄ and evaporated under vacuo to gave 19.8 g (86%) of the title compound as a white solid. ES-MS m/e: 212.1 (M+H ⁺ ).

Example 48

[(3RS,4SR)-3-[(SR)-l-(5-Chloro-pyridin-2-yloxy)-ethyl]-4- (2,4-difluoro-phenyl)-pyrrolidin- l-yl]-[l-(l-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-met hanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2-{(SR)-l-[(3RS,4SR)-4-(2,4-difluoro-phenyl)-pyrrol idin- 3 -yl]-ethoxy} -pyridine (VII-B-4)

- Carboxylic acid: l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (described herein after), ES-MS m/e: 532.2(M+H ⁺ ).

l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid: a) l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester

To a stirred solution of 1-methyl-cyclopropanecarboxylic acid (14.4 g, 0.144 mol) in 200 mL of CH ₂ Cl ₂ was added (27.10 g, 0.141 mol) of EDC, (19.10 g, 0.141 g) of HOBt and Et ₃ N (35.93 mL, 0.259 mol). After one hour at RT, was added piperidine-4-carboxylic acid ethyl ester (18.90 g, 0.120 mol). The mixture was stirred at RT over night and then poured onto water and extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo. Column chromatography (SiO ₂ , EtOAc/H, 1 :1) yielded 26.1 g (92 %) of the title compound as a light yellow oil.

b) 1 -( 1 -Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid

To a stirred solution of l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (26.09 g, 0.109 mol) in 500 mL of a mixture of THF, EtOH and H ₂ O) (1/1/1) was added LiOH. H ₂ O) (6.86 g, 0.163 mol). After one hour at RT, the solvent were evaporated and the residue taken up in CH2C12 and the organic phase was washed with aqueous HCl IM. The organic phases were dried over Na ₂ SO ₄ and evaporated under vacuo to gave 19.8 g (86%) of the title compound as a white solid. ES-MS m/e: 212.1 (M+H ⁺ ).

Example 49

6-{(SR)-l-[(3RS,4SR)-l-(l-Acetyl-piperidine-4-carbonyl)-4 -(4-cyano-phenyl)-pyrrolidin-3- yl]-ethoxy}-nicotinonitrile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 6-{(SR)-l-[(3RS,4SR)-4-(4-Cyano-phenyl)-pyrrolidin-3-yl]-eth oxy}- nicotinonitrile (VII-B-5)

- Carboxylic acid: l-Acetyl-piperidine-4-carboxylic acid (commercially available), ES-MS m/e: 472.3 (M+H ⁺ ). Example 50

4-{(3SR,4RS)-l-(l-Acetyl-piperidine-4-carbonyl)-4-[(SR)-l -(5-trifluoromethyl-pyridin-2- yloxy)-ethyl]-pyrrolidin-3-yl}-benzonitrile

Coupling according to general procedure I: - Pyrrolidine intermediate: 4-{(3SR,4RS)-4-[l-((SR)-5-Trifluoromethyl-pyridin-2-yloxy)-e thyl]- pyrrolidin-3-yl} -benzonitrile (VII-B-6)

- Carboxylic acid: l-Acetyl-piperidine-4-carboxylic acid (commercially available), ES-MS m/e: 515.3 (M+H ⁺ ).

Example 51 4-{(3SR,4RS)-l-(l-Acetyl-piperidine-4-carbonyl)-4-[(SR)-l-(5 -chloro-pyridin-2-yloxy)- ethyl]-pyrrolidin-3-yl}-benzonitrile

Coupling according to general procedure I:

- Pyrrolidine intermediate: 4-{(3SR,4RS)-4-[l-((SR)-5-Chloro-pyridin-2-yloxy)-ethyl]- pyrrolidin-3-yl} -benzonitrile (VII-B-7) - Carboxylic acid: l-Acetyl-piperidine-4-carboxylic acid (commercially available), ES-MS m/e: 481.2 (M+H ⁺ ).

Example 52

{(3S,4R)-3-(4-Chloro-phenyl)-4-[(S)-l-(5-chloro-pyridin-2 -yloxy)-ethyl]-pyrrolidin-l-yl}-[l- (l-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone

Coupling according to general procedure I:

- Pyrrolidine intermediate: 5-Chloro-2- ((S)-I -[(3R,4S)-4-(4-chloro-phenyl)-pyrro lidin-3-yl]- ethoxy} -pyridine (VII-B-8) - Carboxylic acid: l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (described herein after), ES-MS m/e: 530.1 (M+H ⁺ ).

l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid: a) l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester

To a stirred solution of 1-methyl-cyclopropanecarboxylic acid (14.4 g, 0.144 mol) in 200 mL of CH ₂ Cl ₂ was added (27.10 g, 0.141 mol) of EDC, (19.10 g, 0.141 g) of HOBt and Et ₃ N (35.93

mL, 0.259 mol). After one hour at RT, was added piperidine-4-carboxylic acid ethyl ester (18.90 g, 0.120 mol). The mixture was stirred at RT over night and then poured onto water and extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo. Column chromatography (SiO ₂ , EtOAc/H, 1 :1) yielded 26.1 g (92 %) of the title compound as a light yellow oil.

b) 1 -( 1 -Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid

To a stirred solution of l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (26.09 g, 0.109 mol) in 500 mL of a mixture of THF, EtOH and H ₂ O) (1/1/1) was added LiOH. H ₂ O) (6.86 g, 0.163 mol). After one hour at RT, the solvent were evaporated and the residue taken up in CH ₂ Cl ₂ and the organic phase was washed with aqueous HCl IM. The organic phases were dried over Na ₂ SO ₄ and evaporated under vacuo to gave 19.8 g (86%) of the title compound as a white solid. ES-MS m/e: 212.1 (M+H ⁺ ).

Example 53

{(3S,4R)-3-(4-Chloro-3-fluoro-phenyl)-4-[(S)-l-(5-chloro- pyridin-2-yloxy)-ethyl]- pyrrolidin-l-yl}-[l-(l-methyl-cyclopropanecarbonyl)-piperidi n-4-yl]-methanone

Coupling according to general procedure I: - Pyrrolidine intermediate: 5-Chloro-2- ((S)-I -[(3R,4S)-4-(4-chloro-3-fluoro-phenyl)-pyrro lidin- 3 -yl]-ethoxy} -pyridine (VII-B-9)

- Carboxylic acid: l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (described herein after), ES-MS m/e: 548.2 (M+H ⁺ ).

l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid: a) l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester

To a stirred solution of 1-methyl-cyclopropanecarboxylic acid (14.4 g, 0.144 mol) in 200 mL of

CH ₂ Cl ₂ was added (27.10 g, 0.141 mol) of EDC, (19.10 g, 0.141 g) of HOBt and Et ₃ N (35.93

mL, 0.259 mol). After one hour at RT, was added piperidine-4-carboxylic acid ethyl ester (18.90 g, 0.120 mol). The mixture was stirred at RT over night and then poured onto water and extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated under vacuo. Column chromatography (SiO ₂ , EtOAc/H, 1 :1) yielded 26.1 g (92 %) of the title compound as a light yellow oil.

b) 1 -( 1 -Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid

To a stirred solution of l-(l-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (26.09 g, 0.109 mol) in 500 mL of a mixture of THF, EtOH and H ₂ O) (1/1/1) was added LiOH. H ₂ O) (6.86 g, 0.163 mol). After one hour at RT, the solvent were evaporated and the residue taken up in CH ₂ Cl ₂ and the organic phase was washed with aqueous HCl IM. The organic phases were dried over Na ₂ SO ₄ and evaporated under vacuo to gave 19.8 g (86%) of the title compound as a white solid. ES-MS m/e: 212.1 (M+H ⁺ ).