HK1111340B - Dual nk1/nk3 antagonists against schizophrenia - Google Patents

Description

Dual NK1/NK3 antagonists against schizophrenia

The invention relates to the use of a compound of formula or a pharmaceutically active acid addition salt thereof for the preparation of a medicament for the treatment of schizophrenia

Wherein

R¹Is lower alkyl or halogen;

R²is hydrogen or halogen;

R³is- (CHR')_nOH, optionally substituted with- (CHR')_nOH-substituted phenyl, or a saturated, partially saturated or aromatic 5-or 6-membered heterocyclic ring having one heteroatom selected from the group consisting of: -N (R)⁴)-、-N＝、-S-or-S (O)₂And these rings are optionally substituted with- (CHR')_nOH substitution;

r' is independently from "n" hydrogen or- (CH)₂)_nOH；

R⁴Is hydrogen, -S (O)₂-lower alkyl or-c (o) -lower alkyl;

x is-O-, -CH₂O-, -S-or a bond;

n is 1 or 2.

The compounds of formula I may contain some asymmetric carbon atoms. Accordingly, the present invention includes all stereoisomeric forms of the compounds of formula I, including individual enantiomers and mixtures thereof.

The compounds of formula I and their salts have valuable therapeutic properties. It has surprisingly been found that the compounds of formula I show a high affinity for both NK1 and NK3 receptors (dual NK1/NK3 receptor antagonists) and are useful for the treatment of schizophrenia.

Schizophrenia is one of the major neuropsychiatric disorders, characterized by severe chronic psychotic lesions. This devastating disease affects approximately 1% of the world population. Symptoms begin early in adulthood and then follow a period of interpersonal and social dysfunction. Schizophrenia is manifested by auditory and visual hallucinations, paranoia, delusions (positive symptoms), affective retardation, depression, anhedonia, poverty of speech, lack of memory and attention, and social escape (negative symptoms).

The diagnosis of schizophrenia has no specific focal features and no single symptom is consistently present in all patients, therefore, schizophrenia has been discussed but not concluded as a single psychotic disorder or as a diagnosis of a variety of different psychotic disorders. In addition, the ideal anti-schizophrenia drug will preferably have a low dose that allows once-a-day dosing because of the low adherence of schizophrenic patients.

In recent years, clinical studies with selective NK1 and NK2 receptor antagonists have been reported in the literature, showing therapeutic results for emesis, depression, anxiety, pain and migraine (NK1) and asthma (NK2 and NK 1). The most exciting data are for chemotherapy-induced emesis, nausea and depression treated with NK1 receptor antagonists and asthma treated with NK2 receptor antagonists. In contrast, no clinical data of NK3 receptor antagonists were reported in the literature until 2000. Osanentan (SR 142,801) from Sanofi-Synthelabo was the first identified potent selective non-peptide NK3 tachykinin receptor antagonist reported in the literature as useful in the treatment of Schizophrenia (Current Opinion in Investigational Drugs, 2001, 2(7), 950-. The proposed drug SR142,801 has been shown to be active in phase II trials on positive symptoms of schizophrenia, such as behavioral changes, delusions, hallucinations, extreme mood, excitatory activity and allophasis, but not in the treatment of negative symptoms, which are depression, anhedonia, social isolation or lack of memory and attention.

Neurokinin-3 receptor antagonists have been described as useful in pain or inflammation and Schizophrenia (exp. Opinion. ther. patents (2000), 10(6), 939-.

In addition, EP 1192952 describes pharmaceutical compositions containing a combination of an NK3 receptor antagonist and a CNS-permeable NK1 receptor antagonist for the treatment of depression and anxiety.

It has now been found that the combination of the antidepressant, mood-improving properties of the NK1 receptor antagonism and the antipsychotic effects of the NK3 receptor antagonism is suitable for the simultaneous treatment of positive and negative symptoms in schizophrenia.

This advantage can be recognized in the administration of ideal anti-schizophrenia drugs.

The compounds of the formula I are partly known compounds which are described in EP 1035115, WO 02/08232 or WO 02/16324.

They have been described as active at the NK1 receptor and are useful in the treatment of diseases in which this receptor is involved, such as inflammatory conditions including migraine, rheumatoid arthritis, asthma and inflammatory bowel disease, as well as in mediating the emetic reflex and modulating Central Nervous System (CNS) disorders such as parkinson's disease, anxiety, pain, headache (especially migraine), alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema (e.g. caused by thermal injury), chronic inflammatory diseases (e.g. rheumatoid arthritis), asthma/bronchial hyperreactivity and other respiratory diseases (including allergic rhinitis), inflammatory bowel diseases (including ulcerative colitis and crohn's disease), ocular damage and ocular inflammatory diseases.

Neurokinin-1 receptor antagonists are also useful in The treatment of motion sickness, induced emesis or psychoimmune or psychosomatic disorders, see Neurosci. Res., 1996, 7, 187-214, Can.J.Phys., 1997, 75, 612-621, Science, 1998, 281, 1640-1645, Auton. Pharmacol, 13, 23-93, 1993, WO 95/16679, WO 95/18124, WO 95/23798, The New England journal of Medicine, Vol.340, No.3190-195, 1999, US 5,972,938.

Objects of the present invention are the use of compounds of formula I and their pharmaceutically acceptable salts for the treatment of the positive and negative symptoms in schizophrenia, the novel compounds of formula I, the pharmaceutically active acid addition salts thereof, all stereoisomeric forms of the compounds of formula I (including the individual enantiomers and mixtures thereof), the preparation of the above novel compounds, medicaments containing them and their manufacture as well as the use of the above compounds in the control or prevention of illnesses, especially of the kind of illnesses and disorders mentioned above or in the manufacture of corresponding medicaments.

Preferred compounds of the formula I for combating schizophrenia are those in which X is-O-or-CH₂Those of O-, for example the compound 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-ethoxy) -pyridin-3-yl]-N-methyl-isobutyramide, 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-1-hydroxymethyl-ethoxy) -pyridin-3-yl]-N-methyl-isobutyramide or (S) -2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (pyrrolidin-2-ylmethoxy) -pyridin-3-yl]-N-methyl-isobutyramide.

Further preferred are compounds of formula I wherein X is-S-, such as 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (2-hydroxy-ethylsulfanyl) -pyridin-3-yl ] -N-methyl-isobutyramide.

Further preferred compounds are those wherein X is a bond and R is³Is a saturated, partially saturated or aromatic 5-or 6-membered heterocyclic ring having one heteroatom selected from the group consisting of: -N (R)⁴)-、-N＝、-S-or-S (O)₂These rings are optionally substituted with- (CHR')_nAnd (4) OH substitution. This group of compounds is as follows: 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 3']Bipyridin-5-yl]-N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-oxy- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (3-hydroxymethyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -5 '-hydroxymethyl- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 '-hydroxymethyl- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 6 '-tetrahydro- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

(RS) -2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

(RS) -N- [1 '-acetyl-4- (4-fluoro-2-methyl-phenyl) -1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 3' ] bipyridinyl-5-yl ] -2- (3, 5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (3, 6-dihydro-2H-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.)⁶-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl]-N-methyl-isobutyramide, or

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (1, 1-dioxo-hexahydro-1. lamda.)⁶-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl]-N-methyl-isobutyramide.

The following general term definitions as used in this specification apply generally, whether related terms appear alone or in combination.

The term "lower alkyl" as used herein denotes a straight or branched chain alkyl group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. The term "alkyl" denotes a straight or branched chain alkyl group containing 1 to 7 carbon atoms.

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

"saturated, partially saturated or aromatic 5-or 6-membered heterocyclic ring having one hetero atom" includes, for example, pyrrolidin-2-yl, piperidin-4-yl, piperidin-3-yl, pyridin-4-yl, pyridin-3-yl, tetrahydro-pyridin-4-yl, dihydro-thiopyran-4-yl, hexahydro-thiopyran-4-yl and the like.

The term "pharmaceutically acceptable acid addition salts" embraces salts of 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, methanesulfonic acid, p-toluenesulfonic acid and the like.

The compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, as described in schemes 1 to 8 and specific examples 1 to 16, for example, as described hereinafter, which comprises a) reacting a compound of the formula

Intermediates 5A-5B

With a compound of the formula

R³OH

To obtain a compound of the formula

Wherein R is¹、R²And R³Having the meaning given above, the inventors have found that,

or

b) Reacting a compound of the formula

Intermediates 5A-5B

With a compound of the formula

R³SH

To obtain a compound of the formula

Wherein R is¹、R²And R³Having the meaning given above, the inventors have found that,

or

c) Reacting a compound of the formula

Reacting with 3-chloroperbenzoic acid,

to obtain a compound of the formula

Wherein R is¹And R²Having the meaning given above, the inventors have found that,

d) reacting a compound of the formula

Intermediates 5A-5B

With a compound of the formula

To obtain a compound of the formula

Wherein R is¹And R²Have the meanings given above, or

e) Reacting a compound of the formula

With a compound of the formula

(CF₃CO)₂O

To obtain a compound of the formula

Wherein R is¹And R²Having the meaning given above, the inventors have found that,

or

f) Reacting a compound of the formula

With a compound of the formula

CH₃SO₂Cl

To obtain a compound of the formula

Wherein R is¹And R²Having the meaning given above, the inventors have found that,

or

g) Reacting a compound of the formula

With a compound of the formula

(CH₃CO)₂O

To obtain a compound of the formula

Wherein R is¹And R²Having the meaning given above, the inventors have found that,

or

h) Reacting a compound of the formula

Reacting with a compound 3-chloroperbenzoic acid,

to obtain a compound of the formula

Wherein R is¹And R²Having the meaning given above, the inventors have found that,

or

i) Hydrogenation of a compound of the formula

To obtain a compound of the formula

Wherein R is¹And R²Have the meanings given above, and

if desired, converting the resulting compound into a pharmaceutically acceptable acid addition salt.

In general, compounds of formula I can be prepared as follows:

the following abbreviations are used in the schemes:

DMF N, N-dimethylformamide

TFA trifluoroacetic acid

DME ethylene glycol dimethyl ether

KHMDS potassium hexamethyldisilazide

TBDMS tert-butyldimethylsilyl protecting group

THF tetrahydrofuran

MCPBA 3-chloroperbenzoic acid

dppf 1, 1' -bis (diphenylphosphino) ferrocene

RT Room temperature

Scheme 1

Wherein R is¹Have the above-mentioned meanings.

According to scheme 1, intermediates 5A-5B can be prepared as follows:

intermediate 1

To a solution of tert-butyl (6-chloro-4-iodo-pyridin-3-yl) -carbamate in DMF at about-10 deg.C was added sodium hydride ((preparation of tert-butyl 6-chloro-4-iodo-pyridin-3-yl) -carbamate was described in US2002/0022624A 1). The reaction mixture was warmed to room temperature. After about 1h, the mixture was cooled back and methyl iodide was added.

Intermediate 2

Trifluoroacetic acid was added to a solution of (6-chloro-4-iodo-pyridin-3-yl) -methyl-carbamic acid tert-butyl ester in dichloromethane at 0 ℃.

Intermediate 3A

A mixture of (6-chloro-4-iodo-pyridin-3-yl) -methyl-amine, 2-chlorophenylboronic acid, palladium (II) acetate, triphenylphosphine, sodium carbonate solution and 1, 2-dimethoxyethane was heated at about 80 ℃ for 90 min.

Intermediate 3B

Intermediate 3B was obtained following the procedure described above for the preparation of [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -methyl-amine, using 4-fluoro-2-methyl-phenylboronic acid instead of 2-chlorophenylboronic acid.

Intermediate 4

Intermediate 4 was obtained according to the procedure described in WO 0279134a 1.

Intermediate 5A

To a solution of [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -methyl-amine (intermediate 3A) in tetrahydrofuran at about 0 ℃ was added dropwise a solution of potassium bis (trimethylsilyl) amide in tetrahydrofuran. The reaction mixture was stirred at room temperature for 30 min. After cooling to 0 ℃, 2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl chloride (intermediate 4) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for about 1 h.

Intermediate 5B

Intermediate 5B was obtained following the procedure described above for the preparation of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide (intermediate 5A) using [ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -methyl-amine (intermediate 3B) instead of [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -methyl-amine (intermediate 3A).

Scheme 2

Compounds of formula IA may be prepared as follows:

a mixture of intermediate 5A-5B, the corresponding alcohol (e.g. L-prolinol or 2- (benzyloxy) ethanol or 1, 3-dimethoxy-2-propanol), cetyltrimethylammonium bromide, bis (tri-tert-butylphosphine) palladium, NaOH and toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated at about 90 ℃ under argon for up to 3 days.

Scheme 3

Intermediates 5A-5B

The compounds of formula IB can be prepared as follows:

a mixture of intermediate 5A-5B, 2-mercaptoalcohol, and potassium carbonate was heated at about 140 ℃ under argon for 3 h.

Scheme 4

Compounds of formula IC may be prepared as follows:

at about-60 ℃ to formula R³A THF solution of isopropyl magnesium chloride is added to a THF solution of a Br compound, for example 3-bromopyridine. The resulting solution is subjected toHeld at 40 ℃ for about 15min and then warmed to room temperature. A THF solution of zinc chloride was then added to the suspension. The mixture was stirred at room temperature for 2h. After addition of intermediates 5A-5B and a solution of tetrakis (triphenylphosphine) palladium in THF, the reaction mixture was heated for about 16 h.

Then R³In the case of pyridyl, the compounds of formula ID can be obtained using the following method:

to a solution of a compound of formula IC, for example 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide in dichloromethane is added 3-chloroperbenzoic acid at room temperature.

Scheme 5

Trifluoromethanesulfonic acid 5- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-3-yl ester can be prepared as follows:

to a solution of 5- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-3-ol (the preparation of which is described in detail in examples 8a to 8 d) and triethylamine in dichloromethane was added a solution of trifluoromethanesulfonic anhydride in dichloromethane at 0 ℃.

A mixture of 5- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-3-yl trifluoromethanesulfonate, bis (pinacolato) diboron and potassium acetate in N, N-dimethylformamide was deoxygenated by three freeze-thaw cycles. After addition of dichloro (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane adduct, the reaction mixture was stirred at about 80 ℃ overnight. Cooled to room temperature, then sodium carbonate solution, 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide (intermediate 5A-5B), and dichloro (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane adduct were added. The reaction mixture was heated at about 80 ℃ overnight.

Scheme 6

The preparation of intermediates, such as 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 '-methyl- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide and compounds of formula IF can be carried out in analogy to the description of scheme 4.

Compounds of formula IG, for example 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 '-hydroxymethyl- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide, may be prepared as follows:

a solution of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 ' -methyl-1 ' -oxy- [2, 4 ' ] bipyridinyl-5-yl ] -N-methyl-Isobutyramide (IF) and trifluoroacetic anhydride is stirred at room temperature overnight.

Scheme 7

A solution of a protected compound of formula IH, for example 5- { [2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl ] -methyl-amino } -4- (4-fluoro-2-methyl-phenyl) -3 ', 6 ' -dihydro-2 ' H- [2, 4 ' ] bipyridinyl-1 ' -carboxylic acid tert-butyl ester and trifluoroacetic acid in dichloromethane is stirred at room temperature for about 15 min. The mixture containing the compound of formula IH is basified, extracted and dried. To a solution of a compound of formula IH, e.g. 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 6 '-tetrahydro- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide in dichloromethane is added triethylamine and methanesulfonyl chloride at 0 ℃.

The compound of formula IJ may be prepared as described for the preparation of the compound of formula Ii using acetic anhydride in the last step instead of methanesulfonyl chloride.

Scheme 8

The compound of formula IK is obtained in analogy to the procedure described above for the preparation of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (3-hydroxymethyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide (example 7) using 2- (3, 6-dihydro-2H-thiopyran-4-yl) -4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan instead of 3- (hydroxymethyl) phenylboronic acid.

To a solution of a compound of formula IK, for example 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (3, 6-dihydro-2H-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide in dichloromethane at 0 ℃ is added 3-chloroperbenzoic acid. After about 3h, the reaction mixture is diluted with sodium hydroxide solution, extracted and purified to give the compound of formula IL.

Furthermore, compounds of this kind, for example 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lambda⁶-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl]The ethyl acetate solution of-N-methyl-isobutyramide and 1 drop perchloric acid was degassed by three freeze-thaw cycles. After addition of platinum (IV) oxide under argon, the reaction mixture was stirred at room temperature under a hydrogen atmosphere for about 6 h.

As mentioned hereinbefore, the compounds of formula I and their pharmaceutically acceptable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are dual antagonists of neurokinin 1 and 3 receptors.

These compounds were investigated according to the tests given below.

NK ₁

Evaluation of test Compounds for human NK in CHO cells₁NK of receptor₁Receptor affinity, human NK for CHO cells₁Infection of a receptor (using the Semliki virus expression system) and use of³H]Substance P was radiolabeled (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50mM, pH 7.4) containing BSA (0.04%), leupeptin (16.8. mu.g/ml), MnCl₂(3mM) and phosphoramidon (2. mu.M). The binding assay consisted of 250. mu.l of membrane suspension (approximately 1.5. mu.g/well in a 96-well plate), 0.125. mu.l of displacer buffer and 125. mu.l of [ mu.l ], [ solution ]³H]Substance P composition the displacement curve was determined using at least seven concentrations of the compounds the assay tubes were incubated for 60min at room temperature, then the tube contents were rapidly filtered under vacuum through GF/C filters previously soaked for 60min with PEI (0.3%) and washed (3 × 1ml) with HEPES buffer (50mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in duplicate in at least two independent experiments.

NK ₃

In the presence of 10 concentrations of a competitive compound or buffer, the use of³H]SR142801 (final concentration 0.3nM) radiolabel hNK₃Receptor, assay of recombinant human NK in 96-well plate assay₃(hNK₃) Receptor affinity. Nonspecific binding was determined using 10 μ M SB 222200. The assay buffer was composed of Tris-HCl (50mM, pH 7.4), BSA (0.1%), MnCl₂(4mM) and phosphoramidon (1. mu.M). Use of hNK₃Membrane preparations of the receptor (approximately 2.5. mu.g/well in 96-well plates) were initiated for 90min incubation at room temperature. The assay was terminated rapidly under vacuum by filtration through GF/C filters previously soaked for 90min with PEI (0.3%), using ice-cold Tris buffer containing 0.1% BSA(50mM, pH 7.4) wash (3X 0.5 ml). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in duplicate in at least two independent experiments.

The activity of the present compounds is described in the following table:

example numbering	pki NK1	pki NK3
			1	9.25	7.71
2	8.91	8.04
			3	9.07	7.63
4	8.63	8.07
			5	8.89	7.79
6	9.01	7.61
			7	8.92	8.16
8	8.74	8.21
			9	8.81	7.94
10	9.21	8.58
			11	8.96	8.19
12	9.23	7.67

Example numbering	pki NK1	pki NK3
			13	8.79	7.84
14	8.94	7.85
			15	9.23	8.17
16	8.86	7.78

Intermediate 1

(6-chloro-4-iodo-pyridin-3-yl) -methyl-carbamic acid tert-butyl ester

To a solution of 1.00g (2.82mmol) of (6-chloro-4-iodo-pyridin-3-yl) -carbamic acid tert-butyl ester in 10ml of DMF at-10 ℃ was added 0.12g (3.1mmol) of sodium hydride (60% in mineral oil) (preparation of (6-chloro-4-iodo-pyridin-3-yl) -carbamic acid tert-butyl ester is described in US2002/0022624A 1). The reaction mixture was warmed to room temperature. After 1h, the mixture was cooled back to-10 ℃ and 0.44ml (7.1mmol) of methyl iodide were added over 5 min. The reaction mixture was warmed to room temperature. After 2.5h at room temperature, 10ml of saturated NaHCO were added₃The reaction was quenched with aqueous solution and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate 4: 1) to yield 1.06g (100%) of the title compoundIt is a colorless oil.

MS m/e(％)：368(M⁺，1)

Intermediate 2

(6-chloro-4-iodo-pyridin-3-yl) -methyl-amine

To a solution of 8.65g (19.6mmol) (6-chloro-4-iodo-pyridin-3-yl) -methyl-carbamic acid tert-butyl ester in 20ml dichloromethane at 0 ℃ was added 20.0ml (261mmol) of trifluoroacetic acid. After stirring at room temperature for 2h, the reaction mixture was concentrated in vacuo. The residue was treated with 50ml of saturated sodium carbonate solution and extracted three times with 75ml of ethyl acetate. The combined organic layers were washed with 50ml brine, dried over sodium sulfate and concentrated in vacuo to give 6.1g (87%) of the title compound as a light brown solid.

MS m/e(％)：268(M⁺，1)

Intermediate 3A

[ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -methyl-amine

A mixture of 6.05g (19.3mmol) (6-chloro-4-iodo-pyridin-3-yl) -methyl-amine, 23.6g (23.6mmol) 2-chlorophenylboronic acid, 441mg (1.96mmol) palladium (II) acetate, 1.03g (3.93mmol) triphenylphosphine, 47.1ml of a 2M sodium carbonate solution and 50ml 1, 2-dimethoxyethane was heated at 80 ℃ for 90 min. The reaction mixture was cooled to room temperature and diluted with 100ml of ethyl acetate. The aqueous layer was separated and extracted with 100ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography to give 4.1g (83%) of the title compound as a light brown solid.

MS m/e(％)：253(M+H⁺，100)

Intermediate 3B

[ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -methyl-amine

Following the procedure described above for the preparation of [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -methyl-amine using 4-fluoro-2-methyl-phenylboronic acid instead of 2-chlorophenylboronic acid, the title compound was obtained after flash chromatography as an orange solid in 80% yield.

MS m/e(％)：251(M+H⁺，100)

Intermediate 4

2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl chloride

The title compound was obtained according to the procedure described in WO 02/79134A 1.

Intermediate 5A

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide

To a solution of 20g (79mmol) [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -methyl-amine (intermediate 3A) in 200ml tetrahydrofuran was added dropwise a solution of 113ml (94.8mmol) of 0.91M potassium bis (trimethylsilyl) amide in tetrahydrofuran at 0 ℃. The reaction mixture was stirred at room temperature for 30 min. After cooling to 0 ℃ 27.7g (86.9mmol) of 2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl chloride (intermediate 4) are added dropwise. The reaction mixture was warmed to room temperature and stirred at room temperature for 1 h. The reaction mixture was treated with 220ml of 1M sodium bicarbonate solution and extracted with three portions of 200ml of ethyl acetate. The combined organic layers were dried over sodium sulfate and triturated with 150ml ether to give 34.6g (82%) of the title compound as a white solid.

MS m/e(％)：535(M+H⁺，100)

Intermediate 5B

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide

Following the procedure described above for the preparation of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide (intermediate 5A), using [ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -methyl-amine (intermediate 3B) instead of [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -methyl-amine (intermediate 3A) the title compound was obtained after flash chromatography as a light yellow foam in 87% yield.

MS m/e(％)：533(M+H⁺，100)

Example 1

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-ethoxy) -pyridin-3-yl ] -N-methyl-isobutyramide

a) N- [6- (2-benzyloxy-ethoxy) -4- (2-chloro-phenyl) -pyridin-3-yl]-2- (3, 5-bis-trifluoromethyl-benzene Alkyl) -N-methyl-isobutyramide

A mixture of 0.10g (0.19mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide, 0.03ml (0.02mmol)2- (benzyloxy) ethanol and 2ml dioxane was degassed by a two freeze-thaw cycle after addition of 7mg (0.008mmol) tris (dibenzylideneacetone) dipalladium (0), 7.0mg (0.016mmol)1, 3-bis- (2, 6-diisopropyl-phenyl) -3H-imidazol-1-ium chloride and 32mg (0.29mmol) potassium tert-butoxide, the reaction mixture was heated at 100 ℃ under argon for 2H, the mixture was cooled to room temperature, then 10mg (0.089mmol) potassium tert-butoxide, N, After heating at 100 ℃ for an additional 2H, the reaction mixture was cooled to room temperature, diluted with tert-butyl methyl ether, washed with two portions of water, the aqueous layers combined, extracted with two portions of tert-butyl methyl ether, the organic layers combined, dried over sodium sulfate, concentrated in vacuo, and subjected to flash column chromatography to give 60mg (49%) of the title compound as a pale yellow viscous oil.

MS m/e(％)：651(M+H⁺，100)。

b)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-ethoxy) -pyridine-3- Base of]-N-methyl-isobutyramide

To a solution of 60mg (0.092mmol) of N- [6- (2-benzyloxy-ethoxy) -4- (2-chloro-phenyl) -pyridin-3-yl ] -2- (3, 5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide in 2ml of dichloromethane was added 0.13ml (0.13mmol) of a 1M solution of boron trichloride in dichloromethane at room temperature. After consumption of the starting material, 1ml of 1M aqueous hydrochloric acid solution was added. Diluted with water and 2ml of 1M aqueous sodium hydroxide solution and then extracted with three portions of dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography afforded 36mg (70%) of the title compound as an off-white solid.

MS m/e(％)：561(M+H⁺，100)。

Example 2

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-1-hydroxymethyl-ethoxy) -pyridin-3-yl ] -N-methyl-isobutyramide

a)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-methoxy-1-methoxymethyl-ethane Oxy) -pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 0.15g (0.28mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (2-chloro-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide, 0.17g (1.4mmol)1, 3-dimethoxy-2-propanol, 5mg (0.01mmol) cetyltrimethylammonium bromide, 0.1ml 50% NaOH and 1ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated for 30min under microwave irradiation at 130 ℃. After cooling to room temperature, the mixture was diluted with water and extracted with two portions of tert-butyl methyl ether. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography afforded 0.11g (63%) of the title compound as an off-white solid.

MS m/e(％)：619(M+H⁺100)。

b)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-1-hydroxymethyl-ethoxy Yl) -pyridinePyridin-3-yl]-N-methyl-isobutyramide

To a solution of 0.11g (0.21mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-methoxy-1-methoxymethyl-ethoxy) -pyridin-3-yl ] -N-methyl-isobutyramide in 2ml dichloromethane was added 0.41ml (0.41mmol) of a 1M solution of boron tribromide in dichloromethane at 0 ℃. The mixture was warmed to room temperature overnight. Quenched with 1M aqueous hydrochloric acid and then extracted with two portions of dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography afforded 30mg (25%) of the title compound as an off-white solid.

MS m/e(％)：591(M+H⁺，100)。

Example 3

(S) -2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (pyrrolidin-2-ylmethoxy) -pyridin-3-yl ] -N-methyl-isobutyramide

A mixture of 0.20g (0.38mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide, 0.042g (0.41mmol) L-prolinol, 0.003g (0.009mmol) cetyltrimethylammonium bromide, 0.01g (0.02mmol) bis (tri-tert-butylphosphino) palladium (0), 0.05ml 50% NaOH and 1.2ml toluene was degassed by two freeze-thaw cycles, the reaction mixture was heated at 90 ℃ under argon for 3 days, after cooling to room temperature, the mixture was diluted with water, extracted with three parts dichloromethane, the combined organic layers were dried over sodium sulfate, concentrated, subjected to flash column chromatography in vacuo, 44mg (20%) of the title compound are obtained as a pale yellow solid.

MS m/e(％)：598(M+H⁺，100)。

Example 4

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (2-hydroxy-ethylsulfanyl) -pyridin-3-yl ] -N-methyl-isobutyramide

A mixture of 0.25g (0.47mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide, 1.1g (14mmol) 2-mercapto-ethanol and 0.20g (1.4mmol) potassium carbonate was heated at 140 ℃ under argon for 3 h. After cooling to room temperature, the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography afforded 0.13g (50%) of the title compound as a white solid.

MS m/e(％)：575(M+H⁺，100)。

Example 5

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide

To a solution of 0.50g (3.2mmol) of 3-bromopyridine in 6ml of dry THF at-60 deg.C was added 1.6ml (3.2mmol) of a 2M solution of isopropylmagnesium chloride in THF. The resulting orange solution was kept at-40 ℃ for 15min and then warmed to room temperature. After 2h, 4.9ml (4.9mmol) of a 1M solution of zinc chloride in dry THF are added to the orange suspension. The mixture was stirred at room temperature for an additional 2h. After addition of 1.0g (1.9mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide and 0.11g (0.095mmol) tetrakis (triphenylphosphine) palladium (0) in 6ml THF, the reaction mixture was heated at reflux for 16 h. Cooled to room temperature and then quenched with water and 0.5M aqueous sodium hydroxide. The mixture was extracted with four portions of dichloromethane. The organic extracts were combined, washed with two portions of brine, dried over sodium sulfate and concentrated in vacuo. Flash chromatography gave 0.36g (33%) of the title compound as an off-white solid.

MS m/e(％)：576(M+H⁺，100)。

Example 6

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-oxy- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide

To a solution of 70mg (0.12mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide in 2ml dichloromethane was added 33mg (0.13mmol) 3-chloroperbenzoic acid at room temperature. After 3h, a portion of silica gel was added to the reaction mixture, which was then concentrated in vacuo. The residue was transferred to a flash chromatography column. Elution gave 64mg (89%) of the title compound as a white solid.

MS m/e(％)：592(M+H⁺，100)。

Example 7

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (3-hydroxymethyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide

A mixture of 126mg (0.236mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide, 40mg (0.26mmol)3- (hydroxymethyl) phenylboronic acid, 0.5ml 2M aqueous sodium carbonate solution and 2ml 1, 2-dimethoxyethane was degassed by three freeze-thaw cycles after addition of 3mg (0.01mmol) palladium acetate and 6mg (0.02mmol) triphenylphosphine, the reaction mixture was stirred at 90 ℃ under argon for 12h after cooling to room temperature, diluted with 2M sodium carbonate solution, extracted with three portions of tert-butyl methyl ether, the organic layers combined, washed with brine, drying over sodium sulfate, concentration in vacuo flash chromatography afforded 117mg (82%) of the title compound as a white solid.

MS m/e(％)：605(M+H⁺，100)。

Example 8

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -5 '-hydroxymethyl- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide

a) 5-benzyloxy-nicotinic acid methyl ester

To a solution of 13.5g (88.2mmol) of methyl 5-hydroxynicotinate in 220ml of DMF at 0 ℃ 4.6g (97mmol) of sodium hydride (55% oil dispersion) are added in small portions. After stirring at this temperature for 1h, 11ml (93mmol) of benzyl bromide in 40ml of DMF are added dropwise over the course of 15 min. After complete addition, the reaction mixture was warmed to room temperature overnight. The mixture was diluted with water and extracted with five parts of tert-butyl methyl ether. The combined organic extracts were washed with two portions of water, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography afforded 10.7g (50%) of the title compound as a pale yellow solid.

b) (5-benzyloxy-pyridin-3-yl) -methanol

To a solution of 12.2g (50.0mmol) of 5-benzyloxy-nicotinic acid methyl ester in 250ml of toluene is added a solution of 0.69g (30mmol) of lithium borohydride in 30ml of THF at room temperature. The mixture was stirred at 100 ℃ for 5 h. After cooling to 0 ℃ 10ml of water and 60ml of 1M aqueous hydrochloric acid solution are added dropwise. Basified with 80ml of 2M aqueous sodium hydroxide solution, diluted with 200ml of water and extracted with four portions of tert-butyl methyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography afforded 6.4g (59%) of the title compound as an off-white solid.

c) 3-benzyloxy-5- (tert-butyl-dimethyl-silanyloxymethyl) -pyridine

To a solution of 0.75g (3.5mmol) (5-benzyloxy-pyridin-3-yl) -methanol and 0.52g (7.7mmol) imidazole in 12ml DMF at room temperature was added 0.58g (3.8mmol) tert-butyl-dimethyl-silyl chloride. The mixture was stirred for 3 days. Diluted with 0.2M aqueous sodium hydroxide and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 1.1g (98%) of the title compound as a pale yellow oil.

MS m/e(％)：330(M+H⁺，100)。

d)5- (tert-butyl-dimethyl-siloxymethyl) -pyridin-3-ol

A mixture of 1.1g (3.4mmol) 3-benzyloxy-5- (tert-butyl-dimethyl-silanyloxymethyl) -pyridine and 0.36g palladium on charcoal (10%) in 17ml methanol was stirred at room temperature under a hydrogen atmosphere for 2h. The mixture was filtered through Decalite and the filtrate was concentrated in vacuo to give 0.78g (96%) of the crude title compound as a pale yellow solid.

MS m/e(％)：240(M+H⁺，100)。

e) Trifluoromethanesulfonic acid 5- (tert-butyl-dimethyl-siloxymethyl) -pyridin-3-yl ester

A solution of 1.1g (3.9mmol) of trifluoromethanesulfonic anhydride in 8ml of dichloromethane is added dropwise over 20min to a solution of 0.78g (3.3mmol) of 5- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-3-ol and 0.66g (6.5mmol) of triethylamine in 25ml of dichloromethane at 0 ℃. After 20min, the reaction mixture was diluted with water and extracted with two portions of dichloromethane. The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.57g (47%) of the title compound as a pale yellow amorphous resin.

MS m/e(％)：372(M+H⁺，4)。

f)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -5 '-hydroxymethyl- [2, 3']Couplet Pyridin-5-yl]-N-methyl-isobutyramide

A mixture of 0.15g (0.41mmol) of 5- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-3-yl trifluoromethanesulfonate, 0.12g (0.45mmol) of bis (pinacolato) diboron and 0.12g (1.2mmol) of potassium acetate in 4ml of N, N-dimethylformamide was deoxygenated by three freeze-thaw cycles. After addition of 46mg (0.056mmol) of dichloro (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane adduct, the reaction mixture was stirred at 80 ℃ overnight. Cooled to room temperature, then 2ml of 2M aqueous sodium carbonate solution, 0.20g (0.38mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide and 23mg (0.028mmol) dichloro (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane adduct are added. The reaction mixture was heated at 80 ℃ overnight. After cooling to room temperature, the reaction mixture was diluted with 0.1M aqueous sodium hydroxide and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in a mixture of 4ml methanol and concentrated aqueous hydrochloric acid (95: 5) and stirred at room temperature for 90 min. The mixture was diluted with excess 1M sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated. Flash column chromatography afforded 32mg (14%) of the title compound as a pale brown solid.

MS m/e(％)：606(M+H⁺，100)。

Example 9

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 '-hydroxymethyl- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide

a)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 '-methyl- [2, 4']Bipyridine -5-yl]-N-methyl-isobutyramide

A mixture of 90mg (0.41mmol) 4-iodo-2-methyl-pyridine, 0.12g (0.45mmol) bis (pinacolato) diboron and 0.12g (1.2mmol) potassium acetate in 4ml N, N-dimethylformamide was deoxygenated by three freeze-thaw cycles. After addition of 46mg (0.056mmol) of dichloro (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane adduct, the reaction mixture was stirred at 80 ℃ overnight. Cooled to room temperature, then 2ml of 2M aqueous sodium carbonate solution, 0.20g (0.38mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [ 6-chloro-4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide and 23mg (0.028mmol) dichloro (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane adduct are added. The reaction mixture was heated at 80 ℃ overnight. After cooling to room temperature, the reaction mixture was diluted with 0.1M aqueous sodium hydroxide and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Flash column chromatography afforded 28mg (13%) of the title compound as a pale yellow solid.

b)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 ' -methyl-1 ' -oxy- [2, 4 '] Bipyridin-5-yl]-N-methyl-isobutyramide

Following the procedure described above for the preparation of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-oxy- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide (example 6), 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 '-methyl- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide was used instead of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl- Phenyl) - [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide to give the title compound in 97% yield.

MS m/e(％)：606(M+H⁺，100)。

c)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2' -hydroxymethyl - [2, 4']Couplet Pyridin-5-yl]-N-methyl-isobutyramide

A solution of 49mg (0.081mmol) of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 ' -methyl-1 ' -oxy- [2, 4 ' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide and 51mg (0.24mmol) of trifluoroacetic anhydride is stirred at room temperature overnight. An additional 34mg (0.16mmol) of trifluoroacetic anhydride are added and stirring is continued for 20h. After addition of methanol, the reaction mixture was concentrated in vacuo. Flash column chromatography afforded 31mg (63%) of the title compound as a white solid.

MS m/e(％)：606(M+H⁺100)。

Example 10

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 6 '-tetrahydro- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide

a)5- { [2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl]-methyl-amino-4- (4-fluoro-2-methyl) -phenyl) -3 ', 6' -dihydro-2 'H- [2, 4']Bipyridine-1' -carboxylic acid tert-butyl ester

Following the procedure described above for the preparation of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (3-hydroxymethyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide (example 7) using tert-butyl 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate instead of 3- (hydroxymethyl) phenylboronic acid, the title compound was obtained as a white solid in 47% yield. Tert-butyl 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate was prepared as described in P.Eastwood, Tetrahedron Lett.2000, 41, 3705.

MS m/e(％)：680(M+H⁺，100)。

b)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 ', 2 ', 3 ', 6 ' -tetrahydro- [2, 4 '] Bipyridin-5-yl]-N-methyl-isobutyramide

A solution of 0.12g (0.18mmol) of tert-butyl 5- { [2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl ] -methyl-amino } -4- (4-fluoro-2-methyl-phenyl) -3 ', 6 ' -dihydro-2 ' H- [2, 4 ' ] bipyridinyl-1 ' -carboxylate with 0.50ml (6.5mmol) of trifluoroacetic acid in 1.5ml of dichloromethane was stirred at room temperature for 15 min. The mixture was alkalinized by adding 2M aqueous sodium hydroxide solution and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 0.10g (99%) of the crude title compound as an off-white solid.

MS m/e(％)：580(M+H⁺，100)。

c)2- (3, 5-bis-trifluoromethyl-benzeneYl) -N- [4- (4-fluoro-2-methyl-phenyl) -1' -methanesulfonyl -1 ', 2 ', 3 ' 6 ' -tetrahydro- [2, 4 ']Bipyridin-5-yl]-N-methyl-isobutyramide

To a solution of 0.10g (0.17mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 ', 2 ', 3 ', 6 ' -tetrahydro- [2, 4 ' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide in 2ml dichloromethane at 0 deg.C were added 21mg (0.21mmol) triethylamine and 21mg (0.18mmol) methanesulfonyl chloride. After complete addition, the reaction mixture was allowed to warm to room temperature within 30 min. Diluted with water and then extracted with three portions of dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated, and purified by flash chromatography to give 77mg (68%) of the title compound as a white solid.

MS m/e(％)：658(M+H⁺100)。

Example 11

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide

a)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 4']Bipyri Pyridin-5-yl]-N- Methyl-isobutyramide

The title compound was obtained as an off-white solid in 70% yield according to the procedure described above for the preparation of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide (example 5) using 4-iodopyridine instead of 3-bromopyridine.

MS m/e(％)：576(M+H⁺，100)。

b)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 ', 2', 3 ', 4', 5 ', 6' -hexahydro -[2，4′]Bipyridin-5-yl]-N-methyl-isobutyramide

A solution of 0.20g (0.35mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide in 0.020ml (0.35mmol) concentrated sulfuric acid in 4ml methanol was degassed by three freeze-thaw cycles. After addition of 39mg (0.17mmol) of platinum (IV) oxide under argon, the reaction mixture is stirred at room temperature under a hydrogen atmosphere for 16 h. The mixture was concentrated in vacuo. The residue was partitioned between 1M aqueous sodium hydroxide and dichloromethane and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated to give 0.19g (94%) of the crude title compound as a brown solid.

MS m/e(％)：582(M+H⁺，100)。

c)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1' -methanesulfonyl -1 ', 2 ', 3 ', 4 ', 5 ', 6 ' -hexahydro- [2, 4 ']Bipyridin-5-yl]-N-methyl-isobutyramide

Following the procedure described above for the preparation of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 ' -methanesulfonyl-1 ', 2 ', 3 ', 6 ' -tetrahydro- [2, 4 ' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide (example 10c)), using 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 ', 2 ', 3 ', 4 ', 5 ', 6 ' -hexahydro- [2, 4 ' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide instead of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 ', 2 ', 3 ', 6 ' -tetrahydro- [2, 4 ' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide to give the title compound as an off-white solid in 79% yield.

MS m/e(％)：660(M+H⁺，100)。

Example 12

(RS) -2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide

Following the procedure described above for the preparation of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 ' -methanesulfonyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 ' -hexahydro- [2, 4 ' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide (example 11 steps b) and c)), 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 3 ' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide (example 5) was used in step b) instead of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide to give the title compound as an off-white solid in comparable yields.

MS m/e(％)：660(M+H⁺，100)。

Example 13

(RS) -N- [1 '-acetyl-4- (4-fluoro-2-methyl-phenyl) -1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 3' ] bipyridinyl-5-yl ] -2- (3, 5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide

Following the procedure described above for the preparation of (RS) -2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide (example 12), using acetic anhydride instead of methanesulfonyl chloride in the last step, the title compound was obtained in comparable yield as an off-white solid.

MS m/e(％)：624(M+H⁺，100)。

Example 14

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (3, 6-dihydro-2H-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide

a)2- (3, 6-dihydro-2H-thiopyran-4-yl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaboroheterocycles

To a solution of 1.3ml (9.0mmol) of diisopropylamine in 5ml of dry THF at-78 deg.C was added 5.7ml (9.0mmol) of a 1.6M solution of n-butyllithium in hexane. After complete addition, the mixture was allowed to warm to 0 ℃. To this solution was added dropwise a solution of 1.0g (8.6mmol) of tetrahydro-4H-thiopyranone in 5ml of THF at-78 ℃. After 30min, a solution of 3.1g (8.8mmol) N-phenyl-bis (trifluoromethanesulphonimide) in 8ml THF was added dropwise. The reaction mixture was warmed to room temperature and stirred at this temperature for 4 h. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography to give 2.1g (98%) of 3, 6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate.

A mixture of 2.0g (8.1mmol) of 3, 6-dihydro-2H-thiopyran-4-yl trifluoromethanesulphonate, 2.3g (8.9mmol) of bis (pinacolato) diboron, 0.18g (0.24mmol) of dichloro (1, 1 '-bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane, 0.13g (0.24mmol) of 1, 1' -bis (diphenylphosphino) ferrocene and 2.4g (24mmol) of potassium acetate in 20ml of dioxane was stirred at 80 ℃ for 16H. After cooling to room temperature, the reaction mixture was diluted with water and brine (1: 1) and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.97g (53%) of the title compound as an orange resin.

b)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (3, 6-dihydro-2H-thiopyran-4-yl) -4- (4-fluoro-2-methyl- Phenyl) -pyridin-3-yl]-N-methyl-isobutyramide

Following the procedure described above for the preparation of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (3-hydroxymethyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide (example 7) using 2- (3, 6-dihydro-2H-thiopyran-4-yl) -4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan instead of 3- (hydroxymethyl) phenylboronic acid, the title compound was obtained as a light yellow solid in 73% yield.

MS m/e(％)：597(M+H⁺，100)。

Example 15

2- (3, 5-bis-tris)Fluoromethyl-phenyl) -N- [6- (1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.)⁶-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 0.24g (0.40mmol)2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (3, 6-dihydro-2H-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide in 4ml dichloromethane was added 0.21g (0.84mmol) 3-chloroperbenzoic acid at 0 ℃. After 3h, the reaction mixture was diluted with 0.15M aqueous sodium hydroxide and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography afforded 0.23g (92%) of the title compound as an off-white solid.

MS m/e(％)：629(M+H⁺，100)。

Example 16

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (1, 1-dioxo-hexahydro-1. lamda.)⁶-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl]-N-methyl-isobutyramide

0.10g (0.16mmol) of 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lambda⁶-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl]The solution of-N-methyl-isobutyramide with 1 drop of perchloric acid (70%) in 3ml of ethyl acetate is degassed by three freeze-thaw cycles. After addition of 11mg (0.048mmol) of platinum (IV) oxide under argon, the reaction mixture is stirred at room temperature under a hydrogen atmosphere for 6 h. The mixture was filtered through Decalite and the filtrate was concentrated in vacuo. Flash column chromatography afforded 32mg (32%) of the title compound as a white solid.

MS m/e(％)：631(M+H⁺，100)。

Example A

Tablets having the following composition were produced in the usual manner:

mg/tablet

Active substance 5

Lactose 45

Corn starch 15

Microcrystalline cellulose 34

Magnesium stearate 1

Tablet weight 100

Example B

Capsules having the following composition were produced:

mg/capsule

Active substance 10

Lactose 155

Corn starch 30

Talc powder 5

Capsule fill weight 200

The active, lactose and corn starch are mixed first in a mixer and then in a granulator. The mixture was returned to the mixer, talc was added thereto, and mixed well. The mixture was filled by machine into hard gelatin capsules.

Example C

Producing suppositories having the following composition:

mg/suppository

Active substance 15

Suppository base 1285

Total 1300

The suppository base is melted in a glass or steel container, mixed thoroughly, and cooled to 45 ℃. The finely divided active substance is then added thereto and stirred until completely dispersed. The mixture is poured into suppository molds of suitable size, allowed to cool, and the suppositories are removed from the molds and individually packaged in wax paper or metal foil.

Claims (9)

1. The use of a compound of the general formula or a pharmaceutically active acid addition salt thereof for the preparation of a medicament for the treatment of schizophrenia,

wherein

R¹Is lower alkyl or halogen;

R²is hydrogen or halogen;

R³is-(CHR’)_nOH, optionally substituted with- (CHR')_nOH-substituted phenyl, or a saturated, partially saturated or aromatic 5-or 6-membered heterocyclic ring having one heteroatom selected from the group consisting of: -N (R)⁴)-、-N＝、-S-or-S (O)₂These rings are optionally substituted with- (CHR')_nOH substitution;

r, independently of "n", is hydrogen or- (CH)₂)_nOH；

R⁴Is hydrogen, -S (O)₂-lower alkyl or-c (o) -lower alkyl;

x is-O-, -CH₂O-, -S-or a bond;

n is 1 or 2;

wherein lower alkyl represents a straight or branched alkyl group having 1 to 4 carbon atoms.

2. Use of a compound of formula I according to claim 1, wherein X is-O-or-CH₂O-。

3. The use of compounds of formula I according to claim 2, wherein the compounds are

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-ethoxy) -pyridin-3-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-1-hydroxymethyl-ethoxy) -pyridin-3-yl ] -N-methyl-isobutyramide, or

(S) -2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (pyrrolidin-2-ylmethoxy) -pyridin-3-yl ] -N-methyl-isobutyramide.

4. The use of a compound of formula I according to claim 1, wherein X is-S-.

5. Use of a compound of formula I according to claim 4, wherein the compound is

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (2-hydroxy-ethylsulfanyl) -pyridin-3-yl ] -N-methyl-isobutyramide.

6. Use of a compound of formula I according to claim 1, wherein X is a bond and R is³Is a saturated, partially saturated or aromatic 5-or 6-membered heterocyclic ring having one heteroatom selected from the group consisting of: -N (R)⁴)-、-N＝、-S-or-S (O)₂And these rings are optionally substituted with- (CHR')_nAnd (4) OH substitution.

7. The use of compounds of formula I according to claim 6, wherein the compounds are:

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-oxy- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -5 '-hydroxymethyl- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 '-hydroxymethyl- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 6 '-tetrahydro- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

(RS) -2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

(RS) -N- [1 '-acetyl-4- (4-fluoro-2-methyl-phenyl) -1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 3' ] bipyridinyl-5-yl ] -2- (3, 5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (3, 6-dihydro-2H-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.)⁶-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl]-N-methyl-isobutyramide, or

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (1, 1-dioxo-hexahydro-1. lamda.)⁶-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl]-N-methyl-isobutyramide.

8. The use of compounds of the formula I according to claim 1, which are

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-ethoxy) -pyridin-3-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-1-hydroxymethyl-ethoxy) -pyridin-3-yl ] -N-methyl-isobutyramide or

(S) -2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (pyrrolidin-2-ylmethoxy) -pyridin-3-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (2-hydroxy-ethylsulfanyl) -pyridin-3-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) - [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-oxy- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -6- (3-hydroxymethyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -5 '-hydroxymethyl- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -2 '-hydroxymethyl- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 6 '-tetrahydro- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 4' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

(RS) -2- (3, 5-bis-trifluoromethyl-phenyl) -N- [4- (4-fluoro-2-methyl-phenyl) -1 '-methanesulfonyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 3' ] bipyridinyl-5-yl ] -N-methyl-isobutyramide,

(RS) -N- [1 '-acetyl-4- (4-fluoro-2-methyl-phenyl) -1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [2, 3' ] bipyridinyl-5-yl ] -2- (3, 5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (3, 6-dihydro-2H-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl ] -N-methyl-isobutyramide,

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.)⁶-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl]-N-methyl-isobutyramide or

2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (1, 1-dioxo-hexahydro-1. lamda.)⁶-thiopyran-4-yl) -4- (4-fluoro-2-methyl-phenyl) -pyridin-3-yl]-N-methyl-isobutyramide.

9. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 8, which process comprises

a) Reacting a compound of the formula

Intermediates 5A-5B

With a compound of the formula

R³OH

To obtain a compound of the formula

Wherein R is¹、R²And R³Having the meaning given in claim 1,

or

b) Reacting a compound of the formula

Intermediates 5A-5B

With a compound of the formula

R³SH

To obtain a compound of the formula

Wherein R is¹、R²And R³Having the meaning given in claim 1,

or

c) Reacting a compound of the formula

Reacting with 3-chloroperbenzoic acid,

to obtain a compound of the formula

Wherein R is¹And R²Having the meaning given in claim 1,

d) reacting a compound of the formula

Intermediates 5A-5B

With a compound of the formula

To obtain a compound of the formula

Wherein R is¹And R²Having the meaning given in claim 1,

or

e) Reacting a compound of the formula

With a compound of the formula

(CF₃CO)₂O

To obtain a compound of the formula

Wherein R is¹And R²Having the meaning given in claim 1,

or

f) Reacting a compound of the formula

With a compound of the formula

CH₃SO₂Cl

To obtain a compound of the formula

Wherein R is¹And R²Having the meaning given in claim 1,

or

g) Reacting a compound of the formula

With a compound of the formula

(CH₃CO)₂O

To obtain a compound of the formula

Wherein R is¹And R²Having the meaning given in claim 1,

or

h) Reacting a compound of the formula

Reacting with 3-chloroperbenzoic acid,

to obtain a compound of the formula

Wherein R is¹And R²Having the meaning given in claim 1,

or

i) Hydrogenation of a compound of the formula

To obtain a compound of the formula

Wherein R is¹And R²Has the meaning given in claim 1, and

optionally, the resulting compound is converted into a pharmaceutically acceptable acid addition salt.