WO2008034579A1

WO2008034579A1 - 2-heterocyclyl-5-phenoxymethylpyridine derivatives as anticancer agents

Info

Publication number: WO2008034579A1
Application number: PCT/EP2007/008094
Authority: WO
Inventors: Edgar Voss
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2006-09-20
Filing date: 2007-09-18
Publication date: 2008-03-27

Abstract

Objects of the present invention are the compounds of formula I their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above-mentioned compounds in the control or prevention of illnesses such as cancer.

Description

-HETEROCYCLYL-5-PHΞNOXYMETHYLPYRIDINE DERIVATIVES AS ANTICANCER AGENTS

The present invention relates to novel heterocyclic pyridine derivatives, to a process for their manufacture, pharmaceutical compositions containing them and their manufacture as well as the use of these compounds as pharmaceutically active agents.

Background of the Invention

The treatment of cancer diseases is of great importance in medicine. There is a worldwide need for effective cancer therapies in order to achieve a treatment which is appropriate to a patient and is target- orientated. This can be seen in the large number of scientific studies which have recently appeared in the fields of applied oncology and fundamental research relating to cancer therapy.

The effects of tumor inhibitors are due to a very wide variety of mechanisms, only some of which are known. It is not unusual for known tumor drugs to be found to have new mechanisms of action. This is also to be expected in the case of the compounds according to the invention. Many tumor drugs act by way of mechanisms such as blockading the mechanism of cell division in the cell, preventing the tumor from being supplied with nutrients and oxygen (antiangiogenesis), preventing metastasis, preventing the reception and the onward transmission of growth signals to the tumor cell or forcing the tumor cell into programmed cell death (apoptosis).

Because they have different mechanisms of action, including interacting with different intracellular targets, the clinically relevant cytostatic agents are frequently administered in combination in order to achieve a synergistic therapeutic effect.

WO 98/03505, WO 01/77107, WO 03/031442 and WO 03/059907 relate to heterocyclic compounds as tyrosine kinase inhibitors which are useful as anticancer agents. Summarv of the Invention

The present invention relates to compounds of the general formula I,

formula I

wherein

R¹ is hydrogen or alkyl;

R² is hydrogen or alkyl;

R³ is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifiuoromethyl or trifluoromethoxy;

X¹, X², X³, X⁴ and X⁵ independently represent N or (CH or C), with the proviso that at least one and not more than two of X¹, X², X³, X⁴ and X⁵ represent N and the remaining of X¹, X², X³, X⁴ and X⁵ represent (CH or C) wherein only one of X¹, X², X³, X⁴ and X⁵ is C;

A is -CH₂-CH₂-, -CH=CH-, -CH(OCH₃)-CH₂-, -CH(OH)-CH₂-, or -

C(O)-CH₂-; and all pharmaceutically acceptable salts thereof.

The compounds of the present invention show anti-proliferative activity. Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, pharmaceutical compositions containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders as mentioned above like common human cancers (such as colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas) or in the manufacture of corresponding pharmaceutical compositions. Detailed Description of the Invention

1. Definitions:

The term "alkyl" as used herein means a saturated, straight-chain or branched-chain hydrocarbon containing from 1 to 5 carbon atoms, preferably from 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, n- pentyl, 3-methyl-butyl, 2-methyl-butyl, n-hexyl, 3-methyl-pentyl. Preferably alkyl is selected from methyl, ethyl or isopropyl and more preferably alkyl is methyl.

The term "alkoxy" as used herein means an alkyl-O- group wherein the alkyl is defined as above.

As used herein, the term "a therapeutically effective amount" of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.

The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.

As used herein, a "pharmaceutically acceptable carrier" is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions of the invention are contemplated. Supplementary active compounds can also be incorporated into the compositions.

2. Detailed Description:

R¹ is hydrogen or alkyl; preferably alkyl. R² is hydrogen or alkyl preferably alkyl.

R³ is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl or trifluoromethoxy; preferably fluorine, chlorine or trifluoromethyl; and more preferably chlorine or trifluoromethyl.

X¹, X², X³, X⁴ and X⁵ independently represent N or (CH or C), with the proviso that at least one and not more than two of X¹, X², X³, X⁴ and X⁵ represent N and the remaining of X¹, X², X³, X⁴ and X⁵ represent (CH or C) wherein only one of X¹, X², X³, X⁴ and X⁵ is C and the pyridyl residue of formula I is bound via said C. Preferably X¹, X², X³, X⁴ independently represent CH or C wherein only one of X¹, X², X³ and X⁴ is C and the pyridyl residue of formula I is bound via said C; and X⁵ is N.

A is -CH₂-CH₂-, -CH=CH-, -CH(OCH₃)-CH₂-, -CH(OH)-CH₂-, or -C(O)-CH₂-; preferably -CH₂-CH₂-, -CH(OCH₃)-CH₂-, -CH(OH)-CH₂-, or -C(O)-CH₂-; more preferably -CH₂-CH₂-, -CH(OCH₃)-CH₂-, or -CH(OH)-CH₂-; and still more preferably -CH₂-CH₂- or -CH(OCH₃)-CH₂-.

One embodiment of the invention are the compounds according to formula I, wherein

R¹ is hydrogen or alkyl; preferably alkyl;

R² is alkyl;

R³ is fluorine, chlorine or trifluoromethyl; preferably chlorine or trifluoromethyl.

X^!, X², X³, X⁴ independently represent CH or C wherein only one of X¹, X², X³ and X⁴ is C; and

X⁵ is N.

Another embodiment are the compounds according to formula Ia, wherein

formula Ia wherein

R¹ is hydrogen or alkyl;

R² is hydrogen or alkyl;

R³ is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

A is -CH₂-CH₂-, -CH=CH-, -CH(OCH₃)-CH₂-, -CH(OH)-CH₂-, or -

C(O)-CH₂-; and all pharmaceutically acceptable salts thereof.

Another embodiment are the compounds according to formula I or formula Ia, wherein

R¹ is hydrogen or alkyl;

R² is alkyl; and

R³ is fluorine, chlorine or trifluoromethyl, preferably chlorine or trifluoromethyl.

A is -CH₂-CH₂- or -CH=CH-, preferably -CH₂-CH₂-.

R¹ is hydrogen or alkyl;

R² is alkyl; R³ is fluorine, chlorine or trifluoromethyl, preferably chlorine or trifluoromethyl; and A is -CH₂-CH₂- or -CH=CH-, preferably -CH₂-CH₂-.

Such compounds, for example, may be selected from the group consisting of:

6-Methyl-5- [3-methyl-4-(4- [ 1 ,2,3] triazol- 1 -yl-butyl)-phenoxymethyl] -6'- trifluoromethyl-[2,3']bipyridine;

6-Methyl-5-[4-(4-[l,2,3]tπazol-l-yl-butyl)-phenoxymethyl]-6'-trifluoromethyl- [2,3']bipyridine;

6'-Chloro-6-methyl-5- [4-(4- [ 1 ,2,3] triazol- 1 -yl-butyl)-phenoxymethyl] - [2,3']bipyridine; 6'-Chloro-6-methyl-5-[3-methyl-4-(4-[l,2,3]triazol-l-yl-butyl)-phenoxymethyl]- [2,3']bipyridine; and

6-Methyl-5-[3-methyl-4-((E)-4-[l,2,3]triazol-l-yl-but-l-enyl)-phenoxymethyl]- 6'-trifluoromethyl-[2,3']bipyτidine.

A is -CH(OCH₃)-CH₂-, -CH(OH)-CH₂-, or -C(O)-CH₂-, preferably

-CH(OCH₃)-CH₂- or -CH(OH)-CH₂-.

A is -CH(OCH₃)-CH₂-.

R¹ is hydrogen or alkyl; R² is alkyl;

R³ is fluorine, chlorine or trifiuoromethyl, preferably chlorine or trifluoromethyl; and A is -CH(OCH₃)-CH₂-.

Such compounds, for example, may be selected from the group consisting of:

5-[4-(l-Methoxy-4-[l,2,3]triazol-l-yl-butyl)-3-methyl-phenoxymethyl]-6- methyl-6' -trifluoromethyl- [2,3' ] bipyridine;

5- [4- ( 1 -Methoxy-4- [ 1 ,2,3 ] triazol- 1 -yl-butyl) -phenoxymethyl] -6-methyl-6'- trifluoromethyl-[2,3']bipyridine; and

6'-Chloro-5-[4-(l-methoxy-4-[l,2,3]triazol-l-yl-butyl)-3-methyl- phenoxymethyl]-6-methyl-[2,3']bipyridine.

A is -CH(OH)-CH₂-. Another embodiment are the compounds according to formula I or formula Ia, wherein

R¹ is hydrogen or alkyl;

R² is alkyl; R³ is fluorine, chlorine or trifluoromethyl, preferably chlorine or trifluoromethyl; and A is -CH(OH)-CH₂-.

Such compounds, for example, may be selected from the group consisting of:

l-[2-Methyl-4-(6-methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)- phenyl] -4- [ 1 ,2,3 ] triazol- 1 -yl-butan- 1 -ol;

l-[4-(6-Methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl]-4- [ 1 ,2,3 ] triazol- 1 -yl-butan- 1 -ol; and

l-[4-(6'-Chloro-6-methyl-[2,3']bipyridinyl-5-ylmethoxy)-2-methyl-phenyl]-4- [1,2,3] triazol- 1 -yl-butan- 1 -ol.

A is -C(O)-CH₂-.

R¹ is hydrogen or alkyl;

R² is alkyl;

R³ is fluorine, chlorine or trifluoromethyl, preferably chlorine or trifluoromethyl; and A is -C(O)-CH₂-.

Such compounds, for example, may be selected from the group consisting of:

l-[2-Methyl-4-(6-methyl-6'-trifluoromethyl-[2₎3']bipyridinyl-5-ylmethoxy)- phenyl] -4- [ 1 ,2,3] triazol- 1 -yl-butan- 1 -one;

l-[4-(6-Methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl]-4-

[ 1 ,2,3 ] triazol- 1 -yl-butan- 1 -one; and l-[4-(6'-Chloro-6-methyl-[2,3']bipyridinyl-5-ylmethoxy)-2-methyl-phenyl]-4- [ 1 ,2,3 ] triazol- 1 -yl-butan- 1 -one.

Another embodiment are the compounds according to formula I or formula Ia, wherein A is -CH₂-CH₂-, -CH(OCH₃)-CH₂-, -CH(OH)-CH₂-, or -C(O)-CH₂-, preferably -CH₂-CH₂-, -CH(OCH₃)-CH₂- or -CH(OH)-CH₂-.

A is -CH₂-CH₂- or -CH(OCH₃)-CH₂-.

R¹ is hydrogen or alkyl;

R² is alkyl;

R³ is fluorine, chlorine or trifluoromethyl, preferably chlorine or trifluoromethyl; and

A is -CH₂-CH₂-, -CH(OCH₃)-CH₂-, -CH(OH)-CH₂-, or -C(O)-CH₂-, preferably -CH₂-CH₂-, -CH(OCH₃)-CH₂- or -CH(OH)-CH₂-, more preferably -CH₂-CH₂- or -CH(OCH₃)-CH₂-.

Another embodiment of the invention is a process for the manufacture of the compounds of formula I in claim 1, wherein

(a) the compound of formula II

formula II,

wherein R², R³, X¹, X², X³, X⁴ and X⁵ have the significance as given in formula I above, is reacted with a compound of formula III

wherein R¹ and A have the significance given in formula I above, to give the respective compound of formula I;

formula I,

wherein R¹, R², R³, X¹, X², X³, X⁴, X⁵, and A have the significance given in formula I above, to give the respective compound of formula I;

(b) said compound is isolated from the reaction mixture, and

(c) if desired, converted into a pharmaceutically acceptable salt.

The compounds of formula I or a pharmaceutically acceptable salt thereof, which are subject of the present invention, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula I or a pharmaceutically-acceptable salt thereof, are illustrated by the following representative schemes 1 to 3 and examples in which, unless otherwise stated, R¹, R², R³, X¹, X², X³, X⁴, X⁵, and A have the significance given herein before. Necessary starting materials are either commercially available or they may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is e.g. described within the accompanying examples or in the literature cited below with respect to scheme 1 to 3. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. Scheme 1;

In scheme 1 a preferred method for the preparation of the compounds of formula I is described.

I

Scheme 1

In scheme 1, R > 1 , T R)² , τ R>3 , X vl , X v² , X v3 , v X⁴ , X v⁵ , and A have the significance as given above for formula I.

The derivatives of formula I can be obtained by reactions well known to someone skilled in the art, e.g. by alkylation of compounds of formula III with compounds of formula II according to step 1 scheme 1. The alkylation can be carried out in the presence of potassium iodide or sodium iodide in solvents like N,N- dimethylformamide (DMF), methanol, ethanol, isopropanol and 2-butanone. Typical bases for this reaction are sodium methylate, sodium hydride, lithium diisopropyl amide or cesium carbonate. The reaction temperatures may vary from 0⁰C to 150⁰C.

The preparation of the chloromethyl-pyridinylpyridines and chloromethyl- pyridinyldiazines of formula II is described in scheme 2 and scheme 3 below.

The phenolic intermediates of formula III, wherein W is -CH₂-CH₂-, can be prepared e.g. according to US 6,743,924 or US 6,716,863.

Derivatives of formula III, wherein W is -CH=CH- may be prepared e.g. according to US 2005/203064 Al or US 2005/197370 Al. The phenolic intermediates of formula III, wherein A is -C(O)-CH₂- or -CH(OH)- CH₂- can be prepared e.g. by methods described in WO 2006/032453.

The phenolic intermediates of formula III, wherein A- is or -CH(OCHs)-CH₂- are be prepared by methylation of the corresponding alcohols as described in the experimental section.

Scheme 2 and Scheme 3:

In scheme 2 and scheme 3 a preferred method for the preparation of the chloromethyl-pyridinyl-heterocycles of formula II, which represent important intermediates for the preparation of the compounds of formula I is described.

The chloromethyl-pyridinyl-heterocycles of formula II can be prepared by two general methods, the first one shown in scheme 2 involving a Suzuki-Miyaura- Coupling, which allows a general access to this compound class. The second method, that is shown in scheme 3, gives access to compounds of formula I in cases where the ketones represented by formula VIII are easily accessible.

IV

Scheme 2

In scheme 2, R², R³, X¹, X², X³, X⁴, and X⁵ have the significance as given above for formula I and X is iodine or bromine.

In step 1, the compounds of formula IV and formula V are reacted in a coupling reaction (Suzuki-coupling, step 1) which can be performed under different reaction conditions well known in the literature. Preferred reaction conditions are described in Meier, P., et al., Synthesis 4 (2003) 551-554, and WO 2005/040100, including a mixture of 1,2-dimethoxyethane and aqueous sodium carbonate solution, the latter also working as the required base, together with the use of palladium tetrakis- triphenylphospine as catalyst.

Transformation of the obtained pyridine derivatives of VI in step 2, scheme 2, to the corresponding alcohols VII is achieved by complex hydrides, most conveniently with diisobutylaluminiumhydrid (DIBAL) or lithium aluminum hydride in tetrahydrofuran (THF). In step 3, scheme 2, the obtained alcohols of formula VII are reacted with thionyl chloride in dichloromethane to yield the chlorides of formula II.

Scheme 3

In scheme 3, R², R³, X¹, X², X³, X⁴, and X⁵ have the significance as given above for formula I.

Heterocycles of formula II can be prepared by an alternative route shown in scheme 3. In a Mannich-type synthesis a mixture of ketones of formula VIII with para-formaldehyde and dimethylamine hydrochloride in a solvent like ethanol in the presence of an acid like 37% HCl is heated to reflux for 2 to 10 hours to give aminoketones of formula IX (scheme 3, step 1). Reaction of compounds of formula IX with 3-aminocrotonic acid esters of formula X in acetic acid at reflux for 2 to 8 hours gives esters of formula VIII (scheme 3, step 2) (see e.g. WO 2005/049573), which are converted to alcohols of formula VII (scheme 3, step 3) and subsequently to chlorides of formula II (scheme 3, step 4) by the same methods described for the compounds of formula VI and of formula VII in scheme 2, step 2 and scheme 2, step 3).

Scheme 4:

An additional efficient route to heterocycles of formula II is shown in scheme 4.

Scheme 4

In scheme 4, R², R³, X¹, X², X³, X⁴, and X⁵ have the significance as given above for formula I.

Condensation of ketones VIII with dimethyl formamide dimethylacetal (scheme 4, step 1) leads to enaminones of formula XI, that can be reacted in the presence of ammonium acetate with 3-oxo-alkanoic acid alkyl esters (scheme 4, step 2) to give intermediates VI. Transformation (scheme 4, steps 3 and 4)to compounds II is achieved by the methods described in scheme 3 (scheme 3, steps 3 and 4).

The compounds of formula I or formula can contain one or several chiral centers and can then be present in a racemic, enantiomeric or diastereomeric form. The racemates can be separated according to known methods into the enantiomers. For instance, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L- camphorsulfonic acid. Alternatively separation of the enantiomers can also be achieved by using chromatography on chiral HPLC-phases which are commercially available.

Pharmacological activity

The compounds of formula I or formula Ia and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been found that said show anti-proliferative activity. Consequently the compounds of the present invention are useful in the therapy and/or prevention of proliferative disorders such as cancer. The activity of the present compounds as antiproliferative inhibitors is demonstrated by the following biological assay:

CellTiter-GloTM assay in HEK293 cells The CellTiter-Glo™ Luminescent Cell Viability Assay (Promega) is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.

HEK293 cells (human embryonic kidney cell line transformed by Adenovirus 5 fragments, ATCC-No. CRL 1573) were cultivated in Dulbecco's Modified Eagle Medium (DMEM) with Glutamax™ (Invitrogen, 31966-021), 5% Fetal Calf Serum

(FCS, Sigma Cat-No. F4135 (FBS)), lOOUnits/ml penicillin / lOOμg/ml streptomycin (= Pen/Strep from Invitrogen Cat. No. 15140). For the assay the cells were seeded in 384 well plates, 5000 cells per well, in the same medium. The next day the test compounds were added in various concentrations ranging from 3 μM to 0.00015 μM (10 concentrations, 1:3 diluted). After 7 days the CellTiter-Glo™ assay was done according to the instructions of the manufacturer (CellTiter-Glo Luminescent Cell Viability Assay, from Promega). In brief: the cell-plate was equilibrated to room temperature for approximately 30 minutes and than the CellTiter-Glo™ reagent was added. The contents were carefully mixed for 15 minutes to induce cell lysis. After 45 minutes the luminescent signal was measured in Victor 2, (scanning multiwell spectrophotometer, Wallac). Details: 1. day:

Medium: Dulbecco's Modified Eagle Medium (DMEM) with Glutamax™ (Invitrogen, 31966-021), 5 % Fetal Calf Serum (FCS, Sigma Cat-No. F4135 (FBS)), Pen/Strep (Invitrogen Cat. No. 15140).

- HEK293 (ATCC-No. CRL 1573) : 5000 cells in 60 μl per well of 384 well plate (Greiner 781098, white plates)

- Incubate 24 h at 37°C, 5% CO₂

2. day: Induction (Substance testing):

In general the dilution steps are 1:3 a) Add 8 μl of 10 mM stock solution of compound to 72 μl DMSO b) dilute 9x 1:3 (always 30 μl to 60 μl DMSO) in this DMSO dilution row (results in 10 wells with concentrations from 1000 μM to 0.06 μM) c) dilute each concentration 1: 4.8 (10 μl compound dilution to 38 μl medium) d) dilute each concentration 1: 10 (10 μl compound dilution to 90 μl medium) e) add 10 μl of every concentration to 60 μl medium in the cell plate

-resulting in final concentration of DMSO : 0.3 % in every well and resulting in final concentration of compounds from 3 μM to 0.00015 μM

- Incubate 168 h (7 days) at 37°C, 5% CO₂ Analysis:

- Add 30 μl CellTiter-Glo™ Reagent/well, shake 15 minutes at room temperature - incubate further 45 minutes at room temperature without shaking.

Measurement:

Victor 2 scanning multiwell spectrophotometer (Wallac), Luminescence mode Determine IC50 with XL-fit (XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK)).

A significant inhibition of HEK293 cell viability was detected, which is exemplified by the compounds shown in Table 1.

Table 1

The compounds according to this invention and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions. The pharmaceutical compositions 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 above-mentioned pharmaceutical compositions can be obtained by processing the compounds according to this invention with pharmaceutically acceptable, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or it's salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

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

Pharmaceutical compositions comprise e.g. the following: a) Tablet Formulation (Wet Granulation):

Manufacturing Procedure:

1. Mix items 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50⁰C. 3. Pass the granules through suitable milling equipment.

4. Add item 5 and mix for three minutes; compress on a suitable press.

b) Capsule Formulation:

Manufacturing Procedure:

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

Medicaments or pharmaceutical compositions containing a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of the present invention and/or pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable carriers.

In accordance with the invention the compounds of the present invention as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses. Based on their antiproliferative activity, said compounds are useful for the treatment of diseases such as cancer in humans or animals and for the production of corresponding medicaments. The dosage depends on various factors such as manner of administration, species, age and/or individual state of health.

Another embodiment of the invention is pharmaceutical composition, containing one or more compounds of formula I or formula Ia together with one or more pharmaceutically acceptable carriers.

Another embodiment of the invention is pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula I or formula Ia together with one or more pharmaceutically acceptable carriers. Still another embodiment of the invention is said pharmaceutical composition for the inhibition of tumor growth.

Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I or formula Ia, for the treatment of cancer.

Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds of formula I or formula Ia as active ingredients together with pharmaceutically acceptable carriers for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.

Still another embodiment of the invention is the use of a compound of formula I or formula Ia for the manufacture of corresponding pharmaceutical compositions for the inhibition of tumor growth.

Another embodiment of the invention is the use of a compound according to formula I or formula Ia, for the manufacture of corresponding pharmaceutical compositions for the treatment of cancer.

Another embodiment of the invention is the use of the compounds of formula I or formula Ia as anti-proliferating agents.

Still another embodiment of the invention is the use of a compound of formula I or formula Ia for the treatment of cancer.

The following examples are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims. It is understood that modifications can be made in the procedures set forth without departing from the spirit of the invention. Examples: Example 1 l-[4-(6'-Chloro-6-methyl-[2,3']bipyridinyl-5-ylmethoxy)-2-methyl-phenyl]-4- [1,2,3] triazol- 1 -yl-butan- 1 -one Preparation of l-(4-Hydroxy-2-methyl-phenyl)-4-[l,2,3]triazol-l-yl-butan-l-one

i) 4-Chloro-l-(4-methoxy-2-methyl-phenyl)-butan-l-one

2.46 ml (21.95 mmol) 4-Chloro-butyryl chloride dissolved in 5 ml 1,2- dichloroethane were added dropwise to an suspension of 2.67 g (20.0 mmol) aluminum chloride in 20 ml 1,2-dichloroethane (T < 20⁰C!). The reaction mixture was stirred for 10 minutes at 20⁰C. After the dropwise addition of 2.4 g (19.65 mmol) l-Methoxy-3-methyl-benzene dissolved in 3 ml 1,2-dichloroethane it was again stirred at 20⁰C for 1 hour. The reaction mixture was poured on ice. The layers were separated and the aqueous layer was extracted twice with 1,2-dichloroethane. The combined organic layers were washed with 50 ml water, 50 ml NaOH-solution (2%) and 50 ml water. The solvent was evaporated and the residue was stirred in

150 ml n-heptane. Suction filtration gave 1.10 g (25%) of the title compound as a white solid.

¹H-NMR^OOHz, [DJDMSO): δ = 2.04 (quintet, 2H, CH₂-CH₂-CH₂), 2.45 (s, 3H, Ar-CH₃), 3.05 (t, 2H, CH₂CO), 3.69 (t, 2H, CH₂-Cl), 3.81 (s, 3H, OCH₃), 6.85 (s, IH, Ar), 6.87 (d, IH, Ar), 7.84 (d, IH, Ar)

ii) l-(4-Methoxy-2-methyl-phenyl)-4-[l,2,3]triazol-l-yl-butan-l-one 1.00 g (4.41 mmol) 4-Chloro-l-(4-methoxy-2-methyl-phenyl)-butan-l-one was mixed with 20 ml (345.2 mmol) IH-[1, 2,3 ]Triazole and 16 mg (0.1 mmol) potassium iodide. The solution was stirred at 100⁰C for 6 hours. The remaining triazole was distilled off and the residue was dissolved in 100 ml dichloromethane and extracted with 50 ml water. The organic layer was dried and evaporated. The residue was stirred in 10 ml n-heptane. Suction filtration gave 660 mg (58%) of the title compound as a white solid. lH-NMR(400Hz, [DJDMSO): δ = 2.13 (quintet, 2H, CH₂-CH₂-CH₂), 2.44 (s, 3H, Ar-CH₃), 2.93 (t, 2H, CH₂CO), 3.81 (s, 3H, OCH₃), 4.44 (t, 2H, CH₂-triazole), 6.85

(m, 2H, Ar), 7.73 (s, IH, triazole), 7.78 (d, IH, Ar), 8.16 (d, IH, Ar)

iii) l-(4-Hydroxy-2-methyl-phenyl)-4-[ 1,2,3] triazol-1-yl-butan-l-one 8.5 g (29.28 mmol) l-(4-Methoxy-2-methyl-phenyl) -4- [1,2,3 ] triazol- 1 -yl-butan- 1- one were mixed with 80 ml hydrobromic acid solution (48%) and the mixture was stirred at 90⁰C for 16 hours. The solution was cooled and adjusted to pH 13.6 by adding 4 N NaOH-solution. After the extraction with 60 ml toluene the aqueous layer was adjusted to pH 6.3 by adding 6 N hydrochloric acid. A precipitate was formed. It was filtered off and stirred again in 100 ml water to remove the acid. After suction filtration the solid was dried to yield 3.95 g (66 %) of the title compound as a white solid.

Η-NMR(400Hz, [DJDMSO): δ = 2.12 (quintet, 2H, CH₂-CH₂-CH₂), 2.40 (s, 3H, Ar-CH₃), 2.89 (t, 2H, CH₂CO), 4.44 (t, 2H, CH^-triazole), 6.66 (m, 2H, Ar), 7.71 (m, 2H, Ar and triazole), 8.15 (s, IH, triazole), 10.11 (s, IH, OH)

Preparation of 6'-Chloro-5-chloromethyl-6-methyl-[2,3']bipyridine

i) l-(6-Chloro-pyridin-3-yl)-3-dimethylamino-propenone

2.0 g (12.47 mmol) l-(6-Chloro-pyridin-3-yl)-ethanone and 4.74 g (37.41 mmol) Dimethoxymethyl-dimethyl-amine were mixed and stirred under Argon at 100⁰C for 24 hours. The solvent was evaporated and the crystalline residue was treated with butylmethylether and stirred for 30 minutes. The solid was isolated by suction and washed three times with t-butylmethylether. The solid was stirred under ice cooling in 80 ml n-heptane. After suction filtration and washing with n-heptane 1.85 g (66%) of the title compound was isolated as an orange powder. The crude product was used in the next step without further purification. MS: 211.1 (ESI+) 1H-NMR^OOHz, [DJDMSO): δ = 2.95 (s, 3H, N-CH₃), 3.17 (s, 3H, N-CH₃), 5.85

(d, IH, CH-N), 7.57 (d, IH, 5H-pyridine), 7.78 (d, IH, CO-CH), 8.26 (d, IH, 4H- pyridine), 8.89 (s, IH, 2H-pyridine)

ii) 6'-Chloro-6-methyl-[2,3']bipyridinyl-5-carboxylic acid ethyl ester l-(6-Chloro-pyridin-3-yl)-3-dimethylamino-propenone 1.84 g (8.73 mmol) was dissolved in 10 ml acetic acid. After the addition of 3-oxo-butyric acid ethyl ester

1.33 ml (10.48 mmol) and ammonium acetate 875 mg (11.35 mmol) the mixture was stirred under argon for 6 hours at 125°C. After 12 hours at room temperature (r.t.) and evaporation the residue was mixed with ethyl acetate and water. The organic layer was separated and the water was extracted with ethyl acetate. The combined organic layers were washed with sodium carbonate solution (until pH 9 was reached) and water, dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica gel (ethyl acetate/n-heptane 3:1) to yield 1.32 g (53%) of the title compound as a white powder. MS: 277.1 (ESI+) Η-NMR(400Hz. [DJDMSO): δ = 1.35 (t, 3H, CH₂-CH₁), 2.80 (s, 3H, CH₃- pyridine), 4.34 (q, 2H, CH₂-CH₃) 7.66 (d, IH, 5H-pyridine-Cl), 8.04 (d, IH, 4H- pyridine-CH₃), 8.27 (d, IH, 3H-pyridine-CH₃), 8.55 (d, IH, 4H-pyridine-Cl), 9.14 (s, IH, 2H-pyridine-CH₃)

iii) (6'-Chloro-6-methyl-[2,3']bipyridinyl-5-yl)-methanol

Lithium aluminium hydride 1.41 g (37.18 mmol) was suspended in 55 ml tetrahydrofuran and it was stirred for 20 min. Under cooling 6'-Chloro-6-methyl- [2,3']bipyridinyl-5-carboxylic acid ethyl ester 5.30 g (18.58 mmol) dissolved in 55 ml tetrahydrofuran were added dropwise and the reaction mixture was stirred for 2 hours at 0⁰C. 68 ml brine was added and it was stirred at 0⁰C for 1 hour. The solution was carefully adjusted to pH 5 by adding cone, hydrochloric acid. A white precipitate (inorganic salts) was filtered of by suction and washed with tetrahydrofuran (THF). The THF was evaporated and the remaining water was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated to yield 2.95 g (65%) of the title compound as a white powder. The crude product was used in the next step without further purification. MS: 235.2 (ESI+) 1H-NMR^OOHz, [D_ά1 DMSO): δ = 2.50 (s, 3H, CH₃) under solvent, 4.56 (d, 2H, CH₂), 5.33 (t, IH, OH), 7.61 (d, IH, 5-H-pyridine-Cl), 7.83 (d, IH, 4-H-pyridine-

CH₃), 7.90 (d, IH, 3-H-pyridine-CH₃), 8.48 (d, IH, 4-H-pyridine-Cl), 9.07 (s, IH, 2-H-pyridine-Cl)

v) 6'-Chloro-5-chloromethyl-6-methyl-[2,3']bipyridine (6'-Chloro-6-methyl-[2,3']bipyridinyl-5-yl)-methanol 26 g (106.35 mmol) were dissolved in 1.5 1 dichloromethane, the solution was cooled to 0⁰C and thionyl chloride 15.43 ml (212.68 mmol) was added and it was stirred at 0°C for 4 hours and 12 hours at r.t.. The reaction mixture was poured on 1.5 1 ice and sodium carbonate solution was added under vigorous stirring. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica gel (ethyl acetate/n-heptane 1:5) to yield 13.03 g (47%) of the title compound as a light yellow powder. MS: 254.09 (ESI+) Η-NMR(400Hz, [DJDMSO): δ = 2.65 (s, 3H, CH₃), 4.89 (s, 2H, CH₂), 7.63 (d, IH, 5-H-pyridine-Cl), 7.94 (s, 2H, 4-H-pyridine-CH₃ and 3-H-pyridine-CH₃), 8.49

(d, IH, 4-H-pyridine-Cl), 9.09 (s, IH, 2-H-pyridine-Cl) Preparation of l-[4-(6'-Chloro-6-methyl-[2,3']bipyridinyl-5-ylmethoxy)-2- methyl- phenyl] -4- [ 1 ,2,3 ] triazol- 1-yl-butan- 1 -one

l-(4-Hydroxy-2-methyl-phenyl)-4-[l₎2,3]triazol-l-yl-butan-l-one 413 mg (1.63 mmol) was dissolved in 15 ml N,N-dimethylformamide (DMF) and the solution was cooled to 0⁰C. Sodium hydride dispersion 65 mg (60% in mineral oil, 1.63 mmol) was added and it was stirred for 30 minutes. After the addition of 6'-Chloro- 5-chloromethyl-6-methyl-[2,3']bipyridine 100 mg (0.35 mmol) the reaction mixture was stirred at r.t. for 60 hours. It was quenched with 39 ml water and stirred for 1 hour. The product was isolated by suction and washed with a small amount of tert.-butylether. The solid was dried to give 643 mg (81%) of the title compound as a white solid. MS: 462.29 (ESI+)

¹H-NMR^OOHz, [DJDMSO): δ = 2.13 (quintet, 2H, CH₂-CH2-triazole), 2.45 (s, 3H, Ar-CH₃), 2.61 (s, 3H, pyridine-CH₃), 2.93 (t, 2H, CO-CH₂-CH₂), 4.44 (t, 2H, CHa-CHa-triazole), 5.28 (s, 2H, CH₂-O), 6.99 (d, 2H, Ar), 7.64 (d, IH, pyridine),

7.72 (s, IH, triazole), 7.81 (d, IH, Ar), 7.94 (m, 2H, pyridine), 8.16 (s, IH, triazole), 8.51 (d, IH, 4-H-pyridine-Cl), 9.10 (s, IH, 2-H-pyridine-Cl)

Example 2 l-[4-(6'-Chloro-6-methyl-[2,3']bipyridinyl-5-ylmethoxy)-2-methyl-phenyl]-4- [1,2,3] triazol- 1 -yl-butan- 1 -ol

l-[4-(6'-Chloro-6-methyl-[2,3']bipyridinyl-5-ylmethoxy)-2-methyl-phenyl]-4- [ 1,2,3] triazol- 1 -yl-butan- 1 -one 400 mg (0.87 mmol) were dissolved in 40 mL THF. After the addition of sodium borohydride 82 mg (2.16 mmol) and 20 mL propan- 2-ol were added under cooling. The reaction mixture stirred for 3 hours at r.t. Again sodium borohydride 82 mg (2.16 mmol) was added and it was stirred at r.t. for 12 hours. The reaction mixture was adjusted to pH 3 by adding 1 N hydrochloric acid. It was evaporated to dryness. The residue was purified by chromatography on silica gel (dichloromethane/methanol 100:2.5) and by HPL chromatography to yield 129 mg (32%) of the title compound as a white solid. MS: 464.40 (ESI+)

¹H-NMR^OOHz, [DgIDMSO): δ = 1.48 (quintet, 2H, CH₂-CH₂-triazole), 1.90 (m, 2H, CH-CH₂), 2.22 (s, 3H, Ar-CH₃), 2.60 (s, 3H, pyridine-CH₃), 4.40 (t, 2H, CH₂- triazole), 4.69 (q, IH, CH), 5.03 (d, IH, OH), 5.16 (s, 2H, CH₂-O), 6.83 (s, IH, Ar), 6.87 (d, IH, Ar), 7.30 (d, IH, Ar), 7.64 (d, IH, pyridine), 7.70 (s, IH, triazole), 7.89 (m, 2H, pyridine), 8.10 (s, IH, triazole), 8.50 (d, IH, 4-H-pyridine-Cl), 9.09 (s, IH, 2-H-pyridine-Cl)

Example 3

6^f-Chloro-5-[4-(l-metfioxy-4-[l,2,3]triazol-l-yl-butyl)-3-methyl- phenoxymethyl]-6-methyl-[2,3']bipyridine

A solution of 60 mg (0.13 mmol) l-[4-(6'-Chloro-6-methyl-[2,3']bipyridinyl-5- ylmethoxy)-2-methyl-phenyl]-4-[l,2,3]triazol-l-yl-butan-l-ol in 10 ml methanol was treated with 96 μL (1.29 mmol) of trifluoro-acetic acid and stirred under nitrogen in a microwave at 100⁰C and 3 bar for 45 minutes. The solvent was evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed with sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated. The colourless oil 61.2 mg (99%) was used without further purification. MS: 478.45 (ESI+)

¹H-NMRUOOHz, f D.I DMSO): δ = 1.54 (m, 2H, CH₂-CH_rtriazole), 1.85 (m, 2H, CH₂-CH₂-triazole), 2.25 (s, 3H, Ar-CH₃), 2.60 (s, 3H pyridine-CH₃), 3.08 (s, 3H, OCH₃),4.37 (m, 3H, 0-CH-CH₂), 5.16 (s, 2H, OCH₂), 6.90 (m, 2H, Ar), 7.16 (d, IH, Ar), 7.63 (d, IH, pyridine), 7.70 (s, IH, triazole), 7.93 (m, 2H, pyridine), 8.09 (s, IH, triazole), 8.50 (d, IH, 4-H-pyridine-Cl), 9.10 (s, IH, 2-H-pyridine-Cl)

Example 4

6'-Chloro-6-methyl-5-[4-(4-[l,2,3]triazol-l-yl-butyl)-phenoxymethyl]-

[2,3']bipyridine

41 mg (0.19 mmol) 4-[4-(2,3-Dihydro-[l,2,3]triazol-l-yl)-butyl]-phenol (WO 2001077107) were dissolved in 2 ml DMF and the resulting solution was cooled to

0⁰C. 8 mg (0.19 mmol) sodium hydride was added and the reaction mixture was stirred at 0⁰C for 30 minutes. After the addition of 50mg (0.19 mmol) 6'-Chloro-5- chloromethyl-6-methyl-[2,3']bipyridine the reaction mixture was stirred at r.t. for 12 hours. It was quenched with 4 ml water and stirred for 1 hour. The formed precipitate was isolated by suction and washed with 2 ml water, 2 ml n-heptane and

2 ml diethylether. The white solid was dried at 40⁰C to yield 69 mg (83%) of the title compound. MS: 434.30 (ESI+) ¹H-NMRUOOHz, [DgI DMSO): δ = 1.49 (quintet, 2H, CH₂-CH₂-CH₂-IHaZoIe), 1.82 (quintet, 2H, CH₂-CH₂-CH₂-IOaZoIe), 2.52 (m, 2H, Ar-CH₂), 2.60 (s, 3H pyridine- CH₁), 4.40 (t, 2H, CH₂-triazole), 5.16 (s, 2H, OCH₂), 6.97 (m, 2H, Ar), 7.11 (d, 2H, Ar), 7.64 (d, IH, pyridine), 7.70 (s, IH, triazole), 7.91 (m, 2H, pyridine), 8.11 (s, IH, triazole), 8.51 (d, IH, 4-H-pyridine-Cl), 9.10 (s, IH, 2-H-pyridine-Cl)

Example 5

6'-Chloro-6-methyl-5-[3-methyl-4-(4-[ 1,2,3] triazol-l-yl-butyl)-phenoxymethyl]-

[2,3']bipyridine

44 mg (0.19 mmol) 4-[4-(2,3-Dihydro-[l,2,3]triazol-l-yl)-butyl]-3-methyl-phenol (US 2005203064 ) were dissolved in 2 ml DMF and the resulting solution was cooled to 0⁰C. 8 mg (0.19 mmol) sodium hydride was added and the reaction mixture was stirred at 0⁰C for 30 minutes. After the addition of 50 mg (0.19 mmol) 6'-Chloro-5-chloromethyl-6-methyl-[2,3']bipyridine the reaction mixture was stirred at r.t. for 12 hours. It was quenched with 4 ml water and stirred for 1 hour. The formed precipitate was isolated by suction and washed with 2 ml water, 2 ml n- heptane and 2 ml diethylether. The white solid was dried at 40⁰C to yield 71 mg (81%) of the title compound. MS: 448.3 (ESI+) lH-NMR(400Hz, [DJDMSO): δ = 1.43 (quintet, 2H,

1.86 (quintet, 2H, CH₂-CH₂-CH₂-triazole), 2.21 (s, 3H, Ar-CH₃), under solvent (Ar-

CH₂), 2.60 (s, 3H pyridine-CHs), 4.41 (t, 2H, CH₂-triazole), 5.14 (s, 2H, OCH₂), 6.80 (d, IH, Ar), 6.86 (s, IH, Ar), 7.02 (d, 2H, Ar), 7.64 (d, IH, pyridine), 7.71 (s, IH, triazole), 7.91 (m, 2H, pyridine), 8.12 (s, IH, triazole), 8.50 (d, IH, 4-H- pyridine-Cl), 9.10 (s, IH, 2-H-pyridine-Cl)

Example 6 l-[2-Methyl-4-(6-methyl-6'-trifluoromethyl-[2_>3']bipyridinyl-5-ylmethoxy)- phenyl] -4- [ 1 ,2,3] triazol- 1 -yl-butan- 1 -one

Preparation of 5-Chloromethyl-6-methyl-6'-trifluoromethyl-[2,3']bipyridine

i) l-(6-Trifluoromethyl-pyridin-3-yl)-ethanone Magnesium chloride 3.18 g (33.4 mmol) was suspended in 160 ml toluene. After the addition of triethylamine 16.63 ml (119.3 mmol) and malonic acid dimethyl ester 6.58 ml (57.3 mmol) the reaction mixture was stirred for 2.5 hours under light cooling. 6-Trifluoromethyl-nicotinoyl chloride was dissolved in 15 ml toluene and added dropwise under cooling to the reaction mixture. After stirring for 2 hours the mixture was acidified with cone, hydrochloric acid (15 ml). A white precipitate was formed which was dissolved by the addition of water. The water was separated and extracted one time with ethyl acetate and one time with dichloromethane. The combined organic layers were evaporated and the residue was dissolved in 52 ml dimethyl sulfoxide (DMSO) and 2 ml water. The obtained solution was stirred at

155 ⁰C for 2.5 hours. After cooling and the addition of 100 ml ice water it was stirred for 15 minutes. The product was isolated by suction and washed with ice water (3 x 15 ml). The solid was dried at 40⁰C to give 7.11 g (79%) of the title compound as white solid. MS: 189.90 (ESI+)

¹H-NMR^OOHz, [DJDMSO): δ = 2.69 (s, 3H, CH₃), 8.08 (d, IH, 5-H-pyridine), 8.56 (d, IH, 4-H-pyridine), 9.26 (s, IH, 2-H-pyridine)

ii) 3-Dimethylamino-l-(6-trifluoromethyl-pyridin-3-yl)-propenone l-(6-Trifiuoromethyl-pyridin-3-yl)-ethanone 7.0 g (37.01 mmol) and dimethoxymethyl-dimethyl-amine 14.75 ml (111.03 mmol) were mixed and stirred under argon at 100⁰C for 12 hours. After evaporation the residue was purified by chromatography on silica gel (ethyl acetate) to yield 6.65 g (74%) of the title compound as an orange powder. MS: 245.1 (ESI+) Η-NMR(400Hz, rOsl DMSO): δ = 2.97 (s, 3H, CH₃), 3.19 (s, 3H, CH₃), 5.91 (d,

IH, CO-CH), 7.82 (d, IH, CH-N), 7.96 (d, IH, 5-H-pyridine), 8.47 (d, IH, 4-H- pyridine), 9.20 (s, IH, 2-H-pyridine)

iii) 6-Methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-carboxylic acid ethyl ester 3-Dimethylamino-l-(6-trifluoromethyl-pyridin-3-yl)-propenone 6.60 g (27.02 mmol) was dissolved in 30 ml acetic acid. After the addition of 3-oxo-butyric acid ethyl ester 4.10 ml (32.43 mmol) and ammonium acetate 2.70 g (35.13 mmol) the mixture was stirred under argon for 6 hours at 125⁰C. After 12 hours at r.t. again 3- oxo-butyric acid ethyl ester 0.41 ml (3.24 mmol) were added and it was stirred at 125°C for 12 hours. After evaporation the residue was mixed with ethyl acetate and water. The organic layer was separated and the water was extracted with ethyl acetate. The combined organic layers were washed with sodium carbonate solution (until pH9 was reached) and water, dried over sodium sulphate and evaporated to yield 7.77 g (93%) of the title compound as a yellow solid. MS: 311.19 (ES1+) Η-NMR(400Hz, fPgiDMSO): δ = 1.36 (t, 3H, CH₂-CH₁), 2.83 (s, 3H, CH₃), 4.37

(q, 2H, CH₂-CH₃), 8.06 (d, IH, 5-H-pyridine-CH₃), 8.15 (d, IH, 5-H-pyridine- CF₃), 8.33 (d, IH, 4-H-pyridine-CH₃), 8.77 (d, IH, 4-H-pyridine-CF₃), 9.48 (s, IH, 2-H-pyridine-CF₃)

iv) (6-Methyl-6'-trifluoromethyl- [2,3']bipyridinyl-5-yl)-methanol Lithium aluminium hydride (1.88 g (49.63 mmol) was suspended in 80 ml THF and it was stirred for 20 minutes. Under cooling 6-Methyl-6'-trifluoromethyl-

[2,3']bipyridinyl-5-carboxylic acid ethyl ester 7.70 g (24.82 mmol) dissolved in 80 ml THF was added dropwise and the reaction mixture was stirred for 2 hours at 0⁰C. 100 ml brine was added and it was stirred at 0⁰C for 1 hour. The solution was carefully adjusted to pH 5 by adding cone, hydrochloric acid. A white precipitate (inorganic salts) was filtered of by suction and washed with THF. The THF was evaporated and the remaining water was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated to yield 6.54 g (98%) of the title compound as a yellow powder. The crude product was used in the next step without further purification. MS: 269.14 (ESI+)

¹H-NMR^OOHz, fPJDMSO): δ = (s, 3H, CH₃) under solvent, 4.59 (d, 2H, CH₂), 5.37 (t, IH, OH), 7.89 (d, IH, 4-H-pyridine-CH₃), 8.00 (d, 2H, 5-H-pyridine-CH₃ and 5-H- pyridine-CF₃), 8.70 (d, IH, 4-H-pyridine-CF₃), 9.42 (s, IH, 2-H- pyridine-CF₃)

v) 5-Chloromethyl-6-methyl-6'-trifluoromethyl-[2,3']bipyridine

(6-Methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-yl)-methanol 4.3 g (16.03 mmol) were dissolved in 250 ml dichloromethane, the solution was cooled to 0⁰C and thionyl chloride 2.32 ml (32.06 mmol) was added and it was stirred at 0⁰C for 3.5 hours. The reaction mixture was poured on 200 ml ice and sodium carbonate solution was added under vigorous stirring. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated to yield 4.45 g (94 %) of the title compound as a ochre solid. MS: 287.26 (ESI+) Η-NMR(400Hz, fPJDMSO): δ = 2.68 (s, 3H, CH₃), 4.92 (s, 2H, CH₂), 8.03 (m,

3H, 5-H-pyridine-CF₃ and 4,5-H-pyridine-CH₃), 8.72 (d, IH, 4-H-pyridine-CF₃), 9.43 (s, IH, 2-H-pyridine-CF₃) Preparation of 1- [2-Methyl-4-(6-methyl-6'-trifluoromethyl- [2,3']bipyridinyl-5- ylmethoxy)-phenyl] -4- [ 1 ,2,3 ] triazol- 1 -yl-butan- 1 -one l-(4-Hydroxy-2-methyl-phenyl)-4-[l,2,3]triazol-l-yl-butan-l-one 86 mg (0.35 mmol) was dissolved in 4 ml DMF and the solution was cooled to 0⁰C. Sodium hydride dispersion 14 mg (60% in mineral oil, 0.35 mmol) was added and it was stirred for 30 minutes. After the addition of 5-Chloromethyl-6-methyl-6'- trifluoromethyl-[2,3']bipyridine 100 mg (0.35 mmol) the reaction mixture was stirred at r.t. for 12 hours. It was quenched with 10 ml water and stirred for 30 minutes. The product was isolated by suction and washed with small amounts of diisopropyl ether. The solid was dried at 40⁰C to give 137 mg (79%) of the title compound as an off-white solid. MS: 496.45 (ESI+)

¹H-NMR^OOHz, [DgIDMSO): 6 = 2.12 (quintet, 2H, CHj>-CH2-triazole), 2.46 (s, 3H, Ar-CH₃), 2.64 (s, 3H, pyridine-CH₃), 2.94 (t, 2H, CO-CH₂-CH₂), 4.45 (t, 2H, CH₂-CH₂-IHaZoIe), 5.31 (s, 2H, CH₂-O), 7.03 (d, 2H, O-Ar), 7.73 (s, IH, triazole),

7.81 (d, IH, O-Ar), 8.03 (m, 3H, 5-H-pyridine-CF₃ and 4,5-H-pyridine-CH₃), 8.16 (s, IH, triazole), 8.72 (d, IH, 4-H-pyridine-CF₃), 9.44 (s, IH, 2-H-pyridine-CF₃)

Example 7 l-[2-Methyl-4-(6-methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)- phenyl] -4- [1,2,3] triazol- 1 -yl-butan- l-ol

l-[2-Methyl-4-(6-methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)- phenyl] -4- [1,2,3] triazol- 1-yl-butan-l -one [Example 6] 300 mg (0.61 mmol) were dissolved in 45 mL THF. After the addition of sodium borohydride 69 mg (1.83 mmol) and 21 mL propan-2-ol were added under cooling. The reaction mixture was stirred for 48 hours at r.t. Again sodium borohydride 23 mg (0.61 mmol) were added and it was stirred at r.t. for 12 hours. The reaction mixture was adjusted to pH 6-7 by adding ammonium chloride solution and stirring for 1 hour. The organic solvent was removed and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica gel (ethyl acetate/n-heptane 5:1) to yield 227 mg (76%) of the title compound as a white powder.

MS: 498.31 (ESI+) Η-NMR(400Hz, [DgIDMSO): δ = 1.48 (quintet, 2H, Chb-CHrtriazole), 1.88 (m, 2H, CH-CH₂), 2.22 (s, 3H, Ar-CH₃), 2.63 (s, 3H, pyridine-CH₃), 4.40 (t, 2H, CH₂- triazole), 4.70 (q, IH, CH), 5.03 (d, IH, OH), 5.18 (s, 2H, CH₂-O), 6.84 (s, IH, O- Ar), 6.88 (d, IH, O-Ar), 7.31 (d, IH, O-Ar), 7.70 (s, IH, triazole), 7.95 (d, IH, pyridine-CH₃), 8.03 (d, 2H, 5-H-pyridine-CF₃ and pyridine-CH₃), 8.10 (s, IH, triazole), 8.71 (d, IH, 4-H-pyridine-CF₃), 9.44 (s, IH, 2-H-pyridine-CF₃)

Example 8 5-[4-(l-Methoxy-4-[l,2,3]triazol-l-yl-butyl)-3-methyl-phenoxymethyl]-6-methyl-

6'-trifluoromethyl-[2,3']bipyridine

A solution of 60 mg (0.12 mmol) l-[2-methyl-4-(6-methyl-6'-trifluoromethyl- [2,3']bipyridinyl-5-ylmethoxy)-phenyl]-4-[l,2,3]triazol-l-yl-butan-l-ol [Example 7] in 10 ml methanol was treated with 90 μL (1.2 mmol) of trifluoro-acetic acid and stirred under nitrogen in a microwave at 100⁰C and 3 bar for 30 min. The solvent was evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed with sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated. The semisolid residue 29 mg (47%) was used without further purification.

MS: 512.20 (ESI+)

Η-NMR(400Hz, [Dg]DMSO): 5 = 1.54 (m, 2H, CH₂-CH₂- triazole), 1.80 (m, 2H, CH₂-CH₂-triazole), 2.26 (s, 3H, Ar-CH₃), 2.63 (s, 3H pyridine-CH₃), 3.08 (s, 3H, OCH₃),4.38 (m, 3H, 0-CH-CH₂), 5.19 (s, 2H, OCH₂), 6.91 (m, 2H, O-Ar), 7.17(d, IH, O-Ar), 7.70 (s, IH, triazole), 7.97 (d, IH, pyridine-CH₃), 8.04 (m, 2H, 5-H- pyridine-CF₃ and pyridine-CH₃), 8.10 (s, IH, triazole), 8.72 (d, IH, 4-H-pyridine- CF₃), 9.44 (s, IH, 2-H-pyridine-CF₃)

Example 9

6-Methyl-5-[3-methyl-4-(4-[l,2,3]triazol-l-yl-but-l-enyl)-phenoxymethyl]-6'- trifluoromethyl- [ 2,3 ' ] bipyridine

l-[2-Methyl-4-(6-methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)- phenyl]-4-[l,2,3]triazol-l-yl-butan-l-one [Example 7] 100 mg (0.2 mmol) were dissolved in 15 mL tetrahydrofuran. After the addition of sodium borohydride 15 mg (0.39 mmol) and 7 mL propan-2-ol were added under cooling. The reaction mixture stirred for 48 hours at r.t. Again sodium borohydride 8 mg (0.2 mmol) were added and it was stirred at r.t. for 12 hours. The reaction mixture was adjusted to pH 3 by adding 1 N hydrochloric acid. The solvent was removed and the residue was purified by chromatography on silica gel (dichloromethane/methanol 100:3) to yield 27 mg (28%) of the title compound as a white solid. MS: 480.33 (ESI+)

Η-NMR(400HZ, [DJDMSO): δ = 2.12 (s, 3H, Ar-CH₃), 2.68 (s, 3H, pyridine- CH₃), 2.76 (m, 2H, CH=CH-CH₂), 4.54 (t, 2H, CH₂-triazole), 5.2 (s, 2H, CH₂-Cr), 5.94 (m, IH, CH₃-Ar-CH=CH), 6.47 (d, IH, CH₃-Ar-CH=CH), 6.88 (m, 2H, O- Ar), 7.31 (d, IH, O-Ar), 7.71 (s, IH, triazole), 7.95 (d, IH, pyridine-CH₃), 8.03 (d,

2H, 5-H-pyridine-CF₃ and pyridine-CH₃), 8.15 (s, IH, triazole), 8.72 (d, IH, 4-H- pyridine-CF₃), 9.44 (s, IH, 2-H-pyridine-CF₃)

Example 10 l-[4-(6-Methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl]-4- [ 1 ,2,3 ] triazol- 1 -yl-butan- 1 -one

Preparation of l-(4-Hydroxy-phenyl)-4- [1,2,3] triazol-1-yl-butan-l-one

i) l-(4-Methoxy-phenyl)-4-[ 1,2,3] triazol-1-yl-butan-l-one

100 g (0.47 mol) 4-Chloro-l-(4-methoxy-phenyl)-butan-l-one and 1.6 g (9.64 mmol) potassium iodide were mixed with 480 ml (8.4 mol) lH-[l,2,3]Triazole and the mixture was stirred for 6 hours at 100°C. The remaining IH- [1,2,3] Triazole was removed by destination and the residue was dissolved in dichloromethane. The organic layer was washed with 200 ml water, dried over sodium sulfate and evaporated. Recrystallisation (ethyl acetate/n-heptane) gave 85.4 g (53 %) of the title compound as a brown solid. Η-NMR(400Hz, [DJDMSO): δ = 2.14 (quintet, 2H, CH₂-CH₂-CH₂), 2.99 (t, 2H,

CO-CH₂), 3.84 (s, 3H, 0-CH₃), 4.46 (t, 2H, CH₂-triazole), 7.03 (d, 2H, Ar), 7.73 (s, IH, triazole), 7.91 (d, 2H, Ar), 8.16 (s, IH, triazole)

ii) 1- (4- Hydroxy- phenyl)-4-[ 1,2,3] triazol-1-yl-butan-l-one

12.5 g (50.96 mmol) l-(4-Methoxy-phenyl) -4- [1,2,3] triazol-1-yl-butan-l-one were dissolved in 72 ml hydrobromic acid (48%) and the solution was stirred for 12 h at

80 - 90⁰C. After cooling to r.t. the solution was adjusted to pH 13.6 by adding 4 N NaOH. The aqueous layer was extracted with toluene and then adjusted to pH 6.3 by adding 6 N hydrochloric acid. The acidified layer was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was stirred in water and suction filtration gave a white solid. Drying at 50⁰C yielded 8.8 g (75%) of the title compound.

¹H-NMRUOOHz, [DJDMSO): δ = 2.12 (quintet, 2H, CH₂-CH₂-CH₂), 2.94 (t, 2H, CO-CH₂), 4.45 (t, 2H, CH₂-triazole), 6.85 (d, 2H, Ar), 7.73 (s, IH, triazole), 7.82 (d, 2H, Ar), 8.16 (s, IH, triazole), 10.33 (br, IH, OH) l-[4-(6-Methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl]-4- [ 1 ,2,3 ] triazol- 1 -yl-butan- 1 -one l-(4-Hydroxy-phenyl)-4-[l,2,3]triazol-l-yl-butan-l-one 402 mg (1.74 mmol) was dissolved in 20 ml DMF and the solution was cooled to 0⁰C. Sodium hydride dispersion 70 mg (60% in mineral oil, 1.74 mmol) was added and it was stirred for

30 minutes. After the addition of 5-Chloromethyl-6-methyl-6'-trifluoromethyl- [2,3']bipyridine 500 mg (1.74 mmol) the reaction mixture was stirred at r.t. for 12 hours. It was quenched with 50 ml water and stirred for 30 minutes. The product was isolated by suction and washed with small amounts of diisopropyl ether. The solid was dried at 40⁰C to give 689 mg (82%) of the title compound as a light brown solid.

MS: 482.40 (ESI+)

¹H-NMR^OOHz, f DJ DMSO): 6 = 2.15 (quintet, 2H, CHjrCH2-triazole), 2.64 (s, 3H, pyridine-CHj), 2.99 (t, 2H, CO-CH₂-CH₂), 4.46 (t, 2H, CH₂-CHi-triazole), 5.34 (s, 2H, CH₂-O), 7.20 (d, 2H, O-Ar), 7.73 (s, IH, triazole), 7.94 - 8.06 (m, 5H,

O-Ar, 3,5-H-pyridine-CF₃ and 4,5-H-pyridine-CH₃), 8.17 (s, IH, triazole), 8.72 (d, IH, 4-H-pyridine-CF₃), 9.44 (s, IH, 2-H-pyridine-CF₃)

Example 11 l-[4-(6-Methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl]-4- [l,2,3]triazol-l-yl-butan-l-ol

l-[4-(6-Methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl]-4- [ 1,2,3] triazol- 1 -yl-butan- 1 -one [Example 10] 500 mg (1.04 mmol) were dissolved in 500 mL THF. After the addition of sodium borohydride 79 mg (2.08 mmol) and 50 mL propan-2-ol were added under cooling. The reaction mixture stirred at r.t. The reaction mixture was acidified by adding 1 N hydrochloric acid. The solvent was removed and the residue was purified by chromatography on silica gel (dichloromethane/methanol 100:2). After stirring in diisopropylether and suction 237 mg (47%) of the title compound were obtained as a white solid. MS: 484.18 (ESI+) Η-NMR(400Hz, f DJ DMSO): δ = 1.51 (quintet, 2H, CH^-CHrtriazole), 1.79 (m,

2H, CH-CH₂), 2.63 (s, 3H, pyridine-CH₃), 4.37 (t, 2H, CH^-triazole), 4.51 (q, IH, CH), 5.15 (d, IH, OH), 5.20 (s, 2H, CH₂-O), 7.02 (d, 2H, O-Ar), 7.23 (d, 2H, O- Ar), 7.70 (s, IH, triazole), 7.96 (d, IH, pyridine-CH₃), 8.03 (d, 2H, 5-H-pyridine- CF₃ and pyridine-CH₃), 8.09 (s, IH, triazole), 8.71 (d, IH, 4-H-pyridine-CF₃), 9.44 (s, IH, 2-H-pyridine-CF₃) Example 12

5- [4- ( 1 -Methoxy-4- [1,2,3] triazol- 1 -yl-butyl)-phenoxymethyl] -6-methyl-6'- trifluoromethyl- [2,3']bipyridine

A solution of 30 mg (0.12 mmol) l-[4-(6-Methyl-6'-trifluoromethyl- [2,3']bipyridinyl-5-ylmethoxy)-phenyl] -4- [1,2,3] triazol- 1-yl-butan-l-ol [Example

11] in 5 ml methanol was treated with 46 μL (1.24 mmol) of trifluoro-acetic acid and stirred under nitrogen in a microwave at 100⁰C and 3 bar for 45 min. The solvent was evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed with sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated to yield 70 mg of the title compound as a white solid. MS: 498.36 f ESI+) 1H-NMRUOOHz, [DJDMSO): δ = 1.45 - 1.84 (m, 4H, CH-CH₂-CH₂), 2.63 (s, 3H pyridine-CH₃), 3.07 (s, 3H, OCH₃),4.10 (t, IH, O-CH), 4.37 (t, 2H, CH₂-triazole),

5.21 (s, 2H, OCH₂), 7.06 (d, 2H, O-Ar), 7.21 (d, 2H, O-Ar), 7.69 (s, IH, triazole), 7.97 (d, IH, pyridine-CH₃), 8.04 (m, 2H, 5-H-pyridine-CF₃ and pyridine-CH₃), 8.08 (s, IH, triazole), 8.72 (d, IH, 4-H-pyridine-CF₃), 9.44 (s, IH, 2-H-pyridine- CF₃)

Example 13

6-Methyl-5-[4-(4-[l,2,3]triazol-l-yl-butyl)-phenoxymethyl]-6'-trifluoromethyl- [2,3']bipyridine

4-[4-(2,3-Dihydro-[ l,2,3]triazol-l-yl)-butyl]-phenol 378 mg (1.74 mmol) was dissolved in 20 ml DMF and the solution was cooled to 0⁰C. Sodium hydride dispersion 70 mg (60% in mineral oil, 1.74 mmol) was added and it was stirred for

30 minutes. After the addition of 5-Chloromethyl-6-methyl-6'-trifluoromethyl- [2,3']bipyridine 500 mg (1.74 mmol) the reaction mixture was stirred at r.t. for 12 hours. It was quenched with 50 ml water and stirred for 30 minutes. The product was isolated by suction and washed three times with diisopropyl ether. The solid was dried at 40⁰C to give 641 mg (79%) of the title compound as an off-white solid.

MS: 468.38 (ESI+)

¹H-NMRUOOHz, [DJDMSO): δ = 1.15 (quintet, 2H, CH₂-CH₂-CH₂-IHaZoIe), 1.84 (quintet, 2H, CH₂-CH₂-CH₂-IHaZoIe), 2.54 (t, 2H, Ar-CH₂), 2.63 (s, 3H, pyridine-CH₃), 4.39 (t, 2H, CH^-triazole), 5.19 (s, 2H, CH₂-O), 6.98 (d, 2H, O-Ar), 7.11 (d, 2H, O-Ar), 7.71 (s, IH, triazole), 7.96 (d, IH, pyridine), 8.03 (m, 2H, pyridine), 8.11 (s, IH, triazole), 8.72 (d, IH, 4-H-pyridine-CF₃), 9.44 (s, IH, 2-H- pyridine-CFa)

Example 14

6-Methyl-5-[3-methyl-4-(4-[l,2,3]triazol-l-yI-butyl)-phenoxymethyl]-6'- trifluoromethyl-[2,3']bipyridine

4-[4-(2,3-Dihydro-[l,2,3]triazol-l-yl)-butyl]-3-methyl-phenol 162 mg (0.7 mmol) were dissolved in 8 ml DMF and the solution was cooled to 0⁰C. Sodium hydride dispersion 28 mg (60% in mineral oil, 0.7 mmol) was added and it was stirred for 30 minutes. After the addition of 5-Chloromethyl-6-methyl-6'-trifluoromethyl- [2,3']bipyridine 200 mg (0.7 mmol) the reaction mixture was stirred at r.t. for 50 hours. It was quenched with 20 ml water and stirred for 1 hour. The product was isolated by suction and washed with diisopropyl ether. The solid was dried at 40⁰C to give 261 mg (75%) of the title compound as an off-white solid. MS: 482.40 (ESI+) Η-NMR(400Hz, [DgIDMSO): δ = 1.41 (quintet, 2H, CH₂-CH₂-CH₂-triazole),

1.85 (quintet, 2H, CH₂-CH₂-CH₂-triazole), 2.51 (t, 2H, Ar-CH₂), 2.62 (s, 3H, pyridine-CH₃), 4.41 (t, 2H, CH₂- triazole), 5.16 (s, 2H, CH₂-O), 6.81 (d, IH, Ar), 6.87 (s, IH, O-Ar), 7.02 (d, 2H, O-Ar), 7.71 (s, IH, triazole), 7.95 (d, IH, pyridine), 8.03 (m, 2H, pyridine), 8.12 (s, IH, triazole), 8.71 (d, IH, 4-H-pyridine-CF₃), 9.44 (s, IH, 2-H-pyridine-CF₃)

Claims

Patent Claims

1. A compound of formula I,

formula I

wherein

R¹ is hydrogen or alkyl;

R² is hydrogen or alkyl;

X¹, X², X³ , X⁴ and X⁵ independently represent N or (CH or C), with the proviso that a least one and not more than two of X¹, X², X³, X⁴ and X⁵ represent N and the remaining of X¹, X², X³, X⁴ and X⁵ represent (CH or C) wherein only one of X¹, X², X³, X⁴ and X⁵ is C;

A is -CH₂-CH₂-, -CH=CH-, -CH(OCH₃)-CH₂-, -CH(OH)-CH₂-, or -

C(O)-CH₂-; and all pharmaceutically acceptable salts thereof.

2. The compounds according to claim 1, wherein R¹ is hydrogen or alkyl;

R² is alkyl;

R³ is fluorine, chlorine or trifluoromethyl;

X¹, X², X³ , X⁴ independently represent CH or C wherein only one of X¹, X², X³ and X⁴ is C; and and X⁵ is N. A compound of formula Ia,

formula Ia

wherein

R , 1 is hydrogen or alkyl;

R ,2 is hydrogen or alkyl;

R³ is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl or trifluoromethoxy; A is -CH₂-CH₂-, -CH=CH-, -CH(OCH₃)-CH₂-, -CH(OH)-CH₂-, or

C(O)-CH₂-; and all pharmaceutically acceptable salts thereof.

4. The compounds according to claim 3, wherein

R¹ is hydrogen or alkyl;

R is alkyl; and

The compounds according to any one of claims 1 to 4, wherein A is -CH₂-CH₂-, -CH(OCH₃)-CH₂- or -CH(OH)-CH₂-.

The compounds according to any one of claims 1 to 4, wherein A is -CH₂-CH₂- or -CH(OCH₃)-CH₂-.

7. The compounds according claim 1 selected from the group consisting of: 6-Methyl-5-[3-methyl-4-(4-[l,2,3]triazol-l-yl-butyl)-phenoxymethyl]-6' trifluoromethyl- [2,3']bipyridine;

6-Methyl-5-[4-(4-[ l,2,3]triazol-l-yl-butyl)-phenoxymethyl]-6'- trifluoromethyl- [2,3 ' ] bipyridine; 6'-Chloro-6-methyl-5-[4-(4- [1,2,3] triazol-1 -yl-butyl)-phenoxymethyl]- [2,3']bipyridine;

6'-Chloro-6-methyl-5-[3-methyl-4-(4-[l,2,3]triazol-l-yl-butyl)- phenoxymethyl ] - [ 2,3 ' ] bipyridine;

6-Methyl-5-[3-methyl-4-((E)-4-[l,2,3]triazol-l-yl-but-l-enyl)- phenoxymethyl]-6'-trifluorornethyl-[2,3']bipyridine;

5- [4- ( 1 -Methoxy-4- [ 1 ,2,3 ] triazol- 1 -yl-butyl)-3-methyl-phenoxymethyl] -6- methyl-6'-trifluoromethyl-[2,3']bipyridine;

5- [4-( 1 -Methoxy-4- [ 1 ,2,3] triazol- 1 -yl-butyl)-phenoxymethyl] -6-methyl-6'- trifluoromethyl-[2,3']bipyridine;

6'-Chloro-5-[4-(l-methoxy-4-[l,2₎3]triazol-l-yl-butyl)-3-methyl- phenoxymethyl]-6-methyl-[2,3']bipyridine;

l-[2-Methyl-4-(6-methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)- phenyl] -4- [ 1 ,2,3] triazol- 1 -yl-butan- 1 -ol;

l-[4-(6-Methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl]-

4- [ 1 ,2,3 ] triazol- 1 -yl-butan- 1 -ol;

l-[4-(6'-Chloro-6-methyl-[2,3']bipyridinyl-5-ylmethoxy)-2-methyl-phenyl]- 4- [1,2,3] triazol- 1 -yl-butan- l-ol;

l-[2-Methyl-4-(6-methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)- phenyl] -4- [ 1 ,2,3] triazol- 1 -yl-butan- 1 -one;

l-[4-(6-Methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl]- 4- [1,2,3] triazol- 1 -yl-butan- 1 -one;

l-[4-(6'-Chloro-6-methyl-[2,3']bipyridinyl-5-ylmethoxy)-2-methyl-phenyl]- 4- [ 1,2,3] triazol- 1-yl-butan-l -one. A process for the manufacture of the compounds of formula I in claim 1, wherein

(a) the compound of formula II

formula II,

wherein R², R³, X¹, X², X³, X⁴ and X⁵ have the significance as given in formula I above in claim 1, is reacted with a compound of formula III

formula III,

wherein R¹ and A have the significance given in formula I above in claim 1, to give the respective compound of formula I;

formula I,

wherein R¹, R², R³, X¹, X², X³, X⁴, X⁵, and A have the significance given in formula I above in claim 1 , to give the respective compound of formula I;

(b) said compound is isolated from the reaction mixture, and

(c) if desired, converted into a pharmaceutically acceptable salt.

9. A pharmaceutical composition, containing one or more compounds according to claims 1 to 7 together with one or more pharmaceutically acceptable carriers.

10. The pharmaceutical composition according to claim 9 for the treatment of cancer.

11. Use of a compound according to claims 1 to 7, for the manufacture of corresponding pharmaceutical compositions for the treatment of cancer.

12. Use of one or more compounds according to claims 1 to 7 for the manufacture of a medicament for the treatment of cancer.