Case 23548

ARYL-4-ETHYNYL-ISOXAZOLE DERIVATIVES

The present invention is concerned with aryl-4-ethynyl-isoxazole derivatives of formula I

wherein RVR ² /R ³ are independently from each other hydrogen, lower alkyl, halogen, lower alkoxy or amino;

R is lower alkyl;

R ⁵ is optionally substituted aryl or heteroaryl, wherein the substituents are selected from the groups consisting of lower alkyl, lower alkoxy, CF ₃ , halogen, hydroxy, amino, -(CH ₂ ) _n -CN, -C(O)O-lower alkyl, -S(O) ₂ NH ₂ ,

-C(O)-NH-(CH ₂ ) _n -cycloalkyl, -C(O)-NH-heterocyclyl, -C(O)-NH-heteroaryl, optionally substituted aryl, wherein the substituents are selected from halogen; n is 0 or 1; as well as pharmaceutically acceptable acid addition salts thereof.

It has been found that this class of compounds show high affinity and selectivity for GABA A α5 receptor binding sites and might be useful as cognitive enhancer or for the treatment of cognitive disorders like Alzheimer's disease.

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA A receptors, which are members of the ligand-gated ion channel superfamily and (2) GABA B receptors, which are members of the G-protein linked receptor family. The GABA A receptor complex which is a membrane-bound heteropentameric protein polymer is composed principally of α, β and γ subunits.

Presently a total number of 21 subunits of the GABA A receptor have been cloned

MWA/16.03.2007

and sequenced. Three types of sub units (α, β and γ) are required for the construction of recombinant GABA A receptors which most closely mimic the biochemical, electrophysiological and pharmacological functions of native GABA A receptors obtained from mammalian brain cells. There is strong evidence that the benzodiazepine binding site lies between the α and γ subunits. Among the recombinant GABA A receptors, αlβ2γ2 mimics many effects of the classical type-I BzR subtypes, whereas α2β2γ2, α3β2γ2 and α5β2γ2 ion channels are termed type-II BzR.

It has been shown by McNamara and Skelton in Psychobiology, 21:101-108 that the benzodiazepine receptor inverse agonist β-CCM enhance spatial learning in the Morris watermaze. However, β-CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant or convulsant which prevents their use as cognition enhancing agents in humans. In addition, these compounds are non-selective within the GABA A receptor subunits, whereas a GABA A α5 receptor partial or full inverse agonist which is relatively free of activity at GABA A αl and/or α2 and/or α3 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition with reduced or without proconvulsant activity. It is also possible to use GABA A α5 inverse agonists which are not free of activity at GABA A αl and/or α2 and/or α3 receptor binding sites but which are functionally selective for α5 containing subunits. However, inverse agonists which are selective for GABA A α5 subunits and are relatively free of activity at GABA A αl, α2 and α3 receptor binding sites are preferred.

Objects of the present invention are compounds of formula I and pharmaceutically acceptable salts, 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, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.

The most preferred indication in accordance with the present invention is Alzheimer's disease.

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

As used herein, the term "lower alkyl" denotes a straight- or branched-chain alkyl group containing from 1-7, preferably from 1 - 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.

As used herein, the term "lower alkoxy" denotes a straight- or branched-chain alkyl group containing from 1-7, preferably from 1 - 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like as described above, and which is attached via an oxygen atom.

The term "heterocyclyl" denotes a saturated carbon ring, containing one or more heteroatoms, for example O, N or S. Examples for such group are tetrahydropyran-4-yl or piperidin-4-yl.

The term "aryl" denotes an unsaturated carbon ring, for example a phenyl, benzyl or naphthyl group. A preferred aryl group is phenyl.

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

The term "cycloalkyl" denotes a cyclic alkyl ring, having from 3 to 7 carbon ring atoms, for example, cyclopropyl, cyclopentyl or cyclohexyl.

The term "heteroaryl "denotes an aromatic 5 or 6 membered ring containing from one to three heteroatoms, such as N, O or S atoms. Examples of such aromatic heteroaryl rings are furan, pyridine, pyrimidine, pyridazine, isoxazole, imidazole, pyrazole, thiazole, pyrazine, quinoxaline, 4H-5-oxa-2,9b-diaza-cyclopenta [a] naphthalene, 5,6,7,8- tetrahydro-imidazo[l,2-a] pyridine, triazole or thiophen.

The term "optionally substituted aryl or heteroaryl" means that the aryl or heteroaryl may be unsubstituted or substituted by one or more substituents, preferably by one to three substituents.

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

Exemplary preferred are compounds, which have a binding activity (hKi) of lower than 100 nM and are selective for GABA A α5 subunits and are relatively free of activity at GABA A αl, α2 and α3 receptor binding sites.

In a certain embodiment, R , R , and R are all hydrogen.

In a certain embodiment, R , R , and R are independently from each other hydrogen, halogen or lower alkoxy.

In a certain embodiment, R ¹ is hydrogen, R ² is hydrogen or halogen and R ³ is hydrogen, lower alkoxy or halogen.

In a certain embodiment, R is methyl.

In a certain embodiment, R is optionally substituted aryl or heteroaryl, wherein the substituents are selected from the groups consisting of lower alkyl, lower alkoxy, CF3, halogen, hydroxy, amino, CN, -CH ₂ CN, -C(O)O-lower alkyl, -S(O) ₂ NH ₂ , -C(O)-NH-CH ₂ -cycloalkyl, -C(O) -NH-heterocyclyl, -C(O) -NH-heteroaryl, optionally substituted aryl, wherein the substituents are selected from halogen.

Preferred compounds of formula I are those, in which R ⁵ is optionally substituted pyridinyl, and the other substituents are as described above, for example the following compounds

2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyridine, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid methyl ester,

N-cyclopropylmethyl-2-(5-methyl-3-phenyl-isoxazol-4-yleth ynyl)-isonicotinamide,

2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-N-(tetrahydro- pyran-4-yl)-isonicotinamide,

2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-N-(4-methyl-th iazol-2-yl)-isonicotinamide,

2-chloro-6-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyridine, 5-methyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyridine,

2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyridine,

4-methyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyridine,

2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-4-trifluoromet hyl-pyridine,

3-methyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyridine, 6-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridin-3-ylamine ,

5-chloro-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyridine or

4-ethyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyridine.

Also preferred is 2- [3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylethynyl] -pyridine.

Preferred compounds of formula I are further those, in which R is optionally substituted phenyl, and the other substituents are as described above, for example the following compounds

3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-N-(tetrahydro- pyran-4-yl)-benzamide, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid methyl ester or

2-(5-niethyl-3-phenyl-isoxazol-4-ylethynyl)-phenylamine.

Preferred compounds of formula I are further those, in which R ⁵ is optionally substituted pyridazine, and the other substituents are as described above, for example the following compound

3-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyridazine.

Preferred compounds of formula I are further those, in which R ⁵ is optionally substituted imidazole, and the other substituents are as described above, for example the following compounds

5-methyl-4-(l -methyl- lH-imidazol-2-ylethynyl)-3-phenyl-isoxazole,

5-methyl-4-(2-methyl-3H-imidazol-4-ylethynyl)-3-phenyl-is oxazole,

4-(lH-imidazol-2-ylethynyl)-5-methyl-3-phenyl-isoxazole,

5-methyl-4-(l-methyl-5-phenyl-lH-imidazol-2-ylethynyl)-3- phenyl-isoxazole, 5-methyl-4-(5-methyl-l -phenyl- lH-imidazol-2-ylethynyl)-3-phenyl-isoxazole,

3,5-dimethyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-3 H-imidazole-4-carboxylic acid ethyl ester,

4-[l-(3,5-difluoro-phenyl)-2,5-dimethyl-lH-imidazol-4-yle thynyl]-5-methyl-3-phenyl- isoxazole or 4-[l-(4-fluoro-phenyl)-2,5-dimethyl-lH-imidazol-4-ylethynyl] -5-methyl-3-phenyl- isoxazole.

Preferred compounds of formula I are further those, in which R is optionally substituted pyrazole, and the other substituents are as described above, for example the following compounds 5-methyl-4-(4-methyl-lH-pyrazol-3-ylethynyl)-3-phenyl-isoxaz ole,

4- [5-(4-fluoro-phenyl)-l -methyl- lH-pyrazol-3-ylethynyl]-5-methyl-3-phenyl-isoxazole or

4- [5-(3-fluoro-phenyl)-l -methyl- lH-pyrazol-3-ylethynyl]-5-methyl-3-phenyl-isoxazole.

Preferred compounds of formula I are further those, in which R is optionally substituted thiazole, and the other substituents are as described above, for example the following compounds

2-methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-thiaz ole-4-carboxylic acid ethyl ester, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-thiazole-5-carbox ylic acid methyl ester, or

2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-thiazole-4-car boxylic acid methyl ester.

Preferred compounds of formula I are further those, in which R is optionally substituted pyrazine, and the other substituents are as described above, for example the following compounds

2,5-dimethyl-3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyrazine, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -pyrazine,

6-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyrazin-2-ylam ine or 5-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyrazin-2-ylamine .

Preferred compounds of formula I are further those, in which R is optionally substituted quinoxaline, and the other substituents are as described above, for example the following compound 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -quinoxaline.

Preferred compounds of formula I are further those, in which R is optionally substituted 5,5,7,8-tetrahydro-imidazo[l,2-a]pyridine, and the other substituents are as described above, for example the following compound

3-methyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-5,6,7 ,8-tetrahydro-imidazo[l,2- a] pyridine.

The present compounds of formula I and their pharmaceutically acceptable salts may be prepared by methods known in the art, for example, by processes described below, which process comprises

The present compounds of formula I and their pharmaceutically acceptable salts may be prepared by methods known in the art, for example, by processes described below, which process comprises

a) reacting a compound of formula II

with a compound of formula III

X-R ⁵ (X = Cl, Br, I) III

in the presence of a palladium(O) -catalyst, copper(I) salt and a base

to give a compound of formula

wherein R , R , R , R and R are as described above,

or b) reacting a compound of formula II

with a compound of formula V

H- -FT V

in the presence of a palladium(O) -catalyst, copper(I) salt and a base

to give a compound of formula

wherein R , R , R , R and R are as described above,

and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.

The following schemes describe the processes for preparation of compounds of formula I in more detail. The starting materials of formulas III, IV and VI are known compounds or may be prepared according to methods known in the art.

Scheme 1

H- -Ff

V

In accordance with scheme 1, a compound of formula I may be prepared starting from iodide IV (Org. Lett. (17) 5203, 2005) in a Sonogashira-type coupling reaction using a

palladium-catalyst like palladium(II) chloride, a ligand like 1,3- bis(diphenylphosphino)propane, a base like triethylamine and a copper(I) source like copper iodide with a corresponding ethynyl-compound of formula V in a suitable solvent like DMF at ambient or elevated temperature. Alternatively, in a corresponding Sonogashira-type coupling reaction a suitable ethynyl -compound like 2-methyl-but-3- yn-2-ol can be used to afford compound VI which can be transformed by treatment with a base like potassium hydroxide in a suitable solvent like toluene at ambient or elevated temperature to provide the ethynyl-isoxazole compound of formula II. Compounds of formula I may be prepared starting from compounds of formula II in a similar Sonogashira-type coupling reaction with a corresponding aryl- or heteroarylhalide of formula III.

As mentioned earlier, the compounds of formula I and their pharmaceutically usable salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are ligands for GABA A receptors containing the α5 subunit and are therefore useful in the therapy where cognition enhancement is required.

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

Membrane preparation and binding assay

The affinity of compounds at GABA A receptor subtypes was measured by competition for [3H]flumazenil (85 Ci/mmol; Roche) binding to HEK293 cells expressing rat (stably transfected) or human (transiently transfected) receptors of composition αlβ3γ2, α2β3γ2, α3β3γ2 and α5β3γ2.

Cell pellets were suspended in Krebs-tris buffer (4.8 mM KCl, 1.2 mM CaCl2, 1.2 mM MgCL:, 120 mM NaCl, 15 mM Tris; pH 7.5; binding assay buffer), homogenized by polytron for ca. 20 sec on ice and centrifuged for 60 min at 4 ⁰ C (50000 g; Sorvall, rotor: SM24 = 20000 rpm). The cell pellets were resuspended in Krebs-tris buffer and homogenized by polytron for ca. 15 sec on ice. Protein was measured (Bradford method, Bio-Rad) and aliquots of 1 mL were prepared and stored at -80 ⁰ C.

Radioligand binding assays were carried out in a volume of 200 mL (96-well plates) which contained 100 mL of cell memebranes, [3H]flumazenil at a concentration of 1 nM for αl, α2, α3 subunits and 0.5 nM for α5 subunits and the test compound in the range of 10-10 ³ X lO ⁶ M. Nonspecific binding was defined by 10 ⁵ M diazepam and typically represented less than 5% of the total binding. Assays were incubated to equilibrium for 1 hour at 4 ⁰ C and harvested onto GF/C uni-filters (Packard) by filtration using a Packard

harvester and washing with ice-cold wash buffer (50 mM Tris; pH 7.5). After drying, filter-retained radioactivity was detected by liquid scintillation counting. Ki values were calculated using Excel-Fit (Microsoft) and are the means of two determinations.

The compounds of the accompanying examples were tested in the above described assay, and all were found to possess a Ki value for displacement of [3H]flumazenil from a5 sub units of the rat GABA A receptor of 100 nM or less. In a preferred embodiment the compounds of the invention are binding selective for the α5 sub unit relative to the αl, α2 and α3 sub unit.

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

parenterally, e.g. in the form of injection solutions.

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

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

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

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

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

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

Example A

Tablets of the following composition are manufactured 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 of the following composition are manufactured:

mg/capsule

Active substance 10 Lactose 155

Corn starch 30

Talc 5

Capsule fill weight 200

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

Example C

Suppositories of the following composition are manufactured:

mg/supp.

Active substance 15

Suppository mass 1285

Total 1300

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

The following examples 1 - 51 are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof. Example 1 has been described in detail, the remaining compounds have been prepared accordingly.

Example 1 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridine

A mixture of 4-iodo-5-methyl-3-phenylisoxazole (285 mg, 1.00 mmol), palladium(II) acetate (7 mg, 0.03 mmol), l,3-bis(diphenylphosphino)propane (12 mg, 0.03 mmol), triethylamine (348μL, 2.50 mmol) and 2-ethynylpyridine (131 μL, 1.30 mmol) in N,N- dimethylformamide (2 mL) was evaporated and flushed with argon. Cuprous iodide (4 mg, 0.02 mmol) was added and the reaction mixture was stirred for 3 h at 90 ⁰ C before cooling to ambient temperature and separated between aqueous sodium hydroxide ( 1 M, 30 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and washed with aqueous sodium hydroxide (1 M, 30 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (Siθ2, heptane:ethyl acetate = 100:0 to 67:33) afforded the title compound (60 mg, 23%) as a light brown solid. MS: m/e = 261.2 [M+H] ⁺ .

Example 2 3-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridine

As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (285 mg, 1.00 mmol) was converted (using 3-ethynylpyridine instead of 2-ethynylpyridine) to the title compound (Siθ2, heptane:ethyl acetate = 100:0 to 67:33, 150 mg, 58%) which was obtained as a white solid. MS: m/e = 261.2 [M+H] ⁺ .

Example 3 5-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridin-2-ylamine

a) 5-Trimethylsilanylethvnyl-pyridin-2-ylamine

A mixture of 2-amino-5-bromopyridine (50.0 g, 289 mmol), trimethylsilylacetylene (112 mL, 809 mmol), triethylamine (120 mL, 867 mmol), PdCl ₂ (PPh ₃ ) ₂ (4.06 g, 5.78 mmol) and PPh ₃ (1.52 g, 5.78 mmol) in DMF (290 mL) was purged for 10 min with argon. Then cuprous iodide (340 mg, 2.89 mmol) was added and the reaction mixture was heated up to 90 ⁰ C, stirring was continued at 90 ⁰ C for 4.5 h. Cooled to ambient temperature, the reaction mixture was concentrated, poured onto water (300 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water (300 mL) and brine (2 x 250 mL) and dried over magnesium sulfate. Concentration left a dark brown

residue which was purified by flash chromatography with n-heptane and acetone to give the title compound as a brown solid (41.7 g, 76%). MS: m/e = 191.2 [M+H] ⁺ .

b) 5-Ethynyl-pyridin-2-ylamine To a solution of 5-trimethylsilanylethynyl-pyridin-2-ylamine (32.1 g, 169 mmol) in THF ( 150 mL) and methanol (350 mL) at 0 ⁰ C was added potassium carbonate (2.33 g, 16.9 mmol) and the mixture was stirred at 0 ⁰ C for 5 h. It was diluted with ice water (500 mL), extracted with tert-butylmethylether (3 x 500 mL), washed the combined organic layers with brine and dried over magnesium sulfate. Concentration left a dark brown solid, which was dissolved in hot ethyl acetate and precipitated with n-heptane trituration to give the 5-ethynyl-pyridin-2-ylamine ( 14.61 g, 73%) as a light brown solid. MS: m/e = 118.1 [M+H] ⁺ .

c) 5-(5-Methyl-3-phenyl-isoxazol-4-ylethvnyl)-pyridin-2-ylamine As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (285 mg, 1.00 mmol) was converted (using 5-ethynyl-pyridin-2-ylamine instead of 2-ethynylpyridine) to the title compound (SiO ₂ , heptane:ethyl acetate = 100:0 to 67:33, 158 mg, 57%) which was obtained as a light yellow solid. MS: m/e = 276.2 [M+H] ⁺ .

Example 4

4-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-benzonitrile

As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (285 mg, 1.00 mmol) was converted (using 4-ethynyl-benzonitrile instead of 2-ethynylpyridine) to the title compound (SiO ₂ , heptane:ethyl acetate = 100:0 to 67:33, 60 mg, 21%) which was obtained as a white solid. MS: m/e = 285.1 [M+H] ⁺ .

Example 5 3-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid methyl ester

As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (1.14 g, 4.00 mmol) was converted [using 3-ethynyl-benzoic acid methyl ester (prepared according to J. Org. Chem. 46(11), 2280, 1981) instead of 2-ethynylpyridine] to the title compound (SiO ₂ , heptane:ethyl acetate = 100:0 to 90:10, 0.67 g, 53%) which was obtained as a light yellow solid. MS: m/e = 318.1 [M+H] ⁺ .

Example 6 4-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid methyl ester

As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (1.14 g, 4.00 mmol) was converted [using 4-ethynyl-benzoic acid methyl ester (prepared according to J. Org. Chem. 68(12), 4862, 2003) instead of 2-ethynylpyridine] to the title compound (SiO ₂ , heptane:ethyl acetate = 100:0 to 90:10, 0.66 g, 52%) which was obtained as a light yellow solid. MS: m/e = 318.1 [M+H] ⁺ .

Example 7

N-Cyclopropylmethyl-3-(5-methyl-3-phenyl-isoxazol-4-yleth ynyl)-benzamide

a) 3-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl) -benzoic acid 3-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid methyl ester (600 mg, 1.89 mmol) was treated with ethanol (12 mL) and aqueous sodium hydroxide (1 M, 7.56 mL, 7.56 mmol). The reaction mixture was heated for 1.5 h at 80 ⁰ C. After concentration and dilution with water (9 mL) the pH was adjusted tol.5 by adding hydrochloric acid (1 M, 8mL). The resulting suspension was stirred for 30 min at 0 ⁰ C and filtered. Washing with ice-cold water (10 mL) and drying afforded the title compound (546 mg, 95%) as a light brown solid. MS: m/e = 304.1 [M+H] ⁺ .

b) N-Cvclopropylmethyl-3-(5-methyl-3-phenyl-isoxazol-4-ylethvny l)-benzamide

To a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl) -benzoic acid (250 mg; 0.82 mmol) in N,N-dimethylformamide (4.8 mL) was added 2-(lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium tetrafuoroborate (318 mg, 0.99 mmol) at 0 ⁰ C. After stirring for 15 min at this temperature, aminomethylcyclopropane (86 μl, 0.99 mmol) and N- ethyldiisopropylamine (0.85 mL, 4.94 mmol) were added and the reaction mixture was allowed to warm to ambient temperature. After 1.75 h stirring at ambient temperature, it was extracted with dichloromethane (300 mL) and aqueous sodium carbonate (2 M, 75 mL). The combined organic layers were washed with brine (75 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO ₂ , heptane:ethyl acetate = 95:5 to 0:100) afforded the title compound (254 mg, 87%) as a white solid. MS: m/e = 357.1 [M+H] ⁺ .

Example 8 3-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-N-(tetrahydro-pyr an-4-yl)-benzamide

As described for example 7b, 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (250 mg; 0.82 mmol) was converted (using 4-amino-tetrahydropyrane instead of aminomethylcyclopropane) to the title compound (SiCh, heptane:ethyl acetate = 95:5 to 0: 100, 276 mg, 87%) which was obtained as a white solid. MS: m/e = 387.1 [M+H] ⁺ .

Example 9 N-Cyclopropylmethyl-4-(5-methyl-3-phenyl-isoxazol-4-ylethyny l)-benzamide

a) 4-(5-Methγl-3-phenγl-isoxazol-4-γlethγnγl) -benzoic acid

As described for example 7a, 4-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid methyl ester (600 mg, 1.89 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4- ylethynyl) -benzoic acid methyl ester was converted to the title compound (549 mg, 96%) which was obtained as an off-white solid. MS: m/e = 304.1 [M+H] ⁺ .

b) N-Cyclopropylmethyl-4-(5-methyl-3-phenyl-isoxazol-4-ylethyny l)-benzamide As described for example 7b, 4-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (250 mg; 0.82 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid was converted to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0: 100, 108 mg, 39%) which was obtained as a light yellow solid. MS: m/e = 357.1 [M+H] ⁺ .

Example 10

4-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-N-(tetrahydro- pyran-4-yl)-benzamide

As described for example 7b, 4-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (250 mg; 0.82 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid was converted using 4-amino-tetrahydropyrane instead of aminomethylcyclopropane to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0: 100, 281 mg, 88%) which was obtained as a white solid. MS: m/e = 387.1 [M+H] ⁺ .

Example 11 2-Chloro-4-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridine

a) 2-Methyl-4-(5-niethyl-3-phenyl-isoxazol-4-yl)-but-3-vn-2-ol A mixture of 4-iodo-5-methyl-3-phenylisoxazole (5.73 g, 20.1 mmol), palladium(II) acetate (135 mg, 0.60 mmol), l,3-bis(diphenylphosphino)propane (249 mg, 0.60 mmol), triethylamine (7.0 mL, 50.2 mmol) and 2-methyl-3-butyn-2-ol (3.0 mL, 30.7mmol) in N,N-dimethylformamide (40 mL) was evaporated and flushed with argon. Cuprous iodide (77 mg, 0.40 mmol) was added and the reaction mixture was stirred for 23 h at 90 ⁰ C (after 1.75 h and 4.5 h, respectively, further palladium(II) acetate (135 mg, 0.60 mmol), l,3-bis(diphenylphosphino)propane (249 mg, 0.60 mmol), triethylamine (7.0 mL, 50.2 mmol), 2-methyl-3-butyn-2-ol (3.0 mL, 30.7 mmol) and cuprous iodide (77 mg, 0.40 mmol) were added) .before cooled to ambient temperature and separated between aqueous sodium hydroxide (1 M, 600 mL) and ethyl acetate (1000 mL). The aqueous layer was extracted with ethyl acetate (1000 mL) and washed with aqueous sodium hydroxide ( 1 M, 600 mL) . The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiC^, heptane:ethyl acetate = 67:33) afforded the title compound (3.77 g, 78%) as a yellow oil. MS: m/e = 242.2 [M+H] ⁺ .

b) 4-Ethynyl-5-methyl-3-phenyl-isoxazole

To a solution of 2-methyl-4-(5-methyl-3-phenyl-isoxazol-4-yl)-but-3-yn-2-ol (3.77 g, 15.6 mmol) in toluene (38 mL) was added potassium hydroxide (350 mg, 6.24 mmol) and the reaction mixture was stirred for 1.25 h at 110 ⁰ C before being cooled to ambient temperature and separated between ethyl acetate (50OmL) and aqueous ammonium chloride (1 M, 40OmL). The aqueous layer was extracted with ethyl acetate (500 mL) and the combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (Siθ2, heptane:ethyl acetate = 100:0 to 90:10) afforded the title compound (2.50 g, 87%) as a yellow solid. MS: m/e = 184.1 [M+H] ⁺ .

c) 2-Chloro-4-(5-methyl-3-phenyl-isoxazol-4-ylethvnyl) -pyridine

A mixture of 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol), 2-chloro-4- iodopyridine(172 mg, 0.72 mmol), triethylamine (209 μl, 1.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (13 mg, 0.02 mmol) in N,N- dimethylformamide (1.2 mL) was evaporated and flushed with argon. Cuprous iodide (2 mg, 0.01 mmol) was added and the reaction mixture was stirred for 1.5 h at 90 ⁰ C before

it was cooled to ambient temperature and separated between aqueous sodium hydroxide (1 M, 20 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic layers were washed with aqueous sodium hydroxide (1 M, 20 mL), dried over sodium sulfate and concentrated. Purification by chromatography (Siθ2, heptane:ethyl acetate = 100:0 to 80:20) afforded the title compound (160 mg, 91%) as a colorless oil. MS: m/e = 295.0/297.2 [M+H] ⁺ .

Example 12 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid methyl ester

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using methyl 2-iodobenzoate instead of 2-chloro-4-iodopyridine) to the title compound (SiO ₂ , heptane:ethyl acetate = 100:0 to 80:20, 166 mg, 82%) which was obtained as an off-white solid. MS: m/e = 318.1 [M+H] ⁺ .

Example 13 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridin-3-ol

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using 2-iodo-3-hydroxypyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiO ₂ , heptane:ethyl acetate = 95:5 to 50:50, 93 mg, 56%) which was obtained as a light yellow solid. MS: m/e = 377.1 [M+H] ⁺ .

Example 14 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-phenylamine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using 2-iodo-aniline instead of 2-chloro-4-iodopyridine) to the title compound (SiO ₂ , heptane:ethyl acetate = 100:0 to 50:50, 139 mg, 85%) which was obtained as a light brown oil. MS: m/e = 375.1 [M+H] ⁺ .

Example 15 [2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-phenyl]-acetonit rile

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using 2-iodo-phenylacetonitrile instead of 2-chloro-4-

iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 100:0 to 80:20, 156 mg, 87%) which was obtained as a light brown oil. MS: m/e = 375.1 [M+H] ⁺ .

Example 16 N-Cyclopropylmethyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethyny l)-benzamide

a) 2-(5-Methγl-3-phenγl-isoxazol-4-γlethγnγl) -benzoic acid

As described for example 7a, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid methyl ester (100 mg, 0.32 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4- ylethynyl) -benzoic acid methyl ester was converted to the title compound (84 mg, 88%) which was obtained as a light brown solid. MS: m/e = 304.1 [M+H] ⁺ .

b) N-Cyclopropylmethyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethyny l)-benzamide

As described for example 7b, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (60 mg; 0.20 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid was converted to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 27 mg, 38%) which was obtained as a light yellow solid. MS: m/e = 357.1 [M+H] ⁺ .

Example 17 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid methyl ester

a) 2-Iodo-isonicotinic acid methyl ester

To a suspension of 2-iodo-isonicotinic acid (can be prepared according to J. Med. Chem. (19) 490, 1976) (24.9 g, 100 mmol) in methanol (100 mL) was added sulfuric acid (concentrated, 11 mL, 205 mmol) and the mixture was stirred at ambient temperature for 5 days followed by heating to reflux for 3 h. The reaction mixture was cooled to ambient temperature, concentrated and poured into icecold aqueous sodium hydrogencarbonate (half-saturated) and was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by chromatography (SiCh, heptane:ethyl acetate = 85:15 to 80:20) afforded the title compound (20.4 mg, 77%) as a light yellow solid. MS: m/e = 263.0 [M] ⁺ .

b) 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid methyl ester

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (58 mg, 0.32 mmol) was converted (using 2-iodo-isonicotinic acid methyl ester instead of 2-chloro-4-

iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 70 mg, 70%) which was obtained as a light brown solid. MS: m/e = 319.1 [M+H] ⁺ .

Example 18 5-Bromo-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyrimidin e

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (55 mg, 0.30 mmol) was converted (using 5-bromo-2-iodo-pyrimidine instead of 2-chloro-4- iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 58 mg, 56%) which was obtained as a light yellow solid. MS: m/e = 341.9 [M+H] ⁺ .

Example 19 3-Methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridazi ne

a) 3-Iodo-6-methyl-pγridazine

A mixture of 3-chloro-6-methylpyridazine (2.00 g, 15.6 mmol) and hydriodic acid (57% in water, 41.1 mL, 311 mmol) was heated at reflux for 1 h. After cooling to ambient temperature aqueous sodium carbonate (saturated) was added (pH=8) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate and concentrated afforded the title compound (2.80 mg, 82%) as a light yellow solid. MS: m/e = 221.1 [M+H] ⁺ .

b) 3-Methγl-6-(5-methγl-3-phenγl-isoxazol-4-γlethγnγl)-pÎ ³ridazine As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (70 mg, 0.38 mmol) was converted (using 3-iodo-6-methyl-pyridazine instead of 2-chloro-4- iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 84 mg, 80%) which was obtained as a light brown solid. MS: m/e = 276.1 [M+H] ⁺ .

Example 20 3-Chloro-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (64 mg, 0.35 mmol) was converted [using 3-chloro-2-iodopyridine (prepared according to Eur. J. Org. Chem. (24), 4181, 2002) instead of 2-chloro-4-iodopyridine] to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 81 mg, 78%) which was obtained as a light yellow solid. MS: m/e = 295.2/297.3 [M+H] ⁺ .

Example 21 5-Methyl-4-(l-methyl-lH-imidazol-2-ylethynyl)-3-phenyl-isoxa zole

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (73 mg, 0.40 mmol) was converted (using 2-iodo-l-methyl-lH-imidazole instead of 2-chloro-4- iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 32 mg, 30%) which was obtained as a light brown solid. MS: m/e = 264.2 [M+H] ⁺ .

Example 22 5-Methyl-4-(2-methyl-3H-imidazol-4-ylethynyl)-3-phenyl-isoxa zole

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (73 mg, 0.40 mmol) was converted using (4-iodo-2-methyl-lH-imidazole instead of 2-chloro-4- iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 14 mg, 13%) which was obtained as a light brown solid. MS: m/e = 264.2 [M+H] ⁺ .

Example 23 5-Methyl-4-(4-methyl-lH-pyrazol-3-ylethynyl)-3-phenyl-isoxaz ole

As described for example 1 Ic, 4-ethynyl-5-methyl-3-phenyl-isoxazole (73 mg, 0.40 mmol) was converted [using 3-iodo-4-methyl-lH-pyrazole (prepared according to Liebigs Ann. Chem. 595, 200, 1955) instead of 2-chloro-4-iodopyridine] to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 56 mg, 53%) which was obtained as a light brown solid. MS: m/e = 264.2 [M+H] ⁺ .

Example 24

2-Methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-thiaz ole-4-carboxylic acid ethyl ester

a) 5-Iodo-2-methyl-thiazole-4-carboxylic acid ethyl ester

To a solution of ethyl 2-methylthiazole-4-carboxylate (11.2 g, 65.4 mmol) in acetic acid (200 mL) were added sulfuric acid (30%, 20 mL), carbontetrachloride (30 mL), iodine (33.2 g, 131 mmol) and iodic acid (11.5 g, 65.4 mmol) and the reslting reaction mixture was stirred for 19 h at 80 ⁰ C. After addition of aqueous sodium thiosulfate (1 M, 500 mL) it was extracted with ethyl acetate (1000 mL). The combined organic layers were washed with aqueous sodium carbonate (saturated, 1000 mL), dried over sodium sulfate and

concentrated. Purification by chromatography (Siθ2, heptane:ethyl acetate = 95:5 to 20:80) afforded the title compound (9.00 g, 37%) as a white crystalline solid. MS: m/e = 298.1 [M+H] ⁺ .

b ) 2-Methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylethvnyl)-thiazole -4-carboxylic acid ethyl ester

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (51 mg, 0.28 mmol) was converted (using 5-iodo-2-methyl-thiazole-4-carboxylic acid ethyl ester instead of 2-chloro-4-iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 83 mg, 84%) which was obtained as a light brown solid. MS: m/e = 353.2 [M+H] ⁺ .

Example 25 4-(lH-Imidazol-2-ylethynyl)-5-methyl-3-phenyl-isoxazole

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (79 mg, 0.43 mmol) was converted (using 2-iodo-lH-imidazole instead of 2-chloro-4-iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 83 mg, 77%) which was obtained as an off-white solid. MS: m/e = 250.2 [M+H] ⁺ .

Example 26 2,5-Dimethyl-3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyra zine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (66 mg, 0.36 mmol) was converted [using 3-iodo-2,5-dimethyl-pyrazine (prepared from 3-chloro-2,5- dimethyl-pyrazine according to J. Med. Chem. (19) 490, 1976) instead of 2-chloro-4- iodopyridine] to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 89 mg, 85%) which was obtained as a white solid. MS: m/e = 290.1 [M+H] ⁺ .

Example 27

N-Cyclopropylmethyl-2-(5-methyl-3-phenyl-isoxazol-4-yleth ynyl)-isonicotinamide

a) 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid As described for example 7a, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid methyl ester (247 mg, 0.78 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4-

ylethynyl) -benzoic acid methyl ester was converted to the title compound (218 mg, 92%) which was obtained as a light brown solid. MS: m/e = 305.2 [M+H] ⁺ .

b) N-Cyclopropylmethyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethyny l)-isonicotinamide As described for example 7b, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid (50 mg; 0.16 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid was converted to the title compound (SiCh, heptane:ethyl acetate = 95:5 to 0:100, 26 mg, 45%) which was obtained as a yellow solid. MS: m/e = 358.1 [M+H] ⁺ .

Example 28

2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-N-(tetrahydro- pyran-4-yl)-isonicotinamide

As described for example 7b, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid (50 mg; 0.16 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid was converted (using 4-amino-tetrahydropyrane instead of aminomethylcyclopropane) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 46 mg, 73%) which was obtained as a yellow solid. MS: m/e = 388.2 [M+H] ⁺ .

Example 29 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-N-(4-methyl-thiaz ol-2-yl)-isonicotinamide

To a solution of 2-amino-4-methylthiazole (57 mg, 0.50 mmol) in dioxane (1.2 mL) was added trimethylaluminium (2 M in heptane, 251 μl, 0.50 mmol). The resulting red- brown solution was stirred for 1 h at ambient temperature before 2-(5-methyl-3-phenyl- isoxazol-4-ylethynyl)-isonicotinic acid methyl ester (40 mg, 0.13 mmol) was added. The reaction mixture was heated for 2.25 h at 110 ⁰ C before cooling to ambient temperature. Water (29 μL) was added and the mixture was stirred for 10 min at ambient temperature. Magnesium sulfate was added and the mixture was filtered over Hyflo ^® . Concentration and purification by chromatography (SiC^, heptane:ethyl acetate = 95:5 to 0:100) was followed by separation between hydrochloric acid ( 1 M, 30 mL) and ethyl acetate (100 mL). The organic layers were washed with brine, dried over sodium sulfate and were concentrated affording the title compound (48 mg, 96%) as an off-white solid. MS: m/e = 401.2 [M+H] ⁺ .

Example 30 2-Chloro-6-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloro-6-iodopyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiCh, heptane:ethyl acetate = 95:5 to 0:100, 129 mg, 87%) which was obtained as a light yellow oil. MS: m/e = 295.1/297.3 [M+H] ⁺ .

Example 31 5-Methyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-5-methylpyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 75 mg, 55%) which was obtained as a light brown solid. MS: m/e = 275.2 [M+H] ⁺ .

Example 32 5-Methyl-4-(l-methyl-5-phenyl-lH-imidazol-2-ylethynyl)-3-phe nyl-isoxazole

As described for example 1 Ic, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted [using 2-iodo-l-methyl-5-phenyl-lH-imidazole (prepared from 1- methyl-5-phenyl-lH-imidazole according to J. Org. Chem. (43) 4381, 1978) instead of 2- chloro-4-iodopyridine] to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 88 mg, 52%) which was obtained as a light brown solid. MS: m/e = 340.2 [M+H] ⁺ .

Example 33 5-Methyl-4-(5-methyl-l-phenyl-lH-imidazol-2-ylethynyl)-3-phe nyl-isoxazole

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted [using 2-iodo-5-methyl-l-phenyl-lH-imidazole (prepared from 5- methyl-1 -phenyl- lH-imidazole by reaction of 4(5)-methyl-l-phenyl-lH-imidazole with N-iodosuccinimide in N,N-dimethylformamide at ambient temperature) instead of 2- chloro-4-iodopyridine] to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 35 mg, 21%) which was obtained as a brown solid. MS: m/e = 340.2 [M+H] ⁺ .

Example 34 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-pyrazine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloropyrazine instead of 2-chloro-4-iodopyridine) to the title compound (SiCh, heptane:ethyl acetate = 95:5 to 0:100, 78 mg, 60%) which was obtained as a light yellow solid. MS: m/e = 262.1 [M+H] ⁺ .

Example 35 2-Methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-6-methylpyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 83 mg, 60%) which was obtained as a yellow oil. MS: m/e = 275.2 [M+H] ⁺ .

Example 36 2-Methoxy-6-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridin e

As described for example 1 Ic, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-6-methoxypyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 97 mg, 67%) which was obtained as a yellow oil. MS: m/e = 291.2 [M+H] ⁺ .

Example 37

4-Methyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyrid ine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-4-methylpyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 72 mg, 52%) which was obtained as a light brown solid. MS: m/e = 275.2 [M+H] ⁺ .

Example 38 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-4-trifluoromethyl -pyridine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-4-(trifluoromethyl)pyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiCh, heptane:ethyl acetate = 95:5 to 0:100, 124 mg, 76%) which was obtained as an off-white solid. MS: m/e = 329.3 [M+H] ⁺ .

Example 39 3-Methyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-3-methylpyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 91 mg, 66%) which was obtained as a light yellow solid. MS: m/e = 275.2 [M+H] ⁺ .

Example 40 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-6-trifluoromethyl -pyridine

As described for example 1 Ic, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-6-(trifluoromethyl)pyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 135 mg, 82%) which was obtained as a light yellow solid. MS: m/e = 329.3 [M+H] ⁺ .

Example 41

6-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridin-3-ylam ine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 3-amino-6-bromopyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 68 mg, 49%) which was obtained as a light brown foam. MS: m/e = 276.3 [M+H] ⁺ .

Example 42 5-Chloro-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-5-chloropyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiCh, heptane:ethyl acetate = 95:5 to 0:100, 118 mg, 80%) which was obtained as a light yellow solid. MS: m/e = 297.3 [M+H] ⁺ .

Example 43 4-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-benzenesulfonamid e

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 4-iodobenzenesulphonamide instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 120 mg, 71%) which was obtained as a white solid. MS: m/e = 339.2 [M+H] ⁺ .

Example 44 4-Ethyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyridine

As described for example 1 Ic, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-4-ethylpyridine instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 74 mg, 51%) which was obtained as a yellow oil. MS: m/e = 289.1 [M+H] ⁺ .

Example 45

2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-quinoxaline

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloroquinoxaline instead of 2-chloro-4-iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 118 mg, 76%) which was obtained as a light yellow solid. MS: m/e = 312.2 [M+H] ⁺ .

Example 46 6-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-pyrazin-2-ylamine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-amino-6-chloropyrazine instead of 2-chloro-4- iodopyridine) to the title compound (SiCh, heptane:ethyl acetate = 95:5 to 0:100, 47 mg, 34%) which was obtained as a brown solid. MS: m/e = 277.2 [M+H] ⁺ .

Example 47 5-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-pyrazin-2-ylamine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-amino-5-bromopyrazine instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 35 mg, 25%) which was obtained as a brown solid. MS: m/e = 277.2 [M+H] ⁺ .

Example 48 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-pyrimidine

As described for example 1 Ic, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloropyrimidine instead of 2-chloro-4-iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 42 mg, 32%) which was obtained as a brown solid. MS: m/e = 262.2 [M+H] ⁺ .

Example 49

5-Ethyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-pyrimi dine

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloro-5-ethylpyrimidine instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 40 mg, 28%) which was obtained as a brown oil. MS: m/e = 290.1 [M+H] ⁺ .

Example 50

3,5-Dimethyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-3 H-imidazole-4-carboxylic acid ethyl ester

As described for example 1 Ic, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester instead of 2-chloro-4-iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 110 mg, 63%) which was obtained as a light yellow solid. MS: m/e = 350.3 [M+H] ⁺ .

Example 51

3-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-4H-5-oxa-2,9b- diaza- cyclopenta[a]naphthalene

a) 3-Trimethylsilanylethvnyl-4H-5-oxa-2,9b-diaza-cyclopenta[al naphthalene

As described for example 3a, 3-iodo-4H-5-oxa-2,9b-diaza-cyclopenta [a] naphthalene (may be prepared in analogy to WO2002046166, 3.00 g, 10.1 mmol) instead of 2-amino- 5-bromopyridine was converted to the title compound (SiCh, heptane:ethyl acetate = 100:0 to 40:60, 1.74 g, 64%) which was obtained as a light brown oil. MS: m/e = 269.5 [M+H] ⁺ .

b) 3-Ethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[al naphthalene

As described for example 3b, 3-trimethylsilanylethynyl-4H-5-oxa-2,9b-diaza- cyclopenta [a] naphthalene (1.72 g, 6.41 mmol) instead of 5-trimethylsilanylethynyl- pyridin-2-ylamine was converted to the title compound (1.20 g, 95%) which was obtained as a light brown solid. MS: m/e = 197.9 [M+H] ⁺ .

c) 3-(5-Methyl-3-phenyl-isoxazol-4-ylethvnyl)-4H-5-oxa-2,9b-dia za- cvclopenta [ai naphthalene As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (112 mg, 0.39 mmol) was converted (using 3-ethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene instead of 2- ethynylpyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 60 mg, 44%) which was obtained as a light brown solid. MS: m/e = 354.2 [M+H] ⁺ .

Example 52

3-Methyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-5,6,7 ,8-tetrahydro-imidazo[l,2- a] pyridine

a) l-Ethγl-4-iodo-5-methγl-2-propγl-lH-imidazole

To a solution of 3-methyl-5,6,7,8-tetrahydro-imidazo[l,2-a]pyridine (Eur. J. Med. Chem. 10(5), 528, 1975; 1.85 g, 13.6 mmol) in acetic acid (50 mL) was added N-iodsuccinimide (4.28 g, 19.0 mmol) and the reaction mixture was stirred for 3 h at ambient temperature. It was concentrated and the residue extracted with aqueous sodium carbonate (sat.) and ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (Siθ2, dichloromethane:methanol = 100:0 to 93:7) afforded the title compound (3.00 g, 84%) as a dark brown solid. MS: m/e = 262.0 [M] ⁺ .

b) 2-Ethγnγl-3-methγl-5,6,7,8-tetrahγdro-imidazo[l,2-al pyridine

As described for example 3a, l-ethyl-4-iodo-5-methyl-2-propyl-lH-imidazole (2.60 g, 9.92 mmol) instead of 2-amino-5-bromopyridine was converted to 3-methyl-2- trimethylsilanyl-ethynyl-5,6,7,8-tetrahydro-imidazo[l,2-a] pyridine (Siθ2, dichloromethane:methanol = 100:0 to 98:2, 890 mg, 39%) which was obtained as a dark brown semisolid and used further without detailed characterisation. As described for example 3b, 3-methyl-2-trimethylsilanylethynyl-5,6,7,8-tetrahydro-imidaz o [1,2- a] pyridine (890 g, 3.83 mmol) instead of 5-trimethylsilanyl-ethynyl-pyridin-2-ylamine was converted to the title compound (Siθ2, ethyl acetate, 310 mg, 51%)which was obtained as a light brown solid. MS: m/e = 161.3 [M+H] ⁺ .

c) 3-Methyl-2-(5-methyl-3-phenyl-isoxazol-4-ylethvnyl)-5,6,7,8- tetrahvdro-imidazo[l,2- al pyridine

As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (137 mg, 0.48 mmol) was converted (using 2-ethynyl-3-methyl-5,6,7,8-tetrahydro-imidazo[l,2-a]pyridine instead of 2-ethynylpyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 54 mg, 35%) which was obtained as a light brown solid. MS: m/e = 318.2 [M+H] ⁺ .

Example 53 4-[5-(4-Fluoro-phenyl)-l-methyl-lH-pyrazol-3-ylethynyl]-5-me thyl-3-phenyl-isoxazole a) 3-Ethynyl-5-(4-fluoro-phenyl)-l -methyl- lH-pyrazole

To a sultion of (l-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (2.27 g, 11.8 mmol) in methanol (100 mL) were added 5-(4-fluoro-phenyl)-l-methyl-lH-pyrazole-3-

carbaldehyde (maybe prepared in analogy to WO2005014553, 2.00 g, 9.8 mmol) and potassium carbonate (2.84 g, 20.56 mmol) and the resulting yellow suspension was stirred for 19 h at ambient temperature. After extraction with aqueous sodium hydrogencarbonate and ethyl acetate the combined organic layers were washed with brine, dried over sodium sulfate. Concentration and purification by chromatography (SiO ₂ , hexane:ethyl acetate = 100:0 to 75:25) afforded the title compound (1.83 g, 93%) as a white solid. MS: m/e = 201.3 [M+H] ⁺ .

b) 4- [5-(4-Fluoro-phenyl)-l -methyl- lH-pyrazol-3-ylethvnyll-5-methyl-3-phenyl- isoxazole

As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (108 mg, 0.38 mmol) was converted (using 3-ethynyl-5-(4-fluoro-phenyl)-l-methyl-lH-pyrazole instead of 2- ethynylpyridine) to the title compound (SiO ₂ , heptane:ethyl acetate = 95:5 to 0:100, 44 mg, 32%) which was obtained as a yellow solid. MS: m/e = 358.1 [M+H] ⁺ .

Example 54 l-(4-Fluoro-phenyl)-5-methyl-3-(5-methyl-3-phenyl-isoxazol-4 -ylethynyl)-lH- [ 1,2,4] triazole

a) [l-(4-Fluoro-phenyl)-5-methyl-lH-[l,2,4itriazol-3-yl1 -methanol

To a suspension of l-(4-fluoro-phenyl)-5-methyl-lH-[l,2,4]triazole-3-carboxylic acid (may be prepared in analogy to DE3525205, 1986, 10.7 g, 48.4 mmol) in THF ( 50 mL) was added borane (1 M in THF, 121 mL, 121 mmol) and the resulting suspension was heated to reflux for 1 h. After concentration and extraction with aqueous sodium hydrogencarbonate and ethyl acetate the combined organiy layers were washed with brine and dried over sodium sulfate. Concentration and purification by chromatography (SiO ₂ , hexane:ethyl acetate = 100:0 to 33:67) afforded the title compound (4.60 g, 46%) as a white solid. MS: m/e = 208.4 [M+H] ⁺ .

b) l-(4-Fluoro-phenyl)-5-methyl- IH- [ 1,2,41 triazole-3-carbaldehyde

A suspension of [l-(4-fluoro-phenyl)-5-methyl-lH-[l,2,4]triazol-3-yl]-methan ol (2.20 g, 10.6 mmol) and manganese(IV) oxide (10.3 g, 106 mmol) in dichloromethane (110 mL) was heated at reflux for 1 h. After cooling to ambient temperature it was filtered and concentrated affording the title compound (1.80 g, 33%) as a light yellow solid. MS: m/e = 206.3 [M+H] ⁺ .

c) 3-Ethγnγl-l-(4-fluoro-phenγl)-5-methγl- IH- [ 1,2,41 triazole

As described for example 53a, l-(4-Fluoro-phenyl)-5-methyl-lH-[l,2,4]triazole-3- carbaldehyde (1.00 mg, 4.88 mmol) instead of 5-(4-fluoro-phenyl)-l-methyl-lH- pyrazole-3-carbaldehyde was converted to the title compound (25 mg, 6%) which was obtained as a light yellow oil. MS: m/e = 202.3 [M+H] ⁺ .

d ) l-(4-Fluoro-phenyl)-5-methyl-3-(5-methyl-3-phenyl-isoxazol-4 -ylethynyl)-lH- [1,2,41 triazole

As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (108 mg, 0.38 mmol) was converted (using 3-ethynyl-l-(4-fluoro-phenyl)-5-methyl-lH-[l,2,4]triazole instead of 2-ethynylpyridine) to the title compound (SiCh, heptane:ethyl acetate = 95:5 to 0:100, 22 mg, 16%) which was obtained as a light brown solid. MS: m/e = 359.1 [M+H] ⁺ .

Example 55 4-[5-(3-Fluoro-phenyl)-l-methyl-lH-pyrazol-3-ylethynyl]-5-me thyl-3-phenyl-isoxazole

a) 3-Ethynyl-5-(3-fluoro-phenyl)-l -methyl- lH-pyrazole

As described for example 53a, 5-(3-fluoro-phenyl)-l-methyl-lH-pyrazole-3- carbaldehyde (maybe prepared in analogy to WO2005014553, 515 mg, 2.52 mmol) instead of 5-(4-fluoro-phenyl)-l-methyl-lH-pyrazole-3-carbaldehyde was converted to the title compound (500 mg, 99%) which was obtained as a light yellow oil. MS: m/e = 201.1 [M+H] ⁺ .

b) 4- [5-(3-Fluoro-phenyl)-l -methyl- lH-pyrazol-3-ylethynyll-5-methyl-3-phenyl- isoxazole

As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (108 mg, 0.38 mmol) was converted (using 3-ethynyl-5-(3-fluoro-phenyl)-l-methyl-lH-pyrazole instead of 2- ethynylpyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 48 mg, 35%) which was obtained as a light yellow oil. MS: m/e = 358.1 [M+H] ⁺ .

Example 56

4-[l-(3,5-Difluoro-phenyl)-2,5-dimethyl-lH-iniidazol-4-yl ethynyl]-5-niethyl-3-phenyl- isoxazole As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (94 mg, 0.33 mmol) was converted [using l-(3,5-difluoro-phenyl)-4-ethynyl-2,5-dimethyl-lH-imidazole (maybe prepared in analogy to WO2005118568) instead of 2-ethynylpyridine] to the title

compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 41 nig, 32%) which was obtained as an off-white solid. MS: m/e = 390.2 [M+H] ⁺ .

Example 57 4-[l-(4-Fluoro-phenyl)-2,5-dimethyl-lH-imidazol-4-ylethynyl] -5-methyl-3-phenyl- isoxazole

As described for example 1, 4-iodo-5-methyl-3-phenylisoxazole (100 mg, 0.38 mmol) was converted [using 4-ethynyl-l-(4-fluoro-phenyl)-2,5-dimethyl-lH-imidazole (may be prepared in analogy to WO2005118568) instead of 2-ethynylpyridine] to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 48 mg, 37%) which was obtained as an off-white solid. MS: m/e = 372.2 [M+H] ⁺ .

Example 58 2- [3-(3-Chloro-4-methoxy-phenyl)-5-methyl-isoxazol-4-ylethynyl ] -pyridine

As described for example l ie, 3-(3-chloro-4-methoxy-phenyl)-4-ethynyl-5-methyl- isoxazole (134 mg, 0.50 mmol) instead of 4-ethynyl-5-methyl-3-phenyl-isoxazole was converted (using 2-bromopyridine instead of 2-chloro-4-iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 117 mg, 72%) which was obtained as a white solid. MS: m/e = 325.2 [M+H] ⁺ .

Example 59 2- [3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylethynyl] -pyridine

As described for example l ie, 3-(4-chloro-phenyl)-4-ethynyl-5-methyl-isoxazole (109 mg, 0.50 mmol) instead of 4-ethynyl-5-methyl-3-phenyl-isoxazole was converted (using 2-bromopyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiCh, heptane:ethyl acetate = 95:5 to 0:100, 129 mg, 87%) which was obtained as a light brown solid. MS: m/e = 295.1 [M+H] ⁺ .

Example 60 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-thiazole-5-carbox ylic acid methyl ester

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using methyl 2-bromothiazole-5-carboxylate instead of 2-chloro-

4-iodopyridine) to the title compound (Siθ2, heptane:ethyl acetate = 95:5 to 0:100, 139 mg, 86%) which was obtained as a light yellow solid. MS: m/e = 325.2 [M+H] ⁺ .

Example 61 2-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-thiazole-4-carbox ylic acid methyl ester

As described for example l ie, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using methyl 2-bromothiazole-4-carboxylate instead of 2-chloro- 4-iodopyridine) to the title compound (SiCh, heptane:ethyl acetate = 95:5 to 0:100, 113 mg, 70%) which was obtained as a light yellow solid. MS: m/e = 325.2 [M+H] ⁺ .

Example 62 4-(2-Isopropyl-thiazol-4-ylethynyl)-5-methyl-3-phenyl-isoxaz ole

As described for example 1 Ic, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 4-bromo-2-isopropylthiazole instead of 2-chloro-4- iodopyridine) to the title compound (SiC^, heptane:ethyl acetate = 95:5 to 0:100, 23 mg, 15%) which was obtained as a yellow oil. MS: m/e = 309.3 [M+H] ⁺ .