Patent Description:
The free fatty acid receptors are G-protein coupled receptors which bind free fatty acids [<NUM>]. Free fatty acid receptors have broad tissue distribution, e.g., they are expressed in mouth (possibly for sensing fatty taste), digestive system (as energy sensors, and eating sensors), pancreatic Beta cells (to sense feeding), and even in CNS (of yet unknown function). There are at least four different FFARs, each encoded by a separate gene (FFAR1, FFAR2, FFAR3, FFAR4). Preliminary findings suggest that FFAR2 and FFAR3 may interact to form a FFAR2-FFAR3 receptor heteromer. [<NUM>] Free fatty acid receptors (FFA, nomenclature as agreed by the NC-IUPHAR Subcommittee on free fatty acid receptors [<NUM>,<NUM>]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (C14. <NUM> (myristic acid), C16:<NUM> (palmitic acid), C18:<NUM> (oleic acid), C18:<NUM> (linoleic acid), C18:<NUM>, (α-linolenic acid), C20:<NUM> (arachidonic acid), C20:<NUM>,n-<NUM> (EPA) and C22:<NUM>,n-<NUM> (docosahexaenoic acid)) activate FFAR1 [<NUM>, <NUM>, <NUM>] and FFAR4 receptors [<NUM>, <NUM>, <NUM>]. while short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFAR2 [<NUM>, <NUM>, <NUM>] and FFAR3 [<NUM>, <NUM>] receptors. The crystal structure for agonist bound FFAR1 has been described in [<NUM>].

FFAR1 is also known as GPR40, FFAR4 is known as GPR120.

Several known FFAR1 (GPR40) agonists are under development as Type <NUM> diabetic drugs. An example is Fasiglifam (TAK-<NUM>) is a highly potent GPR40 agonist (low nanomolar EC<NUM> on human GPR40) with marked selectivity over other FFA family receptors (i.e., GPR120). It stimulates insulin secretion independently of blood glucose levels, which led to the expectation that TAK-<NUM>, in contrast to other anti-diabetic medicines, would not induce hypoglycemia, while also causing less weight gain [<NUM>]. Although very promising, the development of TAK-<NUM> was terminated in <NUM> due to (liver) toxicity issues in phase III clinical trials. Also the clinical development of other FFAR1 (GPR40) agonists such as LY2881835 [<NUM>] and AMG <NUM> [<NUM>] was stopped because of toxicity issues.

Several agonists for FFAR4 (GPR120), are undergoing preliminary development. In the search for compounds binding and activating FFAR4 (GPR120): for example, GW9508, initially identified as a GPR40 agonist, was shown to also moderately activate GPR120 [<NUM>]. However, the dual specificity of GW9508 for GPR40 and GPR120 represents a confounding variable in the interpretation of results in studies using GW9508 as a result of off-target effects at GPR40. Further research identified several other potential agonists for GPR120 including the plant-derived compound grifolic acid which acts as a partially selective GPR120 agonist [<NUM>], and NCG21 [<NUM>] as well as GSK-137647A [<NUM>], which are reported to be selective for GPR120. Recently, TUG891 has been made commercially available as a GPR120 agonist. TUG891 is reported to be potent and selective for GPR120 demonstrating greater selectivity and potency to GPR120 than GPR40 [<NUM>].

The broad tissue distribution of FFARs and their apparently diverse physiological functions in the body has resulted in the target class being investigated for several types of diseases. The FFAR family's broad tissue distribution and involvement in multiple physiological processes also mean that target selectivity within the FFAR family is a major issue to consider in the context of development of therapeutic molecules. FFAR1/GPR40 has emerged as a target for treatment of (T2DM). T2DM is a disease in which blood sugar homeostasis is regulated improperly by insulin. Insulin is secreted from pancreatic b cells in response to elevated plasma glucose, with several additional types of signals combining to modify its insulin secretion rate from pancreatic b cells. One of those signals comes from free fatty acids circulating in the bloodstream, which typically accompany elevated blood glucose following feeding. In <NUM>, it was demonstrated [<NUM>] that FFAR1/GPR40 is abundantly expressed on the surface of pancreatic beta cells and functions as a receptor for long-chain FFAs, and that these FFAs amplify glucose-stimulated insulin secretion. Agonism of FFAR1/GPR40 in pancreatic beta cells was demonstrated to amplify insulin secretion over a period spanning hours, and even full agonism of the receptor did not appear to result in secretion of insulin levels sufficient to drive hypoglycemia. Hypoglycemia means low blood glucose, and severe hypoglycemia occurs when the blood glucose level becomes so low that a patient is unable to maintain normal activity, and it can result in loss of consciousness and be life threatening (due to oxygen deprivation in the brain which function crucially depends on appropriate glucose supply). Critically, available insulin stimulation drugs for treating T2DM generally have the potential to result in inappropriately high insulin secretion and trigger severe hypoglycemia. Since severe hypoglycemia cannot be triggered by agonizing GPR40, GPR40 agonists therefore have a high potential for the treatment of T2DM.

<NPL>) disclose certain phenoxymethyl <NUM>,<NUM>-oxazoles and <NUM>,<NUM>,<NUM>-oxadiazoles as agonists of FFAR1.

The technical problem underlying the present invention is to provide agonists of FFARs, in particular agonists of FFAR1.

The above technical problem is provided by the embodiments of the present invention as characterized in the claims, the present description and the drawings.

In particular, the present invention provides a compound of general formula (I).

Preferred halide substituents of the invention are selected from CI, Br and F.

In the context of the present invention, the "C<NUM>-C<NUM> alkyl (group)" means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, <NUM>-ethylpropyl, hexyl, isohexyl, <NUM>,<NUM>-dimethylbutyl, <NUM>,<NUM>-dimethylbutyl, <NUM>,<NUM>-dimethylbutyl, <NUM>-ethylbuty, or the like. C<NUM>-C<NUM>-alkyl groups, more preferably those mentioned before, are preferred. It is also to be understood that the above examples and preferred embodiments of "C<NUM>-C<NUM> alkyl" also relate to substituents in which such ""C<NUM>-C<NUM> alkyl" is present. Any alkyl group as referred to herein having more than <NUM> carbons may be a linear or branched chain.

In the context of the present invention, the "C<NUM>-C<NUM>-alkoxy (group)" means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, tert. -butoxy or the like. C<NUM>-C<NUM>-alkoxy groups, more preferably those mentioned before, are preferred. Any alkoxy group as referred to herein having more than <NUM> carbons may be a linear or branched chain.

In the context of the present invention, a "N-mono-C<NUM>-C<NUM>-alkylamino (group)" means, for example, methylamino, ethylamino, propylamino, isopropylamino or the like.

In the context of the present invention, a "N,N-di-C<NUM>-C<NUM>-alkylamino (group)" means, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, or the like. It is to be understood that the C<NUM>-C<NUM>-alkyl groups of the N,N-di-C<NUM>-C<NUM>-alkylamino (group) may also be different from one another.

In the context of the present invention, a "C<NUM>-C<NUM>-cycloalkyl (group)" means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like. C<NUM>-C<NUM>-cycloalkyl groups, more preferably those mentioned before, are preferred.

In the context of the present invention, the <NUM>-membered aryl substituent of <NUM>,<NUM>,<NUM>-triazine or pyrimidine in the definition of R<NUM> of general formula (I) means phenyl.

In the context of the present invention, examples of the "<NUM>- or <NUM>-membered heteraryl (group)" means a <NUM>- or <NUM>-membered monocyclic aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, <NUM> to <NUM> hetero atoms selected from an oxygen atom, a sulfur atom (optionally oxidized) and a nitrogen atom (optionally oxidized). Examples thereof include furyl (e.g., <NUM>-furyl, <NUM>-furyl), thienyl (e.g., <NUM>-thienyl, <NUM>-thienyl), pyridyl (e.g., <NUM>-pyridyl, <NUM>-pyridyl, <NUM>-pyridyl), pyrimidinyl (e.g., <NUM>-pyrimidinyl, <NUM>-pyrimidinyl, <NUM>-pyrimidinyl), pyridazinyl (e.g., <NUM>-pyridazinyl, <NUM>-pyridazinyl), pyrazinyl (e.g., <NUM>-pyrazinyl), pyrrolyl (e.g., <NUM>-pyrrolyl, <NUM>-pyrrolyl, <NUM>-pyrrolyl), imidazolyl (e.g., <NUM>-imidazolyl, <NUM>-imidazolyl, <NUM>-imidazolyl, <NUM>-imidazolyl), pyrazolyl (e.g., <NUM>-pyrazolyl, <NUM>-pyrazolyl, <NUM>-pyrazolyl), thiazolyl (e.g., <NUM>-thiazolyl, <NUM>-thiazolyl, <NUM>-thiazolyl), isothiazolyl (e.g., <NUM>-isothiazolyl, <NUM>-isothiazolyl, <NUM>-isothiazolyl), and the like.

In the context of the present invention, a "non-aromatic <NUM>-to <NUM>-membered heterocyclic group" means a <NUM>- or <NUM>-membered monocyclic non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, <NUM> to <NUM> hetero atoms selected from an oxygen atom, a sulfur atom (optionally oxidized) and a nitrogen atom (optionally oxidized). Examples thereof include azetidinyl (e.g., <NUM>-azetidinyl, <NUM>-azetidinyl), pyrrolidinyl (e.g., <NUM>-pyrrolidinyl, <NUM>-pyrrolidinyl), piperidyl (e.g., piperidino, <NUM>-piperidyl, <NUM>-piperidyl, <NUM>-piperidyl), morpholinyl (e.g., morpholino), thiomorpholinyl (e.g., thiomorpholino), piperazinyl (e.g., <NUM>-piperazinyl, <NUM>-piperazinyl, <NUM>-piperazinyl), oxazolidinyl (e.g., oxazolidin-<NUM>-yl), thiazolidinyl (e.g., thiazolidin-<NUM>-yl), dihydrothiopyranyl (e.g., dihydrothiopyran-<NUM>-yl, dihydrothiopyran-<NUM>-yl), imidazolidinyl (e.g., imidazolidin-<NUM>-yl, imidazolidin-<NUM>-yl), oxazolinyl (e.g., oxazolin-<NUM>-yl), thiazolinyl (e.g., thiazolin-<NUM>-yl), imidazolinyl (e.g., imidazolin-<NUM>-yl, imidazolin-<NUM>-yl), dioxolyl (e.g., <NUM>,<NUM>-dioxol-<NUM>-yl), dioxolanyl (e.g., <NUM>,<NUM>-dioxolan-<NUM>-yl), dihydrooxadiazolyl (e.g., <NUM>,<NUM>-dihydro-<NUM>,<NUM>,<NUM>-oxadiazol-<NUM>-yl), pyranyl (e.g., <NUM>-pyranyl, <NUM>-pyranyl), tetrahydropyranyl (e.g., <NUM>-tetrahydropyranyl, <NUM>-tetrahydropyranyl, <NUM>-tetrahydropyranyl), thiopyranyl (e.g., <NUM>-thiopyranyl), tetrahydrothiopyranyl (e.g., <NUM>-tetrahydrothiopyranyl, <NUM>-tetrahydrothiopyranyl, <NUM>-tetrahydrothiopyranyl), <NUM>-oxidotetrahydrothiopyranyl (e.g., <NUM>-oxidotetrahydrothiopyran-<NUM>-yl), <NUM>,<NUM>-dioxidotetrahydrothiopyranyl (e.g., <NUM>,<NUM>-dioxidotetrahydrothiopyran-<NUM>-yl), tetrahydrofuryl (e.g., tetrahydrofuran-<NUM>-yl, tetrahydrofuran-<NUM>-yl), oxetanyl (e.g., oxetan-<NUM>-yl, oxetan-<NUM>-yl), pyrazolidinyl (e.g., pyrazolidin-<NUM>-yl, pyrazolidin-<NUM>-yl), pyrazolinyl (e.g., pyrazolin-<NUM>-yl), tetrahydropyrimidinyl (e.g., tetrahydropyrimidin-<NUM>-yl), dihydrotriazolyl (e.g., <NUM>,<NUM>-dihydro-<NUM>-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl), tetrahydrotriazolyl (e.g., <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl, dihydropyridyl (e.g., dihydropyridin-<NUM>-yl, dihydropyridin-<NUM>-yl, dihydropyridin-<NUM>-yl, dihydropyridin-<NUM>-yl), tetrahydropyridyl (e.g., <NUM>,<NUM>,<NUM>,<NUM>-tetrahydropyridin-<NUM>-yl, <NUM>,<NUM>,<NUM>,<NUM>-tetrahydropyridin-<NUM>-yl, <NUM>,<NUM>,<NUM>,<NUM>-tetrahydropyridin-<NUM>-yl, <NUM>,<NUM>,<NUM>,<NUM>-tetrahydropyridin-<NUM>-yl) and the like.

In preferred embodiments of the invention R<NUM> is <NUM>,<NUM>,<NUM>-triazinyl substituted as defined above in general formula (I). It is further preferred that, if the <NUM>,<NUM>,<NUM>-triazinyl group is substituted with more than one substituent, the substituents are different. According to further preferred embodiments, the <NUM>,<NUM>,<NUM> triazinyl group is independently substituted with one or two substituents selected from the group consisting of amino, methyl, ethyl, isopropyl and tert. -butyl, which may be in turn substituted with one or more halide, preferably Cl, F and/or Br.

According to particularly preferred compounds of the inventions R<NUM> is selected from the group consisting of
<CHM>
<CHM>
and
<CHM>.

In other preferred embodiments of the invention, R<NUM> is pyrimidinyl substituted as defined above in general formula (I). It is further preferred that, if the pyrimidinyl group is substituted with more than one substituent, the substituents are different. According to further preferred embodiments the pyrimidinyl group is independently substituted by one or more substituents selected from the group consisting of amino (preferably mono- or di-substituted with methyl, more preferably methylamino), methyl and ethyl wherein the latter two groups are substituted with one or more halides as defined above.

According to particular preferred embodiments of the compound of the invention R<NUM> is selected from the group consisting of
<CHM>
<CHM>.

According to further preferred embodiments of the invention are compounds of general formula (I) wherein R<NUM> is independently substituted with one more substituents selected from the group consisting of Cl, Br, F, methyl, triflourmethyl, methoxy and ethoxy. Furthermore, it is preferred that R<NUM> is substituted in at least one meta position and/or at least one ortho position.

According to particularly preferred embodiments of the invention R<NUM> is selected from the group consisting of
<CHM>.

Highly active agonists of GPR40 according to the invention are compounds wherein R<NUM> is not substituted in the para position.

Particularly preferred groups for R<NUM> are selected from the group consisting of
<CHM>
<CHM>
<CHM>
and
<CHM>.

Highly preferred compounds of the invention are compounds shown in <FIG>. <FIG> shows additional compounds specifically preferred for the use as medicaments, in particular for the uses according to the invention as further described below.

Particularly preferred compounds according to the invention are shown in the following Table <NUM> whereby it is to be understood that <NUM>,<NUM>,<NUM>-oxadiazolyl and <NUM>,<NUM>,<NUM>-oxadiazolyl, respectively, compounds presented in Table <NUM> are only disclosed as far as they relate to the compound for use according to the invention as defined in claim <NUM>.

Further particularly preferred compounds of the invention are shown in the following Table <NUM>:.

Further particularly preferred compounds for use according to the invention as defined in claim <NUM> are shown in the following Table <NUM>:.

Further particularly preferred compounds according to the invention are shown in the following Table <NUM> whereby it is to be understood that <NUM>,<NUM>,<NUM>-oxadiazolyl compounds presented in Table <NUM> are only disclosed as far as they relate to the compound for use of claim <NUM>:.

Further particularly preferred compounds according to the invention are shown in the following Table <NUM>:.

According to the invention compounds disclosed herein are to be understood as also including the respective enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable co-crystals or salts and complexes thereof.

Pharmaceutically acceptable salts are typically salts of an organic or inorganic acids generally known in the art as pharmaceutically acceptable, preferably those disclosed in <NPL>. A preferred salt of the invention is the hydrochloride salt of a compound as disclosed herein.

The compounds as defined herein are particularly useful as agonists of GPR40, wherein, according to preferred embodiments, the compound shows a higher selectivity for GPR40 than for GPR120.

More preferably, the compound as defined herein shows a % activation of GPR40 being at least 3fold higher than the % activation of GPR120, with % activation being the hundredfold ratio of activation of GPR40 or GPR120, respectively, by said compound to the activation of GPR40 or GPR120, respectively, by AMG <NUM>. AMG <NUM> is a known potent agonist of GPR40 [<NUM>].

The compounds of the present invention are potent and selective agonists and are preferably provides as such agonists, of FFAR1 (GPR40]. In particular, the compounds as disclosed herein are more selective and potent agonists of FFAR1 than of FFAR4. In preferred embodiments of the invention, a compound as disclosed herein shows an at least <NUM> fold %, more preferably a <NUM> to <NUM> fold, % activation of FFAR1 in comparison to its % activation of FFAR4 (GPR120), with % activation always being the 100fold ratio of activation of the respective receptor by the compound as disclosed herein and the activation of the respective receptor by AMG <NUM>. According to alternative embodiments of the invention, the % activation as used herein may also be expressed by reference to the activation by TAK-<NUM>.

The compounds as disclosed herein are useful as medicaments, preferably for the prevention, improvement of symptoms, suppression of progression or treatment of conditions or diseases in a mammalian (such as, e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) subject as further outlined below.

For medical use the compounds of this disclosure may be used as such or as an active ingredient of a pharmaceutical composition comprising at least one compound of general formula (I) and at least one pharmaceutically acceptable carrier.

Useful pharmaceutically acceptable carriers are various organic or inorganic carrier substances which are conventionally used as preparation materials in the pharmaceutical art. These may be incorporated as excipients, lubricants, binders and disintegrants for solid preparations, or solvents, solubilizing agents, suspending agents, isotonicity agents, buffers and soothing agents for liquid preparations, and the like, in the present pharmaceutical composition. Further ingredients are preferably selected from preparation additives such as preservatives, antioxidants, colorants, sweetening agents and the like, which can be added as necessary.

Preferred examples of excipients include, but are not limited to, lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatinated starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthesis aluminum silicate and magnesium alumino metasilicate.

Preferred examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, talc and colloidal silica.

Preferred binders include, but are not limited to, gelatinated starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.

Preferred disintegrants include, but are not limited to, lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low-substituted hydroxypropylcellulose.

Preferred examples of useful solvents include, but are not limited to, water for injection, physiological brine, Ringer's solution, Ringer lactate, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Preferred solubilizing agents include, but are not limited to, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.

Preferred suspending agents for use in the present inventiuon include, but are not limited to, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; polysorbates; and polyoxyethylene hydrogenated castor oil.

Preferred examples of isotonicity agents are sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose.

Preferred buffer substances include buffers such as phosphate, acetate, carbonate, citrate and the like.

A preferred soothing agent in the context of the invention is benzyl alcohol.

Preferred examples of preservatives for use in the pharmaceutical composition include, but are not limited to, p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.

Preferred antioxidants for use in the invention include, but are not limited to, sulfite and ascorbate.

Preferred colorants include, e.g., aqueous water-soluble food tar colors (e.g., food colors such as Food Color Red Nos. <NUM> and <NUM>, Food Color Yellow Nos. <NUM> and <NUM>, Food Color Blue Nos. <NUM> and <NUM> and the like food colors), water insoluble lake dyes (e.g., aluminum salt of the aforementioned water-soluble food tar color) and natural dyes (e.g., β-carotene, chlorophyll, ferric oxide red).

Preferred sweetening agents are, e.g., saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia.

Preferred dosage forms of the pharmaceutical composition include oral preparations such as tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet), capsules (including soft capsule, microcapsule), granule, powder, troche, syrup, emulsion, suspension, films (e.g., orally disintegrable films) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparations (e.g., dermal preparation, ointment), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop.

Pharmaceutical compositions of the invention may be in the form of release control preparations (e.g., sustained-release microcapsule) such as an immediate-release preparation, a sustained-release preparation and the like.

The pharmaceutical composition can be produced according to a method conventionally used in the field of pharmaceutical formulation.

While the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, dose of the compound of the present invention or as disclosed herein and further parameters such as the specific aids as outlined above, it is typically contained in the pharmaceutical composition at about <NUM> to about <NUM> wt %.

Oral pharmaceutical compositions of the invention may comprise one or more coatings which may be applied as necessary for the purpose of various parameters such as masking of taste, enteric property or durability.

Further specific guidance concerning the ingredients, but also routes for administration, dosage etc., of the pharmaceutical composition can be found in the latest edition of <NPL>).

Any references in the present disclosure to methods of treatment refer to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy.

As defined in claim <NUM>, the invention is also directed to a compound of general formula (I).

The compounds disclosed herein for use in the prevention, improvement of symptoms, suppression of progression or treatment of conditions or diseases involving of conditions or diseases amenable to higher GBR40 (FFAR1) activity, in particular, conditions or diseases involving energy household and metabolism, preferably conditions or diseases involving impaired control of glucose blood levels, more preferably diabetes, most preferred T2DM, and pre-diabetic conditions such as obesity and insulin resistance. The present invention therefore also relates to a method for the prevention, improvement of symptoms, suppression of progression or treatment of diseases involving of conditions or diseases amenable to higher GBR40 (FFAR1) activity, in particular, conditions or diseases involving energy household and metabolism, preferably conditions or diseases involving impaired control of glucose blood levels, more preferably diabetes, most preferred T2DM, and pre-diabetic conditions such as obesity and insulin resistance, which method comprises the step of administering an effective amount of a compound as disclosed herein to a subject, preferably human subject, in need thereof.

The present invention also relates to the use of the disclosed compounds for the preparation of a medicament for the prevention, improvement of symptoms, suppression of progression or treatment of diseases involving of conditions or diseases amenable to higher GBR40 (FFAR1) activity, in particular, conditions or diseases involving energy household and metabolism, preferably conditions or diseases involving impaired control of glucose blood levels, more preferably diabetes, most preferred T2DM, and pre-diabetic conditions such as obesity and insulin resistance.

The administration of the compound disclosed herein is preferably systemic, with oral administration being particularly preferred.

The "effective amount" of the compound disclosed herein varies depending on the administration subject, route of administration, target disease, symptoms, sex of the subject etc. For example, when it is administered orally to an adult patient (body weight <NUM>), its dose is typically about <NUM> to about <NUM>/kg body weight per dose, preferably about <NUM> to about <NUM>/kg body weight per dose, more preferably about <NUM> to about <NUM>/kg body weight per dose, with such exemplary or preferable effective amounts being preferably administered in <NUM> to <NUM> doses per day.

When the compound of formula (I) as disclosed herein is applied to a condition or diseases as outlined above, it can be used in an appropriate combination with a medicament or a treatment method generally employed for the condition or disease, respectively, whereby the compound of the invention (or compound being useful in the invention) can administered with the second, third or more medicament simultaneously or non-simultaneously. Preferred combination therapies according to the invention employ at least one compound of formula (<NUM>) and one or more selected from biduanides such as preferagly Metformin, SGTL2 inhibitors (gliflozins) such as preferably dapagliflohin, DPP-<NUM> inhibitors such as preferably one or more selected from Sitagliptin, Vildagliptin, Saxagliptin and Linagliptin, α-glucosidase inhibitors such as Acarbose, Miglitol and Voglibose, sulfonylurea compounds such as preferably one or more selected from acetohexamide, carbutamide, chlorpropamide, glycyclamide metahexamide, tolazamide, tolbutamide glibenclamide, glibornuride, gliclazide,[ glipizide, gliquidone, glisoxepide, glyclopyramide and glimipiride, glinides such as preferably one or more selected from repaglinide, nateglinide and mitiglinide as well as other agonists of GPR40 and/or GPR120 such as preferably one or more of TAK-<NUM>, LY2881835, AMG6837, GW9608, grifolic acid, NCG21, GSK-137677A and TUG391.

It is to be understood that with respect to all uses according to the invention, a "compound as disclosed herein" refers to the compound of general formula (I) as defined in claim <NUM>.

Preferred embodiments of the compounds of the present disclosure wherein OXA in general formula (I) is <NUM>,<NUM>-oxazolyl are preferably prepared according to one the following general synthesis schemes:
<CHM>
<CHM>
wherein R is as defined as the substituents at the phenyl group as defined in R<NUM> according to general formula (I), R' is H or C<NUM>-C<NUM>-alkyl, and R" is a substituent selected from hydroxyl, amino, C<NUM>-C<NUM>-alkyl, C<NUM>-C<NUM>-cycloalkyl, C<NUM>-C<NUM>-alkoxy, , N-mono- or N,N-di-substituted C<NUM>-C<NUM>-alkylamino, non-aromatic <NUM>- to <NUM>-membered heterocyclyl, <NUM>- membered aryl and <NUM>- to <NUM>-membered heteroaryl, optionally substituted with one or more groups selected from halide, cyano and C<NUM>to C<NUM>-alkyl. <CHM>
wherein R is as defined as the substituents at the phenyl group as defined in R<NUM> according to general formula (I), R' is a substituent selected from hydroxyl, amino, C<NUM>-C<NUM>-alkyl, C<NUM>-C<NUM>-cycloalkyl, C<NUM>-C<NUM>-alkoxy, N-mono- or N,N-di-substituted C<NUM>-C<NUM>-alkylamino, non-aromatic <NUM>- to <NUM>-membered heterocyclyl, <NUM>- membered aryl and <NUM>- to <NUM>-membered heteroaryl,, optionally substituted with one or more groups selected from halide, cyano and C<NUM>to C<NUM>-alkyl. <CHM>
<CHM>
wherein R is as defined as the substituents at the phenyl group as defined in R<NUM> according to general formula (I), R' is a substituent selected from hydroxyl, amino, C<NUM>-C<NUM>-alkyl, C<NUM>-C<NUM>-cycloalkyl, C<NUM>-C<NUM>-alkoxy, N-mono- or N,N-di-substituted C<NUM>-C<NUM>-alkylamino, non-aromatic <NUM>- to <NUM>-membered heterocyclyl, <NUM>- membered aryl and <NUM>- to <NUM>-membered heteroaryl,, optionally substituted with one or more groups selected from halide, cyano and C<NUM> to C<NUM>-alkyl.

The present invention is further illustrated by the following non-limiting examples:
It is to be understood that any <NUM>,<NUM>,<NUM> -oxadiazolyl and <NUM>,<NUM>,<NUM> oxadiazolyl, respectively, compound referred to in the following examples is disclosed only in the context of the compound for use of the invention as defined in claim <NUM>.

To a stirred solution of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethanone (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added sodium diformylamide (<NUM>, <NUM> mmol). The mixture was stirred at ambient temperature for <NUM>. Inorganics was filtered off, and the filtrate was concentrated in vacuo. 5N Hydrochloric acid (<NUM>) was added to the dark oily residue, and the resulting mixture was heated to reflux for <NUM>. The hot solution was separated from dark viscous oil, and was allowed to cool down to ambient temperature. The precipitate formed was filtered and successively washed with 5N hydrochloric acid and diethyl ether affording <NUM>-amino-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethanone hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as yellow crystals. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethanone hydrochloride (<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in a mixture of ethyl acetate (<NUM>) and water (<NUM>), chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM> <NUM>. After the completion of the reaction, the ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording N-(<NUM>-oxo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a pink solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated under reflux for <NUM>. Gas evolution was observed. Then, the reaction mixture was allowed to cool down to RT, and was poured into crashed ice (<NUM>). The precipitate was filtered and washed with water affording <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-trifluoromethylphenyl)ethanone hydrochloride (<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM> <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording N-(<NUM>-oxo-<NUM>-(<NUM>-trifluoromethylphenyl)ethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-(<NUM>-(trifluoromethylphenyl)ethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated to reflux for <NUM>. Gas evolution was observed. Then the reaction mixture was allowed to cool down to ambient temperature, and was poured into crashed ice (<NUM>). The precipitate was filtered and washed with water affording <NUM>-(chloromethyl)-<NUM>-[<NUM>-(trifluoromethyl)phenyl]-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>,<NUM>-dichlorophenyl)ethanone hydrochloride (<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM> <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording N-(<NUM>-oxo-<NUM>-(<NUM>,<NUM>-dichlorophenyl)ethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a colorless solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-(<NUM>,<NUM>-dichlorophenyl)ethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated to reflux for <NUM>. Gas evolution was observed. Then the reaction mixture was allowed to cool down to ambient temperature, and was poured into crashed ice (<NUM>). The precipitate was filtered and washed with water affording <NUM>-(chloromethyl)-<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-bromo-<NUM>-(<NUM>,<NUM>-dichlorophenyl)ethanone (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added sodium diformylamide (<NUM>, <NUM> mmol). The mixture was stirred at ambient temperature for <NUM>. Inorganics was filtered off, and the filtrate was concentrated in vacuo. 5N hydrochloric acid (<NUM>) was added to the dark oily residue, and the resulting mixture was heated to reflux for <NUM>. The hot solution was separated from dark viscous oil, and was allowed to cool down to ambient temperature. The precipitate formed was filtered and successively washed with 5N hydrochloric acid and diethyl ether affording <NUM>-amino-<NUM>-(<NUM>,<NUM>-dichlorophenyl)ethanone hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as colorless crystals. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>,<NUM>-dichlorophenyl)ethanone hydrochloride (<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM> <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording N-(<NUM>-oxo-<NUM>-(<NUM>,<NUM>-dichlorophenyl)ethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (t, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-(<NUM>,<NUM>-dichlorophenyl)ethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated to reflux for <NUM>. Gas evolution was observed. Then the reaction mixture was allowed to cool down to ambient temperature, and was poured into crashed ice (<NUM>). The precipitate was filtered and washed with water affording <NUM>-(chloromethyl)-<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM> CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-bromo-<NUM>-(<NUM>-ethylphenyl)ethanone (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added sodium diformylamide (<NUM>, <NUM> mmol). The mixture was stirred at ambient temperature for <NUM>. Inorganics was filtered off, and the filtrate was concentrated in vacuo. 5N hydrochloric acid (<NUM>) was added to the dark oily residue, and the resulting mixture was heated to reflux for <NUM>. The hot solution was separated from dark viscous oil, and was allowed to cool down to ambient temperature. The reaction mixture was concentrated in vacuo, and the residue was crystallized from 5N hydrochloric acid affording <NUM>-amino-<NUM>-(<NUM>-ethylphenyl)ethanone hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as yellow crystals. <NUM> NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-ethylphenyl)ethanone hydrochloride (<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording N-(<NUM>-oxo-<NUM>-(<NUM>-ethylphenyl)ethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a beige solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM>( br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-(<NUM>-ethylphenyl)ethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated to reflux for <NUM>. Gas evolution was observed. Then the reaction mixture was allowed to cool down to ambient temperature, and was poured into crashed ice (<NUM>). The precipitate was filtered and washed with water affording <NUM>-(<NUM>-ethylphenyl)-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-ethoxyphenyl)ethanone hydrochloride(<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording N-(<NUM>-oxo-<NUM>-(<NUM>-ethoxyphenyl)ethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-(<NUM>-ethoxyphenyl)ethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated to reflux for <NUM>. Gas evolution was observed. Then the reaction mixture was allowed to cool down to ambient temperature, and was poured into crashed ice (<NUM>). Chloroform (<NUM>) was added, and the resulting mixture was stirred for <NUM>. The organic layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording <NUM>-(<NUM>-ethoxyphenyl)-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a brown oil. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-biphenyl-<NUM>-yl-<NUM>-bromoethanone (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added sodium diformylamide (<NUM>, <NUM> mmol). The mixture was stirred at rt for <NUM>. Inorganics was filtered off, and the filtrate was concentrated in vacuo. 5N hydrochloric acid (<NUM>) was added to the dark oily residue, and the resulting mixture was heated to reflux for <NUM>. The hot solution was separated from dark viscous oil, and was allowed to cool down to rt. The precipitate formed was filtered and successively washed with 5N hydrochloric acid and diethyl ether affording <NUM>-amino-<NUM>-biphenyl-<NUM>-ylethanone hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as brown crystals. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS (CI): m/z = <NUM> [M]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-biphenyl-<NUM>-ylethanone hydrochloride (<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM> <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording N-(<NUM>-oxo-<NUM>-biphenyl-<NUM>-ylethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-biphenyl-<NUM>-ylethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated to reflux for <NUM>. Gas evolution was observed. Then the reaction mixture was allowed to cool down to ambient temperature, and was poured into crashed ice (<NUM>). The precipitate was filtered and washed with water affording <NUM>-biphenyl-<NUM>-yl-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole as (<NUM>, <NUM>% purity, <NUM>% yield) a brown solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-fluorophenyl)ethanone (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added sodium diformylamide (<NUM>, <NUM> mmol).

The mixture was stirred at ambient temperature for <NUM>. Inorganics was filtered off, and the filtrate was concentrated in vacuo. 5N hydrochloric acid (<NUM>) was added to the dark oily residue, and the resulting mixture was heated to reflux for <NUM>. The hot solution was separated from dark viscous oil, and was allowed to cool down to ambient temperature. The reaction mixture was concentrated in vacuo, and the residue was crystallized from 5N hydrochloric acid affording <NUM>-amino-<NUM>-(<NUM>-dichloro-<NUM>-fluorophenyl)ethanone hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as colorless crystals. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ddt, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-chloro-<NUM>-fluorophenyl)ethanone hydrochloride (<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM> <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated in vacuo affording N-(<NUM>-oxo-<NUM>-(<NUM>-chloro-<NUM>-fluorophenyl)ethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a colorless solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-(<NUM>-chloro-<NUM>-fluorophenyl)ethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated to reflux for <NUM>. Gas evolution was observed. Then the reaction mixture was allowed to cool down to ambient temperature and was poured into crashed ice (<NUM>). The precipitate was filtered and washed with water affording <NUM>-(<NUM>-chloro-<NUM>-fluorophenyl)-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-naphthyl)ethanone hydrochloride (<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM> <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated in vacuo affording N-(<NUM>-oxo-<NUM>-(<NUM>-naphthyl)ethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. m = <NUM> (yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-(<NUM>-naphthyl)ethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated to reflux for <NUM>. Gas evolution was observed. Then the reaction mixture was allowed to cool down to ambient temperature, and was poured into crashed ice (<NUM>). Chloroform (<NUM>) was added, and the resulting mixture was stirred for <NUM>. The organic layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording <NUM>-(chloromethyl)-<NUM>-(<NUM>-naphthyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a black oil. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-naphthyl)ethanone hydrochloride (<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM> <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording crude N-(<NUM>-oxo-<NUM>-(<NUM>-naphthyl)ethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-(<NUM>-naphthyl)ethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated to reflux for <NUM>. Gas evolution was observed. Then the reaction mixture was allowed to cool down to ambient temperature, and was poured into crashed ice (<NUM>). The mixture was allowed to warm up to ambient temperature, and was extracted with dichloromethane (<NUM> x <NUM>). The dichloromethane solution was dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording crude <NUM>-(chloromethyl)-<NUM>-(<NUM>-naphthyl)-<NUM>,<NUM>-oxazole as a brown oil. It was subjected to column chromatography on Silicagel (<NUM>-<NUM>) (ethyl acetate / hexane) affording <NUM>-(chloromethyl)-<NUM>-(<NUM>-naphthyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (tt, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-bromo-<NUM>-(<NUM>-trifluoromethoxyphenyl)ethanone (<NUM>, <NUM> mmol) in anhydrous ethyl acetate (<NUM>) was added sodium diformylamide (<NUM>, <NUM> mmol). The mixture was stirred at ambient temperature for <NUM>. Inorganics was filtered off, and the filtrate was concentrated in vacuo. 5N hydrochloric acid (<NUM>) was added to the dark oily residue, and the resulting mixture was heated to reflux for <NUM>. The hot solution was separated from dark viscous oil, and was allowed to cool down to <NUM>. The precipitate formed was filtered and successively washed with 10N hydrochloric acid and diethyl ether affording <NUM>-amino-<NUM>-(<NUM>-trifluoromethoxyphenyl)ethanone hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as colorless crystals. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>F NMR (<NUM>, DMSO-d<NUM>) δ -<NUM>. MS (CI): m/z = <NUM> [M]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-trifluoromethoxyphenyl)ethanone hydrochloride (<NUM>, <NUM> mmol) and sodium hydrocarbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, chloroacetyl chloride (<NUM>, <NUM> mmol) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording N-(<NUM>-oxo-<NUM>-(<NUM>-trifluoromethoxyphenyl)ethyl)chloroacetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>F NMR (<NUM>, CDCl<NUM>) δ - <NUM>. MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of N-(<NUM>-oxo-<NUM>-(<NUM>-trifluoromethoxyphenyl)ethyl)chloroacetamide (<NUM>, <NUM> mmol) in phosphoryl chloride (<NUM>, <NUM> mmol) was heated under reflux for <NUM>. Gas evolution was observed. Then, the reaction mixture was allowed to cool down to ambient temperature and was poured into crashed ice (<NUM>). The mixture was allowed to warm up to ambient temperature and was extracted with chloroform (<NUM> x <NUM>). The dichloromethane solution was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated in vacuo affording brown oil. It was subjected to column chromatography on Silicagel (<NUM>-<NUM>) (ethyl acetate/hexane) affording <NUM>-(chloromethyl)-<NUM>-(<NUM>-trifluoromethoxyphenyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a brown oil. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM>. MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethan-<NUM>-one (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added sodium diformylamide (<NUM>, <NUM> mmol) in one portion. The reaction mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off and the filtrate was concentrated in vacuo. Then, 5N hydrochloric acid (<NUM>) was added to the dark oily residue, and the resulting mixture was heated under reflux for <NUM>. The hot solution was separated from dark viscous oil and was allowed to cool down to <NUM>. The formed precipitate was filtered and washed with diethyl ether affording <NUM>-amino-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethan-<NUM>-one hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as colorless crystals. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br. s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethan-<NUM>-one hydrochloride (<NUM>, <NUM> mmol) and sodium hydrogen carbonate (<NUM>, <NUM> mmol) in a mixture of ethyl acetate (<NUM>)/water (<NUM>), <NUM>-chloroacetyl chloride (<NUM>, <NUM> mmol, <NUM>µl) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording <NUM>-chloro-N-[<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-oxoethyl]acetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a beige solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of <NUM>-chloro-N-[<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-oxoethyl]acetamide (<NUM>, <NUM> mmol) in phosphoryl trichloride (<NUM>, <NUM> mmol, <NUM>) was heated under reflux for <NUM>. Gas evolution was observed. Then, the reaction mixture was allowed to cool down to ambient temperature and was poured into crashed ice (<NUM>). The precipitate was filtered and washed with water affording <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a beige solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethan-<NUM>-one (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added sodium diformylamide (<NUM>, <NUM> mmol) in one portion. The reaction mixture was stirred at rt for <NUM>. The precipitate was filtered off and the filtrate was concentrated in vacuo. 5N hydrochloric acid (<NUM>) was added to the dark oily residue and the resulting mixture was heated to reflux for <NUM>. The hot solution was separated from dark viscous oil, and was allowed to cool down to <NUM>. The formed precipitate was filtered and washed with diethyl ether affording <NUM>-amino-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethan-<NUM>-one hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as colorless crystals. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br. s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethan-<NUM>-one hydrochloride (<NUM>, <NUM> mmol) and sodium hydrogen carbonate (<NUM>, <NUM> mmol) in a mixture of ethyl acetate (<NUM>)/water (<NUM>), <NUM>-chloroacetyl chloride (<NUM>, <NUM> mmol, <NUM>µl) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated in vacuo affording <NUM>-chloro-N-[<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-oxoethyl]acetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (br. s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of <NUM>-chloro-N-[<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-oxoethyl]acetamide (<NUM>, <NUM> mmol) in phosphoryl trichloride (<NUM>, <NUM> mmol, <NUM>) was heated under reflux for <NUM>. Gas evolution was observed. Then, the reaction mixture was allowed to cool down to ambient temperature and was poured into crashed ice (<NUM>). The precipitate was filtered and washed with water affording <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethan-<NUM>-one (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added sodium diformylamide (<NUM>, <NUM> mmol) in one portion. The reaction mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off and the filtrate was concentrated in vacuo. 5N hydrochloric acid (<NUM>) was added to the dark oily residue and the resulting mixture was heated to reflux for <NUM>. The hot solution was separated from dark viscous oil, and was allowed to cool down to <NUM>. The formed precipitate was filtered and successively washed with 10N hydrochloric acid and diethyl ether affording <NUM>-amino-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethan-<NUM>-one hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as yellow crystals. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)ethan-<NUM>-one hydrochloride (<NUM>, <NUM> mmol) and sodium hydrogen carbonate (<NUM>, <NUM> mmol) in ethyl acetate (<NUM>)/water (<NUM>) mixture, <NUM>-chloroacetyl chloride (<NUM>, <NUM> mmol, <NUM>µl) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM>. The ethyl acetate layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated in vacuo affording <NUM>-chloro-N-[<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-oxoethyl]acetamide (<NUM>, <NUM>% purity, <NUM>% yield) as a beige solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (br s, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of <NUM>-chloro-N-[<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-oxoethyl]acetamide (<NUM>, <NUM> mmol) in phosphoryl trichloride (<NUM>, <NUM> mmol, <NUM>) was heated under reflux for <NUM>. Gas evolution was observed. Then, the reaction mixture was allowed to cool down to ambient temperature and was poured into crashed ice (<NUM>). The precipitate was filtered and washed with water affording <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>'-chloro-<NUM>'-hydroxyacetophenone (<NUM>, <NUM> mmol) in anhydrous DMF (<NUM>) were successively added <NUM>-bromo-<NUM>-methanesulfonylpropane (<NUM>, <NUM> mmol) and anhydrous potassium carbonate (<NUM>, <NUM> mmol). The reaction mixture was heated <NUM> for <NUM>. Inorganics was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (<NUM>) and was successively washed with water (<NUM> x <NUM>), <NUM>% aq. NaOH (<NUM>) and dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated in vacuo affording <NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]ethan-<NUM>-one (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (p, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled solution of <NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]ethan-<NUM>-one (<NUM>, <NUM> mmol) in anhydrous THF (<NUM>) N,N,N-trimethylanilinium dibromane bromide (<NUM>, <NUM> mmol) was added portionwise. Then, the reaction mixture was allowed to warm up to ambient temperature and stirred for <NUM>. The precipitate was filtered off and the filtrate was concentrated in vacuo affording crude target bromoketone as a dark solid. It was subjected to column chromatography on Silicagel (<NUM>-<NUM>) affording <NUM>-bromo-<NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]ethan-<NUM>-one (<NUM>, <NUM>% purity, <NUM>% yield) as a colorless solid. It was used in the next step without further purification. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M]+.

To a stirred solution of <NUM>-bromo-<NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]ethan-<NUM>-one (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added sodium diformylamide (<NUM>, <NUM> mmol) in one portion. The reaction mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off and the filtrate was concentrated in vacuo. 5N Hydrochloric acid (<NUM>) was added to the dark oily residue, and the resulting mixture was heated to reflux for <NUM>. The hot solution was separated from dark viscous oil and was allowed to cool down to ambient temperature. The precipitate formed was filtered and washed with diethyl ether affording <NUM>-amino-<NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]ethan-<NUM>-one hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dq, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dq, J = <NUM>, <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To an ice-chilled stirred slurry of <NUM>-amino-<NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]ethan-<NUM>-one hydrochloride (<NUM>, <NUM> mmol) and sodium hydrogen carbonate (<NUM>, <NUM> mmol) in a mixture of ethyl acetate (<NUM>)/water (<NUM>), <NUM>-chloroacetyl chloride (<NUM>, <NUM> mmol, <NUM>µl) was added dropwise. The reaction mixture was stirred at <NUM>-<NUM> for <NUM>. The precipitate was filtered and washed with diethyl ether affording crude <NUM>-chloro-N-<NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]-<NUM>-oxoethylacetamide (<NUM>, <NUM> % purity, <NUM>% yield) as a beige solid. The product was used in the next step without further purification. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred slurry of <NUM>-chloro-N-<NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]-<NUM>-oxoethylacetamide (<NUM>, <NUM> mmol) in phosphoryl trichloride (<NUM>, <NUM> mmol, <NUM>) was heated to reflux for <NUM>. Gas evolution was observed. Then, the reaction mixture was allowed to cool down to ambient temperature and was poured into crashed ice (<NUM>). Then, chloroform (<NUM>) was added and the resulting mixture was stirred for <NUM>. The organic layer was separated and dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated in vacuo affording <NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

A stirred mixture of <NUM>-chloro-N,<NUM>-dimethylpyrimidin-<NUM>-amine (<NUM>, <NUM> mmol) and thiourea (<NUM>, <NUM> mmol) in anhydrous ethanol (<NUM>) was heated under reflux for <NUM>. The reaction mixture was concentrated in vacuo and the residue was subjected to column chromatography affording <NUM>-methyl-<NUM>-(methylamino)pyrimidine-<NUM>-thiol (<NUM>, <NUM>% purity, <NUM>% yield) as a colorless solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-(chloromethyl)-<NUM>-(<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added of <NUM>-(diaminomethylene)thiourea (<NUM>, <NUM> mmol). The reaction mixture was heated <NUM> for <NUM>. The precipitate was filtered and successively washed with acetonitrile (<NUM> x <NUM>) and acetone (<NUM> x <NUM>) affording (E)-N-[amino([<NUM>-(<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)methylidene]guanidine hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. It was used in the next step without further purification. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-(chloromethyl)-<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM> mmol) in anhydrous acetonitrile (<NUM>) was added <NUM>-(diaminomethylene)thiourea (<NUM>, <NUM> mmol). The reaction mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off and the filtrate was concentrated in vacuo and treated with acetone (<NUM>). The obtained precipitate was filtered and washed with acetone (<NUM> x <NUM>) affording N-[amino([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)methylidene]guanidine hydrochloride (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-(chloromethyl)-<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM> mmol) in anhydrous DMF (<NUM>) was added potassium acetylsulfanide (<NUM>, <NUM> mmol). The reaction mixture was stirred at ambient temperature for <NUM>. Inorganics was filtered off and the filtrate was concentrated in vacuo. The dark oily residue was dissolved in dichloromethane (<NUM>) and washed with water (<NUM>). The organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated in vacuo affording <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>% purity, <NUM>% yield) as a dark oil. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM> mmol) in anhydrous DMF (<NUM>) was added potassium acetylsulfanide (<NUM>, <NUM> mmol). The reaction mixture was stirred at ambient temperature for <NUM>. Inorganics was filtered off and the filtrate was concentrated in vacuo. The dark oily residue was dissolved in dichloromethane (<NUM>) and washed with water (<NUM>). The organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated in vacuo affording <NUM>-([<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>% purity, <NUM>% yield) as a dark oil. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-(chloromethyl)-<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM> mmol) in anhydrous DMF (<NUM>) was added potassium acetylsulfanide (<NUM>, <NUM> mmol). The reaction mixture was stirred at ambient temperature for <NUM>. Inorganics was filtered off and the filtrate was concentrated in vacuo. The dark oily residue was dissolved in dichloromethane (<NUM>) and washed with water (<NUM>). The organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated in vacuo affording <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

I<NUM> (<NUM>, <NUM> mmol, <NUM> equiv) and CCl<NUM> (<NUM>) were added to the solution of <NUM>,<NUM>-dimethylpyrimidin-<NUM>-amine (<NUM>, <NUM> mol, <NUM> equiv) in <NUM> % aqueous solution of H<NUM>SO<NUM> (<NUM>). The resulting mixture was heated to reflux and <NUM> of the <NUM> % aqueous solution of H<NUM>O<NUM> (<NUM>, <NUM> mol, <NUM> equiv) were added dropwise monitoring that the organic phase was dark red. The resulting mixture was stirred under reflux for <NUM> (until the organic phase became yellow). Then, the reaction mixture was cooled to room temperature, aqueous layer was separated and diluted with aqueous solution of NaOH to pH <NUM>. The formed precipitate was filtered on, washed with H<NUM>O (<NUM>) and dried in vacuo at <NUM> to obtain pure product (<NUM>, <NUM> %): m/z = <NUM> [M+H]+.

<NUM>-Amino-<NUM>-methylpyrimidine-<NUM>-thiol (<NUM>, <NUM> mmol, <NUM> equiv), NaOH (<NUM>, <NUM> mmol, <NUM> equiv) and EtOH (<NUM>) were mixed together. The resulting mixture was stirred for <NUM> at room temperature followed by the dropwise addition of the solution tert-butyl <NUM>-iodopiperidine-<NUM>-carboxylate (<NUM>, <NUM> mmol, <NUM> equiv) in hot EtOH (<NUM>). Then, the reaction mixture was stirred for <NUM> at <NUM>. After all starting material was consumed, as was shown by LCMS, the resulting mixture was allowed to cool down to room temperature and the volatiles were removed under reduced pressure. The obtained residue was subjected to HPLC (Waters Sunfire <NUM>*<NUM> C18 <NUM> mkm column and mixture of H<NUM>O-CH<NUM>OH as a mobile phase) to afford pure product (<NUM>, <NUM> %): m/z = <NUM> [M+H]+.

tert-Butyl <NUM>-((<NUM>-amino-<NUM>-methylpyrimidin-<NUM>-yl)thio)piperidine-<NUM>-carboxylate (<NUM>, <NUM> mmol, <NUM> equiv) was dissolved in a <NUM> solution of HCl in dioxane (<NUM>). The resulting mixture was stirred overnight at room temperature. After the completion of the reaction, monitored by LCMS, the formed precipitate was filtered off, washed wit E<NUM>O (<NUM>) and air-dried to afford pure product (<NUM>, <NUM> %, 2HCl): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-(chloromethyl)-<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>µmol) in anhydrous DMF (<NUM>) were successively added <NUM>-amino-<NUM>-ethyl-<NUM>,<NUM>-dihydro-<NUM>,<NUM>,<NUM>-triazine-<NUM>-thione (<NUM>, <NUM>µmol) and N,N-diisopropylethylamine (<NUM>, <NUM>µmol, <NUM>µl). The resulting mixture was stirred at ambient temperature for <NUM>. The volatiles were removed in vacuo. The oily residue was treated with water (<NUM> x <NUM>) and the formed precipitate was filtered affording <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-ethyl-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a beige solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-methyl-<NUM>-(methylamino)pyrimidine-<NUM>-thiol (<NUM>, <NUM>µmol) in anhydrous DMF (<NUM>) were successively added <NUM>-(chloromethyl)-<NUM>-(<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>µmol) and N,N-diisopropylethylamine (<NUM>, <NUM>µmol, <NUM>µl). The resulting mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off and the filtrate was concentrated in vacuo The dark oily residue was purified by HPLC (eluent MeCN/H<NUM>O <NUM>% => <NUM>%) affording <NUM>-([<NUM>-(<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-N,<NUM>-dimethylpyrimidin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a beige solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-amino-<NUM>-methylpyrimidine-<NUM>-thiol (<NUM>, <NUM>µmol) in anhydrous DMF (<NUM>) were successively added <NUM>-(chloromethyl)-<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>µmol) and N,N-diisopropylethylamine (<NUM>, <NUM>µmol, <NUM>µl). The resulted mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off and the filtrate was concentrated in vacuo. The dark oily residue was purified by HPLC (eluent MeCN/H<NUM>O <NUM>% => <NUM>%) affording <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-methylpyrimidin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a grey solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br. s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>µmol) in anhydrous DMF (<NUM>) were successively added <NUM>-amino-<NUM>-methyl-<NUM>,<NUM>-dihydro-<NUM>,<NUM>,<NUM>-triazine-<NUM>-thione (<NUM>, <NUM>µmol) and N,N-diisopropylethylamine (<NUM>, <NUM>µmol). The resulting mixture was stirred at ambient temperature for <NUM>. The volatiles were removed in vacuo. The oily residue was treated with water (<NUM> x <NUM>), and the precipitate formed was filtered affording <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-methyl-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a beige solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>µmol) in anhydrous DMF (<NUM>) were successively added <NUM>-amino-<NUM>-ethyl-<NUM>,<NUM>-dihydro-<NUM>,<NUM>,<NUM>-triazine-<NUM>-thione (<NUM>, <NUM>µmol) and N,N-diisopropylethylamine (<NUM>, <NUM>µmol). The resulting mixture was stirred at ambient temperature for <NUM>. The volatiles were removed in vacuo. The oily residue was treated with water (<NUM> x <NUM>) and the precipitate formed was filtered affording <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-ethyl-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a beige solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>µmol) in anhydrous DMF (<NUM>) were successively added <NUM>-amino-<NUM>-methylpyrimidine-<NUM>-thiol (<NUM>, <NUM>µmol) and N,N-diisopropylethylamine (<NUM>, <NUM>µmol). The resulting mixture was stirred at ambient temperature for <NUM>. The volatiles were removed in vacuo. The oily residue was treated with water (<NUM> x <NUM>) and the formed precipitate was filtered affording <NUM>-[({<NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]-<NUM>,<NUM>-oxazol-<NUM>-yl}methyl)sulfanyl]-<NUM>-methylpyrimidin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a beige solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>(m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred solution of <NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]-<NUM>-(chloromethyl)-<NUM>,<NUM>-oxazole (<NUM>, <NUM>µmol) in anhydrous DMF (<NUM>) were successively added <NUM>-amino-<NUM>-(trifluoromethyl)pyrimidine-<NUM>-thiol (<NUM>, <NUM>µmol) and N,N-diisopropylethylamine (<NUM>, <NUM>µmol, <NUM>µl). The resulting mixture was stirred at ambient temperature for <NUM>. The volatiles were removed in vacuo and the oily residue was subjected to HPLC (eluent MeCN/H<NUM>O) to afford <NUM>-[({<NUM>-[<NUM>-chloro-<NUM>-(<NUM>-methanesulfonylpropoxy)phenyl]-<NUM>,<NUM>-oxazol-<NUM>-yl}methyl)sulfanyl]-<NUM>-(trifluoromethyl)pyrimidin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) <NUM>-<NUM> (br. s <NUM>), δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred slurry of (E)-N-[amino([<NUM>-(<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)methylidene]guanidine hydrochloride (<NUM>, <NUM>µmol) in anhydrous THF (<NUM>) were successively added cyclopropanecarbonyl chloride (<NUM>, <NUM>µmol, <NUM>µl), triethylamine (<NUM>, <NUM>µmol, <NUM>µl) and sodium sulfate (<NUM>, <NUM>µmol). The reaction mixture was stirred <NUM> at ambient temperature and then was heated <NUM> for <NUM>. The precipitate was filtered off and the filtrate was concentrated in vacuo. The dark oily residue was purified by HPLC (eluent MeCN/H2O <NUM>% => <NUM>%) affording <NUM>-cyclopropyl-<NUM>-([<NUM>-(<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a yellow oil. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (tt, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dq, J = <NUM>, <NUM>, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred slurry of N-[amino([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)methylidene]guanidine hydrochloride (<NUM>, <NUM>µmol) in anhydrous THF (<NUM>) were successively added trifluoroacetyl <NUM>,<NUM>,<NUM>-trifluoroacetate (<NUM>, <NUM>µmol, <NUM>µl), triethylamine (<NUM>, <NUM>µmol, <NUM>µl) and sodium sulfate (<NUM>, <NUM>µmol). The reaction mixture was stirred <NUM> at ambient temperature, and then was heated <NUM> for <NUM>. The precipitate was filtered off and the filtrate was concentrated in vacuo. The dark oily residue was purified by HPLC (eluent MeCN/H<NUM>O <NUM>% => <NUM>%) affording <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-(trifluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a grey solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(fluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off, and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O <NUM>% => <NUM>%) affording <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-(fluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(difluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O <NUM>% => <NUM>%) affording <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-(difluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a brown solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O <NUM>% => <NUM>%) affording <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a colorless solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br. s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-[(<NUM>-amino-<NUM>-chloro-<NUM>,<NUM>,<NUM>-triazin-<NUM>-yl)amino]ethan-<NUM>-ol (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off, and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O <NUM>% => <NUM>%) affording <NUM>-[<NUM>-amino-<NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-yl]aminoethan-<NUM>-ol (<NUM>, <NUM>% purity, <NUM>% yield) as a colorless solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(morpholin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off, and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O <NUM>% => <NUM>%) affording <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-(morpholin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a colorless solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM> mmol) in methanol (<NUM>) was added a solution of potassium hydroxide (<NUM>, <NUM> mmol) in water (<NUM>). The mixture was stirred at rt for <NUM>. Then a solution of <NUM>-chloro-<NUM>-methoxy-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM> mmol) in DMSO (<NUM>) was added via a syringe. The resulted mixture was stirred at ambient temperature for additional <NUM>. The precipitate was filtered off and washed with methanol, and the filtrate was concentrated in vacuo. The dark oily residue was subjected to HPLC (eluent MeCN/H<NUM>O <NUM>% => <NUM>%) affording <NUM>-([<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-methoxy-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a colorless solid. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-N<NUM>,N<NUM>-dimethyl-<NUM>,<NUM>,<NUM>-triazine-<NUM>,<NUM>-diamine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O) affording <NUM>-({[<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methyl}thio)-N,N-dimethyl-<NUM>,<NUM>,<NUM>-triazine-<NUM>,<NUM>-diamine (<NUM>, <NUM>% purity, <NUM>% yield) as a solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (br. s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(morpholin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off, and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O) affording <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-(morpholin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off, and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O) affording <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(difluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O) affording <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-(difluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(fluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off, and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O) affording <NUM>-([<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)-<NUM>-(fluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(fluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off, and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O) affording <NUM>-({[<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methyl}sulfanyl)-<NUM>-(fluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off, and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O) affording <NUM>-({[<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methyl}sulfanyl)-<NUM>-(<NUM>-methylpiperazin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(morpholin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off, and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O) affording <NUM>-({[<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methyl}sulfanyl)-<NUM>-(morpholin-<NUM>-yl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

To a stirred under argon solution of <NUM>-([<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methylsulfanyl)ethan-<NUM>-one (<NUM>, <NUM>µmol) in DMSO (<NUM>) were successively added <NUM>-chloro-<NUM>-(difluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>µmol) and a solution of potassium hydroxide (<NUM>, <NUM>µmol) in water (<NUM>). The mixture was stirred at ambient temperature for <NUM>. The precipitate was filtered off, and the filtrate was subjected to HPLC (eluent MeCN/H<NUM>O) affording <NUM>-({[<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methyl}sulfanyl)-<NUM>-(difluoromethyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (<NUM>, <NUM>% purity, <NUM>% yield) as a solid. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). MS (CI): m/z = <NUM> [M+H]+.

<NUM>-Imino-<NUM>-methyl-<NUM>,<NUM>-dihydropyrimidine-<NUM>-thiol (<NUM>, <NUM> mmol, <NUM> equiv), NaOH (<NUM>, <NUM> mmol, <NUM> equiv) and EtOH (<NUM>) were mixed together. The resulting mixture was stirred for <NUM> at room temperature followed by the dropwise addition of the solution of <NUM>-(<NUM>-chloroethyl)-<NUM>-(p-tolyl)-<NUM>,<NUM>,<NUM>-oxadiazole (<NUM>, <NUM> mmol, <NUM> equiv) in hot EtOH (<NUM>). Then, the reaction mixture was stirred for <NUM> at <NUM>. After all starting material was consumed, as was shown by LCMS, the resulting mixture was allowed to cool down to room temperature and the volatiles were removed under reduced pressure. The obtained residue was subjected to HPLC (Waters Sunfire <NUM>*<NUM> C18 <NUM> mkm column and mixture of H<NUM>O-CH<NUM>OH as a mobile phase) to afford pure product (<NUM>, <NUM> %). : m/z = <NUM> [M+H]+.

Following the above procedure all compounds of the series were obtained. The molar ratio of the reagents and reaction conditions were kept the same in each reaction of the series. The exact amounts of the reagents and the yields of the products are in the attached Excel file.

DMF (<NUM>), NaH (<NUM>, <NUM> mmol, <NUM> equiv) and (<NUM>-phenyl-<NUM>,<NUM>,<NUM>-oxadiazol-<NUM>-yl)methanol (<NUM>, <NUM> mmol, <NUM> equiv) were mixed together in a round-bottom flask. After the completion of gas evolution, <NUM>-chloro-<NUM>-methylpyrimidin-<NUM>-amine (<NUM>, <NUM> mmol, <NUM> equiv) was added and the resulting mixture was stirred at room temperature overnight. Then, the reaction mixture was diluted with a mixture of EtOAc (<NUM>) and H<NUM>O (<NUM>). The organic phase was separated, dried over Na<NUM>SO<NUM>, filtered off and concentrated under reduced pressure. The residue was purified using HPLC (Waters Sunfire <NUM>*<NUM> C18 <NUM> mkm column and mixture of H<NUM>O-CH<NUM>OH as a mobile phase) to obtain pure product (<NUM>, <NUM> %): m/z = <NUM>,<NUM> [M+H]+.

<NUM>-(<NUM>-Ethylphenyl)-<NUM>,<NUM>,<NUM>-oxadiazole-<NUM>-thiol (<NUM>, <NUM> mmol, <NUM> equiv), NaOH (<NUM>, <NUM> mmol, <NUM> equiv) and EtOH (<NUM>) were mixed together. The resulting mixture was stirred for <NUM> at room temperature followed by the dropwise addition of the solution <NUM>-(iodomethyl)-<NUM>-methylpyrimidin-<NUM>(<NUM>H)-imine (<NUM>, <NUM> mmol, <NUM> equiv) in hot EtOH (<NUM>). Then, the reaction mixture was stirred for <NUM> at <NUM>. After all starting material was consumed, as was shown by LCMS, the resulting mixture was allowed to cool down to room temperature and the volatiles were removed under reduced pressure. The obtained residue was subjected to HPLC (Waters Sunfire <NUM>*<NUM> C18 <NUM> mkm column and mixture of H<NUM>O-CH<NUM>OH as a mobile phase) to afford pure product (<NUM>, <NUM> %): m/z = <NUM>,<NUM> [M+H]+.

TEA (<NUM>, <NUM> mmol, <NUM> equiv) and <NUM>-(benzo[d][<NUM>,<NUM>]dioxol-<NUM>-yl)-<NUM>-(chloromethyl)-<NUM>,<NUM>,<NUM>-oxadiazole (<NUM>, <NUM> mmol, <NUM> equiv) were added to the solution of <NUM>-methyl-<NUM>-(piperidin-<NUM>-ylthio)pyrimidin-<NUM>-amine (<NUM>, <NUM> mmol, <NUM> equiv, 2HCl) in DMF (<NUM>). The resulting mixture was stirred at <NUM> for <NUM>. After LCMS showed full conversion of starting material, the reaction mixture was allowed to cool down to room temperature and diluted with a mixture of EtOAc (<NUM>) and H<NUM>O (<NUM>). The organic phase was separated, dried over Na<NUM>SO<NUM>, filtered off and concentrated in vacuo. The obtained solid was subjected to HPLC (Waters Sunfire <NUM>*<NUM> C18 <NUM> mkm column and mixture of H<NUM>O-CH<NUM>OH as a mobile phase) to afford pure product (<NUM>, <NUM> %). : m/z = <NUM>,<NUM> [M+H]+.

<NUM>-(<NUM>-Chloro-<NUM>-methoxyphenyl)-<NUM>-(chloromethyl)oxazole (<NUM>, <NUM> mmol, <NUM> equiv) and <NUM>-mercapto-<NUM>-methylpyrimidin-<NUM>(<NUM>H)-one (<NUM>, <NUM> mmol, <NUM> equiv) were mixed together in anhydrous DMF (<NUM>). The resulting mixture was stirred for <NUM> followed by the addition of DIPEA (<NUM>, <NUM> mmol, <NUM> equiv). Then, the reaction mixture was heated <NUM> in sealed vial for <NUM>. After the completion of the reaction, monitored by LCMS, the volatiles were removed under reduced pressure. The residue was subjected to HPLC (Waters Sunfire <NUM>*<NUM> C18 <NUM> mkm column and mixture of H<NUM>O-CH<NUM>OH as a mobile phase) to afford pure product (<NUM>, <NUM> % yield) :): m/z = <NUM>,<NUM> [M+H]+.

DIPEA (<NUM>, <NUM> mmol, <NUM> equiv) was added to a stirred slurry of N-[amino({[<NUM>-(<NUM>-chlorophenyl)-<NUM>,<NUM>-oxazol-<NUM>-yl]methyl}sulfanyl)methylidene]guanidine (<NUM>, <NUM> mmol, <NUM> equiv, HCl) and thiophene-<NUM>-carbonyl chloride (<NUM>, <NUM> mmol, <NUM> equiv) in anhydrous THF (<NUM>). The reaction mixture was heated <NUM> in sealed vial for <NUM>. After all starting material was consumed, as was shown by LCMS, the solvent was removed in vacuo. The obtained solid was dissolved in DMSO (<NUM>) and filtered off. The filtrate was subjected to HPLC (Waters Sunfire <NUM>*<NUM> C18 <NUM> mkm column and mixture of H<NUM>O-CH<NUM>OH as a mobile phase) to afford pure product (<NUM>, <NUM> % yield): m/z = <NUM>,<NUM> [M+H]+.

<NUM>-(p-Tolyl)-<NUM>,<NUM>,<NUM>-oxadiazole-<NUM>-thiol (<NUM>, <NUM> mmol, <NUM> equiv), DMSO (<NUM>) and TEA (<NUM>, <NUM> mmol, <NUM> equiv) were mixed together in an <NUM> vessel. The resulting mixture was stirred for <NUM> followed by the addition of <NUM>-chlorobenzo[d]oxazole (<NUM>, <NUM> mmol, <NUM> equiv). The resulting mixture was stirred at <NUM> for <NUM>. After the completion of the reaction, monitored by LCMS, the resulting suspension was filtered off and the obtained filtrate was subjected to HPLC (Waters Sunfire <NUM>*<NUM> C18 <NUM> mkm column and mixture of H<NUM>O-CH<NUM>OH as a mobile phase) to afford pure product (<NUM>, <NUM> %). : :m/z = <NUM>,<NUM> [M+H]+.

<NUM>,<NUM>-Diamino-<NUM>,<NUM>,<NUM>-triazine-<NUM>-thiol (<NUM>, <NUM> mmol, <NUM> equiv), DMSO (<NUM>) and <NUM>-(chloromethyl)-<NUM>-(<NUM>-methoxyphenyl)oxazole (<NUM>, <NUM> mmol, <NUM> equiv) were mixed together and stirred for <NUM> at room temperature. Then, the <NUM> solution of KOH (<NUM>, <NUM> mmol, <NUM> equiv) was added and the reaction mixture was stirred at <NUM> for <NUM>. The obtained mixture was placed in autoclave and CO<NUM> was blown in. The resulting mixture was stirred for <NUM> in the autoclave. After the completion of the reaction, the reaction mixture was filtered off and the obtained filtrate was subjected to HPLC (Waters Sunfire <NUM>*<NUM> C18 <NUM> mkm column and mixture of H<NUM>O-CH<NUM>OH as a mobile phase) to afford pure product (<NUM>, <NUM> %):m/z = <NUM>,<NUM> [M+H]+.

DIPEA (<NUM>, <NUM> mmol, <NUM> equiv) was added to the solution of <NUM>-methyl-<NUM>H-benzo[d]imidazole-<NUM>-thiol (<NUM>, <NUM> mmol, <NUM> equiv) and <NUM>-(benzo[d][<NUM>,<NUM>]dioxol-<NUM>-yl)-<NUM>-(chloromethyl)-<NUM>,<NUM>,<NUM>-oxadiazole (<NUM>, <NUM> mmol, <NUM> equiv) in DMF (<NUM>). The resulting mixture was stirred at <NUM> overnight. After the completion of the reaction, monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (<NUM>) and filtered off. The filtrate was subjected to HPLC (Waters Sunfire <NUM>*<NUM> C18 <NUM> mkm column and mixture of H<NUM>O-CH<NUM>OH as a mobile phase) to afford pure product (<NUM>, <NUM> %): m/z = <NUM>,<NUM> [M+H]+.

DIPEA (<NUM>, <NUM> mmol) was added to the solution of <NUM>-amino-<NUM>-ethyl-<NUM>,<NUM>,<NUM>-triazine-<NUM>(<NUM>H)-thione (<NUM>, <NUM> mmol) in DMSO (<NUM>). The resulting mixture was stirred for <NUM> followed by the addition of <NUM>-(chloromethyl)-<NUM>-(<NUM>-chlorophenyl)oxazole (<NUM>, <NUM> mmol). The reaction mixture was stirred at room temperature for <NUM> and then for <NUM> at <NUM>. After all starting material was consumed, as was shown by LCMS, the resulting mixture was filtered off and the filtrate was subjected to HPLC (Waters SunFire C18 <NUM>-<NUM><NUM> mkm column and H<NUM>O-MeCN as a mobile phase, Run Time = <NUM>) to afford pure product (<NUM>, <NUM>%); LCMS : <NUM> (M+<NUM>).

Assays for agonistic activity of compounds as decribed herein on GPR40 are carried out in mammalian cells which provide a readout for GPR40 activation. Primarily stable cell lines of HEK cells, which measure B-arrestin recruitment to heterologously expressed GPR40 via BRET readout. This involves co-expressing in one cell two components, namely a B-arrestin tagged with one element of the BRET assay (fluorescent protein or Luciferase) and the GPR40 tagged with the other element of the assay (fluorescent protein or Luciferase). A fluorescent protein (FP) was fused to the C-terminus of the receptor and was co-expressed in HEK293T cells with luciferase (Luc) fused the N-terminus of G-protein subunit G gamma <NUM> (Gγ). Furthermore, a fluorescent protein (FP) was fused to the C-terminus of the receptor and was co-expressed in HEK293T cells with luciferase (Luc) fused to the N-terminus of beta-Arrestin-<NUM>. <NUM> after transfections, cells were incubated with increasing doses of GPR40 reference ligand AMG <NUM> or a compound as disclosed herein and changes in BRET were measured.

pEC50 data and % activation (% activation = (activation of GPR40 by compound of invention/activation of GPR40 by AMG-<NUM>)*<NUM>) data of preferred compounds of the invention are shown in <FIG> and of preferred compounds for use in the invention are shown in <FIG>.

Compound Z1558775684 was synthesized according to Example <NUM>. Metformin was acquired from Teva Pharmaceutical Industries Ltd. , Petach Tikwa, Israel, Lot <NUM><NUM><NUM>.

METHOCEL F4M Hydroxypropyl methylcellulose (Dow Chemical Company, Midland, USA).

Syringes for injection, <NUM> without needle, Medicare S-3SI1, (Dopomoga-<NUM> Ltd, Ukraine). Stainless steel animal feeding tube 20ga x <NUM> (Intech Solomon, USA) D-(+)-Glucose monohydrate (Sigma, <NUM>-<NUM>). On Call Plus glucometer (Acon Laboratories, Inc. , USA) and specific test strips (REF G133-<NUM>). Sterile plastic tubes different volumes (Falcon, Eppendorf). Ethanol, <NUM> % (Ukrorgsynthesis Ltd, Ukraine) Stainless Steel Scissors for microsurgery.

Balance Sartorius LE225D, d = <NUM>. Water purification system NANOpure Diamond D11911 (Thermo Scientific Barnstead, USA). Ultrasonic bath (Daihan, Korea; WUC-A03H). Micropipettes <NUM>-<NUM>µL, <NUM>-<NUM>µL, <NUM>-<NUM>, <NUM>-<NUM>µL (Eppendorf, Hamburg, Germany).

C57BL/6N is a mouse strain commonly used in glucose metabolism studies.

The animals were individually identified by earmarking. The cages were labeled with tags indicating the ID numbers and earmarks of mice, the study code, sex, and route of administration, start and end date of the experimental period.

During the acclimatization period (<NUM> days) <NUM>-<NUM> animals were kept in each cage. All animals were monitored daily. Animals free from any clinical symptoms of sickness were used in the study.

Animals were randomly assigned to groups according to the standard procedure <NUM> days prior to the starting day of the study. Each cage contained animals from a uniform experimental group.

Each experimental group consisted of five male C57BI/6N mice. Animals were dosed once perorally with <NUM>/kg of tested compound Z1558775684. A control group was dosed with vehicle on the same schedule. Metformin at the dosage of <NUM>/kg was used as reference compound. All mice were observed for clinical signs of gross toxicity before administration.

Mice were <NUM> months old, body weight ranged from <NUM> to <NUM> at arrival. Average body weight across all experimental groups was <NUM> (SD = <NUM>, CV = <NUM> %).

Compound Z1558775684 was dissolved/suspended in DMSO - PEG400 - physiological saline (<NUM>%:<NUM>%:<NUM>%) at concentration <NUM>/ml. Metformin was dissolved in the same vehicle at concentration <NUM>/ml. The test samples were administered per os in the volume corresponding to <NUM>/kg body weight.

Single doses of test samples were administered <NUM> before glucose treatment at <NUM> p.

Seven days of acclimatization, <NUM> treatment day, <NUM> day for data analysis.

The blood glucose level was measured after <NUM>-hour fasting using Call Plus glucometer and specific test strips. Blood was obtained from the tail vein by incision of the tail tip, <NUM>-<NUM>µl of blood was used for each assay.

Non-parametric statistical analysis (criteria of Wilcoxon-Mann-Whitney U) for independent samples was used to calculate the significance. The experiments were performed according to the Bienta Standard Operating Procedures/Manuals.

Claim 1:
A compound of general formula (I)

        R<NUM>-S-CH<NUM>-OXA-R<NUM>     (I)

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable cocrystals or salts, and complexes thereof;
wherein
OXA is <NUM>,<NUM>-oxazolyl;
the group R<NUM>-S-CH<NUM> is bound to C<NUM> of the <NUM>,<NUM>-oxazolyl and the group R<NUM> is bound to C<NUM> of the <NUM>,<NUM>-oxazolyl;
R<NUM> is a <NUM> membered heteroaryl group selected from the group consisting of <NUM>,<NUM>,<NUM>-triazinyl and pyrimidinyl being independently substituted with one or more substituents selected from the group consisting of hydroxyl, amino, C<NUM>-C<NUM>-alkyl, C<NUM>-C<NUM>-cycloalkyl, C<NUM>-C<NUM>-alkoxy, N-mono- or N,N-di-substituted C<NUM>-C<NUM>-alkylamino, nonaromatic <NUM>- to <NUM>-membered heterocyclyl, <NUM>-membered aryl and <NUM>- to <NUM>-membered heteroaryl which substituents may be unsubstituted or substituted with one or more groups selected from the group consisting of halide, cyano and C<NUM>-C<NUM>-alkyl, wherein the <NUM>-membered aryl and <NUM>- to <NUM>-membered heteroaryl group, respectively, may be fused to said <NUM>,<NUM>,<NUM>-triazinyl or pyrimidyl group, respectively, and
R<NUM> is phenyl being unsubstituted or being substituted with one or more substituents selected from the group consisting of halide, cyano, amino, C<NUM>-C<NUM>-alkyl, C<NUM>-C<NUM>-cycloalkyl which may be optionally substituted with one or more halides, C<NUM>-C<NUM>-alkoxy which may optionally substituted with one or more halides, hydroxy-C<NUM>-C<NUM>-alkyl, sulfonyl-C<NUM>-C<NUM>-alkyl, sulphamidyl-N-C<NUM>-C6-alkyl and carboxamidyl-N-mono- or - N,N-di-C<NUM>-C<NUM>-alkyl;
with the proviso that the following compounds are excluded:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>