New compounds and their uses

Abstract

The present invention relates to new compounds having appetite-suppressing effects and their uses as a drug for treating diseases and disorders, especially metabolic syndrome. In particular, the present invention relates to compounds of general formula (I) and their uses as a drug for treating diseases and disorders, especially metabolic syndrome.

Description

[0001] 1 NEW COMPOUNDS AND THEIR USES FIELD OF THE INVENTION The present invention relates to new compounds, in particular compounds capable of ameliorating the metabolic syndrome, and their uses, especially for the treatment of diseases and disorders. 5 BACKGROUND OF THE INVENTION Today millions of people are obese. At the individual level, obesity reduces life expectancy by 3-4 years causing complications such as type 2 diabetes, psychosocial disorders, cancers among many others. Therapeutic options for weight loss exist in the form of lifestyle therapy, weight-lowering drugs and / or bariatric surgeries depending on the disease severity and complications. Unfortunately, all offer a poor 10 benefit / risk ratio to reduce obesity and to prevent the onset of obesity-associated complications. Anti-obesity or weight loss drugs are pharmacological agents that reduce or control weight. These drugs may alter either appetite, absorption of calories and / or energy expenditure. In the United States, orlistat (Xenical) is currently approved by the FDA for long-term use. It reduces intestinal fat absorption by inhibiting pancreatic lipase. However, severe liver damage has been 15 reported as side effects. Rimonabant (Acomplia), a second drug, works via a specific blockade of the endocannabinoid system. It had been approved in Europe for the treatment of obesity but has not received approval in the United States or Canada due to safety concerns. The European Medicines Agency in October 2008 recommended the suspension of the sale of rimonabant as the risks seem to be greater than the benefits. Sibutramine (Meridia), which acts in the brain to inhibit deactivation of 20 the neurotransmitters, thereby decreasing appetite, was withdrawn from the United States and Canadian markets in October 2010 due to cardiovascular concerns. Lorcaserin, marketed under the brand name Belviq, is a weight-loss drug developed by Arena Pharmaceuticals. It reduces appetite by activating a type of serotonin receptor known as the 5-HT2C receptor in a region of the brain called the hypothalamus, which is known to control appetite. However, it was removed from the market in 25 the United States in 2020 due to its increased risk of cancer. Qsymia (phentermine-topiramate) was approved by the FDA in 2012 for the chronic treatment of obesity. Combining the appetite suppressant amphetamine-like properties of phentermine to topiramate, an anticonvulsive drug bearing weight loss potential, provides modest results on obesity treatments. However, common adverse effects such as insomnia, constipation, dizziness, paresthesia, dysgeusia and dry mouth are associated to its use 30 and, even more cardiovascular risks and possible kidney alterations have been reported. Contrave is the combination of naltrexone, an opioid antagonist, with bupropion, originally prescribed as an antidepressant, and was recently approved by FDA and EMA for the treatment of obesity. Common side effects are nausea, constipation, headache, dizziness, vomiting, insomnia, dry mouth and diarrhea. Its use is contraindicated in case of hypertension, seizure and alimentary disorder 35 antecedents. Liraglutide is a GLP-1 receptor mono-agonist. It was approved by FDA and EMA for the 2 treatment of obesity. Semaglutide is another GLP-1 receptor mono-agonist, approved by FDA and EMA for the treatment of obesity in 2021. Liraglutide and Semaglutide treatment is frequently associated with gastrointestinal side effects, nausea, diarrhea, constipation and vomiting. Because of potential side effects, and limited evidence of benefits in weight reduction, anti-obesity 5 drugs are only prescribed for obesity where it is hoped that the benefits of the treatment outweigh its risks. Therefore, there is a strong need of an appetite suppressor with a high efficacy and a good safety profile. 10 SUMMARY OF THE INVENTION The present invention relates to compounds capable of reducing food intake and their uses for the treatment of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, 15 cardiovascular diseases, and medication-induced weight gain. In addition, the present invention relates to new compounds, a pharmaceutical or veterinary composition comprising a new compound according to the disclosure and their uses as a drug. More particularly, the present invention relates to a compound of formula (I) for use as appetite suppressant, in particular for the treatment of a disease, disorder or condition selected from the group 20 consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain, wherein the compound has the formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof. 25 In a first aspect, the invention relates to a compound of the following general formula (I): or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein 30 the dotted line represents the presence or absence of a bond; W represents -CH-, -N- or -NH-; 3 V represents -N-, -CH- or -C(R2)-, with R2being a (C1-C6)alkyl, each X, Y and Z represents, independently of each other, -CH-, -NH- or -N-; provided that at least two of X, Y and Z represents -N- or -NH-; R5is a moiety selected in the group constituted of cyclohexyl, piperazinyl, morpholinyl, 3-pyridinyl, 4- 5 pyridinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, quinuclidinyl, imidazolyl, and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1- C6)alkoxy; or R5is selected from the list constituted of an unsubstituted 2-pyridinyl; unsubstituted 2- or 3-pyrazolyl; a 1-piperidinyl optionally substituted with at least one, preferably one or two, oxo, OH, 10 Me or N(CH3)2; or 1-pyrrolidinyl unsubstituted or substituted with at least NRARB; R and R’ are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; RAand RBare, independently of each other, an hydrogen atom or a (C1-C3)alkyl provided that RAand RBare not both hydrogen atom; R6is an hydrogen atom or a (C1-C6)alkyl, preferably an hydrogen atom or a methyl; 15 R7is a moiety selected in the group consisting of (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C6-C12)aryl and (C5-C14)heteroaryl; said group being optionally substituted with at least one, such as one or two, - OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or - C(O)NR11R12; R8is a (C1-C6)alkyl group optionally substituted with one, two or three halo or a phenyl, preferably one, 20 two or three halo, more preferably two or three fluorine; R9is a (C1-C6)alkoxy or (C1-C6)alkyl; R10is a H or (C1-C6)alkyl; and R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle; 25 provided that R7is not an unsubstituted phenyl; provided that when R5is 1-piperidinyl, R7is not a 1-piperidinyl; provided that when R5is 1-morpholinyl, R7is not a 1-morpholinyl; and provided that said compound is not a compound of following formula (A37), (C1), (C2), or (C3): The invention further relates to the above compound of general formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for use as a drug. 5 The invention further relates to the above compound of general formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for use as appetite suppressant, in particular for the treatment of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders 10 including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain. In another aspect, the invention relates to a compound of the following general formula (I): 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for use as appetite suppressant, in particular for the treatment of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain, 20 wherein the dotted line represents the presence or absence of a bond; W represents -CH-, -N- or -NH-; V represents -N-, -CH- or -C(R2)-, with R2being a (C1-C6)alkyl, CF3, or the moiety each X, Y and Z represents, independently of each other, -CH-, -NH- or -N-; provided that at least two 25 of X, Y and Z represents -N- or -NH-; 5 R5is a moiety selected in the group constituted of cyclohexyl, phenyl, pyrazolyl, piperazinyl, morpholinyl, pyridinyl, piperidinyl, pyrrolidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, quinuclidinyl, imidazolyl and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted with at least a halo, hydroxy (OH), -NRR’, CN, (C1-C6)alkyl or (C1-C6)alkoxy; 5 R and R’ are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; R6is an hydrogen atom or a (C1-C6)alkyl, preferably an hydrogen atom or a methyl; and R7is CF3; or a moiety selected in the group consisting of (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3- C8)heterocycloalkyl, (C6-C12)aryl and (C5-C14)heteroaryl; said group being optionally substituted with at least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, 10 -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12; R8is a (C1-C6)alkyl group optionally substituted with one, two or three halo or a phenyl, preferably one, two or three halo, more preferably two or three fluorine; R9is a (C1-C6)alkoxy or (C1-C6)alkyl; R10is a H or (C1-C6)alkyl; 15 R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds capable of reducing food intake and their uses as appetite 20 suppressant, in particular for the treatment of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain. In addition, the present invention relates to new compounds, a pharmaceutical or veterinary composition comprising 25 a new compound according to the disclosure and their uses as a drug. Definitions According to the present invention, the terms below have the following meanings: The term “Cx-Cy” in which x and y are integers, as used in the present disclosure, means that the corresponding hydrocarbon chain comprises from x to y carbon atoms. If, for example, the term C1-C630 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5, or 6 carbon atoms. If, for example, the term C1-C4is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 4 carbon atoms, especially 1, 2, 3 or 4 carbon atoms. If, for example, the term C1-C3is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1, 2, or 3 carbon atoms. C0-C3means that the 6 corresponding hydrocarbon chain may comprise from 0 to 3 carbon atoms, especially 0, 1, 2 or 3 carbon atoms. In particular, when in the context of C0, the hydrocarbon chain is absent. The term “alkyl” refers to a saturated, linear or branched aliphatic group. The term “(C1-C6)alkyl” more specifically means methyl, ethyl, propyl, isopropyl, butyl (n-butyl, i-butyl, sec-butyl and tert-butyl), 5 pentyl, or hexyl. The term “(C1-C4)alkyl” more specifically means methyl, ethyl, propyl, isopropyl, or butyl (n-butyl, i-butyl, sec-butyl and tert-butyl). The term “(C1-C3)alkyl” more specifically means methyl, ethyl , isopropyl or propyl. In a particular aspect, the “alkyl” is a methyl. By “Me”, it refers to a methyl. The term “alkenyl” refers to an unsaturated, linear or branched aliphatic group, having at least one 10 carbon-carbon double bond. The term “C2-C6alkenyl” refers to an alkenyl having 2 to 6 carbon atoms. The term alkenyl (or C2-C6alkenyl) includes for instance ethenyl, propenyl, butenyl, pentenyl, or hexenyl. The term “alkynyl” refers to an unsaturated, linear or branched aliphatic group, having at least one carbon-carbon triple bond. The term “C2-C6alkynyl” refers to an alkynyl having 2 to 6 carbon atoms. 15 The term alkynyl (or C2-C6alkynyl) includes for instance ethynyl, propynyl, butynyl, pentynyl, or hexynyl. The term « heteroalkyl » refers to an alkyl as defined herein, wherein the aliphatic carbon chain comprises at one or both of its two ends (in particular, the end attached to the remainder of the molecule), and / or is interrupted by at least one heteroatom such as O, N or S. Examples of heteroalkyl 20 are in particular alcoxy (-O-alkyl), alkylthio (-S-alkyl), and alkylamino (-NH(alkyl) or -N(alkyl)2). A « C1-C6heteroalkyl » refers to a heteroalkyl having 1 to 6 carbon atoms and at least one heteroatom such as O, N or S. Examples of heteroalkyl (or C1-C6heteroalkyl) include, but are not limited to, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, hexyloxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, 25 methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, or hexylamino. The term “alkoxy” or “alkyloxy” corresponds to the alkyl group as above defined bonded to the molecule by an -O- (ether) bond. (C1-C6)alkoxy includes methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, pentyloxy, or hexyloxy. (C1-C4)alkoxy includes methoxy, ethoxy, propyloxy, isopropyloxy or 30 butyloxy. (C1-C3)alkoxy includes methoxy, ethoxy, propyloxy or isopropyloxy. In a particular aspect, the “alkoxy” or “alkyloxy” is a methoxy. The term “cycloalkyl” corresponds to a saturated or unsaturated mono-, bi- or tri-cyclic alkyl group comprising between 3 and 20 cyclic atoms of carbons. It also includes fused, bridged, or spiro- connected cycloalkyl groups. The term “cycloalkyl” includes for instance cyclopropyl, cyclobutyl, 35 cyclopentyl, and cyclohexyl. The term “spirocycloalkyl” includes for instance a spirocyclopentyl. In a 7 particular aspect, the term “cycloalkyl” corresponds to a saturated monocycloalkyl group comprising between 3 and 7 atoms of carbons. In a particular aspect, the cycloalkyl group is cyclopropyl or cyclohexyl. The term “heterocycloalkyl” corresponds to a saturated or unsaturated cycloalkyl group as above 5 defined further comprising at least one heteroatom such as nitrogen, oxygen, or sulfur atom, preferably at least one nitrogen atom or oxygen atom. An heterocycloalkyl is thus a saturated or unsaturated mono-, bi- or tri-cyclic group comprising between 5 and 20 cyclic atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulfur atom. It also includes fused, bridged, or spiro-connected heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not 10 limited to aziridinyl, azepanyl, diazepanyl, dioxolanyl, benzo [1,3] dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, phthalimidyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, pyrimidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiooxetanyl, thiopyranyl, thiomorpholinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, 15 dihydrofuranyl, dihydrothiopyranyl, dihydrothiophenyl, dihydropiperidinyl, tetrahydropiperidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. In a particular aspect, the heterocycloalkyl group is for instance azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or pyrrolidinyl. In another particular aspect, the heterocycloalkyl group is morpholinyl. "Cycloalkyl" and "heterocycloalkyl" also include cycloalkenyl and heterocycloalkenyl which correspond 20 respectively to a cycloalkyl having at least one carbon-carbon double bond and a heterocycloalkyl having at least one carbon-carbon double bond such as cyclohexenyl, and dihydropyranyl. The term “aryl” corresponds to a mono- or bi-cyclic aromatic hydrocarbons having from 6 to 12 carbon atoms. For instance, the term “aryl” includes phenyl, biphenyl, naphthyl, or anthracenyl. In a particular aspect, the aryl is a phenyl. 25 The term “heteroaryl” as used herein corresponds to an aromatic, mono- or poly-cyclic group comprising between 5 and 14 cyclic atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulfur atom. As used herein, the term “heteroaryl” further includes the “fused arylheteroaryl”, “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl”. The terms “fused arylheteroaryl” may for instance include non-exhaustively quinolinyl, indole, or benzoxazole. The 30 terms “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl” correspond to a bicyclic group in which an aryl as above defined or a heteroaryl is respectively bounded to the heterocycloalkyl or the cycloalkyl as above defined by at least two carbons. In other terms, the aryl or the heteroaryl shares a carbon bond with the heterocycloalkyl or the cycloalkyl. Examples of such mono- and poly-cyclic heteroaryl group, fused arylheterocycloalkyl and fused arylcycloalkyl may be: pyridinyl, thiazolyl, 35 thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienopyridinyl, benzofuranyl, 8 thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phtalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β- 5 carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxindolyl, benzoxazolyl, benzothiazolyl, benzothiphenyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepinyl, benzazepinyl, benzoxazepinyl, isatinyl, dihydropyridyl, pyrimidinyl, s- 10 triazinyl, oxazolyl, or thiofuranyl. In a particular aspect, the heteroaryl is for instance pyridinyl, pyrimidyl, 1,2,4-triazinyl or benzoxazolyl. In a particular aspect, the heteroaryl is for instance tetrazolyl or 1,2,3-trizolyl. In a particular aspect, the heteroaryl is for instance thiophenyl. The term piperidinyl preferably encompasses 1-, 2-, 3- or 4-piperidinyl; considering that the 1- piperidinyl moiety refers to the piperidinyl moiety that is bound to the compound via the nitrogen 15 atom. The term pyridinyl preferably encompasses 2-, 3- or 4-pyridinyl, more preferably2-, 3- or 4-pyridinyl; considering that 1-pyridinyl moiety refers to the pyridinyl moiety that is bound to the compound via the nitrogen atom. The term pyrrolidinyl preferably encompasses 1-, 2-, or 3-pyrrolidinyl; considering that the 1- 20 pyrrolidinyl moiety refers to the pyrrolidinyl moiety that is bound to the compound via the nitrogen atom. The term “fused” when applied to the description of two rings corresponds to a bicyclic group in which the first ring is respectively bounded to the second ring by at least two carbons. The term “halogen” corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine, 25 a chlorine or an iodine. The expression “substituted by at least” or “substituted by” means that the group is substituted by one or several substituents of the list. For instance, the expression “a (C1-C6)alkyl substituted by at least one halogen” or “a (C1-C6)alkyl substituted by a halogen” may include a fluoromethyl (-CH2F), a difluoromethyl (-CHF2), or a trifluoromethyl (-CF3). 30 The expression “optionally substituted” means that the group is not substituted or substituted by one or several substituents of the list. By “-CO-“ or “-C(O)-“, it refers to an oxo group. By “-SO-“ or “-S(O)-“, it refers to a sulfinyl group. By “- SO2-“ or “-S(O2)-“, it refers to a sulfonyl group. The “stereoisomers” are isomeric compounds that have the same molecular formula and sequence of 35 bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The 9 stereoisomers include enantiomers, diastereoisomers, Cis-trans and E-Z isomers, conformers, and anomers. In a preferred embodiment of the invention, the stereoisomers include diastereoisomers and enantiomers. The “tautomers” are isomeric compounds that differ only in the position of the protons and the 5 electrons. The “pharmaceutically salts” include inorganic as well as organic acids salts. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, lactic, tartaric, methanesulfonic 10 and the like. Further examples of pharmaceutically inorganic or organic acid addition salts include the pharmaceutically salts listed in J. Pharm. Sci. 1977, 66, 2, and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002. In a preferred embodiment, the salt is selected from the group consisting of maleate, chlorhydrate, bromhydrate, and methanesulfonate. The “pharmaceutically salts” also include inorganic as well as organic base 15 salts. Representative examples of suitable inorganic bases include sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt. Representative examples of suitable salts with an organic base includes for instance a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. In a preferred embodiment, the salt is selected from the group consisting of sodium and potassium salt. 20 As used herein, the terms “treatment”, “treat” or “treating” refer to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease. In certain aspects, such terms refer to the amelioration or eradication of the disease, or symptoms associated with it. In other aspects, this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a 25 disease. As used herein, the terms “subject”, “individual” or “patient” are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human, including adult and child. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others. 30 The terms “quantity,” “amount,” and “dose” are used interchangeably herein and may refer to an absolute quantification of a molecule. As used herein, the terms "active principle", "active ingredient" and "active pharmaceutical ingredient" are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect. 10 As used herein, the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder. As used herein, the term “effective amount” refers to a quantity of an active ingredient or of a 5 pharmaceutical composition which prevents, removes or reduces the deleterious effects of the disease. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the disease, etc. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the disease to be treated, as well as of the weight, the age and the global health of the subject to be treated, as 10 well as of the judgment of the doctor. In particular, an amount is effective, for example, when its administration results in one or more of weight loss, management of weight, suppression of appetite for food, control of food intake, loss of body fat, prevention or modulation of hypoglycaemia, prevention or modulation of hyperglycaemia, promotion of insulin synthesis, or reduction in food intake. 15 As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients. 20 s of the invention In a first aspect, the invention relates to a compound of the following general formula (I): or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, 25 wherein the dotted line represents the presence or absence of a bond; W represents -CH-, -N- or -NH-; V represents -N-, -CH- or -C(R2)-, with R2being a (C1-C6)alkyl, each X, Y and Z represents, independently of each other, -CH-, -NH- or -N-; provided that at least two 30 of X, Y and Z represents -N- or -NH-; 11 R5is a moiety selected in the group constituted of cyclohexyl, piperazinyl, morpholinyl, 3-pyridinyl, 4- pyridinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, quinuclidinyl, imidazolyl, and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1- 5 C6)alkoxy; or R5is selected from the list constituted of an unsubstituted 2-pyridinyl; unsubstituted 2- or 3-pyrazolyl; a 1-piperidinyl optionally substituted with at least one, preferably one or two, oxo, OH, Me or N(CH3)2; or 1-pyrrolidinyl unsubstituted or substituted with at least NRARB; R and R’ are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; RAand RBare, independently of each other, an hydrogen atom or a (C1-C3)alkyl provided that RAand RB10 are not both hydrogen atom; R6is an hydrogen atom or a (C1-C6)alkyl, preferably an hydrogen atom or a methyl; R7is a moiety selected in the group consisting of (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C6-C12)aryl and (C5-C14)heteroaryl; said group being optionally substituted with at least one, such as one or two, - OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or - 15 C(O)NR11R12; R8is a (C1-C6)alkyl group optionally substituted with one, two or three halo or a phenyl, preferably one, two or three halo, more preferably two or three fluorine; R9is a (C1-C6)alkoxy or (C1-C6)alkyl; and R10is a H or (C1-C6)alkyl; 20 R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle; provided that R7is not an unsubstituted phenyl; provided that when R5is 1-piperidinyl, R7is not a 1-piperidinyl; provided that when R5is 1-morpholinyl, R7is not a 1-morpholinyl; and 25 provided that said compound is not a compound of following formula (A37), (C1), (C2), or (C3): 12 In a specific aspect, the invention relates to a compound of the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond; W represents -CH-, -N- or -NH-; 5 V represents -N-, -CH- or -C(R2)-, with R2being a (C1-C6)alkyl, each X, Y and Z represents, independently of each other, -CH-, -NH- or -N-; provided that at least two of X, Y and Z represents -N- or -NH-; R5is a moiety selected in the group constituted of cyclohexyl, piperazinyl, morpholinyl, 3-pyridinyl, 4- pyridinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, 10 quinuclidinyl, imidazolyl, and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1- C6)alkoxy; or R5is selected from the list constituted of an unsubstituted 2-pyridinyl; unsubstituted 2- or 3-pyrazolyl; a 1-piperidinyl optionally substituted with at least one, preferably one or two, oxo, OH, Me or N(CH3)2; or 1-pyrrolidinyl unsubstituted or substituted with at least NRARB; 15 R and R’ are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; RAand RBare, independently of each other, an hydrogen atom or a (C1-C3)alkyl provided that RAand RBare not both hydrogen atom; R6is an hydrogen atom or a (C1-C6)alkyl, preferably an hydrogen atom or a methyl; R7is a moiety selected in the group consisting of (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl and (C5- 20 C14)heteroaryl; said group being optionally substituted with at least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or - C(O)NR11R12; or R7is a (C6-C12)aryl substituted with at least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12; R8is a (C1-C6)alkyl group optionally substituted with one, two or three halo or a phenyl, preferably one, 25 two or three halo, more preferably two or three fluorine; R9is a (C1-C6)alkoxy or (C1-C6)alkyl; and R10is a H or (C1-C6)alkyl; R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle; 30 provided that when R5is 1-piperidinyl, R7is not a 1-piperidinyl; provided that when R5is 1-morpholinyl, R7is not a 1-morpholinyl; and provided that said compound is not a compound of following formula (A37), (C1), (C2), or (C3):

[0002] 5 In a specific aspect, in the compound of formula (I), V represents -CH- or -C(R2)-, with R2being as defined above. The compounds of following formula (A37), (C1), (C2), (C3) or (C4) are excluded from the scope of the invention: 10 The compounds of general formula (I) wherein R7is an unsubstituted phenyl are excluded from the scope of the invention. 15 14 The compounds of general formula (I) wherein R5and R7are 1-piperidinyl are excluded from the scope of the invention. The compounds of general formula (I) wherein R5and R7are 1-morpholinyl are excluded from the scope of the invention. 5 In a preferred aspect, V represents -CH- or -C(R2)-, with R2being In a preferred aspect, V represents -CH- or -C(R2)-, with R2being More particularly, V is -CH-. 10 In a specific aspect, in the compound of formula (I), W represents -N- or -NH-. In a specific aspect, in the compound of formula (I), each X, Y and Z represents, independently of each other, -CH-, -NH- or -N-; provided that at least two of X, Y and Z represents -N- or -NH-. For example, X, Y and Z may be as defined in the following combination: - X, Y and Z are -NH- or -N-; or 15 - X and Y are -NH- or -N-, and Z is -CH-; or - X and Z are -NH- or -N-, and Y is -CH-; or - Y and Z are -NH- or -N-, and X is -CH-. In a preferred aspect of the invention, X, Y and Z are NH- or -N-, preferably -N-. 20 In a specific embodiment, V is -CH-; W is -N- or -NH-; and X, Y and Z are N. In a specific embodiment, V is -C(R2)-, with R2being are N. In a specific embodiment, V, W, X, Y and Z are N. In a specific embodiment, V and W are -CH-, and X, Y and Z are N. 25 In another specific aspect, the compound of the invention is of the following formula (Ia) to (If), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof:

[0003] wherein 5 the dotted line represents the presence or absence of a bond, preferably the absence of a bond; and V, R5, R6and R7are as defined above. In particular, V is -CH- or -C(R2)-, with R2being as defined above, preferably with R2being . More particularly, V is -CH-. In another specific aspect, the compound of the invention is of the following formula (Ia) to (If), 10 preferably (Ia) or (Ib), more preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof: wherein the dotted line represents the presence or absence of a bond, preferably the absence of a bond; and 15 V, R5, R6and R7are as defined above. In particular, V is -CH- or -C(R2)-, with R2being as defined above, preferably with R2being More particularly, V is -CH-. 16 In a specific aspect, in the compound of formula (I) or (Ia) to (If), preferably (I), (Ia) or (Ib), R6is an hydrogen atom or a (C1-C3)alkyl. Preferably, R6is an hydrogen atom or a methyl. More preferably, R6is an hydrogen atom. In a specific aspect of the invention, in the compound of formula (I) or (Ia) to (If), preferably (I), (Ia) or 5 (Ib), R5is a moiety selected in the group constituted of (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, and (C5-C14)heteroaryl; said group being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; R and R’ being as defined above. In particular, R5is a moiety selected in the group constituted of (C5-C8)cycloalkyl, (C5-C8)heterocycloalkyl, and (C5- C8)heteroaryl, preferably constituted of (C5-C8)heterocycloalkyl, and (C5-C8)heteroaryl; said group10 being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1- C6)alkyl or (C1-C6)alkoxy; R and R’ being as defined above. In these definitions, the heterocycloalkyl or heteroaryl preferably comprises at least one nitrogen cyclic atom, preferably one or two nitrogen cyclic atoms, or one nitrogen cyclic atom and one oxygen cyclic atom. The terms (C3-C6)heterocycloalkyl preferably encompass piperidinyl, piperazinyl, oxopiperazinyl, pyrrolyl, pyrrolinyl, morpholinyl, 15 quinuclidinyl, and pyrrolidinyl. The terms (C5-C8)heteroaryl preferably encompass pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, hydroxypyridinyl, imidazolyl, and pyrazolyl. In a specific aspect of the invention, in the compound of formula (I) or (Ia) to (If), preferably (I), (Ia) or (Ib), R5is a moiety selected in the group constituted of cyclohexyl, pyrazolyl, piperazinyl, morpholinyl, 20 pyridinyl, piperidinyl, pyrrolidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, quinuclidinyl, imidazolyl, and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy. In a specific aspect, R5is a moiety selected in the group constituted of cyclohexyl, piperazinyl, 25 morpholinyl, 3-pyridinyl, 4-pyridinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, quinuclidinyl, imidazolyl, and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, - CN, (C1-C6)alkyl or (C1-C6)alkoxy; or R5is selected from the list constituted of an unsubstituted 2- pyridinyl; unsubstituted 2- or 3-pyrazolyl; a 1-piperidinyl optionally substituted with at least one, 30 preferably one or two, oxo, OH, Me or N(CH3)2; or 1-pyrrolidinyl unsubstituted or substituted with at least NRARB; R and R’ being, independently of each other, an hydrogen atom or a (C1-C6)alkyl; and RAand RBbeing, independently of each other, an hydrogen atom or a (C1-C3)alkyl provided that RAand RBare not both hydrogen atom. 17 In a specific aspect, R5is a moiety selected in the group constituted of piperazinyl, 3-pyridinyl, 4- pyridinyl, and 4-piperidinyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; or R5is a 1-piperidinyl optionally substituted with at least one, preferably one or two, oxo, OH, Me or N(CH3)2; R and R’ being, 5 independently of each other, an hydrogen atom or a (C1-C6)alkyl. In a specific aspect, R5is a moiety selected in the group constituted of 4-pyridinyl and 4-piperidinyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), - NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy. 10 In a preferred embodiment, R5is a moiety selected in the group constituted of moieties of general formula (III) to (XXI) : 15 18 wherein R13and R14are, independently of each other, an hydrogen atom, halo preferably fluorine or bromine, -NH2, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; R15is an hydrogen atom or a (C1-C3)alkyl; 5 one of R16and R17is oxo and the other is an hydrogen atom; R18and R19are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R20and R21are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; 10 R22and R22’ are, independently of each other, an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R23is -H or (C1-C3)alkyl; and R25and R26are, independently of each other, an hydrogen atom or a (C1-C3)alkyl. 15 In a preferred embodiment, R5is a moiety selected in the group constituted of moieties of general formula (III) to (XXI) : 19 R13and R14are, independently of each other, an hydrogen atom, halo preferably fluorine or bromine, -NH2, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; R15is an hydrogen atom or a (C1-C3)alkyl; 5 one of R16and R17is oxo and the other is an hydrogen atom; R18and R19are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R20and R21are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; 10 R22is an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1- C3)alkyl; R23is -H or (C1-C3)alkyl. In a preferred embodiment, R5is a moiety selected in the group constituted of moieties of general 15 formula (III) to (XXI) : 20 wherein R13and R14are, independently of each other, an hydrogen atom, halo preferably fluorine or bromine, -NH2, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; R18and R19are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, 5 or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R20and R21are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R22is an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1- C3)alkyl; 10 R23is -H or (C1-C3)alkyl. In a preferred embodiment, R5is a moiety selected in the group constituted of: 15 wherein R13and R14are, independently of each other, an hydrogen atom or (C1-C6)alkyl; R18and R19are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R20and R21are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, 20 or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R22is an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1- C3)alkyl; and R23is (C1-C3)alkyl, preferably methyl. 25 In a preferred embodiment, R5is a moiety selected in the group constituted of: wherein R13and R14are, independently of each other, an hydrogen atom or (C1-C6)alkyl; R20and R21are, independently of each other, an hydrogen atom or halo, preferably hydrogen atom; 5 R22is an hydrogen atom, halo, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl. In a specific embodiment, the compound of the invention is of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein 10 the dotted line represents the presence or absence of a bond, V is -CH-; W is -N- or -NH-; X, Y and Z are -N-. R5is a moiety selected in the group constituted of moieties of formula (III) to (XXI), preferably 15 R5is a moiety of general formula (III), (V), (VII), (VIII), (IX) or (XVIII); more preferably R5is a moiety of general formula (III), (VII) or (IX); R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and R7is as defined above. 20 In a specific embodiment, the compound of the invention is of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, V is -C(R2)-, with R2being as defined above, preferably R2being W is -N- or -NH-; 25 X, Y and Z are -N-. 22 R5is a moiety selected in the group constituted of moieties of formula (III) to (XXI), preferably is a moiety of general formula (III), (V), (VII), (VIII), (IX) or (XVIII); more preferably R5is a moiety of general formula (III), (VII) or (IX); R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and 5 R7is as defined above. In a specific embodiment, the compound of the invention is of formula (Ia) to (If), preferably (Ia) or (Ib), more preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein 10 the dotted line represents the presence or absence of a bond, preferably the absence of a bond; V is -CH- or -C(R2)-, with R2being as defined above, preferably R2being R5is a moiety selected in the group constituted of moieties of formula (III) to (XXI), preferably is a moiety of general formula (III), (V), (VII), (VIII), (IX) or (XVIII); more preferably R5is a moiety 15 of general formula (III), (VII) or (IX); R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and R7is as defined above. In a specific embodiment, the compound of the invention is of formula (Ia) to (If), preferably (Ia) or 20 (Ib), more preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, preferably the absence of a bond; V is -CH- ; 25 R5is a moiety of general formula (III), (VII) or (IX), preferably (III); R6is an hydrogen atom; and R7is as defined above. In a specific aspect of the invention, R7is a moiety selected in the group consisting of (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C6-C12)aryl and (C5-C14)heteroaryl; said group being optionally substituted with30 at least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, - NH2, -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12; provided that R7is not an unsubstituted phenyl. In a specific aspect of the invention, R7is a moiety selected in the group consisting of (C3-C8)cycloalkyl, (C3- C8)heterocycloalkyl, (C6-C12)aryl and (C5-C14)heteroaryl; said group being optionally substituted with at 23 least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, (C1-C6)alkyl, -NH2, - NHC(O)R9, -C(O)OR10, or -C(O)NR11R12; provided that R7is not an unsubstituted phenyl. In particular, R7is a moiety selected in the group consisting of (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C6-C12)aryl and (C5-C10)heteroaryl; preferably (C3-C6)cycloalkyl, (C6-C10)aryl and (C5-C8)heteroaryl; said group being 5 optionally substituted with at least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12; provided that R7is not an unsubstituted phenyl. In these definitions, the heterocycloalkyl or heteroaryl preferably comprises at least one, such as one or two, nitrogen cyclic atom or sulfur cyclic atom; more preferably, the heterocycloalkyl and heteroaryl are a nitrogen-heterocycloalkyl and nitrogen-heteroaryl. The terms 10 (C3-C6)heterocycloalkyl preferably encompass piperidinyl, piperazinyl, pyrrolyl, pyrrolinyl, and pyrrolidinyl. The terms (C5-C8)heteroaryl preferably encompass pyridinyl, pyrazinyl, thiophenyl, pyrimidinyl, pyridazinyl, imidazolyl, and pyrazolyl. In a preferred aspect, R7is a moiety selected in the group constituting of a (C3-C6)cycloalkyl preferably 15 cyclopropyl and cyclohexyl; and (C5-C6)heteroaryl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, - NHC(O)R9, -C(O)OR10or -C(O)NR11R12; or R7is a phenyl substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12. Preferably, R7is a (C5-C6)-heteroaryl group; in particular pyridinyl, pyrimidinyl, 20 pyridazinyl, pyrazinyl, thiophenyl, imidazolyl, and pyrazolyl; particularly pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and thiophenyl; more particularly pyridinyl; said heteroaryl group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12; or R7is a phenyl substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1- 25 C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12. In a preferred embodiment, R7is a moiety selected in the group consisting of a pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; said moiety being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or - 30 C(O)NR11R12; or R7is a phenyl substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12In a preferred embodiment, R7is a pyridinyl; a pyrimidinyl; or a phenyl substituted with at least one group selected from (C1-C6)alkoxy, -OCHF2, halogen preferably chlorine or fluorine, (C1-C6)alkyl, -NH2, - 35 NHC(O)R9, -C(O)OR10or -C(O)NR11R12. 24 In a preferred embodiment, R7is a pyridinyl or a phenyl substituted with at least one group selected from (C1-C6)alkoxy, -OCHF2, halogen preferably chlorine or fluorine, (C1-C6)alkyl, -NH2, -NHC(O)R9, - C(O)OR10or -C(O)NR11R12. 5 In a specific embodiment, R7is a phenyl substituted with at least one group selected from (C1-C6)alkoxy, -OCHF2, halogen preferably chlorine or fluorine, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or - C(O)NR11R12; or an unsubstituted pyridinyl. 10 In a specific embodiment, the compound of the invention is of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, V is -CH-; W is -N- or -NH-; 15 X, Y and Z are -N-. R5is a moiety selected in the group constituted of moieties of formula (III) to (XXI), preferably is a moiety of general formula (III), (V), (VII), (VIII), (IX) or (XVIII); more preferably R5is a moiety of general formula (III), (VII) or (IX); R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and 20 R7is a moiety selected in the group constituting of a (C3-C6)cycloalkyl; (C3-C6)heterocycloalkyl; and (C5-C6)heteroaryl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, - C(O)OR10or -C(O)NR11R12; or R7is a phenyl substituted with at least one group selected from - OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR1025 or -C(O)NR11R12. In a specific embodiment, the compound of the invention is of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, 30 V is -C(R2)-, with R2being as defined above, preferably R2being W is -N- or -NH-; X, Y and Z are -N-. 25 R5is a moiety selected in the group constituted of moieties of formula (III) to (XXI), preferably is a moiety of general formula (III), (V), (VII), (VIII), (IX) or (XVIII); more preferably R5is a moiety of general formula (III), (VII) or (IX); R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and 5 R7is a moiety selected in the group constituting of a (C3-C6)cycloalkyl; (C3-C6)heterocycloalkyl; and (C5-C6)heteroaryl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, - C(O)OR10or -C(O)NR11R12; or R7is a phenyl substituted with at least one group selected from - OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR1010 or -C(O)NR11R12. In a specific embodiment, the compound of the invention is of formula (Ia) to (If), preferably (Ia) or (Ib), more preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein 15 the dotted line represents the presence or absence of a bond, preferably the absence of a bond; V is -CH- or -C(R2)-, with R2being as defined above, preferably R2being R5is a moiety selected in the group constituted of moieties of formula (III) to (XXI), preferably is a moiety of general formula (III), (V), (VII), (VIII), (IX) or (XVIII); more preferably R5is a moiety 20 of general formula (III), (VII) or (IX); R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and R7is a moiety selected in the group constituting of a (C3-C6)cycloalkyl; (C3-C6)heterocycloalkyl; and (C5-C6)heteroaryl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -25 C(O)OR10or -C(O)NR11R12; or R7is a phenyl substituted with at least one group selected from - OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12. In a specific embodiment, the compound of the invention is of formula (Ia) to (If), preferably (Ia) or 30 (Ib), more preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, preferably the absence of a bond; 26 V is -CH-; R5is a moiety of general formula (III), (VII) or (IX), preferably (III); R6is an hydrogen atom; and R7is a moiety selected in the group constituting of a (C3-C6)cycloalkyl; (C3-C6)heterocycloalkyl; 5 and (C5-C6)heteroaryl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, - C(O)OR10or -C(O)NR11R12; or R7is a phenyl substituted with at least one group selected from - OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12. 10 In the above aspects or embodiments, R8is a (C1-C6)alkyl group optionally substituted with one, two or three halo or a phenyl, preferably one, two or three halo, more preferably two or three fluorine; R9is a (C1-C6)alkoxy or (C1-C6)alkyl; 15 R10is a hydrogen atom or (C1-C6)alkyl, preferably (C1-C6)alkyl; and R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle. Preferably, in the above aspects or embodiments, 20 R8is a methyl optionally substituted with one, two or three halo, preferably two or three fluorine; R9is a (C1-C6)alkoxy or (C1-C6)alkyl; R10is a Hydrogen atom or (C1-C6)alkyl; and R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle such as a 4- 25 methylpiperazine. In the above embodiments, R7is preferably a pyridinyl or phenyl substituted with -OCHF2, a fluorine, a chlorine, bromine, -OMe, -CN, -CF3, a methyl, or -NH2. 30 In the above embodiments, R7is preferably a pyridinyl or phenyl substituted with -OCHF2, a fluorine, a chlorine, -OMe, a methyl, or -NH2. In the above embodiments, R7is preferably phenyl substituted with -OCHF2, a fluorine, a chlorine, - OMe, a methyl, or -NH2. 35 27 In a specific aspect of the invention, the compound of general formula (I) is advantageously selected from the compounds as shown in Table 1 below, and any pharmaceutical salt, stereoisomer, tautomer thereof. Preferably, the compound of the invention is A , A-29, A-30, A-31, A-32, A-34, A-36, A-38, A-39, A-41-ent-I, A-41-ent-II, A-41-rac, A-42, A-46, A-58, A-58-H2, A-59, A-60, A-62, A-64, A-67, A-70, 5 A-71, A-72-Me2, A-73, A-75, A-76, A-78, A-82, A-83, A-84, A-85, A-87, A-88, A-89, A-90, A-92, A-94, A- 95, A-96, A-97, A-99, A-101, A-103, A-105, A-106, A-108, A-109, A-110, A-111, A-112, A-113, A-114, A- 115, A-116, A-117, A-121, A-124, A-125, A-127, A-128, A-129, A-130, A-131, A-132, A-135, A-136, A- 141, A-148, A-149, A-150, A-151, A-152, A-161, A-163, A-166, A-168, A-169, A-171, A-172, A-174, B23 or B26. Preferably, the compound of the invention is A-27, A-29, A-30, A-31, A-32, A-34, A-36, A-38, A-10 39, A-41-ent-I, A-41-ent-II, A-41-rac, A-42, A-46, A-58, A-58-H2, A-59, A-60, A-62, A-64, A-67, A-70, A- 71, A-72-Me2, A-73, A-75, A-76, A-78, A-82, A-83, A-84, A-85, A-87, A-88, A-89, A-90, A-92, A-94, A-95, A-96, A-97, A-99, A-101, A-103, A-105, A-106, A-108, A-109, A-110, A-111, B23 or B26. More preferably, the compound of the invention is , A-31, A-32, A-34, A-36, A-41-ent-I, A-41-ent-II, A-46, A-59, A- 60, A-62, A-64, A-67, A-71, A-72-Me2, A-75, A-82, A-83, A-84, A-85, A-87, A-88, A-89, A-90, A-105, A-15 106, A-108, A-109, A-111, A-112, A-113, A-114, A-117, A-124, A-125, A-127, A-128, A-129, A-130, A- 132, A-135, A-136, A-148, A-149, A-150, A-152, A-161, A-163, A-168, A-169, or B23. More preferably, the compound of the invention is , A-31, A-32, A-34, A-36, A-41-ent-I, A-41-ent-II, A-46, A-59, A- 60, A-62, A-64, A-67, A-71, A-72-Me2, A-75, A-82, A-83, A-84, A-85, A-87, A-88, A-89, A-90, A-105, A- 106, A-108, A-109, A-111 or B23. 20 More preferably, the compound of the invention is A-31, A-32, A-34, A-36, A-59, A-60, A-64, A-67, A- 75, A-83, A-84, A-85, A-87, A-88, A-89, A-111, A-113, A-114, A-117, A-125, A-127, A-128. A-129, A-130, A-135, A-148, A-149, A-150, A-152, A-161, A-168 or B23. More preferably, the compound of the invention is A-31, A-32, A-34, A-36, A-59, A-60, A-64, A-67, A-75, A-83, A-84, A-85, A-87, A-88, A89, A- 111, or B23. 25 The invention also relates to a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for use as a drug. The invention also relates to a compound of general formula (I) as defined above, or a pharmaceutically 30 acceptable salt, stereoisomer, tautomer or solvate thereof, for use as appetite suppressant, in particular for treating and / or preventing of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain. 35 28 The invention also relates to a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for use for treating and / or preventing metabolic syndrome, in particular obesity. 5 The invention also relates to a pharmaceutical composition comprising a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and a pharmaceutically acceptable excipient. The pharmaceutical composition of the invention can further comprise another active ingredient. The invention also relates to a pharmaceutical composition comprising a compound of general formula 10 (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for use as appetite suppressant, in particular for treating and / or preventing of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced 15 weight gain. In a particular aspect, the compound of the invention is as disclosed above and has an appetite suppressor effect as measured in the assay disclosed in the example section. Preferably, the food intake reduction in % compared to vehicle is of at least 10, 15, 20, 25, 30, 35, 40, 45 or 50%. 20 Compounds for use according to the invention The invention also relates to a compound of the following general formula (I): or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, 25 for use as appetite suppressant, wherein the dotted line represents the presence or absence of a bond; W represents -CH-, -N- or -NH-; V represents -N-, -CH- or -C(R2)-, with R2being a (C1-C6)alkyl, CF3, or the moiety 29 each X, Y and Z represents, independently of each other, -CH-, -NH- or -N-; provided that at least two of X, Y and Z represents -N- or -NH-; R5is a moiety selected in the group constituted of cyclohexyl, phenyl, pyrazolyl, piperazinyl, morpholinyl, pyridinyl, piperidinyl, pyrrolidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, 5 quinuclidinyl, imidazolyl, and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted with at least a halo, hydroxy (OH), -NRR’, CN, (C1-C6)alkyl or (C1-C6)alkoxy; R and R’ are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; R6is an hydrogen atom or a (C1-C6)alkyl, preferably an hydrogen atom or a methyl; and R7is CF3; or a moiety selected in the group consisting of (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3- 10 C8)heterocycloalkyl, (C6-C12)aryl and (C5-C14)heteroaryl; said group being optionally substituted with at least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12; R8is a (C1-C6)alkyl group optionally substituted with one, two or three halo or a phenyl, preferably one, two or three halo, more preferably two or three fluorine; 15 R9is a (C1-C6)alkoxy or (C1-C6)alkyl; R10is a H or (C1-C6)alkyl; R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle. 20 In this aspect, the compound of general formula (I) for use according to the invention are in particular for use for treating and / or preventing a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain. 25 In a specific aspect, in the compound of formula (I) for use according to the invention, V represents - CH- or -C(R2)-, with R2being as defined above. In a preferred aspect, V represents -CH- or -C(R2)-, with R2being In a preferred aspect, V represents -CH- or -C(R2)-, with R2being 30 More particularly, V is -CH-. 30 In a specific aspect, in the compound of formula (I) for use according to the invention, W represents - N- or -NH-. In a specific aspect, in the compound of formula (I) for use according to the invention, each X, Y and Z 5 represents, independently of each other, -CH-, -NH- or -N-; provided that at least two of X, Y and Z represents -N- or -NH-. For example, X, Y and Z may be as defined in the following combination: - X, Y and Z are -NH- or -N-; or - X and Y are -NH- or -N-, and Z is -CH-; or - X and Z are -NH- or -N-, and Y is -CH-; or 10 - Y and Z are -NH- or -N-, and X is -CH-. In a preferred aspect, X, Y and Z are NH- or -N-, preferably -N-. In a specific embodiment, V is -CH-; W is -N- or -NH-; and X, Y and Z are N. In a specific embodiment, V is -C(R2)-, with R2being are N. 15 In a specific embodiment, V, W, X, Y and Z are N. In a specific embodiment, V and W are -CH-, and X, Y and Z are N. In another specific aspect, the compound for use according to the invention is of the following formula (Ia) to (If), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof: 20 wherein the dotted line represents the presence or absence of a bond, preferably the absence of a bond; and 31 V, R5, R6and R7are as defined above. In particular, V is -CH- or -C(R2)-, with R2being as defined above, preferably with R2being More particularly, V is -CH-. In another specific aspect, the compound for use according to the invention is of the following formula 5 (Ia) to (If), preferably (Ia) or (Ib), more preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof: wherein the dotted line represents the presence or absence of a bond, preferably the absence of a bond; and 10 V, R5, R6and R7are as defined above. In particular, V is -CH- or -C(R2)-, with R2being as defined above, preferably with R2being . More particularly, V is -CH-. In a specific aspect, in the compound of formula (I) or (Ia) to (If), preferably (I), (Ia) or (Ib), for use according to the invention, R6is an hydrogen atom or a (C1-C3)alkyl. Preferably, R6is an hydrogen atom 15 or a methyl. More preferably, R6is an hydrogen atom. In a specific aspect, in the compound of formula (I) or (Ia) to (If), preferably (I), (Ia) or (Ib), for use according to the invention, R5is a moiety selected in the group constituted of (C3-C8)cycloalkyl, (C3- C8)heterocycloalkyl, (C6-C12)aryl, and (C5-C14)heteroaryl; said group being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; R and R’20 being as defined above. In particular, R5is a moiety selected in the group constituted of (C5- C8)cycloalkyl, (C5-C8)heterocycloalkyl, phenyl, and (C5-C8)heteroaryl, preferably constituted of (C5- C8)heterocycloalkyl, and (C5-C8)heteroaryl; said group being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; R and R’ being as defined above. In these definitions, the heterocycloalkyl or heteroaryl comprises at least one nitrogen 25 cyclic atom, preferably one or two nitrogen cyclic atoms, or one nitrogen cyclic atom and one oxygen cyclic atom. The terms (C3-C6)heterocycloalkyl preferably encompass piperidinyl, piperazinyl, 32 oxopiperazinyl, pyrrolyl, pyrrolinyl, morpholinyl, quinuclidinyl, and pyrrolidinyl. The terms (C5- C8)heteroaryl preferably encompass pyridinyl, pyrazinyl, thiophenyl, pyrimidinyl, pyridazinyl, hydroxypyridinyl, imidazolyl, and pyrazolyl. In a specific aspect, in the compound of formula (I) or (Ia) to (If), preferably (I), (Ia) or (Ib), for use 5 according to the invention, R5is a moiety selected in the group constituted of cyclohexyl, phenyl, piperazinyl, morpholinyl, pyridinyl, piperidinyl, pyrrolidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, quinuclidinyl, imidazolyl, and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy. 10 In a particular embodiment, R5is a phenyl, (C5-C6)-heterocycloalkyl or (C5-C6)-heteroaryl group, preferably comprising one or two nitrogen atom; said group being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; R and R’ being as defined above. Preferably, R5is a pyridinyl, pipéridinyl, piperazinyl; said group being optionally15 substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1- C6)alkoxy; R and R’ being as defined above. In the above embodiment, pyridinyl is preferably 4-pyridinyl; piperazinyl is preferably 1,4- piperazinyl; morpholinyl is preferably 1,4-morpholinyl; piperidinyl is preferably 4-piperidinyl; and pyrrolidinyl is preferably 1-pyrrolidinyl. 20 In a specific aspect, R5is a moiety selected in the group constituted of cyclohexyl, piperazinyl, morpholinyl, 3-pyridinyl, 4-pyridinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, quinuclidinyl, imidazolyl, and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, - CN, (C1-C6)alkyl or (C1-C6)alkoxy; or R5is selected from the list constituted of an unsubstituted 2- 25 pyridinyl; unsubstituted 2- or 3-pyrazolyl; a 1-piperidinyl optionally substituted with at least one, preferably one or two, oxo, OH, Me or N(CH3)2; or 1-pyrrolidinyl unsubstituted or substituted with at least NRARB; R and R’ being, independently of each other, an hydrogen atom or a (C1-C6)alkyl; and RAand RBbeing, independently of each other, an hydrogen atom or a (C1-C3)alkyl provided that RAand RBare not both hydrogen atom. 30 In a specific aspect, R5is a moiety selected in the group constituted of piperazinyl, 3-pyridinyl, 4- pyridinyl, and 4-piperidinyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; or R5is a 1-piperidinyl optionally substituted with at least one, preferably one or two, oxo, OH, Me or N(CH3)2; R and R’ being, 35 independently of each other, an hydrogen atom or a (C1-C6)alkyl. 33 In a specific aspect, R5is a moiety selected in the group constituted of 4-pyridinyl and 4-piperidinyl; said moiety being optionally substituted with at least one, such as one or two, halo, hydroxy (OH), - NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy. 5 In a preferred embodiment, R5is a moiety selected in the group constituted of moieties of general formula (II) to (XXII) : 10 34 wherein R13and R14are, independently of each other, an hydrogen atom, halo preferably fluorine or bromine, -NH2, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; R15is an hydrogen atom or a (C1-C3)alkyl; 5 one of R16and R17is -C(O) and the other is an hydrogen atom; R18and R19are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R20and R21are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; 10 R22and R22’ are, independently of each other, an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl R23is H or (C1-C3)alkyl; R23’ is -C(O)R24or a phenyl optionally substituted with at least one halo preferably fluorine or chlorine, 15 (C1-C6)alkyl or (C1-C6)alkoxy; R24is (C1-C6)alkyl or a phenyl; and R25and R26are, independently of each other, an hydrogen atom or a (C1-C3)alkyl. In a preferred embodiment, R5is a moiety selected in the group constituted of: 20 wherein R13and R14are, independently of each other, an hydrogen atom or (C1-C6)alkyl; R18and R19are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, 25 or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; 35 R20and R21are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R22and R22’ are, independently of each other, an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; 5 R23is (C1-C3)alkyl, preferably methyl; R23’ is -C(O)R24or a phenyl optionally substituted with at least one halo preferably fluorine or chlorine, (C1-C6)alkyl or (C1-C6)alkoxy; and R24is (C1-C6)alkyl or a phenyl. 10 In a preferred embodiment, R5is a moiety selected in the group constituted of: wherein R13and R14are, independently of each other, an hydrogen atom or (C1-C6)alkyl; and 15 R20and R21are, independently of each other, an hydrogen atom or halo, preferably hydrogen atom; R22is an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1- C3)alkyl. In a specific embodiment, the compound for use according to the invention is of formula (I), or a 20 pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, V is -CH-; W is -N- or -NH-; X, Y and Z are -N-. 25 R5is a moiety selected in the group constituted of moieties of formula (II) to (XXII), preferably is a moiety of general formula (III), (V), (VI), (VII), (VIII), (IX), (XVIII) or (XXII); more preferably R5is a moiety of general formula (III), (VII) or (IX); R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and R7is as defined above. 30 36 In a specific embodiment, the compound for use according to the invention is of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, V is -C(R2)-, with R2being as defined above, preferably R2being 5 W is -N- or -NH-; X, Y and Z are -N-. R5is a moiety selected in the group constituted of moieties of formula (II) to (XXII), preferably is a moiety of general formula (III), (V), (VI), (VII), (VIII), (IX), (XVIII) or (XXII); more preferably R5is a moiety of general formula (III), (VII) or (IX); 10 R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and R7is as defined above. In a specific embodiment, the compound for use according to the invention is of formula (Ia) to (If), 15 preferably (Ia) or (Ib), more preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, preferably the absence of a bond; V is -CH- or -C(R2)-, with R2being as defined above, preferably R2being 20 R5is a moiety selected in the group constituted of moieties of formula (II) to (XXII), preferably is a moiety of general formula (III), (V), (VI), (VII), (VIII), (IX), (XVIII) or (XXII); more preferably R5is a moiety of general formula (III), (VII) or (IX); R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and R7is as defined above. 25 In a specific embodiment, the compound for use according to the invention is of formula (Ia) to (If), preferably (Ia) or (Ib), more preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, preferably the absence of a 30 bond; 37 V is -CH- ; R5is a moiety of general formula (III), (VII) or (IX), preferably (III); R6is an hydrogen atom; and R7is as defined above. 5 In a specific aspect of the invention, R7is CF3; or a moiety selected in the group consisting of (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C6-C12)aryl and (C5-C14)heteroaryl; said group being optionally substituted with at least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12. In particular, R7is a (C1- 10 C6)alkyl; CF3; or a moiety selected in the group consisting of (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C6-C12)aryl and (C5-C10)heteroaryl; preferably (C3-C6)cycloalkyl, (C6-C10)aryl and (C5-C8)heteroaryl; said group being optionally substituted with at least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12. In these definitions, the heterocycloalkyl or heteroaryl preferably comprises at least one, such as one or two, 15 nitrogen cyclic atom or sulfur cyclic atom; more preferably, the heterocycloalkyl and heteroaryl are a nitrogen-heterocycloalkyl and nitrogen-heteroaryl. The terms (C3-C6)heterocycloalkyl preferably encompass piperidinyl, piperazinyl, pyrrolyl, pyrrolinyl, and pyrrolidinyl. The terms (C5-C8)heteroaryl preferably encompass pyridinyl, pyrazinyl, thiophenyl, pyrimidinyl, pyridazinyl, imidazolyl, and pyrazolyl. 20 In a preferred aspect, R7is a (C1-C6)alkyl; CF3; or a moiety selected in the group constituting of a (C3- C6)cycloalkyl preferably cyclopropyl and cyclohexyl, phenyl, and (C5-C6)heteroaryl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12. Preferably, R7is CF3; or a 25 moiety selected in the group constituting of phenyl and (C5-C6)-heteroaryl, in particular phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiophenyl, imidazolyl, and pyrazolyl, particularly phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiophenyl, more particularly phenyl and pyridinyl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12; 30 In a specific embodiment, R7is a (C1-C6)alkyl; CF3; a cyclopropyl; a cyclohexyl; a pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; or a phenyl optionally substituted with at least one group selected from (C1- C6)alkoxy, -OCHF2, halogen preferably chlorine or fluorine, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12. In a preferred embodiment, R7is a pyridinyl; pyrazinyl, pyrimidinyl; pyridazinyl; or a 38 phenyl optionally substituted with at least one group selected from (C1-C6)alkoxy, -OCHF2, halogen preferably chlorine or fluorine, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12. In a specific embodiment, the compound for use according to the invention is of formula (I), or a 5 pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, V is -CH-; W is -N- or -NH-; X, Y and Z are -N-. 10 R5is a moiety selected in the group constituted of moieties of formula (II) to (XXII), preferably is a moiety of general formula (III), (V), (VI), (VII), (VIII), (IX), (XVIII) or (XXII); more preferably R5is a moiety of general formula (III), (VII) or (IX); R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and R7is a (C1-C6)alkyl; CF3; or a moiety selected in the group constituting of a (C3-C6)cycloalkyl; 15 phenyl; and (C5-C6)heteroaryl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, - NHC(O)R9, -C(O)OR10or -C(O)NR11R12. In a specific embodiment, the compound for use according the invention is of formula (I), or a 20 pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, V is -C(R2)-, with R2being as defined above, preferably R2being W is -N- or -NH-; X, Y and Z are -N-. 25 R5is a moiety selected in the group constituted of moieties of formula (II) to (XXII), preferably is a moiety of general formula (III), (V), (VI), (VII), (VIII), (IX), (XVIII) or (XXII); more preferably R5is a moiety of general formula (III), (VII) or (IX); R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and R7is a (C1-C6)alkyl; CF3; or a moiety selected in the group constituting of a (C3-C6)cycloalkyl; (C3- 30 C6)heterocycloalkyl; phenyl; and (C5-C6)heteroaryl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12. 39 In a specific embodiment, the compound for use according to the invention is of formula (Ia) to (If), preferably (Ia) or (Ib), more preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, preferably the absence of a 5 bond; V is -CH- or -C(R2)-, with R2being as defined above, preferably R2being R5is a moiety selected in the group constituted of moieties of formula (II) to (XXII), preferably is a moiety of general formula (III), (V), (VI), (VII), (VIII), (IX), (XVIII) or (XXII); more preferably R5is a moiety of general formula (III), (VII) or (IX); 10 R6is an hydrogen atom or a (C1-C3)alkyl, preferably an hydrogen atom; and R7is a (C1-C6)alkyl; CF3; or a moiety selected in the group constituting of a (C3-C6)cycloalkyl; (C3- C6)heterocycloalkyl; phenyl; and (C5-C6)heteroaryl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12. 15 In a specific embodiment, the compound for use according to the invention is of formula (Ia) to (If), preferably (Ia) or (Ib), more preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond, preferably the absence of a 20 bond; V is -CH-; R5is a moiety of general formula (III), (VII) or (IX), preferably (III); R6is an hydrogen atom; and R7is a (C1-C6)alkyl; CF3; or a moiety selected in the group constituting of a (C3-C6)cycloalkyl; (C3- 25 C6)heterocycloalkyl; phenyl; and (C5-C6)heteroaryl; said group being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, bromine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or -C(O)NR11R12. In the above aspects or embodiments, 30 R8is a (C1-C6)alkyl group optionally substituted with one, two or three halo, preferably two or three fluorine; R9is a (C1-C6)alkoxy or (C1-C6)alkyl; R10is a hydrogen atom or (C1-C6)alkyl, preferably (C1-C6)alkyl; and 40 R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle. Preferably, in the above aspects or embodiments, 5 R8is a methyl optionally substituted with one, two or three halo, preferably two or three fluorine; R9is a (C1-C6)alkoxy or (C1-C6)alkyl; R10is a Hydrogen atom or (C1-C6)alkyl; and R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle such as a 4- 10 methylpiperazine. In the above embodiments, R7is preferably a (C1-C6)alkyl; CF3; a cyclopropyl; a cyclohexyl; a pyridinyl; or a phenyl unsubstituted or substituted with -OCHF2, a fluorine, a chlorine, -OMe, a methyl, or -NH2. 15 In the above embodiments, R7is preferably a pyridinyl or phenyl substituted with -OCHF2, a fluorine, a chlorine, bromine, -OMe, -CN, -CF3, a methyl, or -NH2. In a specific aspect, the compound of general formula (I) for use according to the invention is advantageously selected from the compounds as shown in Table 1 and 2 below, and any pharmaceutical salt, stereoisomer, tautomer thereof. Preferably, the compound of the invention is A- 20 27, A-29, A-30, A-31, A-32, A-34, A-35, A-36, A-37, A-38, A-39, A-41-ent-I, A-41-ent-II, A-41-rac, A-42, A-46, A-58, A-58-H2, A-59, A-60, A-62, A-64, A-67, A-70, A-71, A-72, A-72-Me2, A-73, A-75, A-76, A-78, A-82, A-83, A-84, A-85, A-87, A-88, A-89, A-90, A-92, A-94, A-95, A-96, A-97, A-99, A-101, A-103, A-105, A-106, A-108, A-109, A-110, A-111, A-112, A-113, A-114, A-115, A-116, A-117, A-121, A-124, A-125, A- 127, A-128, A-129, A-130, A-131, A-132, A-135, A-136, A-141, A-148, A-149, A-150, A-151, A-152, A-25 161, A-163, A-166, A-168, A-169, A-171, A-172, A-174, B23, B26, A-22, B-1, B-2, B-3, B-5, B-9, B-14, B- 15, B-16, B-17, B-19, B-20, B-24, B-25, B-27, B-29, B-30, B-31 or B-32. Preferably, the compound of the invention is A-27, A-29, A-30, A-31, A-32, A-34, A-35, A-36, A-37, A-38, A-39, A-41-ent-I, A-41-ent-II, A- 41-rac, A-42, A-46, A-58, A-58-H2, A-59, A-60, A-62, A-64, A-67, A-70, A-71, A-72, A-72-Me2, A-73, A- 75, A-76, A-78, A-82, A-83, A-84, A-85, A-87, A-88, A-89, A-90, A-92, A-94, A-95, A-96, A-97, A-99, A-30 101, A-103, A-105, A-106, A-108, A-109, A-110, A-111, B23, B26, A-22, B-1, B-2, B-3, B-5, B-9, B-14, B- 15, B-16, B-17, B-19, B-20, B-24, B-25, B-27, B-29, B-30, or B-31. More preferably, the compound of the invention is A-27, A-31, A-32, A-34, A-35, A-36, A-41-ent-I, A-41-ent-II, A-46, A-59, A-60, A-62, A-64, A- 67, A-71, A-72-Me2, A-75, A-82, A-83, A-84, A-85, A-87, A-88, A-89, A-90, A-105, A-106, A-108, A-109, A-111, A-112, A-113, A-114, A-117, A-124, A-125, A-127, A-128, A-129, A-130, A-132, A-135, A-136, A- 35 148, A-149, A-150, A-152, A-161, A-163, A-168, A-169, B23, A-22, B-1, B-2, B-3, B-9, B-14, B-15, B-16, 41 B-20, B-24, B-25, B-27, B-30, or B-31. More preferably, the compound of the invention is A-27, A-31, A-32, A-34, A-35, A-36, A-37, A-41-ent-I, A-41-ent-II, A-46, A-59, A-60, A-62, A-64, A-67, A-71, A-72- Me2, A-75, A-82, A-83, A-84, A-85, A-87, A-88, A-89, A-90, A-105, A-106, A-108, A-109, A-111, B23, A- 22, B-1, B-2, B-3, B-9, B-14, B-15, B-16, B-20, B-24, B-25, B-27, B-30, or B-31. More preferably, the 5 compound of the invention is A-31, A-32, A-34, A-36, A-59, A-60, A-64, A-67, A-75, A-83, A-84, A-85, A- 87, A-88, A-89, A-111, A-113, A-114, A-117, A-125, A-127, A-128. A-129, A-130, A-135, A-148, A-149, A-150, A-152, A-161, A-168, B23, B-1, B-2, B-3, B-9, B-15, B-20, B-24, B-25, B-27, or B-31. More preferably, the compound of the invention is A-31, A-32, A-34, A-36, A-37, A-59, A-60, A-64, A-67, A- 75, A-83, A-84, A-85, A-87, A-88, A-89, A-111, B23, B-1, B-2, B-3, B-9, B-15, B-20, B-24, B-25, B-27, or 10 B-31. In a particular aspect, the compound for use according to the invention is as disclosed above and has an appetite suppressor effect as measured in the assay disclosed in the example section. Preferably, the food intake reduction in % compared to vehicle is of at least 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50%. 15 The present invention also includes isotopically labelled, especially2H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially2H (deuterium) labelled compounds of formula (I) and pharmaceutically acceptable salts thereof are within the scope 20 of the present invention. Substitution of hydrogen with the heavier isotope2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub- 25 embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials. Pharmaceutical or veterinary compositions and the uses thereof 30 As illustrated by examples, the inventors have demonstrated the therapeutic interest of the new compounds of the invention. Accordingly, the present invention relates to a pharmaceutical or veterinary composition comprising any new compound according to the present invention. Preferably, the pharmaceutical or veterinary composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient. The present invention relates to the use of any new compound 35 according to the invention as a drug or as a medicine. The invention further relates to a method for 42 treating a disease in a subject, wherein a therapeutically effective amount of any new compound according to the invention, is administered to said subject in need thereof. The invention also relates to the use of any new compound according to the invention, for the manufacture of a medicine. The invention also relates to a pharmaceutical composition comprising any new compound according to 5 the invention for use as a drug. The terms “any new compound” mean herein any compounds as defined in the section “compounds of the invention” herein above. More particularly, the present invention provides compounds having an appetite-suppressor effect as shown by their capacity to reduce the food intake. Beneficial or desired clinical results from the compound of the present invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or 10 solvate thereof, include, without limitation, reduced body weight, decreased weight-gain, reduced appetite, weight loss, management of weight, suppression of an appetite for food, controlled food intake, reduced or stabilized body fat content, reduced or stabilized blood or serum glucose and blood or serum insulin levels, amelioration, palliation, stabilization, diminishment of extent of obesity- related diseases, or a delay or slowing of obesity related disease progression. By treatment is meant 15 inhibiting or reducing an increase in obesity-related symptoms (e.g. weight gain) when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant condition. Therefore, the compounds of the present invention are of interest as appetite suppressant. Accordingly, the present invention relates to any compound according to the present invention or a 20 pharmaceutical or veterinary composition comprising it for use as appetite suppressant. The present invention relates to the use of any compound according to the present invention or a pharmaceutical or veterinary composition comprising it as appetite suppressant. The invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of any compound according to the present invention or a pharmaceutical or veterinary composition 25 comprising it is administered to said subject in need thereof. The invention also relates to the use of any compound according to the present invention or a pharmaceutical or veterinary composition comprising it for the manufacture of a medicine for use as appetite suppressant. The present invention also relates to any compound according to the present invention or a pharmaceutical or veterinary composition comprising it for use for the treatment of a metabolic 30 disease, an eating disorder, a syndrome or a medication-induced weight gain. The present invention relates to the use of any compound according to the present invention or a pharmaceutical or veterinary composition comprising it for the treatment of a metabolic disease, an eating disorder, a syndrome or a medication-induced weight gain. The invention further relates to a method for treating a metabolic disease, an eating disorder, a syndrome or a medication-induced weight gain in a subject, 35 wherein a therapeutically effective amount of any compound according to the present invention or a 43 pharmaceutical or veterinary composition comprising it is administered to said subject in need thereof. The invention also relates to the use of any compound according to the present invention or a pharmaceutical or veterinary composition comprising it for the manufacture of a medicine for the treatment of a metabolic disease, an eating disorder, a syndrome or a medication-induced weight gain. 5 The metabolic disease can be selected from the non-exhaustive list comprising obesity, diabetes (type 1 or type 2 diabetes), hypertension, non-alcoholic steatohepatitis (NASH), Non-alcoholic fatty liver disease (NAFLD), insulin resistance, coronary heart disease, cardiovascular diseases (such as congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, or peripheral artery disease), and dyslipidemia. 10 The eating disorders can be selected from the non-exhaustive list comprising bulimia nervosa, binge eating disorder, night eating syndrome, compulsive overeating, anxiety, depression, Gourmand syndrome, Prader-Willi syndrome. The syndromes can be selected from metabolic syndrome, Cohen syndrome, Bardet-Biedl syndrome, polycystic ovary syndrome and MOMO syndrome. 15 The subject to be treated may have a disorder that leads to weight gain through excessive consumption of food, such as a disorder selected from binge eating disorder, subclinical binge eating, Prader-Willi syndrome and metabolic syndrome (also known as syndrome X or insulin-resistance syndrome). The subject may have other excess weight-related metabolic disorders. Examples of these include insulin resistance, glucose intolerance, pre-diabetes, increased fasting glucose, type 2 diabetes, hypertension, 20 dyslipidemia (or a combination of these metabolic risk factors), glucagonomas, stroke, respiratory dysfunction, or renal disease. Body mass index (BMI) is a simple index of weight-for-height that is commonly used for human adults to assess whether a patient is "overweight" or "obese". It is defined as an individual’s weight in kilograms divided by the square of his or her height in meters (kg / m2). The most commonly used 25 definitions, established by the World Health Organization (WHO) in 1997 and published in 2000, provide the following classifications based on BMI: overweight = human adult with BMI of between about 25 to about 29.99 kg / m2; class I obesity = a human adult with BMI from between about 30 kg / m2 to about 34.99 kg / m2; severe obesity (class II obesity) = a human adult with BMI of between about 35 kg / m2 to about 39.99 kg / m2; morbid obesity (class III obesity) = a human adult with BMI of 30 between about 40 kg / m2 and 44.99 kg / m2. Some physicians / clinicians / surgeons may also refer to super obesity, being a BMI of greater than about 45 kg / m2 in a human adult subject. In addition, the compounds of the present invention are also of interest in order to promote weight loss in a subject. Then, the invention may relate to a method for promoting weight loss or preventing weight gain comprising administering a compound of the present invention or a composition 35 comprising it to the subject. In a particular embodiment, the subject can be obese. In this context, for 44 human being, the Body Mass Index (BMI) is higher or equal to 30. In an alternative embodiment, the subject can be overweight. The overweight can be only minor, e.g. unsightly but without any threat to the health. In this context, the Body Mass Index (BMI) is lower than 30. In this aspect, the method is a non-therapeutic method. For instance, the goal could be improved the physical appearance by 5 reducing the weight. The subject may have a normal body mass index (up to 25). The compound according to the invention or the pharmaceutical composition according to the invention may be administered by any conventional route of administration. In particular, the compound or the pharmaceutical composition of the invention can be administered by a topical, enteral, oral, parenteral, intranasal, intravenous, intraperitoneal, intra-arterial, intramuscular, 10 intratumoral, subcutaneous or intraocular administration and the like. In particular, the compound according to the invention or the pharmaceutical composition according to the invention can be formulated for a topical, enteral, oral, parenteral, intranasal, intravenous, intraperitoneal, intra- arterial, intramuscular, intratumoral, subcutaneous or intraocular administration and the like. Preferably, the compound according to the invention or the pharmaceutical composition according to 15 the invention is administered by enteral or parenteral route of administration. When administered parenterally, the compound according to the invention or the pharmaceutical composition according to the invention is preferably administered by intravenous or intraperitoneal route of administration. When administered enterally, the compound according to the invention or the pharmaceutical composition according to the invention is preferably administered by oral route of administration. 20 The pharmaceutical composition comprising the molecule is formulated in accordance with standard pharmaceutical practice (Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York) known by a person skilled in the art. For oral administration, the composition can be formulated into conventional oral dosage forms such 25 as tablets, capsules, powders, granules and liquid preparations such as syrups, elixirs, and concentrated drops. Nontoxic solid carriers or diluents may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. For compressed tablets, binders, which are agents which impart cohesive qualities to powdered materials, are also necessary. For 30 example, starch, gelatine, sugars such as lactose or dextrose, and natural or synthetic gums can be used as binders. Disintegrants are also necessary in the tablets to facilitate break-up of the tablet. Disintegrants include starches, clays, celluloses, algins, gums and crosslinked polymers. Moreover, lubricants and glidants are also included in the tablets to prevent adhesion to the tablet material to surfaces in the manufacturing process and to improve the flow characteristics of the powder material 45 during manufacture. Colloidal silicon dioxide is most commonly used as a glidant and compounds such as talc or stearic acids are most commonly used as lubricants. For transdermal administration, the composition can be formulated into ointment, cream or gel form and appropriate penetrants or detergents could be used to facilitate permeation, such as dimethyl 5 sulfoxide, dimethyl acetamide and dimethylformamide. For transmucosal administration, nasal sprays, rectal or vaginal suppositories can be used. The active compound can be incorporated into any of the known suppository bases by methods known in the art. Examples of such bases include cocoa butter, polyethylene glycols (carbowaxes), polyethylene sorbitan monostearate, and mixtures of these with other compatible materials to modify the melting point or 10 dissolution rate. Pharmaceutical compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration. The compound according to the invention or the pharmaceutical composition according to the 15 invention may be administered as a single dose or in multiple doses. Preferably, the treatment is administered regularly, preferably between every day and every month, more preferably between every day and every two weeks, more preferably between every day and every week, even more preferably the treatment is administered every day. In a particular embodiment, the treatment is administered several times a day, preferably 2 or 3 times a day, even more preferably 3 times a day. 20 The treatment may last as long as the disease persists. The amount of compound according to the invention or of pharmaceutical composition according to the invention to be administered has to be determined by standard procedure well known by those of ordinary skills in the art. Physiological data of the patient (e.g. age, size, and weight) and the routes of administration have to be taken into account to determine the appropriate dosage, so as a 25 therapeutically effective amount will be administered to the patient. In a preferred embodiment, the total compound dose for each administration of the compound according to the invention or of the pharmaceutical composition according to the invention is comprised between 0.00001 and 1 g. The form of the pharmaceutical compositions, the route of administration and the dose of 30 administration of the compound according to the invention, or the pharmaceutical composition according to the invention can be adjusted by the man skilled in the art according to the type and severity of the disease, and to the patient, in particular its age, weight, sex, and general physical condition. The pharmaceutical composition of the invention can further comprise at least another active 35 ingredient. 46 The present invention also relates to the combined use of a compound of the present invention with at least another active ingredient or with an appropriate dietary regimen. Further aspects and advantages of the present invention will be described in the following examples, which should be regarded as illustrative and not limiting. 5 Examples of compounds according to the invention Table 1 47 48 49 53 56 57 Abbreviations (as used hereinbefore or hereinafter): Ac acetyl 5 AcOEt ethyl acetate AcOH acetic acid aq. aqueous atm atmosphere Boc tert-butyloxycarbonyl 10 CAN cerium ammonium nitrate d days DCM dichloromethane DIBAL-H diisobutylaluminium hydride DIPEA diisopropylethylamine, Hünig's base 15 DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMF-DMA N,N-dimethylformamide dimethyl acetal DMSO dimethylsulfoxide dppf 1,1′-bis(diphenylphosphino)ferrocene 58 EDC-HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ESI-MS electrospray ionization – mass spectrometry Et ethyl Et2O diethylether 5 Et3N triethylamine EtOAc ethyl acetate EtOH ethanol Ex. example FC flash chromatography on silica gel 10 GC-MS gas chromatography – mass spectrometry h hour(s) hept heptane(s) Hex hexane HOBt hydroxybenzotriazole 15 HPLC high performance liquid chromatography iPrMgCl isopropylmagnesium chloride iPrOH isopropyl alcohol KOtBu potassium tert-butoxide kg kilogram(s) 20 LC-MS liquid chromatography – mass spectrometry LDA lithium diisopropylamide LiCl lithium chloride LiHMDS Lithium hexamethyldisilazide Lit. Literature 25 mCPBA meta-chloroperoxybenzoic acid MeCN acetonitrile MeOH methanol mg milligram(s) mL milliliter(s) 30 min minute(s) MnO2manganese(IV) oxide MsCl methanesulfonyl chloride MTBE methyl tert-butyl ether MW microwave 35 nBuLi n-butyllithium 59 NaOMe sodium methoxide NBS N-bromosuccinimide nBu n-butyl nBuOH n-butanol 5 NEt3triethylamine NMR nuclear magnetic resonance spectroscopy OAc acetate p-TsOH p-toluenesulfonic acid Pd / C palladium on charcoal 10 Pd2(dba)3tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(dtbpf) [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Ph phenyl PIDA phenyliodine(III) diacetate 15 PMB para-methoxybenzyl PPh3triphenyl phosphine prep. Preparative Pt / C platinum on charcoal Py pyridine 20 Py·HCl pyridinium hydrochloride QD quaque die (once daily) RT room temperature s second(s) 25 sat. saturated (if not indicated otherwise: sat. aq.) SEM 2-(Trimethylsilyl)ethoxy]methyl tBu tert-butyl = tertiary butyl tBuOK potassium tert-butoxide TEA triethylamine 30 TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography tRretention time triflate trifluoromethanesulfonate 35 Xantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) 60 XPhos Dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane SYNTHESIS General Synthesis of 5,7-substituted Triazolo[1,5-a]pyrimidines 5 10 15 Intermediates synthesis Synthesis of α,β-unsaturated ketones or 1,3-diketones 61 A mixture of 1-(pyridin-4-yl)ethan-1-one (2.00 mL, 18.2 mmol) and N,N- dimethylformamide dimethylacetal (1.45 mL, 9.90 mmol) was stirred at 130 °C in a pressure tube for 16 h. After cooling to room temperature, MTBE (50 mL) was added. Precipitates were filtered and washed with MTBE (50 mL) to afford (E)-3- (Dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one (1.83 g, 57%) as yellow solid.1H NMR (400 MHz, CDCl3) δ 8.75 – 8.65 (m, 2H), 7.83 (d, J = 12.3 Hz, 1H), 7.73 – 7.61 (m, 2H), 5.64 (d, J = 12.3 Hz, 1H), 3.18 (s, 3H), 2.95 (s, 3H). GC-MS (m / z): 177.1 [M+H]+. A mixture of 1-(pyridin-4-yl)ethan-1-one (1.00 mL, 9.00 mmol) and 1,1-dimethoxy-N,N- dimethylethan-1-amine (1.45 mL, 9.90 mmol) was stirred at 130 °C in a pressure tube for 16 h. After cooling to room temperature, the mixture was evaporated and the residue was purified by column chromatography (EtOAc / Hex) to afford (E)-3- (dimethylamino)-1-(pyridin-4-yl)but-2-en-1-one (556 mg, 32%) as yellow solid.1H-NMR (400 MHz, CDCl3) δ 8.70 – 8.60 (m, 2H), 7.65 – 7.59 (m, 2H), 5.58 (s, 1H), 3.10 (s, 6H), 2.67 (s, 3H). GC-MS (m / z): 190.2. To a solution of isopropyl methyl ketone (2.49 mL, 23.2 mmol) in THF (40 mL), LDA (freshly prepared, 0.54 M in THF, 38.7 mL, 20.9 mmol) was added dropwise at -78 °C and the reaction mixture was stirred at -78 °C for 30 min.4-Pyridinecarboxaldehyde (2.18 mL, 23.2 mmol) in dry THF (20 mL) was added dropwise at -78 °C stirring continued at -78 °C for 1h. AcOH (1.33 mL, 23.2 mmol) in THF (5 mL) was added and the reaction mixture was stirred at room temperature for 18h. Water (50 mL) was added and the mixture was extracted with EtOAc (3x80 mL). EtOAc extracts were combined, washed with brine (20 mL), dried over Na2SO4and evaporated. Purification of residue by column chromatography (hexanes / acetone) afforded (Z)-1-Hydroxy-4-methyl-1-(pyridin-4-yl)pent-1- en-3-one as colorless oil (1.055 g, 24%). The apparent oxidation from enone to diketone stems from a disproportionation of enone to diketone and fully saturated pentanone.1H-NMR 400 MHz, CDCl3δ (ppm): δ 15.83 (s, 1H), 8.77 – 8.71 (m, 2H), 7.70 – 7.65 (m, 2H), 6.22 (s, 1H), 2.66 (sept, J = 6.9 Hz, 1H), 1.22 (d, J = 6.9 Hz, 6H). ESI-MS (m / z): 192 [M+H]+. To a solution of 3,3-dimethyl-2-butanone (850 mg, 8.49 mmol) in THF (20 mL), 4- pyridinecarboxaldehyde (1.19 mL, 12.6 mmol) was added at 0 °C and the mixture was stirred for 5 min. A solution of t-BuOK (95 mg, 0.844 mmol) in THF (10 mL) was added dropwise to the reaction mixture and stirring was continued at 0 °C for 2h. AcOH (0.483 mL, 8.44 mmol) was added and the reaction mixture was stirred at room temperature for 18h. Water (10 mL) was added and reaction mixture was extracted with EtOAc (3x30 mL), dried over Na2SO4and evaporated. Purification of the residue by column chromatography (hexanes / acetone) afforded (E)-4,4-Dimethyl-1-(pyridin-4-yl)pent-1-en-3-one as colorless oil (320 mg, 20%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): δ 8.65 – 8.61 (m, 2H), 7.76 – 7.73 (m, 2H), 7.67 (d, J = 15.7 Hz, 1H), 7.49 (d, J = 15.7 Hz, 1H), 1.18 (s, 9H). ESI-MS (m / z): 190 [M+H]+. Similar to (E)-4,4-dimethyl-1-(pyridin-4-yl)pent-1-en-3-one, (E)-1-cyclohexyl-3-(pyridin- 4-yl)prop-2-en-1-one was obtained from cyclohexyl methyl ketone (699 mg, 47%).1H- NMR 400 MHz, DMSO-d6 δ (ppm): δ 8.68 – 8.56 (m, 2H), 7.71 – 7.66 (m, 2H), 7.53 (d, J = 16.2 Hz, 1H), 7.25 (d, J = 16.2 Hz, 1H), 2.81 – 2.72 (m, 1H), 1.87 – 1.80 (m, 2H), 1.78 – 1.70 (m, 2H), 1.69 – 1.60 (m, 1H), 1.39 – 1.25 (m, 4H), 1.24 – 1.12 (m, 1H). ESI-MS (m / z): 216 [M+H]+. 62 a cold solution of cyclohexanecarboxaldehyde (560 mg, 5.00 mmol) and 4- oroacetophenone (575 g, 4.16 mmol) in THF (10 mL), a solution of t-BuOK (70.0 g, 0.624 mmol) in THF (5 mL) was added dropwise. The reaction mixture was rred at room temperature for 8h. EtOAc (15 mL) was added and the mixture ashed with water (15 mL), brine (15 mL), dried over Na2SO4and evaporated. The sidue was purified by column chromatography (EtOAc / Hexane) to afford (E)-3- clohexyl-1-(4-fluorophenyl)prop-2-en-1-one as yellow oil (480 mg, 50%).1H MR (400 MHz, CDCl3) δ 8.06 - 7.91 (m, 2H), 7.18 – 7.09 (m, 2H), 7.01 (dd, J = 15.5, 15.5 Hz, 1H), 2.31 – 2.18 (m, 1H), 1.89 – 1.65 (m, 5H), 1.39 – 1.16 (m, 5H). ESI- +. To a solution of 1-(4-(difluoromethoxy)phenyl)ethan-1-one (445 mg, 2.39 mmol) and quinuclidine-4-carbaldehyde (1.59 g, 14.9 mmol) in THF (7 mL), a solution of t-BuOK (215 mg, 1.91 mmol) in THF (4 mL) was added dropwise at -20 °C. The reaction mixture was stirred at -20 °C for 2h and at 0 °C for 1h. DCM (80 mL) was added and the mixture washed with water (40 mL), brine (40 mL), dried over Na2SO4and evaporated. The residue was purified by column chromatography (DCM / MeOH / NEt3) to afford (E)-1-(4- (difluoromethoxy)phenyl)-3-(quinuclidin-4-yl)prop-2-en-1-one as white solid R 400 MHz, CDCl3δ (ppm): 7.98 – 7.93 (m, 2H), 7.22 – 7.16 (m, 2H), 6.90 (d, J = = 16.0 Hz, 1H), 6.60 (t, J = 73.1 Hz, 1H), 3.08 – 2.99 (m, 6H), 1.70 – 1.59 (m, 6H). +H]+. o a solution of LiHMDS (1M in THF, 5.42 mL, 5.42 mmol) in THF (6.5 mL) was dded a solution of 1-(4-(difluoromethoxy)phenyl)ethan-1-one (917 mg, 4.93 mmol) in THF (4 mL) at -70 °C. A solution of tert-butyl 3,3-difluoro-4- ormylpiperidine-1-carboxylate (575 mg, 2.46 mmol) in THF (2 mL) was added ropwise at this temperature. The reaction mixture was stirred at -70 °C for 1 , and then an aq. solution of citric acid (1.0 M, 11.3 mL) was added and the mixture was warmed to room temperature. Water (100 mL) was added and the mixture was extracted with EtOAc (4×20 mL). EtOAc extracts were combined, washed with water (3×20 mL), brine (2×20 mL), dried over Na2SO4and evaporated. The residue was dissolved in DCM (12 mL) and the solution cooled to 0 °C. NEt3(1.72 mL, 12.3 mmol) was added, followed by slow addition of methanesulfonyl chloride (0.46 mL, 5.91 mmol). The reaction mixture was stirred at 0 °C for 1.5 h and then heated to reflux for 40 min. DCM (20 mL) and then sat. NaHCO3solution (60 mL) was added. After stirring at room temperature for 40 min, the water layer was separated and extracted with DCM (4×20 mL). The organic layers were combined, dried over Na2SO4and evaporated. The residue was purified by chromatography (EtOAc / hexanes) to afford tert-butyl (E)-4- (3-(4-(difluoromethoxy)phenyl)-3-oxoprop-1-en-1-yl)-3,3-difluoropiperidine-1-carboxylate as a beige solid (1.30 g, 63%).1H NMR (300MHz, CDCl3): δ 7.99-7.44 (m, 2H), 7.22-7.18(m, 2H), 7.10-6.94 (m, 2H), 6.60 (t, J=73 Hz, 1H), 4.50-4.10 (m, 2H), 3.20-2.73 (m, 3H), 1.91-1.83 (m, 2H), 1.48 (s, 9H). ESI-MS (m / z): 362.5 [M+H]+To a solution of dimethyl carbonate (1.26 g, 14.0 mmol) in toluene (5.5 mL), NaH (0.537 g, 60% in min. oil w / w, 13.4 mmol) was added and the mixture was brought to reflux. A solution of 1-[4-(difluoromethoxy)phenyl]ethan-1- one (1.00 g, 5.37 mmol) in toluene (3 mL) was added dropwise over 10 min. After the evolution of hydrogen ceased (10 min), the reaction mixture was cooled down to room temperature. AcOH (1.6 mL) was added. Ice-cold 63 water was slowly added until the solid was dissolved completely. EtOAc (50 mL) was added, the organic layer was separated, washed with water (10 mL), brine (10 mL), dried over Na2SO4and evaporated. The residue was purified by flash chromatography (EtOAc / hexane) to afford ethyl 3-(4- (difluoromethoxy)phenyl)-3-oxopropanoate (1.10 g, 84%).1H-NMR 300 MHz, DMSO-d6 δ (ppm): δ 8.07 – 8.00 (m, 2H), 7.43 (t, J = 73.6 Hz, 3H), 7.35 – 7.28 (m, 2H), 4.21 (s, 2H), 3.65 (s, 3H). ESI-MS (m / z): 245 [M+H]+. A mixture of 1-(4-(dimethylamino)phenyl)ethan-1-one (1.92 g, 11.8 mmol) and 1,1- dimethoxy-N,N-dimethylmethanamine (1.56 mL, 11.8 mmol) was stirred at 120 °C in a pressure tube for 72 h. After cooling to room temperature, the mixture was evaporated to afford (E)-3-(dimethylamino)-1-(4-(dimethylamino)phenyl)prop-2-en-1-one as yellow solid 2.28 g (89%).1H NMR (400 MHz, CDCl3) δ 7.92 – 7.83 (m, 2H), 7.76 (d, J = 12.4 Hz, 1H), 6.70 – 6.64 (m, 2H), 5.74 (d, J = 12.4 Hz, 1H), 3.02 (s, 12H). LC-MS (m / z): 219.2 [M+H]+. To a solution of 1-(4-(difluoromethoxy)phenyl)ethan-1-one (500 mg, 2.69 mmol) and 6-(dimethylamino)nicotinaldehyde (403 mg, 2.69 mmol) in MeOH (4 mL), a solution of NaOH (140 mg, 3.49 mmol) in MeOH (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2h. Filtration and washing of precipitates with water / MeOH (5 mL) afforded (E)-1-(4-(difluoromethoxy)phenyl)-3-(6-(dimethylamino)pyridin-3-yl)prop- 2-en-1-one as white solid (700 mg, 82%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): δ 8.45 (d, J = 1.9 Hz, 1H), 8.24 – 8.18 (m, 2H), 8.14 (dd, J = 9.2, 2.5 Hz, 1H), 7.76 – 7.65 (m, 2H), 7.42 (t, J = 73.9 Hz, 1H), 7.35 – 7.29 (m, 2H), 3.12 (s, 6H). ESI-MS (m / z): 319.2 [M+H]+. To solution of 4-(dimethylamino)benzaldehyde (1.60 g, 10.7 mmol) and 1- (4-(difluoromethoxy)phenyl)ethan-1-one (2.00 g, 10.7 mmol) in MeOH (20 mL) was added a solution of NaOH (1.28 g, 32.2 mmol) in water (10 mL). The resulting mixture was stirred at 40 °C for 16 h. Ice-cold water (50 mL) was added. Precipitates were filtered and washed with water (50 mL). Recrystallization of the solid from EtOH / H2O (9 / 1) yielded (E)-1-(4- (difluoromethoxy)phenyl)-3-(4-(dimethylamino)phenyl)prop-2-en-1-one as bright yellow solid (2.37 g, 69%).1H NMR (300 MHz, CDCl3) δ 8.10 – 7.97 (m, 2H), 7.87 – 7.74 (m, 1H), 7.60 – 7.49 (m, 2H), 7.34 – 7.27 (m, 1H), 7.24 – 7.15 (m, 2H), 6.74 – 6.66 (m, 2H), 6.60 (t, J = 73.3 Hz, 1H). ESI: 318.2 [M+H]+. To solution of KOH (355 mg, 6.44 mmol) in MeOH (40 mL) and H2O (10 mL) at 0 °C, 4-pyridinecarboxaldehyde (0.51 mL, 5.37 mmol) was added. The reaction mixture was stirred 10 min and then 1-[4- (difluoromethoxy)phenyl]ethan-1-one (1.00 g, 5.37 mmol) was added portionwise at 0 °. The reaction mixture was stirred at 0-8 °C for 24h. Ice cold water (60 mL) was added and the mixture was extracted with DCM (3x40 mL). Organic extracts were combined, dried over Na2SO4and evaporated. Purification by column chromatography (EtOAc / hexanes) yielded (E)-1-(4- (difluoromethoxy)phenyl)-3-(pyridin-4-yl)prop-2-en-1-one as white solid (505 mg, 34%).1H NMR (300 MHz, CDCl3) δ 8.75 – 8.67 (m, 2H), 8.13 – 8.01 (m, 2H), 7.78 – 7.59 (m, 2H), 7.54 – 7.43 (m, 2H), 7.30 – 7.22 (m, 1H), 6.63 (t, J = 72.9 Hz, 1H). ESI: 276.2 [M+H]+. 64 To a solution of 1-[4-(difluoromethoxy)phenyl]ethan-1-one (1.00 g, 5.37 mmol) and pyridine-3-caboxaldehyde (1.04 g, 9.67 mmol) in THF (10 mL), a solution of t-BuOK (60.3 mg, 0.54 mmol) in THF (10 ml) was at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Cold water (70 mL) was added and the precipitates were filtered. The solid was crystallized from EtOH / water to afford 1-(4-(difluoromethoxy)phenyl)-3-(pyridin-3-yl)prop- 2-en-1-one as white solid (1.26 g, 85%).1H NMR (400 MHz, CDCl3) δ 8.83 – 8.76 (m, 1H), 8.57 (d, J = 4.8 Hz, 1H), 8.04 – 7.96 (m, 2H), 7.88 (dt, J = 8.0, 5.7 Hz, 1H), 7.50 (d, J = 15.7 Hz, 1H), 7.30 (dd, J = 8.0, 4.8 Hz, 1H), 7.19 – 7.13 Hz, 1H). ESI-MS (m / z): 276.4 [M+H]+. Similar to (1-(4-(difluoromethoxy)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one, 1-(4-(difluoromethoxy)phenyl)-3-(pyridin-2-yl)prop-2-en-1-one was obtained from pyridine-2-caboxaldehyde (1.12 g, 76%).1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 4.4 Hz, 1H), 8.12 – 7.94 (m, 3H), 7.76 – 7.62 (m, 2H), 7.49 – 7.37 (m, 1H), 7.31 – 7.21 (m, 1H), 7.17 – 7.00 (m, 2H), 6.55 (t, J = 73.1 Hz, 1H). ESI-MS (m / z): 276.4 [M+H]+. A solution of 1-(4-fluorophenyl)propan-1-one (700 mg, 4.60 mmol) and 4- dinecarboxaldehyde (493 mg, 4.60 mmol) in EtOH (5 mL) was stirred at 45°C 5 min. The reaction mixture was then cooled down to room temperature and olution of NaOH (184 mg, 4.60 mmol) in EtOH / H2O (10 mL, 1:1) was added pwise. The reaction mixture was stirred at the same temperature for 1 h, then red at 60°C for 4 h. Additional 1.0 eq. of NaOH was added to the mixture and ring continued at the 60°C for 3 h. Water (20 mL) was added and the mixture extracted with DCM (3×40 mL). DCM extracts were combined, dried over The residue was purified by column chromatography (hexane / Et2O) to afford -methyl-3-(pyridin-4-yl)prop-2-en-1-one as slightly yellow solid (300 mg, 27%). O-d6δ (ppm): 8.67 – 8.61 (m, 2H), 7.91 – 7.84 (m, 2H), 7.50 – 7.43 (m, 2H), 7.41 00 (m, 1H), 2.16 (d, J = 1.5 Hz, 3H). ESI-MS (m / z): 242.2 [M+H]+. o a solution of 4-pyridinecarboxaldehyde (427 mg, 3.99 mmol) and 1-(2- rifluoromethyl)pyrimidin-5-yl)ethan-1-one (527 mg, 2.77 mmol) in THF (2 mL) nd Et2O (2.5 mL), a solution of t-BuOK (31 mg, 0.28 mmol) in THF (1.5 mL) was dded dropwise over 30 min at -20 °C. The reaction mixture was stirred at -20 C for 1 h. Et3N (0.77 mL, 5.54 mmol) and MsCl (258 mL, 3.33 mmol) was added nd the mixture was stirred for 15 min. Cold water (15 mL) was added and the ixture was extracted with EtOAc (3×15 mL). EtOAc extracts were combined and evaporated at room temperature. The residue was purified by column chromatography (EtOAc / hexanes) to afford (E)-3-(pyridin-4-yl)-1-(2-(trifluoromethyl)pyrimidin-5- yl)prop-2-en-1-one as an orange solid (220 mg, 28%).1H NMR (400 MHz, CDCl3) δ 9.42 (s, 2H), 8.76 (d, J = 5.5 Hz, 2H), 7.82 (d, J = 15.8 Hz, 1H), 7.55 (d, J = 15.8 Hz, 1H), 7.52 – 7.45 (m, 2H). 65 A mixture of 2-chloro-5-(difluoromethoxy)pyrimidine (1.46 g, 8.06 mmol), 1- ethoxyvinyltributyltin (4.10 mL, 12.1 mmol) and PdCl2(PPh3)2(453 mg, 0.64 mmol) in DMF (15 mL) was stirred at 100 °C for 2.5 h. After cooling to room temperature, sat. NaHCO3(40 mL) was added and the mixture was extracted with EtOAc (3x30 mL). EtOAc extracts were combined, dried over Na2SO4and evaporated. The residue was purified by column chromatography (EtOAc / hexanes) to afford vinyl ether (2.27 g) as yellow oil which was dissolved in DCM (15 mL) and aq. HCl (1M, 20 mL) was added. The reaction mixture was stirred at room temperature for 5h. The organic layer was separated and the aqueous layer was extracted EtOAc (2x20 mL). The combined organic layers were dried over Na2SO4and evaporated. Purification by column chromatography (EtOAc / hexanes) afforded 1-(5- (difluoromethoxy)pyrimidin-2-yl)ethan-1-one (0.91 g, 60%) as yellow oil.1H NMR (300 MHz, CDCl3) δ 8.76 (s, 2H), 6.70 (t, J = 71.0 Hz, 1H), 2.78 (s, 3H). ESI-MS (m / z): 189.0. To a solution of 4- pyridinecarboxaldehyde (1.03 g, 9.87 mmol) and 1-(5-(difluoromethoxy)pyrimidin-2-yl)ethan-1-one (1.65 g, 8.79 mmol) in MeOH (35 mL) and water (35 mL), piperidine (1.00 mL, 9.87 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1h. The pH was adjusted to 6 by 1M HCl and the mixture was extracted EtOAc (2x50 mL). EtOAc extracts were combined, dried over Na2SO4and evaporated. The residue was purified by column chromatography (EtOAc / hexanes) to afford (E)-1-(5- (difluoromethoxy)pyrimidin-2-yl)-3-(pyridin-4-yl)prop-2-en-1-one (256 mg, 10%) as yellow solid.1H NMR (300 MHz, CDCl3) δ 8.86-8.82 (m, 2H), 8.71 (dd, J = 1.644.45 Hz, 2H), 8.28 (d, J = 16.1 Hz, 1H), 7.90 (d, J = 16.1 Hz, 1H), 7.53 (dd, J = 1.644.45 Hz, 2H), 6.73 (t, J = 70.9 Hz, 1H). ESI-MS (m / z): 278.0. A solution of 1-(3-chloro-5-(difluoromethoxy)pyridin-2-yl)ethan-1-one (1.5 g, 7 mmol) in a mixture of EtOH (18 mL) and H2O (6 mL) was cooled to 5 °C, before 4-pyridinecarboxaldehyde (0.8 g, 7 mmol) and K2CO3(2 g, 15 mmol) was added. The reaction mixture was stirred at 5 °C for 2 h. After work-up with EtOAc (E)-1 (3-chloro-5-(difluoromethoxy)pyridin-2-yl)-3-(pyridin-4-yl)- prop-2-en-1-one (1.5 g, 69%) was obtained and used for the next step 11.0 [M+H]+. A solution of 1-(3-methyl-5-(difluoromethoxy)pyridin-2-yl)ethan-1-one (1.4 g, 7 mmol) in a mixture of EtOH (18 mL) and H2O (6 mL) was cooled to 0 °C, before 4-pyridinecarboxaldehyde (0.8 g, 7 mmol) and KOH (841 mg, 15 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h. After work-up with EtOAc (E)-1 (3-methyl-5-(difluoromethoxy)pyridin-2-yl)-3- (pyridin-4-yl)-prop-2-en-1-one (0.75 g, 37%) was obtained and used for the next step immediately. LC-MS: 291.2 [M+H]+. N N R Me KOt +RBu, R7O THF O 0 °C - RT R7O To an ice-cooled solution of 4-pyridinecarboxaldehyde (771 mg, 7.20 mmol) and cyclopropyl methyl ketone (505 mg, 6.00 mmol) in THF (10 mL), a solution of t-BuOK (66 mg, 0.50 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 1h. Water (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL), the extracts were combined, washed with brine (50 mL), dried over Na2SO4and evaporated. The residue was purified by column chromatography (EtOAc / hexane) 66 to afforded (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one as colorless transparent solid (1.02 g, 98%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.68 – 8.62 (m, 2H), 7.52 – 7.45 (m, 1H), 7.42 – 7.36 (m, 2H), 7.02 – 6.95 (m, 1H), 2.28 – 2.20 (m, 1H), 1.21 – 1.16 (m, 2H), 1.05 – 0.99 (m, 2H). ESI (m / z): 174.2 [M+H]+. lar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-phenyl-3-(pyridin- )prop-2-en-1-one was obtained from acetophenone (1.82 g, 87%).1H-NMR 400 z, CDCl3δ (ppm): 8.72 – 8.66 (m, 2H), 8.06 – 7.99 (m, 2H), 7.74 – 7.65 (m, 2H), 7.65 57 (m, 1H), 7.57 – 7.48 (m, 2H), 7.52 – 7.44 (m, 2H). ESI-MS (m / z): 210.1 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-3-(Pyridin-4-yl)- 1-(p-tolyl)prop-2-en-1-one was obtained from 4-methylacetophenone (1.05 g, 95%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.70 – 8.66 (m, 2H), 7.96 – 7.91 (m, 2H), 7.72 – 7.62 (m, 2H), 7.48-7.44 (m, 2H), 7.34-7.29 (m, 2H), 2.44 (s, 3H). Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- luorophenyl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 4- luoroacetophenone (2.14 g, 94%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.72 – 8.66 m, 2H), 8.10 – 8.03 (m, 2H), 7.73 – 7.60 (m, 2H), 7.49 – 7.44 (m, 2H), 7.23 – 7.16 m, 2H). ESI-MS (m / z): 228.2 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- chlorophenyl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 4- chloroacetophenone (2.22 g, 91%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.74 – 8.63 m, 2H), 8.02 – 7.91 (m, 2H), 7.77 – 7.57 (m, 2H), 7.55 – 7.40 (m, 4H). ESI-MS m / z): 244.1 [M+H]+. imilar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- romophenyl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 4- romoacetophenone (2.44 g, 85%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.72 – 8.66 m, 2H), 7.93 – 7.85 (m, 2H), 7.75 – 7.65 (m, 2H), 7.68 – 7.56 (m, 2H), 7.49 – 7.43 m, 2H). ESI-MS (m / z): 289.1 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- methoxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 4- methoxyacetophenone (2.27 g, 95%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.70 – 8.64 (m, 2H), 8.08 – 8.00 (m, 2H), 7.67 (s, 2H), 7.49 – 7.43 (m, 2H), 7.04 – 6.95 (m, 2H), 3.90 (s, 3H). ESI-MS (m / z): 240.1 [M+H]+. 67 Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4-n- butoxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 4-n- butoxyacetophenone (750 mg, 57%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.71 – 8.65 (m, 2H), 8.06 – 8.00 (m, 2H), 7.69 – 7.66 (m, 2H), 7.50 – 7.44 (m, 2H), 7.04 – 6.95 (m, 2H), 4.06 (d, J = 6.5, 2H), 1.87 – 1.75 (m, 2H), 1.52 (sext, J = 7.4, 2H), 1.00 (t, J = 7.4, 3H). ESI-MS (m / z): 282.3 [M+H]+. imilar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- opropoxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 4- opropoxyacetophenone (700 mg, 56%).1H-NMR 400 MHz, CDCl3δ (ppm): .70 – 8.65 (m, 2H), 8.05 – 7.99 (m, 2H), 7.68 (s, 2H), 7.49 – 7.44 (m, 2H), 7.00 6.93 (m, 2H), 4.68 (sept, J = 6.1 Hz, 1H), 1.39 (d, J = 6.0 Hz, 6H). ESI-MS m / z): 268.3 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(2,4- difluorophenyl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 2,4- difluoroacetophenone (590 mg, 75%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.73 – 8.64 (m, 2H), 7.94 (td, J = 8.6, 6.5 Hz, 1H), 7.68 (dd, J = 15.7, 1.9 Hz, 1H), 7.53 (dd, J = 15.7, 3.2 Hz, 1H), 7.47 – 7.43 (m, 2H), 7.07 – 6.98 (m, 1H), 6.93 (ddd, J = 11.0, 8.6, 2.4 Hz, 1H). ESI-MS (m / z): 246.3 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(2,4,6- trifluorophenyl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 2,4,6- trifluoroacetophenone (500 mg, 66%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.72 – 8.66 (m, 2H), 7.47 (d, J = 16.1 Hz, 1H), 7.44 – 7.38 (m, 2H), 7.18 (dt, J = 16.0, 1.6 Hz, 1H), 6.83 – 6.74 (m, 2H). ESI-MS (m / z): 264.3 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- (difluoromethoxy)phenyl)-3-(2-methoxypyridin-4-yl)prop-2-en-1-one was obtained from 4-difluoromethoxyacetophenone and 2-methoxypyridine-4- carboxaldehyde (2.86 g, 62%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.25 – 8.20 (m, 1H), 8.08 – 8.03 (m, 2H), 7.69 – 7.54 (m, 2H), 7.26 – 7.21 (m, 2H), 7.10 – 7.06 (m, 1H), 6.92 – 6.89 (m, 1H), 6.62 (t, J = 72.8 Hz, 1H), 3.97 (s, 3H). ESI- MS (m / z): 306.2 [M+H]+ . Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- fluorophenyl)-3-(2-methylpyridin-4-yl)prop-2-en-1-one was obtained from 4- fluoroacetophenone and 2-methylpyridine-4-carboxaldehyde (630 mg, 72%).1H- NMR 400 MHz, CDCl3δ (ppm): 8.57 (dd, J = 5.2, 0.8 Hz, 1H), 8.10 – 8.03 (m, 2H), 7.71 – 7.58 (m, 2H), 7.34 – 7.31 (m, 1H), 7.30 – 7.27 (m, 1H), 7.24 – 7.16 (m, 2H), 2.62 (s, 3H). ESI-MS (m / z): 242.2 [M+H]+. 68 ilar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- orophenyl)-3-(2-bromopyridin-4-yl)prop-2-en-1-one was obtained from 4- oroacetophenone and 2-bromopyridine-4-carboxaldehyde (5.30 g, 79%).1H- R 400 MHz, CDCl3δ (ppm): 8.47 – 8.41 (m, 1H), 8.11 – 8.02 (m, 2H), 7.69 – 7.66 , 1H), 7.62 (s, 2H), 7.44 – 7.39 (m, 1H), 7.24 – 7.17 (m, 2H). ESI-MS (m / z): 307.1 +H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- (difluoromethoxy)phenyl)-3-(2-fluoropyridin-4-yl)prop-2-en-1-one was obtained from 4-difluoromethoxyacetophenone and 2-fluoropyridine-4- carboxaldehyde (971 mg, 82%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.60 – 8.55 (m, 1H), 8.52 – 8.47 (m, 1H), 8.10 – 8.03 (m, 2H), 7.82 – 7.72 (m, 2H), 7.53 – 7.46 (m, 1H), 7.28 – 7.21 (m, 2H), 6.63 (t, J = 72.9 Hz, 1H). ESI-MS (m / z): 294.1 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- (difluoromethoxy)phenyl)-3-(3-fluoropyridin-4-yl)prop-2-en-1-one was obtained from 4-difluoromethoxyacetophenone and 3-fluoropyridine-4- carboxaldehyde (1.02 g, 69%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.60 – 8.55 (m, 1H), 8.52 – 8.47 (m, 1H), 8.10 – 8.03 (m, 2H), 7.82 – 7.72 (m, 2H), 7.53 – 7.46 (m, 1H), 7.28 – 7.21 (m, 2H), 6.63 (t, J = 72.9 Hz, 1H). . ESI-MS (m / z): 294.1 [M+H]+. ilar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- orophenyl)-3-(3-methylpyridin-4-yl)prop-2-en-1-one was obtained from 4- oroacetophenone and 3-methylpyridine-4-carboxaldehyde (580 mg, 83%).1H- R 400 MHz, CDCl3δ (ppm): 8.55 – 8.48 (m, 2H), 8.11 – 8.03 (m, 2H), 7.97 (d, J 5.6 Hz, 1H), 7.54 (d, J = 15.6 Hz, 1H), 7.47 (d, J = 5.1 Hz, 1H), 7.24 – 7.16 (m, 2H), 5 (s, 3H). ESI-MS (m / z): 242.3 [M+H]+. milar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(4- uorophenyl)-3-(6-methoxypyridin-3-yl)prop-2-en-1-one was obtained from 4- uoroacetophenone and 6-methoxynicotinaldehyde (580 mg, 83%).1H-NMR 400 Hz, CDCl3δ (ppm): 8.40-8.37 (m, 1H), 8.08-8.01 (m, 2H), 7.93-7.87 (m, 1H), 81-7.74 (m, 1H), 7.44-7.37 (m, 1H), 7.23-7.14 (m, 2H), 6.83-6.79 (m, 1H), 3.99 , 3H). ESI-MS (m / z): 258 [M+H]+. milar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(2-chloro-4- orophenyl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 2-chloro-4- oroacetophenone (987 mg, 72%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.64-8.59 , 2H), 7.50 (dd, J=8.5 and 6.0 Hz, 1H), 7.37-7.32 (m, 3H), 7.18 (s, 1H), 7.15 (dd, .5 and 2.4 Hz, 1H), 7.07 – 7.00 (m, 1H). ESI-MS (m / z): 262.2 [M+H]+. 69 imilar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(2-methyl-4- uorophenyl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 2-methyl-4- uoroacetophenone (1.11 g, 81%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.71-8.64 m, 2H), 7.59 (dd, 1H, J=8.5 and 5.8 Hz), 7.43-7.39 (m, 3H), 7.32 (s, 1H), 7.04-6.95 m, 2H), 2.50 (s, 3H). ESI-MS (m / z): 242 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, ethyl (E)-4-(3- (pyridin-4-yl)acryloyl)benzoate was obtained from ethyl 4-acetylbenzoate (8.51 g, 90%).1H-NMR 400 MHz, DMSO-d6δ (ppm): 8.72 – 8.65 (m, 2H), 8.31 – 8.24 (m, 2H), 8.19 – 8.09 (m, 3H), 7.88 – 7.82 (m, 2H), 7.76 – 7.68 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H). ESI-MS (m / z): 282.2 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-3-(pyridin-4- yl)-1-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one was obtained from 4- trifluoromethoxyacetophenone (1.37 g, 92%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.72 – 8.67 (m, 2H), 8.11 – 8.05 (m, 2H), 7.74 – 7.69 (m, 1H), 7.65 – 7.59 (m, 1H), 7.50 – 7.45 (m, 2H), 7.38 – 7.32 (m, 2H). ESI-MS (m / z): 294.2 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-3-(pyridin-4- yl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one was obtained from 4- trifluoromethylacetophenone (622 mg, 45%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.76 – 8.68 (m, 2H), 8.16 – 8.08 (m, 2H), 7.83 – 7.77 (m, 2H), 7.73 (d, J = 15.8 Hz, 1H), 7.62 (d, J = 15.8 Hz, 1H), 7.51 – 7.46 (m, 2H). Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(pyridin-3- )-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 3-acetylpyridine (400 mg, 7%).1H-NMR 400 MHz, DMSO-d6δ (ppm): 9.38 – 9.34 (m, 1H), 8.86 (dd, J = 4.8, .7 Hz, 1H), 8.70 – 8.66 (m, 2H), 8.50 – 8.47 (m, 1H), 8.18 (d, J = 15.7 Hz, 1H), 7.89 7.85 (m, 2H), 7.74 (d, J = 15.7 Hz, 1H), 7.66 – 7.60 (m, 1H). ESI-MS (m / z): 211.2 M+H]+. milar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1,3-di(pyridin-4- )prop-2-en-1-one was obtained from 4-acetylpyridine (300 mg, 17%).1H-NMR 00 MHz, CDCl3δ (ppm): 8.90 – 8.85 (m, 2H), 8.75 – 8.69 (m, 2H), 7.79 – 7.76 (m, H), 7.74 (d, J = 16.0 Hz, 1H), 7.56 (d, J = 16.0 Hz, 1H), 7.50 – 7.45 (m, 2H). ESI-MS m / z): 211.1 [M+H]+. imilar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(6- romopyridin-3-yl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 1-(6- romopyridin-3-yl)ethan-1-one (2.13 g, 77%).1H-NMR 400 MHz, DMSO-d6δ ppm): 9.16 (d, J = 2.4 Hz, 1H), 8.72 - 8.66 (m, 2H), 8.40 (dd, J = 8.5, 2.4 Hz, 1H), .14 (d, J = 15.7 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.88 - 7.84 (m, 2H), 7.74 (d, J = 5.7 Hz, 1H). ESI-MS (m / z): 291.1 [M+H]+. 70 Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(5- (difluoromethoxy)pyridin-2-yl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 1-(5-(difluoromethoxy)pyridin-2-yl)ethan-1-one (2.03 g, 89%). (2.03 g, 89%).1H-NMR (400 MHz, CDCl3) δ 8.71-8.67 (m, 2H), 8.58 (dd, J = 2.7 0.6 Hz, 1H), 8.41 (d, J = 16.1 Hz, 1H), 8.25 (dd, J = 8.70.6 Hz, 1H), 7.80 (d, J = 16.1 Hz, 1H), 7.64 (dt, J = 8.72.70.6 Hz, 1H), 7.57-7.51 (m, 2H), 6.67 (t, J = 72.0 Hz, 1H). ESI (m / z): 277.2 [M+H]+. imilar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(5- difluoromethoxy)-3-fluoropyridin-2-yl)-3-(pyridin-4-yl)prop-2-en-1-one was btained from 1-(5-(difluoromethoxy)-3-fluoropyridin-2-yl)ethan-1-one (1.20 g, 9%).1H NMR (300 MHz, DMSO) δ 8.72-8.66 (m, 2H), 8.44 (d, J=2.0 Hz, 1H), 8.14 d, J=16.0 Hz, 1H), 7.76 (d, J=16.0 Hz, 1H), 8.53 – 8.49 (m, 2H), 7.41 (dd, J=10.8, .3 Hz, 1H), 6.68 (t, J=71.2 Hz, 1H). ESI-MS (m / z): 295.0 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(2- methoxypyrimidin-5-yl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 1- (2-Methoxypyrimidin-5-yl)ethan-1-one (950 mg, 80%).1H NMR (300 MHz, CDCl3) δ 9.15 (s, 2H), 8.75 – 8.64 (m, 2H), 7.76 (d, J = 15.7 Hz, 1H), 7.54 (d, J = 15.7 Hz, 1H), 7.50 – 7.41 (m, 2H), 4.14 (s, 3H) ppm. ESI-MS (m / z): 242.0 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1-(5- (difluoromethoxy)pyrazin-2-yl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 1-(5-(difluoromethoxy)pyrazin-2-yl)ethan-1-one (prepared analogously to 1-(5-(difluoromethoxy)pyrimidin-2-yl)ethan-1-one) (230 mg, 27%).1H NMR (300 MHz, DMSO) δ 9.00 (d, J=1.3 Hz, 1H), 8.75 (d, J=1.3 Hz 1H), 8.70 – 8.66 (m, 2H), 8.26 (d, J=16.0 Hz, 1H), 7.84 (d, J=16.0 Hz, 1H), 7.83 (t, J=72.0 Hz, 1H), 8.80 – 8.76 (m, 2H). ESI-MS (m / z): 278.1 [M+H]+. A mixture of 6-bromopyridazin-3-ol (1.00 g, 5.71 mmol), sodium chlorodifluoroacetate (1.74 g, 11.4 mmol) and Cs2CO3(3.72 g, 11.4 mmol) in anhydrous DMF (5 mL) was stirred at 80 °C for 16h. The reaction mixture was cooled to ambient temperature and water (50 mL) was added. The mixture was extracted with DCM (3x50 mL). DCM extracts were combined, dried over Na2SO4and evaporated. Purification of the residue by column chromatography (EtOAc / hexanes) afforded 3-bromo-6- (difluoromethoxy)pyrazine (570 mg, 44%) as pale oil. ESI-MS (m / z): 226.4 [M+H]+. The above bromide, (560 mg, 2.49 mmol), Pd(OAc)2(51 mg, 0.22 mmol), dppf (185 mg, 0.44 mmol), K2CO3(450 mg, 3.25 mmol) and butyl vinyl ether (1.25 g, 12.5 mmol) in DMF (5 mL) was stirred at 110°C for 5h. The reaction mixture was cooled to ambient temperature and filtered through a celite pad. The pad was rinsed with EtOAc (50 mL). Filtrates were washed with sat. NaHCO3(20 mL), brine (20 mL), dried over Na2SO4and evaporated. The residue was dissolved in DCM (5 mL) and 1M HCl (aq.5 mL) was added. The mixture was stirred at room temperature for 1h, and then extracted with DCM (3x10 mL). DCM extracts were combined, dried over Na2SO4and evaporated. Purification of the residue by column chromatography (EtOAc / hexanes) afforded 1-(6-(difluoromethoxy)pyridazin-3-yl)ethan-1-one (200 mg 98%) as pale oil. 711H NMR (300 MHz, DMSO) δ 8.24 (d, J=9.1 Hz, 1H), 7.78 (t, J=71.3 Hz, 1H), 7.28 (d, J=9.1 Hz, 1H), 2.86 (s, 3H). ESI-MS (m / z): 189.0 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-1- (6-(difluoromethoxy)pyridazin-3-yl)-3-(pyridin-4-yl)prop-2-en-1-one was obtained from 1-(6- (difluoromethoxy)pyridazin-3-yl)ethan-1-one (208 mg, 71%).1H NMR (300 MHz, DMSO) δ 8.76 – 8.66 (m, 2H), 8.53 – 8.42 (m, 1H), 8.37 (d, J=9.1 Hz, 1H), 7.94 – 7.83 (m, 1H), 7.79 (t, J=71.0 Hz, 1H), 7.57 – 7.50 (m, 2H), 7.33 (d, J=9.1 Hz, 1H). ESI-MS (m / z): 278.1 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-3-(pyridin-4-yl)-1- (thiophen-3-yl)prop-2-en-1-one was obtained from 3-acetylthiophene (600 mg, 70%). 1H-NMR 400 MHz, CDCl3δ (ppm): 8.73 – 8.66 (m, 2H), 8.20 (dd, J = 2.9, 1.3 Hz, 1H), 7.71 (d, J = 15.7 Hz, 1H), 7.68 (dd, J = 5.1, 1.3 Hz, 1H), 7.53 (d, J = 15.7 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.40 (dd, J = 5.1, 2.9 Hz, 1H). ESI-MS (m / z): 216.2 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-3-(pyridin-4-yl)-1- (thiophen-2-yl)prop-2-en-1-one was obtained from 2-acetylthiophene (650 mg, 76%). 1H-NMR 400 MHz, CDCl3δ (ppm): 8.75 – 8.66 (m, 2H), 7.89 (dd, J = 3.8, 1.1 Hz, 1H), 7.74 (d, J = 15.6 Hz, 1H), 7.74 (dd, J = 4.9, 1.1 Hz, 1H), 7.54 (d, J = 15.6 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.22 (dd, J = 4.9, 3.8 Hz, 1H). ESI-MS (m / z): 216.2 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (E)-3-(pyridin-4-yl)-1- (5-chlorothiophen-2-yl)prop-2-en-1-one was obtained from 2-acetyl-5-chloro- thiophene (250 mg, 27%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.79 – 8.64 (m, 2H), 7.73 (d, J = 15.6 Hz, 1H), 7.67 (d, J = 4.1 Hz, 1H), 7.49 – 7.44 (m, 2H), 7.45 (d, J = 15.6 Hz, 1H), 7.04 (d, J = 4.1 Hz, 1H). ESI-MS (m / z): 250.1 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (tert-Butyl (E)-3-(3- (pyridin-4-yl)acryloyl)pyrrolidine-1-carboxylate was obtained from tert-butyl 3- acetylpyrrolidine-1-carboxylate (1.07 g, 5.00 mmol).1H-NMR 400 MHz, CDCl3δ (ppm): 8.77 – 8.53 (m, 2H), 7.48 – 7.41 (m, 1H), 7.39 – 7.30 (m, 2H), 6.95 – 6.84 (m, 1H), 4.25 – 3.88 (m, 2H), 3.02 – 2.68 (m, 3H), 2.00 – 1.92 (m, 1H), 1.77 – 1.65 (m, 1H), 1.40 (s, 9H). ESI-MS (m / z): 303.1 [M+H]+. Similar to (E)-1-cyclopropyl-3-(pyridin-4-yl)prop-2-en-1-one, (tert-Butyl (E)-3-(3- (pyridin-4-yl)acryloyl)piperidine-1-carboxylate was obtained from tert-butyl 3- acetylpiperidine-1-carboxylate (522 mg, 55%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.75 – 8.56 (m, 2H), 7.58 – 7.47 (m, 1H), 7.45 – 7.38 (m, 2H), 7.02 – 6.90 (m, 1H), 4.33 – 3.94 (m, 2H), 3.06 – 2.73 (m, 3H), 2.09 – 1.98 (m, 1H), 1.84 – 1.72 (m, 1H), 1.70 – 1.50 (m, 2H), 1.47 (s, 9H). ESI-MS (m / z): 317.2 [M+H]+. Cyclization of 1,3-diketones with amino-heterocycles A mixture of 3-amino-5-trifluoromethyl-1,2,4-triazole (4.00 g, 26.3 mmol) and ethyl acetoacetate (16.8 mL, 131.5 mmol) was stirred at room temperature for 30 minutes in a pressure tube. Toluene (40 mL) and p- toluenesulfonic acid (0.250 g, 1.32 mmol) was added and the reaction mixture was stirred at 110 °C for 18h. After cooling to room temperature, precipitates were filtered, washed with toluene (10 mL) and dried under vacuum to afford 5-methyl- 72 2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one as brown powder (2.11 g, 37%).1H-NMR (400 MHz, DMSO) δ 13.58 (s, 1H), 5.99 (s, 1H), 2.35 (s, 3H). ESI: 219.0 [M+H]+. was carefully added to 25 mL of crushed ice. pH was adjusted to 10 by 10 % NaOH. Additional water (15 ml) was added and the mixture was extracted with DCM (3×20 mL). DCM extracts were combined, washed with water (3×20 mL), dried over Na2SO4and evaporated to afford 7-chloro-5-methyl-2- (trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine as yellow solid (420 mg, 77%). 1H-NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 2.68 (s, 3H). ESI: 237.0 [M+H]+. extracted with EtOAc (3×30 mL). The combined organic layer was dried 73 over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc) to afford 7-chloro-5-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[1,5- a]pyrimidine as a white solid (150 mg, 23%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): δ 8.76 (s, 1H), 8.42 – 8.38 (m, 3H), 7.43 (t, J = 73.5 Hz, 1H), 7.41 – 7.36 (m, 3H). ESI-MS (m / z): 297 [M+H]+. A mixture of 5-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (2.10 g, 9.12 mmol) and POCl3(21.2 mL, 228 mmol) was stirred at 90 °C in a sealed pressure tube. After 2h, the mixture was evaporated, in the end co- evaporated with toluene. Crushed ice (100 mL) was added to the residue, followed by aq.10 % NaOH until pH 10. The mixture was stirred at 30 min at room temperature keeping the pH constant. Water (50 mL) was added and the mixture was extracted with DCM (3×250 mL). DCM extracts were combined, dried over anhydrous Na2SO4and evaporated. The residue was purified by flash column chromatography (Hexane / EtOAc) to afford 7-chloro-5-(4-fluorophenyl)-[1,2,4]triazolo-[1,5-a]pyrimidine as slightly yellow solid (1.55 g, 68%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): δ 8.76 (s, 1H), 8.43 – 8.36 (m, 3H), 7.47 – 7.40 (m, 2H). ESI- MS (m / z): 249 [M+H]+. 8.58 (m, 1H), 8.47 – 8.37 (m, 2H), 7.51 – 7.42 (m, 2H). ESI-MS (m / z): 317.1 [M+H]+. To an ice-cooled solution of 4-pyridinecarboxaldehyde (1.38 g, 14.0 mmol) and 4-fluoroacetophenone (1.50 g, 10.0 mmol) in THF (10 mL), a solution of t-BuOK (112 mg, 1.00 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 1h. EtOAc (20 mL) was added and the mixture extracted with water (50 mL), brine (50 mL), the aqueous phase was separated and dried over Na2SO4and evaporated. The residue was crystallized from EtOH (5 ml) to afford enone A as slightly yellow solid (2.14 g, 94%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.72 – 8.66 (m, 2H), 8.10 – 8.03 (m, 2H), 7.73 – 7.60 (m, 2H), 7.49 – 7.44 (m, 2H), 7.23 – 7.16 (m, 2H). ESI-MS (m / z): 228.2 [M+H]+. To а solution of A (500 mg, 2.20 mmol) in DMF (2 mL), 3-aminotriazole (278 mg, 3.30 mmol) was added. The reaction mixture was stirred at 110 °C for 2h. Water (30 mL) was added to the cooled reaction mixture and the precipitates were filtered off. The obtained solid was dissolved in chloroform (10 ml) and manganese (IV) oxide (1.26 g, 14.3 mmol) was added. The reaction mixture was stirred at room temperature. After 18h, the reaction mixture was filtered through a celite pad. The filtrate was 74 evaporated and the residue was crystallized from DCM / MeOH (5 ml) to afford A-36 as a yellow powder (190 mg, 30%).1H-NMR 400 MHz, CDCl3 δ (ppm): 8.96 – 8.90 (m, 2H), 8.56 (s, 1H), 8.33 – 8.24 (m, 2H), 8.07 – 8.01 (m, 2H), 7.69 (s, 1H), 7.31 – 7.21 (m, 2H). ESI (m / z): 292.1 [M+H]+. 5 Route R1: Synthesis exemplified on compound B-9 A suspension of (E)-3-(dimethylamino)-1-(pyridin-4-yl)but-2-en-1-one e (330 mg, 1.74 mmol) and 4H- 1,2,4-triazol-3-amine (146 mg, 1.74 mmol) in acetic acid (5 mL) was stirred at reflux for 16 h and then partly evaporated. pH was adjusted to 8 by 10 % aq. NaHCO3. Precipitates were filtered and washed with water (25 ml) to afford B-9 as slightly beige solid (230 mg, 63%).1H-NMR (400 MHz, CDCl3) δ: 8.96 10 – 8.83 (m, 2H), 8.51 (s, 1H), 8.02 – 7.94 (m, 2H), 7.17 (s, 1H), 2.81 (s, 3H). LC-MS (m / z): 212.2 [M+H]+. In a similar manner, the following compounds were prepared with the appropriate starting materials: 75 76 77 78 79 80 81 82 83 Route R2: Synthesis exemplified on compound A-34 To a solution of dimethyl carbonate (23.5 mL, 0.279 mol) in toluene (180 mL) under argon, NaH (60% 5 in min. oil w / w, 10.7 g, 0.269 mol) was added and mixture was brought to reflux. A solution of 1-[4- (difluoromethoxy)phenyl]ethan-1-one (20.0 g, 0.107 mol) in toluene (100 mL) was added dropwise over 1h. After the evolution of hydrogen ceased (30 min), the reaction mixture was cooled down to room temperature and AcOH (30 mL) was added. Ice-cold water was slowly added until the solid was dissolved completely. EtOAc (600 mL) was added. The organic layer was separated, extracted with 10 water (120 mL), brine (120 mL), dried over Na2SO4and evaporated. The residue was purified by column chromatography (hexane / EtOAc) to afford ketoester B as yellow oil (23.6 g, 90%).1H-NMR 300 MHz, DMSO-d6 δ (ppm): δ 8.07 – 8.00 (m, 2H), 7.43 (t, J = 73.6 Hz, 3H), 7.35 – 7.28 (m, 2H), 4.21 (s, 2H), 3.65 (s, 3H). ESI-MS (m / z): 245 [M+H]+. A mixture of B (5.00 g, 20.5 mmol) and 3-amino-1,2,4-triazole (2.58 g, 30.7 mmol) was heated at 165 15 °C for 4 h in a sealed pressure tube. The reaction mixture was cooled down to room temperature and treated with toluene (50 mL). Precipitates were filtered, washed with MTBE (15 mL) and dried to afford C as yellowish solid which was used without further purification (4.95 g, 87%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): δ 8.40 (s, 1H), 8.03 – 7.98 (m, 2H), 7.50 (s, 1H), 7.38 (t, J = 73.7 Hz, 1H), 7.34 – 7.29 (m, 2H), 6.38 (s, 1H). ESI-MS (m / z): 279 [M+H]+. 20 A mixture of C (4.90 g, 17.6 mmol) and POCl3(41.0 mL, 440 mmol) was stirred at 90 °C in a sealed pressure tube. After 1h the mixture was evaporated (in the end co-evaporated with toluene). Crushed ice (150 mL) was added to the residue and 10 % NaOH (40 mL) was added until pH 10. This mixture was stirred for 30 min at room temperature keeping pH constant. Water (100 mL) was added and the mixture was extracted with DCM (3×300 mL). DCM extracts were combined, dried over anhydrous 25 Na2SO4and evaporated. The residue was purified by column chromatography (hexanes / EtOAc) to afford D as slightly yellow solid (2.06 g, 39%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): δ 8.76 (s, 1H), 8.42 – 8.38 (m, 3H), 7.43 (t, J = 73.5 Hz, 1H), 7.41 – 7.36 (m, 2H). ESI-MS (m / z): 297 [M+H]+. 84 To a solution of ethyl 1-methylpiperidine-4-carboxylate (242 mg, 1.42 mmol) in dry THF (2.8 mL), LDA (freshly prepared, 0.54 M in THF, 4.72 mL, 2.55 mmol) was added dropwise at -78 °C. The reaction mixture was stirred 1 h at -30 °C and a solution of D (420 mg, 1.42 mmol) in dry THF (8 mL) was added dropwise at -30 °C. The reaction mixture was let come to room temperature and stirred for 18h. 5 Saturated NH4Cl (15 mL) and water (30 mL) were added and the mixture was extracted with EtOAc (3×75 mL). Combined EtOAc extracts were extracted with brine (20 mL), dried over Na2SO4and evaporated. The residue was purified by column chromatography (Hexane / EtOAc) to afford E as brown solid (195 mg, 32%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): δ 8.67 (s, 1H), 8.50 – 8.43 (m, 2H), 7.92 (s, 1H), 7.44 (t, J = 73.6 Hz, 1H), 7.42 – 7.37 (m, 2H), 4.00 (q, J = 7.0 Hz, 2H), 2.62 – 2.54 (m, 2H), 2.53 – 10 2.44 (m, 6H), 2.21 (s, 3H), 0.91 (t, J = 7.1 Hz, 3H). ESI-MS (m / z): 432 [M+H]+. To a solution of E (180 mg, 0.417 mmol) in MeOH (2 mL) and THF (1 mL), a solution of 2M NaOH (0.63 mL, 1.25 mmol) was added. The reaction mixture was stirred at 50 °C for 4h. Water (5 mL) was added and the mixture was extracted with DCM (3×20 mL). The combined organic extracts were dried over Na2SO4and evaporated. The residue was purified by column chromatography (MeOH / DCM) to afford 15 A-34 as yellowish solid (145 mg, 96%).1H-NMR 400 MHz, CDCl3 δ (ppm): δ 8.48 (s, 1H), 8.23 – 8.18 (m, 2H), 7.34 (s, 1H), 7.29 – 7.24 overlapping with CDCl3 (m, 2H), 6.61 (t, J = 73.1 Hz, 1H), 3.53 (tt, J = 12.0, 3.3 Hz, 1H), 3.11 – 3.05 (m, 2H), 2.39 (s, 3H), 2.28 – 2.21 (m, 4H), 2.02 – 1.89 overlapping with H2O (m, 2H). ESI-MS (m / z): 360 [M+H]+. To a solution of A-34 (215 mg, 0.598 mmol) in DCM (10 mL) and Et2O (10 mL), HCl (2M in Et2O, 1.50 20 mL, 2.99 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 30 min and evaporated. The residue was purified by reversed-phase flash chromatography and lyophilized to afford A-34·HCl as a white solid (185 mg, 78%).1H-NMR 400 MHz, MeOH-d4 δ (ppm): δ 8.90 (s, 1H), 8.47 – 8.41 (m, 2H), 7.95 (s, 1H), 7.39 – 7.34 (m, 2H), 7.03 (t, J = 73.1 Hz, 1H), 3.96 – 3.87 (m, 1H), 3.81 – 3.71 (m, 2H), 3.42 – 3.26 (overlapping with MeOH-d4, m, 2H), 2.99 (s, 3H), 2.58 – 2.48 (m, 2H), 2.47 – 2.35 (m, 2H). ESI- 25 MS (m / z): 360 [M+H]+. Route R2: Synthesis exemplified on compound A-27 To solution of intermediate D (145 mg, 0.489 mmol) in DMF (1 mL), 1-methyl-piperazine (0.109 ml, 0.978 mmol) was added and mixture was stirred at 100 °C for 18h. After cooling to room temperature water (30 mL) was added. Filtration and washing of precipitates with water yielded A-27 as yellowish 30 solid (150 mg, 85%).1H-NMR 300 MHz, DMSO-d6 δ (ppm): δ 8.50 (s, 1H), 8.36 – 8.29 (m, 2H), 7.39 (t, J = 74.0Hz, 1H), 7.36 – 7.30 (m, 2H), 7.08 (s, 1H), 4.01 – 3.90 (m, 4H), 2.59 – 2.52 (m, 4H), 2.26 (s, 3H). ESI-MS (m / z): 361 [M+H]+. Route R2: Synthesis exemplified on compound A-65 To solution of 4-methylpiperazin-2-one (151 mg, 1.33 mmol) and intermediate D (300 mg, 1.21 mmol) 35 in dry 1,4-dioxane (6 mL) was added Cs2CO3(590 mg, 1.81 mmol) at room temperature and the reaction mixture was degassed for 10 min. Then, Xantphos (105 mg, 0.181 mmol) and Pd(OAc)2(14 mg, 0.060 85 mmol) were added and the mixture was stirred at 100 °C for 18h. After cooling to room temperature, the mixture was filtered through a celite pad, which was rinsed with EtOAc (10 mL) and the filtrate was evaporated. The residue was purified by column chromatography (EtOH / DCM) to afford A-65 as yellowish solid (110 mg, 28%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): δ 8.67 (s, 1H), 8.42 – 8.36 (m, 2H), 5 8.19 (s, 1H), 7.49 – 7.41 (m, 2H), 3.98 – 3.91 (m, 2H), 3.29 (s, 2H), 2.86 (t, J = 5.4 Hz, 2H), 2.37 (s, 3H). ESI-MS (m / z): 327 [M+H]+. Route R2: Synthesis exemplified on compound B-2 A mixture of commercially available 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine (1.00 g, 5.93 mmol), morpholine (520 µL, 5.93 mmol) and K2CO3(985 mg, 7.12 mmol) in dioxane (20 mL) was stirred 10 at 110 °C for 3 h in a pressure vessel. After cooling to room temperature, the mixture was filtered and washes with iPrOH (25 mL). The filtrate was concentrated and the residue (1.20 g) was recrystallized from EtOH / MTBE (75mL) to afford B-2 as slightly yellow solid (930 mg, 71%).1H-NMR (400 MHz, DMSO- d6) δ: 8.42 (s, 1H), 6.57 (s, 1H), 3.80 (s, 8H), 2.49 (s, over-lapped with DMSO, 3H). LC-MS (m / z): 220.2 [M+H]+. 15 In a similar manner, the following compounds were prepared with the appropriate starting materials: 86 87 88 89 Route R3: Exemplified on compound B-30 and A-105 A suspension of (E)-3-(dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one (1.80 g, 10.2 mmol) and 4H- 5 1,2,4-triazol-3-amine (859 mg, 10.2 mmol) in AcOH (5 mL) was stirred at reflux for 5 h and then partly evaporated. The pH was adjusted to 8 by 10 % aq. NaHCO3. Precipitates were filtered, washed with water (75 mL) and crystallized from EtOH to afford B-30 as yellowish solid (1.01 g, 63%).1H-NMR (400 MHz, CDCl3) δ: 8.95 (d, J = 4.5 Hz, 1H), 8.94 – 8.88 (m, 2H), 8.60 (s, 1H), 8.05 – 7.99 (m, 2H), 7.33 (d, J = 4.5 Hz, 1H). LC-MS (m / z): 198.1 [M+H]+. 10 To a 1.3 M solution of iPrMgCl·LiCl in THF (3.12 mL, 4.07 mmol), 5-bromo-2-fluoro-4-methylpyridine (455 µL, 3.80 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2h and then added dropwise to a suspension of B-30 (500 mg, 2.54 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 16h. Water (15 mL) was added and the mixture was extracted with EtOAc (3x30 mL). The organic phases were combined and washed 15 with brine (20 mL), dried over Na2SO4and evaporated. Purification of the residue by column chromatography (CHCl3 / EtOH) afforded 5-(6-fluoro-2-methylpyridin-3-yl)-7-(pyridin-4-yl)-4,5- dihydro[1,2,4]triazolo[1,5-a]pyrimidine as beige foam (380 mg, 49%).1H-NMR 400 MHz, CDCl3 δ (ppm): 1H NMR (400 MHz, Chloroform-d) δ 8.67 – 8.59 (m, 2H), 8.16 (s, 1H), 7.52 – 7.44 (m, 2H), 7.38 (s, 1H), 6.77 – 6.74 (m, 1H), 6.27 (s, 1H), 5.81 (dd, J = 3.8, 1.5 Hz, 1H), 5.25 (dd, J = 3.8, 1.9 Hz, 1H), 2.44 20 (s, 3H). ESI-MS (m / z): 309.2 [M+H]+. 90 To а solution of the above prepared dihydrotriazolopyrimidine (370 mg, 1.20 mmol) in water (10 mL), CAN (1.15 g, 2.10 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and then the pH was adjusted to 8 with 10% Na2CO3. Precipitates were filtered and washed with water (20 mL) and then with DCM (50 mL). The organic filtrate was evaporated. Purification of the residue by 5 column chromatography (DCM / MeOH) afforded A-105 as white solid (200 mg, 54%).1H-NMR 400 MHz, CDCl3 δ (ppm): 8.99 – 8.91 (m, 2H), 8.64 (s, 1H), 8.46 (s, 1H), 8.09 – 8.02 (m, 2H), 7.47 (s, 1H), 6.99 – 6.96 (m, 1H), 2.68 (s, 3H). ESI (m / z): 307.1 [M+H]+. In a similar manner, the following compounds were prepared with the appropriate starting materials: 91 92 93 94 95 96 Synthesis of Compound A-17 To suspension of A-15, synthesized via general route 1, (300 mg, 0.78 mmol) in methanol (5 mL), sodium borohydride (296 mg, 7.83 mmol) was added. The reaction mixture was stirred at reflux. After 5 1h, the mixture was cooled to room temperature and poured into cold water (15 mL). Precipitates were filtered, washed with water (15 mL) and purified by reverse-phase chromatography (MeCN / H2O) to afford A-17 as slightly yellow solid (150 mg, 50%).1H-NMR spectrum (400 MHz, DMSO) δ 7.55 – 7.47 (m, 2H), 7.37 – 7.32 (m, 2H), 7.23 (t, J = 74.0 Hz, 1H), 7.19 – 7.14 (m, 2H), 7.09 – 7.00 (m, 2H), 6.69 – 6.61 (m, 2H), 5.24 (dd, J = 11.0, 4.6 Hz, 1H), 4.75 – 4.63 (m, 1H), 2.87 (s, 6H), 2.36 – 2.26 (m, 1H), 2.16 10 – 2.03 (m, 1H). ESI: 386.3[M+H]+. Similarly, compound A-41-rac was obtained from A-31 after purification by column chromatography with DCM / MeOH (141 mg, 73%)1H-NMR 400 MHz, CDCl3δ (ppm): mixture of diastereomers (1:0.09), major cis-diastereomer δ 8.61-8.57 (m, 2H), 7.47-7.42 (m, 2H), 7.37 (s, 1H), 7.19-7.09 (m, 4H), 6.54 (s, 15 1H), 6.50 (t, J=73.4 Hz, 1H), 5.33 (dd, J=10.95.0 Hz, 1H), 4.74 (dd, J=11.32.3 Hz, 1H), 2.60-2.50 (m, 1H), 2.30-2.17 (m, 1H). ESI-MS (m / z): 344.5 [M+H]+. The enantiomers of the major cis-diastereomer were separated by chiral HPLC on Chiralpak IH column using DCM / heptane / iPrOH (0.1% diethylamine) as eluent (retention time A41-ent-I: 33.2 min; A-41-ent-II: 7.4 min). 20 Synthesis of Compound A-21 3-(Dimethylamino)-1-(4-(dimethylamino)phenyl)prop-2-en-1-one (450 mg, 2.05 mmol) and 4H-1,2,4- triazol-3-amine (173 mg, 2.05 mmol) were melted at 165 °C for 30 min. The mixture was cooled to room temperature and was ground to a powder in MTBE (20 mL). Solids were filtered, washed with MTBE (25 mL) to afford 4-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)-N,N-dimethylaniline as a yellow solid 25 (425 mg, 87%).1H-NMR (400 MHz, CDCl3) δ 8.74 (d, J = 4.8 Hz, 1H), 8.53 (s, 1H), 8.25 – 8.13 (m, 2H), 7.17 (d, J = 4.8 Hz, 1H), 6.88 – 6.76 (m, 2H), 3.10 (s, 6H). ESI: 240.2 [M+H]+. To a suspension of the above prepared compound (240 mg, 1.00 mmol) in dry THF (5 ml), (4-(difluoromethoxy)- phenyl)magnesium iodide (1.28 M in THF, 1.75 mL, 1.50 mmol) was added dropwise at -15 °C. The mixture was stirred at room temperature for 2 h. Cold water (7 mL) was added and the mixture was 97 extracted with EtOAc (3x20 mL). EtOAc extracts were combined, dried over Na2SO4and evaporated. The residue was recrystallized from 5% Hex / EtOAc (10 mL) to afford A-21 (98 mg, 25%) as orange solid. 1H-NMR (400 MHz, DMSO-d6) δ: 7.51 – 7.38 (m, 5H), 7.19 – 7.11 (m, 2H), 6.76 (t, J = 74.5 Hz, 1H), 6.75 – 6.70 (m, 2H), 6.34 – 6.27 (m, 1H), 5.45 (dd, J = 4.7, 1.9 Hz, 1H), 5.26 (dd, J = 4.7, 1.8 Hz, 1H), 2.96 (s, 5 6H). LC-MS (m / z): 384.2 [M+H]+. Synthesis of Compound A-22 To suspension of commercially available 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine (350 mg, 2.08 mmol) in toluene (15 mL), (4-(dimethylamino)phenyl)boronic acid (685 mg, 4.16 mmol), Pd(PPh3)4(120 mg, 0.104 mmol), 2M Na2CO3(4.15 ml, 8.30 mmol) and EtOH (0.91 mL) were added. The resulting 10 suspension was stirred at 120 °C for 40 h. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was diluted with EtOAc (50 mL), extracted with brine (25 mL), dried over Na2SO4and evaporated. The residue was purified by column chromatography (DCM / EtOAc) to afford A-22 as yellow solid (230 mg, 44%).1H-NMR (400 MHz, DMSO) δ: 8.58 (s, 1H), 8.29 – 8.23 (m, 2H), 7.47 (s, 1H), 6.91 – 6.84 (m, 2H), 3.05 (s, 6H), 2.63 (s, 3H). ESI (m / z): 254.2 [M+H]+. 15 Synthesis of Compound A-31-NO To an ice-cooled solution of compound A-31 (300 mg, 0.88 mmol) in DCM (12 mL), a solution of mCPBA (436 mg, 1.77 mmol) in DCM (8 mL) was added. The reaction mixture was stirred at room temperature for 30h. Saturated NaHCO3(20 mL) was added and the mixture was extracted with CHCl3(3x50 mL). The organic extracts were combined, extracted with brine (50 mL), dried over Na2SO4and evaporated. 20 EtOH (20 mL) was added to the residue and the mixture was stirred at reflux for 10 min. Insoluble parts were filtered, washed with EtOH to afford A-31-NO as a white solid (75 mg, 34 %).1H-NMR 400 MHz, DMSO-d6 δ 8.77 (s, 1H), 8.55-8.50 (m, 4H), 8.54 – 8.58 (m, 2H), 8.36 (s, 1H), 7.44 (t, J=73.7 Hz, 1H), 7.43-7.38 (m, 2H); ESI (m / z): 356.4 [M+H]+. Synthesis of Compound A-50 25 To a suspension of compound A-51, synthesized via general route 1, (650 mg, 1.76 mmol) and potassium iodide (405 mg, 2.44 mmol) in MeCN (10 mL), trimethylsilylchloride (265 mg, 2.44 mmol) was added. The reaction mixture was stirred at 65 °C for 2h. Water (20 mL) was added to the cooled reaction mixture and the resulting precipitates were filtered and washed with MeOH (5 mL) to afford A-50 as beige powder (402 mg, 64 %).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 12.01 (s, 1H), 8.73 (s, 1H), 30 8.51 – 8.46 (m, 2H), 8.22 (s, 1H), 7.65 – 7.62 (m, 1H), 7.43 (t, J = 73.7 Hz, 1H), 7.42 – 7.37 (m, 2H), 7.27 – 7.26 (m, 1H), 6.93 – 6.89 (m, 1H). ESI (m / z): 356.0[M+H]+. Synthesis of Compound A-49 To a suspension of the above obtained A-50 (180 mg, 0.51 mmol) in AcOH (5 mL), Pt / C 5% (20 mg, 0.09 mmol) was added. The reaction mixture was stirred at room temperature under H2atmosphere. After 35 18h, the mixture was filtered through a celite pad, washed with MeOH (10 mL) and the combined 98 filtrates were evaporated. Saturated NaHCO3solution (30 mL) was added to residue (pH 8) and the mixture was extracted with EtOAc (3x30mL). The organic extracts were combined, dried over Na2SO4and evaporated. Crystallization of the residue from MeOH (5 mL) afforded A-49 as beige solid (134 mg, 74%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 8.70 (s, 1H), 8.46 – 8.38 (m, 2H), 7.85 (s, 1H), 7.79 – 7.72 5 (m, 1H), 7.43 (t, J = 73.6 Hz, 1H), 7.42 – 7.37 (m, 2H), 4.01 – 3.91 (m, 1H), 41-3.28 (m, 2H), 2.81 – 2.66 (m, 2H), 2.32 – 2.23 (m, 1H), 2.17 – 2.05 (m, 1H). ESI (m / z): 360.2[M+H]+. Synthesis of Compound A-61 To suspension of A-62 (200 mg, 0.64 mmol) in DCM (10 mL), Dess-Martin periodinane (15% in DCM, 6.60 mL, 3.19 mmol) was added. The reaction mixture was stirred at room temperature overnight.10% 10 Na2SO3and sat. NaHCO3solutions (50 mL and 50 mL) were added and the organic layer was separated. The aq. phase was extracted with DCM (3×30 mL), organic extracts were combined, washed with brine (30 mL), dried over Na2SO4and evaporated. The residue was recrystallized from water / EtOH to afford A-61 as white solid (155 mg, 78%).1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.18 – 8.09 (m, 2H), 7.24 – 7.14 (m, 2H), 6.71 (s, 1H), 4.22 (t, J = 6.2 Hz, 4H), 2.78 (t, J = 6.2 Hz, 4H). ESI-MS (m / z): 312.4 [M+H]+. 15 Synthesis of Compound A-73·HCl A mixture of compound A-77, prepared via general route 1, (600 mg, 1.62 mmol), tert-butyl carbamate (228 mg, 1.95 mmol), Pd(OAc)2(18.2 mg, 0.08 mmol), Xantphos (141 mg, 0.24 mmol) and Cs2CO3(792 mg, 2.44 mmol) in dioxane (7 mL) was stirred at 100 °C for 4h. EtOAc (30 mL) was added and the mixture extracted with water (50 mL), brine (50 mL), dried over Na2SO4and evaporated. The residue20 was purified by column chromatography (EtOAc / Hexane) to afford tert-Butyl (4-(5-(4-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)carbamate as a yellow powder (290 mg, 44 %).1H-NMR 400 MHz, CDCl3 δ (ppm): 8.61 – 8.58 (m, 1H), 8.56 (s, 1H), 8.55 – 8.52 (m, 1H), 8.32 – 8.26 (m, 2H), 7.95 (s, 1H), 7.75 – 7.72 (m, 1H), 7.70 (s, 1H), 7.30 – 7.22 (m, 2H), 1.56 (s, 9H). ESI (m / z): 407.3 [M+H]+. To an ice-cooled suspension of the above prepared carbamate (275 mg, 0.68 mmol) in MeOH (2 mL), 25 HCl (4M in dioxane, 5 mL, 162 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18h and then evaporated. Solids were filtered and washed with DCM / MeOH mixture (5 mL) to afford A-73·HCl as a yellow powder (200 mg, 86 %).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 8.82 (s, 1H), 8.64 – 8.49 (m, 4H), 8.39 (s, 1H), 8.28 – 8.23 (m, 1H), 8.04 – 8.00 (m, 1H), 7.62 – 7.58 (m, 1H), 7.53 – 7.46 (m, 2H). ESI (m / z): 307.2 [M+H]+. 30 Synthesis of Compound A-76 To а solution of compound A-77, prepared via general route 1, (850 mg, 2.29 mmol) in DMF (5 mL), Pd(PPh3)4(133 mg, 0.11 mmol) and Zn(CN)2(162 mg, 1.38 mmol) was added. The reaction mixture was stirred at 120 °C for 2h and then filtered hot through a cellulose filter. The filtrate was cooled to room temperature and water (30 mL) was added. Precipitates were filtered and washed with MeOH / acetone 35 to afford A-76 as a brown powder (551 mg, 76 %).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 9.11 – 9.05 99 (m, 1H), 8.92 – 8.88 (m, 1H), 8.79 (s, 1H), 8.71 – 8.66 (m, 1H), 8.52 – 8.46 (m, 2H), 8.45 (s, 1H), 7.53 – 7.42 (m, 2H). ESI (m / z): 317.1 [M+H]+. Synthesis of Compound A-82 To an ice-cooled solution of 1-(4-fluoro-2-methylphenyl)ethan-1-one (6.00 g, 32.23 mmol) and 4- 5 pyridinecarboxaldehyde (6.21 g, 58.02 mmol) in THF (15 mL), a solution of t-BuOK (362 mg, 3.22 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 2h and concentrated under reduced pressure. EtOAc (200 mL) was added and mixture extracted with water (2x50 mL), brine (50 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography (EtOAc / hexanes). Product containing fractions were evaporated and the residue10 suspended in MTBE (50 mL). Solids were filtered to afford (E)-1-(4-(Difluoromethoxy)phenyl)-3- (pyridin-4-yl)prop-2-en-1-one as slightly yellow solid (7.04 g, 79%).1H-NMR 400 MHz, CDCl3 δ 8.73 – 8.66 (m, 2H), 8.10 – 8.01 (m, 2H), 7.75 – 7.58 (m, 2H), 7.50 – 7.44 (m, 2H), 7.26 – 7.22 (m, 2H), 6.62 (t, J = 72.8 Hz, 1H). ESI-MS (m / z): 276.3 [M+H]+. A solution of the above prepared enone (950 mg, 3.45 mmol) and methyl 5-amino-1H-1,2,4-triazole- 15 3-carboxylate (638 mg, 4.49 mmol) in DMF (5 mL) was stirred at 150 °C for 2 h. After cooling to room temperature, EtOAc (50 mL) was added and the mixture extracted with water (2x25 mL), brine (25 mL), dried over Na2SO4and evaporated. The residue was purified by column chromatography (DCM / MeOH) and crystallization from EtOH / H2O to afford methyl-5-(4-(difluoromethoxy)phenyl)-7-(pyridin-4-yl)- [1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate as slightly yellow solid (447 mg, 33%).1H-NMR 400 MHz, 20 DMSO-d6 δ 8.96 – 8.90 (m, 2H), 8.55-8.48 (m, 2H), 8.44 (s, 1H), 8.22-8.18 (m, 2H), 7.45 (t, 1H, J=73.6 Hz), 7.45-7.40 (m, 2H), 3.96 (s, 3H). ESI: 398.2 [M+H]+. To a suspension of the above prepared ester (447 mg, 1.13 mmol) in MeOH (4 mL), 3M NaOH (4 mL) and THF (12 mL) was added. The mixture was stirred at room temperature for 2h and then concentrated under reduced pressure. pH of the residue was adjusted to 2 by 5M HCl and the mixture 25 was stirred at 0-5 °C (ice bath) for 1h. Precipitates were filtered and washed with MeOH / MeCN (15 mL, 1:1) to afford 5-(4-(Difluoromethoxy)phenyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-2- carboxylic acid as slightly pink solid (382 mg, 89%).1H-NMR 400 MHz, DMSO-d6 δ 8.99-8.90 (m, 2H), 8.55-8.48 (m, 2H), 8.43 (s, 1H), 8.29 – 8.24 (m, 2H), 7.45 (t, 1H, J=73.6 Hz), 7.45-7.40 (m, 2H). ESI: 384.2 [M+H]+. 30 To a suspension of the above prepared acid (360 mg, 0.94 mmol) in dry DMF (15 mL), N-methyl- piperazine (110 μL, 0.99 mmol), HOBt (153 mg, 1.13 mmol) and EDC·HCl (216 mg, 1.13 mmol) were added. The reaction mixture was stirred at 45 °C for 1h. EtOAc (50 mL) was added and the mixture extracted with water (2x30 mL), brine (30 mL), dried over Na2SO4and evaporated. The residue was purified by column chromatography (EtOAc / MeOH) and reverse phase column chromatography 35 (MeCN / H2O) to afford A-82 as white foam (226 mg, 52%).1H-NMR 400 MHz, CDCl3 δ 8.96 – 8.88 (m, 100 2H), 8.33 – 8.27 (m, 2H), 8.08 – 8.02 (m, 2H), 7.77 (s, 1H), 7.34 – 7.28 (m, 2H), 6.64 (t, J = 73.0 Hz, 1H), 3.96 – 3.80 (m, 4H), 2.61 – 2.44 (m, 4H), 2.35 (s, 3H). ESI-MS (m / z): 466.3 [M+H]+. Synthesis of compound B-29 Similar to B-23, methyl 5-methyl-7-(pyridin-4-yl)-[1,2,4]triazolo[1,5a]-pyrimidine-2-carboxylate was 5 synthesized from (E)-3-(dimethylamino)-1-(pyridin-4-yl)but-2-en-1-one and methyl 5-amino-1H-1,2,4- triazole-3-carboxylate in refluxing AcOH. LC-MS (m / z): 270.1 [M+H]+. The crude methyl ester (240 mg, 0.891 mmol) was suspended in MeOH (3 mL) and 3M NaOH (3 mL) was added. The reaction mixture was stirred at room temperature for 1h before it was partly evaporated. 5M HCl was added to the residue until pH reached 4. Precipitates were filtered and washed with water (20 mL) to afford 5- 10 methyl-7-(pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid as slightly beige solid (183 mg, 80%). ESI: 256.1 [M+H]+. To a suspension of the crude acid (180 mg, 0.705 mmol) in dry DMF (5 mL), 1-methyl-piperazine (157 μL, 1.41 mmol), HOBt (54.0 mg, 0.353 mmol) and EDC·HCl (183 mg, 0.952 mmol) were added. After stirring at 40 °C for 6h, the reaction mixture was evaporated. The residue was purified by reverse-phase chromatography (eluent MeCN / H2O) to afford B-29 as slightly 15 pink solid (204 mg, 85%).1H-NMR (400 MHz, CDCl3) δ 8.90 – 8.85 (m, 2H), 8.03 – 7.98 (m, 2H), 7.24 (s, 1H), 3.90 – 3.81 (m, 4H), 2.82 (s, 3H), 2.56 – 2.50 (m, 2H), 2.48 – 2.43 (m, 2H), 2.33 (s, 3H). ESI-MS (m / z): 338.2 [M+H]+. Synthesis of compound A-86 and A-90 Similar to A-35, from (E)-1-(4-bromophenyl)-3-(pyridin-4-yl)prop-2-en-1-one, 5-(4-Bromophenyl)-7- 20 (pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidine was obtained (951 mg, 37%).1H-NMR 400 MHz, CDCl3δ (ppm): 8.99 – 8.89 (m, 2H), 8.58 (s, 1H), 8.20 – 8.11 (m, 2H), 8.09 – 8.01 (m, 2H), 7.76 – 7.66 (m, 3H). ESI (m / z): 353.1 [M+H]+. A mixture of the above prepared bromide (400 mg, 1.14 mmol), tert-butyl carbamate (160 mg, 1.36 mmol), Pd(OAc)2(13 mg, 0.06 mmol), Xantphos (99 mg, 0.17 mmol) and Cs2CO3(694 mg, 2.13 mmol) 25 in dioxane (5 mL) was stirred at 100 °C for 1h. EtOAc (30 mL) was added and the mixture extracted with water (50 mL), brine (50 mL), dried over Na2SO4and evaporated. The residue was crystallized from MeOH (5 mL) to afford tert-butyl (4-(7-(pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl)phenyl)carbamate as a yellow powder (332 mg, 75 %).1H-NMR 400 MHz, CDCl3 δ (ppm): 9.76 (s, 1H), 8.95 – 8.85 (m, 2H), 8.70 (s, 1H), 8.39 – 8.32 (m, 2H), 8.26 – 8.21 (m, 3H), 7.73 – 7.65 (m, 2H), 1.51 30 (s, 9H). ESI (m / z): 389.3 [M+H]+. To ice-cooled suspension of the above prepared carbamate (320 mg, 0.82 mmol) in MeOH (2 mL), HCl (35% in water, 5 mL, 57.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18h and then evaporated. Precipitates were filtered and washed with MeOH (5 mL) to afford A-86·HCl as a slightly brown powder (254 mg, 85 %).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 101 9.11 – 9.01 (m, 2H), 8.72 (s, 1H), 8.61 – 8.52 (m, 2H), 8.34 – 8.23 (m, 3H), 7.04 – 6.95 (m, 2H). ESI (m / z): 289.1 [M+H]+. To аn ice-cooled suspension of A-86·HCl (350 mg, 0.97 mmol) in DCM (10 mL), triethylamine (294 mg, 2.90 mmol) and 3-methoxypropionyl chloride (142 mg, 1.16 mmol) was added. The reaction mixture 5 was stirred at room temperature for 18h, then extracted with water (20 mL) and brine (10 mL), dried over Na2SO4and evaporated. The residue was purified by column chromatography (DCM / MeOH) to afford A-90 as an orange powder (266 mg, 73 %).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 8.96 – 8.89 (m, 2H), 8.61 (s, 1H), 8.54 (s, 1H), 8.28 – 8.22 (m, 2H), 8.08 – 8.01 (m, 2H), 7.79 – 7.72 (m, 2H), 7.70 (s, 1H), 3.79 – 3.74 (m, 2H), 3.49 (s, 3H), 2.72 – 2.66 (m, 2H). ESI (m / z): 375.2 [M+H]+. 10 Synthesis of compound A-87 A mixture of 2,6-dichloro-4-iodopyridine (5.0 g, 18.3 mmol), 4-fluorobenzeneboronic acid (2) (2.55 g, 18.3 mmol), K2CO3(7.56 g, 54.8 mmol) and Pd(dppf)Cl2·CH2Cl2(1.49 g, 1.83 mmol) in dioxane (30 mL) and water (10 mL) was stirred at 70°C for 1 h. The reaction mixture was filtered through a pad of celite, the filter cake was washed with EtOAc (100 mL) and the combined filtrates were evaporated. The15 residue was purified by column chromatography (EtOAc / hexanes) to afford 2,6-dichloro-4-(4- fluorophenyl)pyridine as white solid (3.50 g, 79%).1H-NMR 400 MHz, CDCl3 δ (ppm): 7.62 – 7.54 (m, 2H), 7.43 (s, 2H), 7.23 – 7.15 (m, 2H). ESI-MS (m / z): 242.5 [M+H]+. A mixture of the above prepared pyridine (2.57 g, 10.6 mmol), pyridine-4-boronic acid (1.44 g, 11.7 mmol), K2CO3(4.40 g, 31.8 mmol) and PdCl2(dtbpf) (415 mg, 0.64 mmol) in dioxane (60 mL) and water 20 (20 mL) was stirred at 85°C for 30 min. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, the filter cake was washed with EtOAc (70 mL). The aqueous layer was separated from the rest of filtrate and the organic phase was dried over Na2SO4and evaporated. The residue was purified by column chromatography (EtOAc / hexanes) to afford 6-chloro-4-(4- fluorophenyl)-2,4'-bipyridine as slightly orange solid (1.47 g, 49%).1H-NMR 400 MHz, CDCl3 δ (ppm): 25 8.79 – 8.73 (m, 2H), 7.96 – 7.91 (m, 2H), 7.86 (d, J = 1.4 Hz, 1H), 7.69 – 7.62 (m, 2H), 7.53 (d, J = 1.4 Hz, 1H), 7.25 – 7.19 (m, 2H). ESI-MS (m / z): 285.2 [M+H]+. A mixture of the above prepared pyridine (1.47 mg, 5.16 mmol), tert-butyl carbamate (907 mg, 7.74 mmol), Pd(OAc)2(58 mg, 0.26 mmol), Xantphos (300 mg, 0.52 mmol) and Cs2CO3(3.36 g, 10.3 mmol) in dioxane (20 mL) was stirred at 110°C for 1.5 h. After cooling to room temperature, the reaction 30 mixture was filtered through a pad of celite, the filter cake was washed with EtOAc (100 mL) and filtrates were evaporated. The residue was purified by column chromatography (EtOAc / hexanes) to afford tert-butyl (4-(4-fluorophenyl)-[2,4'-bipyridin]-6-yl)carbamate as white solid (1.52 g, 81%).1H- NMR 400 MHz, CDCl3 δ (ppm): 8.74 – 8.69 (m, 2H), 8.22 (d, J = 1.4 Hz, 1H), 7.91 – 7.87 (m, 2H), 7.75 – 7.68 (m, 2H), 7.64 (d, J = 1.4 Hz, 1H), 7.39 (s, 1H), 7.22 – 7.14 (m, 2H), 1.56 (s, 9H). ESI-MS (m / z): 366.4 35 [M+H]+. 102 To a solution of the above prepared carbamate (430 mg, 1.18 mmol) in DCM (3 mL), HCl (4 M in dioxane 8.83 mL, 35.3 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated, in the end co-evaporated with toluene (2 × 15 mL). The residue was suspended in iPrOH (5 mL) and DMF-DMA (196 µL, 1.47 mmol) was added. The reaction mixture was 5 stirred at reflux for 2 h, then cooled to 50°C. NH2OH·HCl (102 mg, 1.47 mmol) was added and the mixture was stirred at 50°C. After 16 h, the reaction mixture was evaporated and the residue was purified by column chromatography (DCM / MeOH) to afford (E)-N-(4-(4-fluorophenyl)-[2,4'-bipyridin]- 6-yl)-N'-hydroxyformimidamide as slightly grey solid (215 mg, 63%).1H-NMR (400 MHz, DMSO-d6 δ (ppm): 10.25 (s, 1H), 9.59 (d, J = 10.0 Hz, 1H), 8.81 – 8.73 (m, 2H), 8.41 – 8.33 (m, 2H), 8.17 (d, J = 10.0 10 Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.95 – 7.86 (m, 2H), 7.51 (d, J = 1.3 Hz, 1H), 7.46 – 7.36 (m, 2H). ESI-MS (m / z): 309.3 [M+H]+. To the mixture of the above prepared hydroxyformimidamide (360 mg, 1.17 mmol) in THF (7 mL), trifluoroacetic anhydride (195 μL, 1.40 mmol) was added at 0°C. The reaction mixture was warmed to room temperature, stirred for 16 h and then evaporated. The residue was purified by column15 chromatography (DCM / acetone) to afford A-87 as white solid (70 mg, 21%).1H-NMR (400 MHz, DMSO- d6 δ (ppm): 8.86 – 8.81 (m, 2H), 8.61 (s, 1H), 8.29 (d, J = 1.9 Hz, 1H), 8.19 – 8.15 (m, 2H), 8.13 – 8.05 (m, 2H), 7.89 (d, J = 1.9 Hz, 1H), 7.44 – 7.35 (m, 2H). ). ESI-MS (m / z): 291.3 [M+H]+. Synthesis of compound A-128 Similar to the synthesis of A-87, tert-butyl N-[4-(6-fluoropyridin-3-yl)-[2,4'-bipyridine]-6-yl]carbamate 20 was prepared using 2-fluoropyridyl-5-boronic acid in the first Suzuki coupling. LC-MS: (m / z): 366.6 [M]+. A solution of carbamate (685mg, 1.87mmol) in dioxane (14 mL) was dropwise treated with a solution of 4M HCl in dioxane (20 mL). The resulting mixture was stirred at room temperature for 6h. The solvent was removed under reduced pressure, the residue was dissolved in H2O, washed with EtOAc (3 x 35 mL), and DCM (3 x 40 mL). The aqueous layer was neutralized with 2M NaOH solution to 25 bring the pH to 8. The product was extracted with EtOAc (3 x 35 mL), the organic layers were combined, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to deliver 4-(6- fluoropyridin-3-yl)-[2,4'-bipyridine]-6-amine (350mg, 70%) of 4-(6-fluoropyridin-3-yl)-[2,4'-bipyridine]- 6-amine.1H NMR (300 MHz, DMSO-d6) δ 8.72 – 8.60 (m, 3H), 8.39 (td, J = 8.2, 2.7 Hz, 1H), 8.11 – 8.01 (m, 2H), 7.58 (d, J = 1.4 Hz, 1H), 7.36 (dd, J = 8.6, 2.9 Hz, 1H), 6.81 (d, J = 1.4 Hz, 1H), 6.33 (s, 2H). LC-30 MS: (m / z): 266.75 [M]+. To a solution of the amine (345mg, 1.3mmol) in EtOH (10 mL) was added DMF- DMA (0.26 mL, 1.95 mmol). The reaction mixture was heated at 75°C for 20h, cooled down to room temperature, and concentrated in vacuo to dryness. The crude imidamide used without further purification. A solution thereof in MeOH (8.3 mL) was treated with hydroxylamine hydrochloride (126 mg, 1.3 mmol). The reaction was stirred at room temperature for 1 hour, and then the mixture was 35 concentrated in vacuo. The residue was triturated with water, the solid was collected by filtration, and 103 washed with water. The solid was dried under vacuum to deliver N'-[6-fluoro-6'-(pyridin-4-yl)-[3,4'- bipyridine]-2'-yl]-N-hydroxymethanimidamide (400mg, 79%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.57 (d, J = 9.9 Hz, 1H), 8.76 – 8.70 (m, 3H), 8.44 (td, J = 8.2, 2.7 Hz, 1H), 8.26 – 8.22 (m, 2H), 8.16 (d, J = 10.0 Hz, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.42 (dd, J = 8.6, 5 2.9 Hz, 1H). LC-MS: (m / z): 309.55 [M]+. A solution of the above prepared imidamide (400 mg, 1.29 mmol) in Eaton’s reagent (2.4 mL) was heated at 105 °C for 1h. The reaction mixture was allowed to cool to room temperature, diluted with ice-water, and basified with solid K2CO3to bring the pH to 8. The resulting solution was washed with EtOAc (2x60mL), the organic layers were discarded. The aqueous layer was concentrated under reduced pressure to dryness. The residue was suspended in10 DMSO, filtered, and the solid was triturated several times with Et2O to deliver 2-fluoro-5-[5-(pyridin- 4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]pyridine (30mg, 8%) as a yellow solid. LC-MS: (m / z): 291.6 [M]+. A suspension of the above prepared fluoride (178mg, 0.61mmol) in MeOH was treated with 25% NaOMe in MeOH (2.4 mL) and the resulting mixture was heated at 70 °C for 18h. The reaction mixture was allowed to cool to room temperature, diluted with ice-water, and extracted with EtOAc (2x20mL). 15 The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using DCM / MeOH (0-3% of MeOH) to deliver A-128 (40 mg, 20%) as a white solid.1H-NMR (300 MHz, DMSO-d6δ (ppm): 8.91 – 8.75 (m, 3H), 8.61 (s, 1H), 8.39 (dd, J = 8.7, 2.7 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.21 – 8.11 (m, 2H), 7.93 (d, J = 1.9 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 3.95 (s, 3H). ESI-MS (m / z): 304.1 [M+H]+. 20 Synthesis of compound A-129 Similar to the synthesis of A-128, using 3-pyridine boronic acid in the first Suzuki coupling, compound A-129 was synthesized.1H-NMR (400 MHz, DMSO-d6δ (ppm): 9.24 (d, J = 2.4 Hz, 1H), 8.92 – 8.78 (m, 2H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.65 (s, 1H), 8.44 (dd, J = 10.2, 1.8 Hz, 2H), 8.29 – 8.15 (m, 2H), 7.99 (d, J = 1.9 Hz, 1H), 7.59 (dd, J = 8.0, 4.8 Hz, 1H). ESI-MS (m / z): 274.0 [M+H]+. 25 Synthesis of compound A-88 and A-93A To a solution of commercially available 5,7-dichloro-1H-imidazo[4,5-b]pyridine (2.82 g, 15.0 mmol) in DMF (15 mL) at 0 °C, NaH (660 mg, 60% in min. oil w / w, 16.5 mmol) was added. The reaction mixture was stirred at 0 °C for 10 min and SEM-Cl (2.92 mL, 16.5 mmol) was added dropwise. After stirring at 0 °C for 1 h, water (20 mL) was added and the mixture extracted with EtOAc (3x75 mL). The combined 30 organic extracts were extracted with brine (50 mL), dried over Na2SO4and evaporated. The residue was purified by column chromatography (EtOAc / hexanes) to afford 5,7-dichloro-3-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine as yellow oil (2.06 g, 43%).1H-NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.35 (s, 1H), 5.64 (s, 2H), 3.69 – 3.54 (m, 2H), 1.02 – 0.87 (m, 2H), -0.03 (s, 9H). GC-MS (m / z): 319.1. 104 The mixture of the above prepared dichloride (2.00 g, 6.28 mmol), (4-fluorophenyl)boronic acid (967 mg, 6.91 mmol), K2CO3(2.61 g, 18.9 mmol) and PdCl2(dtbpf) (205 mg, 0.314 mmol) in dioxane (16 mL) and water (4 mL) was stirred at 65 °C for 3 h. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3x30 mL). EtOAc extracts were combined, extracted 5 with brine (25 mL), dried over Na2SO4and evaporated. The residue was purified by column chromatography (EtOAc / hexanes) to afford 7-chloro-5-(4-fluorophenyl)-3-((2-(trimethylsilyl)ethoxy)- methyl)-3H-imidazo[4,5-b]pyridine (1.16 g, 49%) as white solid.1H-NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.19 – 8.06 (m, 2H), 7.43 (s, 1H), 7.26 – 7.18 (m, 2H), 5.68 (s, 2H), 3.71 – 3.60 (m, 2H), 0.98 – 0.90 (m, 2H), -0.02 (s, 9H). LC-MS (m / z): 378.2 [M+H]+. 10 The mixture of the above prepared chloride (500 mg, 1.32 mmol), pyridin-4-ylboronic acid (325 mg, 2.64 mmol), K2CO3(549 mg, 3.97 mmol) and Pd(dppf)Cl2(145 mg, 0.199 mmol) in dioxane (12 mL) and water (3 mL) was stirred at 90 °C for 1 h in a pressure tube. After cooling to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (3x25 mL). EtOAc extracts were combined, extracted with brine (20 mL), dried over Na2SO4and evaporated. The residue was purified 15 by column chromatography (Hex / EtOAc) to afford A-93A (520 mg, 94%) as colorless solid.1H-NMR (400 MHz, CDCl3) δ 8.84 – 8.70 (m, 2H), 8.31 (s, 1H), 8.23 – 8.16 (m, 2H), 8.07 – 8.00 (m, 2H), 7.95 (s, 1H), 7.31 – 7.23 (m, 2H), 5.80 (s, 2H), 3.79 – 3.68 (m, 2H), 1.05 – 0.95 (m, 2H), -0.05 (s, 9H). LC-MS (m / z): 421.2 [M+H]+. A solution of A-93A (250 mg, 0.595 mmol) in 5M HCl (1.5 mL) and EtOH (5.0 mL) was stirred at reflux 20 for 3 h. EtOH was evaporated and 10% Na2CO3was added to the residue until pH reached 8. Precipitates were filtered and washed with water (20 mL) and MTBE (30 mL) to afford A-88 as white powder (136 mg, 79%).1H-NMR (400 MHz, DMSO) δ 13.40 (br s, 1H), 8.76 – 8.67 (m, 2H), 8.59 (s, 1H), 8.55 – 8.41 (m, 2H), 8.26 – 8.17 (m, 3H), 7.48 – 7.38 (m, 2H). ESI-MS (m / z): 291.1 [M]+. Synthesis of compound A-132 25 In a similar fashion to A-88, compound A-132 was prepared using (pyridin-3-yl)boronic acid in the first Suzuki coupling.1H NMR (300 MHz, DMSO-d6, significant peak broadening observed) δ 13.58 (br, 1H), 9.57 (br, 1H), 8.76 (br, 4H), 8.64 (s, 1H), 8.35 (s, 1H), 8.27 (br, 2H), 7.63 (br, 1H). LC-MS (m / z): 274.2 [M+H]+. Synthesis of compound A-130 30 2,4-Dichloro-6-nitroaniline (200mg, 0.97 mmol), pyridine-4-boronic acid (120 mg, 0.97 mmol) and K2CO3(400 mg, 3 equiv) were dissolved in a mixture of dioxane and water (7.2 mL, 5:1 vol) under inert atmosphere. After degassing for 10 min, PdCl2(dtbpf) (94 mg, 0.15 equiv) was added and the resulting mixture was stirred at 70°C for 20h. The mixture was cooled down to room temperature, filtrated through a pad of Celite, and washed with AcOEt. The solvents were removed under reduced pressure35 to dryness. The crude material was purified by silica gel column chromatography using DCM / MeOH (0- 105 3% of MeOH) as an eluent to deliver a mixture of desired product contaminated with the second regioisomer. This mixture was repurified by silica gel column chromatography using Hexane / AcOEt (0- 40% of AcOEt) as an eluent to deliver 120 mg (Y: 50%) of 4-chloro-2-nitro-6-(pyridin-4-yl)aniline as a light yellow solid.1H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J = 5.8 Hz, 2H), 8.11 (s, 1H), 7.48 (d, J = 5.9 5 Hz, 3H), 7.03 (s, 2H). ESI-MS (m / z): 249.4 [M+H]+. A mixture of 4-chloro-2-nitro-6-(pyridin-4-yl)aniline (420mg, 1.69mmol) and SnCl2·2H2O (1.14 g, 3 equiv) in formic acid (4.8 mL) was heated at 130°C for 30 min in microwave oven. After cooling, the reaction mixture was diluted with water (50mL) and neutralized with 2M aq. NaOH to pH 7. The resulting mixture was extracted with AcOEt (3 x 150mL). The combined organic phases were dried over 10 Na2SO4, filtered, and concentrated under reduced pressure to deliver 340mg (Y: 88%) of the product as a light beige solid.1H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.68 (d, J = 5.3 Hz, 2H), 8.40 (s, 1H), 8.18 (dd, J = 10.0, 5.8 Hz, 2H), 7.77 – 7.58 (m, 2H). EI-MS (m / z): 229.5 [M]+. 6-Chloro-4-(pyridin-4-yl)-1H-1,3-benzodiazole (120mg, 0.52mmol), 4-fluorophenylboronic acid (80 mg, 1.1 equiv) and K2CO3(185 mg, 3 equiv) were dissolved in a mixture of dioxane and water (2.6 mL, 4:1 15 vol) under inert atmosphere. After degassing for 10 min, PdCl2(dtbpf) (43 mg, 0.15 equiv) was added and the reaction mixture was stirred at 90°C for 14h. The resulting suspension was cooled down to room temperature, filtered through a pad of Celite, washed with AcOEt, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography using DCM / MeOH / Et3N (100 / 0 / 1 to 94 / 5 / 1) as an eluent to deliver the desired 20 product as a brown oil. The material was repurified by preparative TLC plate DCM / MeOH / Et3N (94:5:1). The synthesis was repeated to deliver altogether 210 mg of A-130 as a brown solid with the HPLC purity ca. 93%. The final compound was obtained after the purification by reverse-phase flash chromatography (H2O / MeCN) to deliver A-130 as a light yellow solid (80 mg, 29%).1H NMR (300 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.74 (d, J = 5.8 Hz, 2H), 8.50 – 8.16 (m, 3H), 7.91 (tt, J = 5.6, 2.9 Hz, 4H), 7.38 25 (t, J = 8.8 Hz, 2H). LC-MS (m / z): 290.1 [M+H]+. Synthesis of compound A-131 In a similar fashion to A-130, compound A-131 was prepared using 3-pyridylboronic acid in the last coupling step to deliver the product as white solid (104 mg, 42%).1H NMR (300 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.04 (d, J = 2.4 Hz, 1H), 8.69 (d, J = 5.1 Hz, 2H), 8.58 (dd, J = 4.7, 1.6 Hz, 1H), 8.45 – 8.15 (m, 4H), 30 7.92 (d, J = 10.6 Hz, 2H), 7.51 (dd, J = 8.0, 4.7 Hz, 1H). LC-MS (m / z): 273.1 [M+H]+. Synthesis of compounds A-142·2HCl and A-143 In a similar fashion to A-31, 5-(6-bromopyridin-3-yl)-7-(pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidine was prepared using (E)-1-(6-bromopyridin-3-yl)-3-(pyridin-4-yl)prop-2-en-1-one (593 mg, 30 %).1H- NMR 400 MHz, DMSO-d6 δ (ppm): 9.39 (d, J = 2.4 Hz 1H), 8.95 - 8.90 (m, 2H), 8.82 (s, 1H), 8.71 (dd, J = 35 8.52.4 Hz, 1H), 8.45 (s, 1H), 8.30 - 8.25 (m, 2H), 7.95 (d, J = 8.5 Hz, 1H). ESI-MS (m / z): 353.2 [M+H]+. 106 A mixture of the above prepared bromide (400 mg, 1.13 mmol), tert-butyl carbamate (159 mg, 1.36 mmol), Pd(OAc)2(13 mg, 0.06 mmol), Xantphos (99 mg, 0.17 mmol) and Cs2CO3(738 mg, 2.27 mmol) in dioxane (5 mL) was stirred at 100°C for 1h. EtOAc (30 mL) was added and the mixture washed with water (50 mL), brine (50 mL), dried over Na2SO4and evaporated. The residue was purified by column 5 chromatography (DCM / Acetone) to afford tert-butyl (5-(7-(pyridin-4-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl)pyridin-2-yl)carbamate as a yellow solid (380 mg, 86 %).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 10.27 (s, 1H), 9.29 (d, J = 2.4 Hz 1H), 8.93 – 8.87 (m, 2H), 8.74 (s, 1H), 8.75 – 8.70 (m, 1H), 8.34 (s, 1H), 8.28 - 8.22 (m, 2H), 8.03 (d, J = 8.5 Hz, 1H), 1.51 (s, 9H). ESI (m / z): 390.5 [M+H]+. To an ice-cooled suspension of the above prepared carbamate (380 mg, 0.97 mmol) in MeOH (5 mL), 10 HCl (35% in water, 5 mL, 57.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18h and then evaporated. The residue was suspended in MeOH (5 mL) and the mixture was heated to reflux, cooled to room temperature and solids were filtered to afford A- 142·2HCl as a yellow powder (320 mg, 90 %).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 9.09 (d, J = 2.0 Hz, 1H), 8.98 – 8.02 (m, 2H), 8.82 (dd, J = 2.0, 9.5 Hz,1H), 8.78 (s, 1H), 8.36 (s, 1H), 8.33-8.29 (m, 2H), 7.17 15 (d, J = 9.5 Hz, 1H). ESI (m / z): 290.3 [M+H]+. A mixture of the above prepared 5-(6-bromopyridin-3-yl)-7-(pyridin-4-yl)-[1,2,4]triazolo[1,5- a]pyrimidine (400 mg, 1.13 mmol), acetamide (100 mg, 1.70 mmol), Pd(OAc)2(13 mg, 0.06 mmol), Xantphos (99 mg, 0.17 mmol) and Cs2CO3(738 mg, 2.27 mmol) in dioxane (5 mL) was stirred at 100 °C for 3h. EtOAc (30 mL) was added and the mixture washed with water (50 mL), brine (50 mL), dried over 20 Na2SO4and evaporated. The residue was purified by column chromatography (DCM / acetone). Product containing fractions were combined and evaporated, the residue was suspended in EtOH (5 mL). The mixture was heated to reflux, cooled to room temperature and solids were filtered to afford A-143 as a yellow solid (100 mg, 26 %).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 10.89 (s, 1H), 9.34 (d, J = 2.4 Hz, 1H), 8.96-8.86 (m, 2H), 8.76 (dd, J = 2.4, 8.8 Hz, 1H), 8.75 (s, 1H), 8.36 (s, 1H), 8.32-8.21 (m, 3H), 2.15 25 (s, 3H). ESI (m / z): 332.1 [M+H]+. Synthesis of Compound A-100 To a suspension of A-99 (1.52 g, 4.42 mmol) in ethanol (35 mL) was added 3N NaOH (8 mL) and MeCN (10 mL). The mixture was stirred at room temperature for 1h. The reaction mixture was acidified with 5M HCl to pH 4 and stirred at 0-5 °C (ice bath) for 1h. The precipitate was filtered and crystallized from 30 EtOH / H2O to afford A-100 as a beige solid (1.37 g, 98%).1H NMR (400 MHz, DMSO-d6) δ 13.3-13.2 (br s, 1H), 8.93 – 8.88 (m, 2H), 8.80 (s, 1H), 8.57 – 8.51 (m, 2H), 8.40 (s, 1H), 8.30 – 8.25 (m, 2H), 8.18-8.11 (m, 2H). ESI (m / z): 318.2 [M+H]+. Synthesis of Compound A-101 To a solution of A-100 (250 mg, 0.79 mmol) in DMF (15 mL), a 2M solution of dimethylamine in THF 35 (433 μL, 0.87 mmol), HOBt (128 mg, 0.95 mmol) and EDC·HCl (181 mg, 0.95 mmol) were added. After 107 stirring at room temperature for 22h, the mixture was concentrated in vacuo. Purification of the residue by reverse phase column chromatography (MeCN / water) afforded A-101 as white solid (264 mg, 97%).1H-NMR (400 MHz, DMSO-d6) δ 8.93 – 8.87 (m, 2H), 8.77 (s, 1H), 8.50 – 8.44 (m, 2H), 8.37 (s, 1H), 8.30 – 8.24 (m, 2H), 7.65-7.59 (m, 2H), 3.02 (s, 3H), 2.96 (s, 3H). ESI (m / z): 345.2 [M+H]+. 5 Synthesis of Compound A-102 To a solution of A-100 (250 mg, 0.79 mmol) in DMF (15 mL), N-methylpiperazine (96 μL, 0.87 mmol), HOBt (128 mg, 0.95 mmol), EDC·HCl (181 mg, 0.95 mmol) were added. After stirring at room temperature for 22h, the mixture was evaporated. The residue was purified on reverse phase column chromatography (MeCN / water). Product containing fractions were evaporated and EtOH was added. 10 A-102 precipitated as white solid (103 mg, 33%).1H-NMR (400 MHz, DMSO-d6) δ 8.93 – 8.87 (m, 2H), 8.78 (s, 1H), 8.50 – 8.45 (m, 2H), 8.37 (s, 1H), 8.30 – 8.25 (m, 2H), 7.64-7.58 (m, 2H), 3.73-3.57 (m, 2H), 3.47-3.30 (m, 2H), 2.46-2.25 (m, 4H), 2.21 (s, 3H). ESI (m / z): 400.3 [M+H]+. Synthesis of Compound B-1 A mixture of 7-chloro-5-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (400 mg, 1.69 15 mmol) and morpholine (0.219 mL, 2.54 mmol) in DMF (10 mL) was stirred at 100 °C for 16h. After cooling to room temperature, water (20 mL) and DCM (30 mL) was added. The organic layer was separated, extracted with sat. NaHCO3(20 mL), dried over Na2SO4and evaporated. Purification of the residue by column chromatography (eluent: MeOH / DCM) yielded B-1 as yellowish solid (390 mg, 80%). 1H-NMR spectrum (400 MHz, DMSO) δ 6.79 (s, 1H), 3.88 – 3.75 (m, 8H), 2.53 (s, 3H). ESI-MS (m / z): 20 288.1 [M+H]+. Synthesis of Compound B-31 A mixture of commercially available 7-chloro-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (500 mg, 2.25 mmol), 4-(tributylstannyl)pyridine (993 mg, 2.70 mmol), Pd(PPh3)4(260 mg, 0.23 mmol), CuI (2.57 g, 13.5 mmol) and LiCl (476 mg, 11.2 mmol) in DMSO (5 mL) was stirred at 20 °C for 1 h. Aq. KF 25 solution (3.5 M, 10 mL) was added and the reaction mixture was stirred for 30 min. The mixture was filtered through a celite pad, the pad was washed with MeOH (50 mL) and the combined filtrates were evaporated. Purification of the residue by column chromatography (CHCl3 / acetone) and reversed- phase chromatography (MeCN / water) yielded B-31 as slightly grey powder (80 mg, 12%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 9.02 (s, 1H), 8.97 – 8.88 (m, 2H), 8.29 (s, 1H), 8.25 – 8.16 (m, 2H). ESI-MS 30 (m / z): 266.2 [M+H]+. Synthesis of Compound A-103 A mixture of 7-Chloro-5-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine, prepared according to route 1, (470 mg, 1.89 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1- carboxylate (667 mg, 2.27 mmol) K2CO3(784 mg, 5.67 mmol) and PdCl2(dtbpf) (123 mg, 0.19 mmol) in 35 dioxane (12 mL) and water (4 mL) was stirred at 60 °C for 3 h. Temperature was raised to 70°C and the 108 reaction mixture was stirred for 16 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, the filter cake was washed with EtOAc (50 mL). The water layer was separated from the rest of the filtrate and the organic phase was evaporated. The residue was purified by column chromatography (DCM / acetone, 10:1, 7:1) to provide A-103 as slightly grey solid (130 mg, 5 25%).1H-NMR 400 MHz, DMSO-d6 δ (ppm): 13.74 (s, 1H), 9.20 – 9.07 (m, 1H), 8.90 –80.80 (m, 1H), 8.76 (s, 1H), 8.51 – 8.44 (m, 2H), 8.37 (s, 1H), 7.49 – 7.42 (m, 2H). ESI-MS (m / z): 281.2 [M+H]+. Synthesis of Compound B-32 Similar to the synthesis of A-103, compound B-32 was prepared from 5-chloro-7- methyltriazolo[1,5]pyrimidine.1H-NMR 400 MHz, DMSO-d6 δ (ppm): 13.68 (br s, 1H), 8.97 – 8.68 (m, 10 2H), 8.66 (s, 1H), 7.74 (s, 1H), 2.64 (s, 3H). ESI-MS (m / z): 201.1 [M+H]+. Synthesis of Compound A-121 To а suspension of compound A-104 (230 mg, 0.79 mmol) in MeOH (15 mL), NaOMe (30% in MeOH, 400 µL, 2.00 mmol) was added. Reaction mixture was stirred at reflux. After 30 min, the mixture was filtered through a pad of silica gel. The pad was rinsed with DCM / MeOH 95 / 5, the filtrate was 15 evaporated and the residue was recrystallized from EtOH to afforded A-121 as white solid (232 mg, 97%).1H-NMR (400 MHz, CDCl3) δ 9.03 – 8.99 (m, 1H), 8.97 – 8.89 (m, 2H), 8.58 – 8.52 (m, 2H), 8.07 – 7.99 (m, 2H), 7.66 (s, 1H), 6.96 – 6.91 (m, 1H), 4.05 (s, 3H). ESI (m / z): 305.1 [M+H]+. Synthesis of Compound A-123 A mixture of A-121 (130 mg, 0.43 mmol) and Py·HCl (250 mg, 2.14 mmol) was stirred at 150 °C for 2 h. 20 Na2CO3(10% aqueous, 10 mL) was added, precipitates were filtered, washed with water (20 mL) and then with hot EtOH (50 mL) to afforded A-123 as beige solid (95 mg, 77%).1H-NMR (400 MHz, DMSO) δ 12.38 (s, 1H), 8.92 – 8.85 (m, 2H), 8.71 – 8.64 (m, 2H), 8.43 (dd, J = 9.7, 2.8 Hz, 1H), 8.26 – 8.18 (m, 3H), 6.53 (d, J = 9.7 Hz, 1H). ESI (m / z): 291.1 [M+H]+. Synthesis of Compound A-150 25 A mixture of compound A-149 (1.99 g, 5.63 mmol), Zn(CN)2(397 mg, 3.38 mmol), Pd2(dba)3(258 mg, 0.28 mmol) and dppf (312 mg, 0.56 mmol) in DMF / H2O (99:1, 15 mL) was stirred at 115 °C for 3h. After cooling to room temperature, a mixture of aq. sat. NH4Cl-conc.NH4OH-H2O (4-1-4, 80 mL) was added and the mixture was stirred at 0 °C for 30 min (ice bath). Precipitates were filtered at pH = 9, washed with cold aq. sat. NH4Cl-conc.NH4OH (4:1:4, 60 mL) and cold water (150 mL) until the pH of the filtrate 30 was in the range of 7-8. The solids were purified by column chromatography (DCM / MeOH) and additionally treated with cold EtOH (2x15 mL) to afford the title compound as beige solid (1.28 g, 76%). 1H-NMR (400 MHz, CDCl3) δ 9.01 (dd, J = 2.10.8 Hz, 1H), 8.96-8.94 (m, 2H), 8.90 (dd, J = 8.30.8 Hz, 1H), 8.67 (s, 1H), 8.64 (s, 1H), 8.22 (dd, J = 8.32.1 Hz, 1H), 8.17-8.12 (m, 2H). ESI (m / z): 300.1 [M+H]+. Synthesis of Compound A-148 109 A mixture of 5,7-dichloro-[1,2,4]triazolo[1.5-a]pyridine (2.20 g, 11.7 mmol), PdCl2(dtbpf) (763 mg, 1.17 mmol), 4-pyridinboronic acid (1.58 g, 12.9 mmol) and K2CO3(4.85 g, 35.1 mmol) in dioxane / H2O (9:1, 15mL) was stirred at 100 °C for 3h. The reaction mixture was filtered through a celite pad, the pad was rinsed with EtOAc (20 mL). Then water (10 mL) and EtOAc (20 mL) were added to the filtrate. The 5 organic layer was separated and the aqueous layer was additionally extracted with EtOAc (2 × 15mL). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (EtOAc) to give 7-chloro-5-(pyridin-4-yl)-[1,2,4]triazolo[1,5- a]pyridine as a beige solid (1.80 g, 65%).1H NMR (300 MHz, CDCl3): δ 8.89‒8.87 (m, 2H), 8.42 (s, 1H), 7.92‒7.88 (m, 2H), 7.87 (m, 1H), 7.28‒7.24 (m, overlap with CDCl3, 1H). ESI-MS (m / z): 231.1 [M+H]+. A 10 mixture of the above prepared chloride (850 mg, 3.68 mmol), (Bpin)2(1.22 mg, 4.79 mmol), KOAc (1.09 mg, 11.1 mmol), XPhos (105 mg, 0.22 mmol) and Pd2(dba)3(101 mg, 0.11 mmol) in dry dioxane (3 mL) was stirred at 100 °C for 3h. After cooling to room temperature, a solution of 2-bromo-5- difluoromethoxypyridine (743 mg, 3.32 mmol) in dioxane / H2O (9:1, 15 mL) and K2CO3(1.53 mg, 11.1 mmol) were added and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was 15 filtered through celite and the filtrate was evaporated. The residue was purified by column chromatography using EtOAc to afford A-148 as a white solid (607 mg, 49% for 2 steps).1H-NMR (300 MHz, CDCl3): δ 8.87–8.85 (m, 2H), 8.64–8.63 (m, 1H), 8.45 (s, 1H), 8.33 (d, J= 1.8 Hz, 1H), 8.10 (d, J= 1.8 Hz, 1H), 8.01 – 7.99 (m, 2H), 7.97 – 7.94 (m, 1H), 7.69 – 7.65 (m, 1H), 6.64 (t, J= 72.3 Hz, 1H). ESI-MS (m / z): 340.20 [M+H]+. 20 Synthesis of Compound A-159 A solution of B-9 (1.20 g, 5.68 mmol) in DMF-DMA (9 mL) was stirred at reflux for 3 hours. After cooling to room temperature, MTBE (20 mL) was added. Precipitates were filtered and washed with MTBE (50 mL) to afford N,N-dimethyl-2-(7-(pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)ethen-1-amine (1.31 g, 87%) as yellow solid.1H NMR (300 MHz, DMSO) δ 8.89 – 8.73 (m, 2H), 8.30 (s, 1H), 8.10 – 8.03 (m, 25 2H), 8.00 (d, J = 12.9 Hz, 1H), 7.33 (s, 1H), 5.29 (d, J = 12.9 Hz, 1H), 3.02 (s, 6H). LC-MS (m / z): 267.2 [M+H]+. A suspension of the enamine prepared above (1.30 g, 4.92 mmol), KMnO4(1.55 g, 9.84 mmol) and K2CO3(1.36 g, 9.84 mmol) in water / t-BuOH (1:1, v / v, 20 mL) was stirred for 5 hours at room temperature. The reaction mixture was filtered, the filtrate was evaporated and the residue was 30 purified by reverse phase chromatography (MeCN / water) to afford A-159 (985 mg, 83%) as white solid. 1H-NMR spectrum (400 MHz, DMSO) δ 9.10 – 8.99 (m, 2H), 8.97 (s, 1H), 8.49 – 8.41 (m, 2H), 8.23 (s, 1H). LC-MS (m / z): 242.1 [M+H]+. Synthesis of Compound A-172 A suspension of A-159 (400 mg, 1.66 mmol), p-toluenesulfonic acid (29 mg, 0.17 mmol) in 35 ethylenediamine (1.10 mL, 16.60 mmol) and ethylene glycol (5 mL) was stirred at 190 °C for 4 hours. 110 Ethylene glycol and other volatiles were evaporated and the residue was transferred to a C18 silica gel plug. The C18 plug was eluted with (MeCN / water, 3:2). Evaporation of product containing fractions afforded a mixture (100 mg) of 5-(4,5-dihydro-1H-imidazol-2-yl)-7-(pyridin-4-yl)-[1,2,4]triazolo[1,5- a]pyrimidine and A-172. It was dissolved in DMF (3 mL), MnO2(328 mg, 3.77 mmol) was added and 5 the reaction mixture was stirred at room temperature for 18h and then evaporated. The residue was purified by reverse phase chromatography (MeCN / water) to afford A-172 (35 mg, 8%) as slightly yellow solid. NMR (300 MHz, DMSO) δ 13.61 (s, 1H), 8.97 – 8.82 (m, 2H), 8.73 (s, 1H), 8.25 – 8.09 (m, 3H), 7.55 – 7.41 (m, 1H), 7.29 (s, 1H). LC-MS (m / z): 264.0 [M+H]+. Synthesis of Compound A-164 10 A mixture of A-114 (200 mg, 0.76 mmol), sodium chlorodifluoroacetate (240 mg, 1.57 mmol) and Cs2CO3(1.0 g, 3.1 mmol) in DMF (5 mL) was stirred at 90 °C for 16h. After cooling to room temperature, the reaction mixture was evaporated. Aq. HCl (3M, 2 mL) was added to the residue and the mixture was stirred at room temperature for 2h. The pH was adjusted to 9 by 1M NaOH and the mixture was extracted with EtOAc (2x20 mL). EtOAc extracts were combined, washed with brine (20 ml), dried over 15 Na2SO4and evaporated. Purification by column chromatography (EtOAc / MeOH) afforded A-164 as slightly brown amorphous solid. (88 mg, 37%).1H NMR (400 MHz, DMSO) δ 9.32-9.30 (1H, m), 8.95- 8.90 (2H, m), 8.73 (1H, s), 8.68-8.66 (1H, m), 8.25-8.21 (3H, m), 7.90 (t, 1H, J=59.0 Hz). ESI-MS (m / z): 314.1 [M+H]+. Synthesis of Compound B-6 20 To solution of B-5 (500 mg, 2.29 mmol) in DCM (3 mL), AcOH (1.30 mL, 22.9 mmol) and formaldehyde (37% in water, 1.20 mL, 16.0 mmol) was added. The mixture was stirred at room temperature for 1 h. NaBH(OAc)3(1.46 g, 6.87 mmol) was added and the mixture was stirred for 16h, and then evaporated. The residue was purified by reverse phase chromatography (MeOH / 0.1M HCl aq. solution) to afford B- 6 as slightly yellow solid (220 mg, 41%).1H-NMR (400 MHz, CDCl3) δ: 8.30 (s, 1H), 6.15 (s, 1H), 3.89 – 25 3.77 (m, 4H), 2.69 – 2.62 (m, 4H), 2.58 (s, 3H), 2.38 (s, 3H). LC-MS (m / z): 233.2 [M+H]+. Synthesis of Compound B-8·HCl Similar to the synthesis of B-6, compound B-8 was prepared from B-7 (275 mg, 65%).1H-NMR 400 MHz, DMSO-d6δ (ppm): δ 10.94 (s, 1H), 8.63 (s, 1H), 7.18 (s, 1H), 3.69 – 3.57 (m, 1H), 3.58 – 3.38 (m, 2H), 3.28 – 3.12 (m, 2H), 2.77 (d, J = 4.5 Hz, 3H), 2.65 (s, 3H), 2.36 – 2.26 (m, 2H), 2.19 – 2.04 (m, 2H). ESI- 30 MS (m / z): 232 [M+H]+. BIOLOGICAL ACTIVITY Results The effect of the compounds on the food intake reduction versus vehicle in diet-induced obese mice 35 over 2h (0 = <20%, + = 20-40%, ++ = 40-60%, +++ = >60%) and 24h (0 = <5%, + = 5-20%, ++ = 20-40%, 111 +++ = >40%) after oral application as suspension or solution formulation is provided in Tables A and B. This animal model is recognized as being a predictive model for obesity and food intake in human as illustrated for instance by Kleinert et al (Nat Rev Endocrinol. 2018 Mar;14(3):140-162). Accordingly, the utility of the compounds of the present invention as appetite suppressant is well shown. 5 Table A 112 Table B 5 Furthermore, upon daily oral dosing of compounds as suspension or solution formulations for five consecutive days, diet-induced obese mice show a reduction in food intake leading to a significant body weight loss compared to vehicle-treated mice as a further demonstration of the usefulness of these compounds in the improvement of the metabolic syndrome. The percentage of body weight loss compared to starting body weight against vehicle is given in Table C. 10 Table C Materials and Methods Mice 15 Four-month-old male C57BL / 6J mice (Charles River, Sulzfeld, Germany) were individually housed in wire- mesh hanging cages or in standard mice cages at room temperature (21° ± 1°C) and at an artificial 12-hour 113 light / 12-hour dark cycle. Animals were able to see, hear, and smell their conspecifics in neighboring cages and were not socially isolated. Water, food (60% high-fat diet, Ssniff Spezialdiäten GmbH, Germany), and bedding were provided ad libitum, if not indicated differently. All procedures for mice handling and experimental interventions were according to Swiss Animal Welfare laws, approved by the “Kantonales 5 Veterinäramt Zürich,” and conform to the principles of EU regulations. Animals were adapted to novel housing situations and feeding schedules as well as oral treatment with vehicle at least for 1 week. Mice comp Individual compounds were applied orally by gavage in a daily dose of between 3 and 50 mg / kg in a vehicle suitable for oral administration as suspensions or solutions (Gad & Cassidy et al., Interntaional Journal of 10 Toxicology, 2006, 25, 499) known by a person skilled in the art. A minimum of n≥8 animals were dosed per group. Mice feeding behavior Ad libitum fed or 16-hour-fasted mice received the candidate compounds by oral gavage within 60 min before dark onset. Food was made available at dark onset to the 16-hour-fasted mice. Food intake was 15 measured continuously in undisturbed mice using an automated system (BioDAQ, Research Diets, NJ, USA). This system measures food hopper weight (±0.01 g) at 1-Hz resolution. The microstructure of feeding was analyzed using proprietary software (BioDAQ Monitoring Software) as follows: Absolute food hopper weight changes smaller than 0.02 g within a 5-s time interval were counted as food-seeking bouts. Absolute food hopper weight changes of 0.02 g or larger represent a meal and were summed into a single 20 meal based on a 10-min intermeal interval. Food intake reduction in % compared to vehicle after 24h in mice is calculated as following: 100-(mean(veh)-mean(cpd)) / mean(veh)*100. Body weight reduction in % compared to vehicle is calculated as follows: Mean of ((individual body weight of vehicle treated animal on day 5) / (individual body weight of vehicle 25 treated animal on day 0)*100) minus mean of ((individual body weight of compound treated animal on day 5) / (individual body weight of compound treated animal on day 0)*100). Comparative compounds A-160 and A-165 as described below are tested as comparative examples 30 Remarks: in the specification, if there is an inconsistency between a chemical structure and the associated name, the structure prevails

Claims

1. 114 CLAIMS 1. A compound of the following general formula (I): 5 or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, wherein the dotted line represents the presence or absence of a bond; W represents -CH-, -N- or -NH-; V represents -N-, -CH- or -C(R2)-, with R2being a (C1-C6)alkyl, 10 each X, Y and Z represents, independently of each other, -CH-, -NH- or -N-; provided that at least two of X, Y and Z represents -N- or -NH-; R5is a moiety selected in the group constituted of cyclohexyl, piperazinyl, morpholinyl, 3-pyridinyl, 4- pyridinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, quinuclidinyl, imidazolyl, and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted 15 with at least one, such as one or two, halo, hydroxy (OH), -NRR’, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; or R5is selected from the list constituted of an unsubstituted 2-pyridinyl; unsubstituted 2- or 3-pyrazolyl; a 1- piperidinyl optionally substituted with at least one, preferably one or two, oxo, OH, Me or N(CH3)2; or 1- pyrrolidinyl unsubstituted or substituted with at least NRARB; R and R’ are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; 20 RAand RBare, independently of each other, an hydrogen atom or a (C1-C3)alkyl provided that RAand RBare not both hydrogen atom; R6is an hydrogen atom or a (C1-C6)alkyl, preferably an hydrogen atom or a methyl; R7is a moiety selected in the group consisting of (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C6-C12)aryl and (C5-C14)heteroaryl; said group being optionally substituted with at least one, such as one or two, -OR8, 25 halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12; R8is a (C1-C6)alkyl group optionally substituted with one, two or three halo or a phenyl, preferably two fluorine; R9is a (C1-C6)alkoxy or (C1-C6)alkyl; and R10is a H or (C1-C6)alkyl; 115 R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle; provided that R7is not an unsubstituted phenyl; provided that when R5is 1-piperidinyl, R7is not a 1-piperidinyl; 5 provided that when R5is 1-morpholinyl, R7is not a 1-morpholinyl; and provided that said compound is not a compound of following formula (A37), (C1), (C2), or (C3): 10 2. The compound of claim 1, wherein V is -CH- and / or X, Y and Z represent -N-.

3. The compound of claim 1 or 2, wherein said compound is of the following formula (Ia) to (If), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof: 15 wherein 116 the dotted line represents the presence or absence of a bond, preferably the absence of a bond; and V, R5, R6and R7are as defined in claim 1 or 2.

4. The compound of claim 1 or 2, wherein said compound is of the following formula (Ia) or (Ib), 5 preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof: wherein the dotted line represents the presence or absence of a bond, preferably the absence of a bond; and V, R5, R6and R7are as defined in claim 1 or 2. 10 5. The compound of claim 4, wherein V is -CH.

6. The compound of any one of claims 1 to 5, wherein R7is a moiety selected in the group consisting of a (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C6-C12)aryl and (C5-C10)heteroaryl; said group being 15 optionally substituted with at least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10, or -C(O)NR11R12; R8to R12being as defined in claim 1; provided that R7is not an unsubstituted phenyl.

7. The compound of any one of claims 1 to 6, wherein R7is a moiety selected in the group consisting 20 of a pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; said moiety being optionally substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, - NHC(O)R9, -C(O)OR10or -C(O)NR11R12; or R7is a phenyl substituted with at least one group selected from -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, -NHC(O)R9, -C(O)OR10or - C(O)NR11R12; R8to R12being as defined in claim 1. 25 8. The compound of any one of claims 1 to 7, wherein R5is a moiety selected in the group constituted of: 117 wherein 5 R13and R14are, independently of each other, an hydrogen atom, halo preferably fluorine or bromine, - NH2, -CN, (C1-C6)alkyl or (C1-C6)alkoxy; R15is an hydrogen atom or a (C1-C3)alkyl; one of R16and R17is -C(O) and the other is an hydrogen atom; R18and R19are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or 10 a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R20and R21are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl;; R22is an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1- C3)alkyl; 15 R23is an hydrogen atom or a (C1-C3)alkyl .

9. The compound of any one of claims 1 to 8, wherein R5is a moiety selected in the group constituted 20 118 wherein R13and R14are, independently of each other, an hydrogen atom or (C1-C6)alkyl; and R20and R21are, independently of each other, an hydrogen atom or halo, preferably hydrogen atom; R22is an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1- 5 C3)alkyl.

10. The compound of claim 1, wherein V is -CH-; X, Y and Z represents -N-; R6is a hydrogen atom; R5is as defined in claim 9; and R7is as defined in claim 1. 10 11. The compound of claim 1, wherein V is -CH-; X, Y and Z represents -N-; R6is a hydrogen atom; R5is a moiety of formula (IX) as defined in claim 9; and R7is as defined in claim 1.

12. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, selected in the group consisting of: 119 120 121 H2N N NFF FH2 122 123 124 125 12613. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for use as a drug.127 14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for use as appetite suppressant, in particular for the treatment of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet- 5 Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication- induced weight gain.

15. A compound of the following general formula (I):10 or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for use as appetite suppressant, in particular for the treatment of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain, 15 wherein the dotted line represents the presence or absence of a bond; W represents -CH-, -N- or -NH-; V represents -N-, -CH- or -C(R2)-, with R2being a (C1-C6)alkyl, CF3, or the moietyeach X, Y and Z represents, independently of each other, -CH-, -NH- or -N-; provided that at least two of 20 X, Y and Z represents -N- or -NH-; R5is a moiety selected in the group constituted of cyclohexyl, phenyl, piperazinyl, morpholinyl, pyridinyl, piperidinyl, pyrrolidinyl, hydroxypyridinyl, oxopiperazinyl, oxopiperidinyl, quinuclidinyl, imidazolyl, and 3,6- or 2,5-diazobycycloheptanyl; said moiety being optionally substituted with at least a halo, hydroxy (OH), -NRR’, CN, (C1-C6)alkyl or (C1-C6)alkoxy; 25 R and R’ are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; R6is an hydrogen atom or a (C1-C6)alkyl, preferably an hydrogen atom or a methyl; and R7is CF3; or a moiety selected in the group consisting of (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3- C8)heterocycloalkyl, (C6-C12)aryl and (C5-C14)heteroaryl; said group being optionally substituted with at least one, such as one or two, -OR8, halogen preferably chlorine or fluorine, CN, CF3, (C1-C6)alkyl, -NH2, - 30 NHC(O)R9, -C(O)OR10, or -C(O)NR11R12;128 R8is a (C1-C6)alkyl group optionally substituted with one, two or three halo or a phenyl, preferably two fluorine; R9is a (C1-C6)alkoxy or (C1-C6)alkyl; R10is a H or (C1-C6)alkyl; 5 R11and R12are, independently of each other, an hydrogen atom or a (C1-C6)alkyl; or R11and R12together with the carbon atom to which they are bound, form a cycloalkyl or an heterocycle.

16. The compound for use according to claim 15, wherein V is -CH- or -C(R2)-; R2being as defined in claim 15; and / or X, Y and Z represents -N-. 10 17. The compound for use according to claim 15 or 16, wherein said compound is of the following formula (Ia) to (If), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof:15 wherein the dotted line represents the presence or absence of a bond, preferably the absence of a bond; and V, R5, R6and R7are as defined in claim 15 or 16.

18. The compound of claim 17, wherein V is -CH. 20 19. The compound for use according to claim 15 or 16, wherein said compound is of the following formula (Ia) or (Ib), preferably (Ia), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof:25 wherein129 the dotted line represents the presence or absence of a bond, preferably the absence of a bond; and V, R5, R6and R7are as defined in claim 15 or 16.

20. The compound for use according to any one of claims 15 to 19, wherein R5is a moiety selected in 5 the group constituted of 10130 wherein R13and R14are, independently of each other, an hydrogen atom, halo preferably fluorine or bromine, NH2, CN, (C1-C6)alkyl or (C1-C6)alkoxy; R15is an hydrogen atom or a (C1-C3)alkyl; 5 one of R16and R17is C(O) and the other is an hydrogen atom; R18and R19are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R20and R21are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; 10 R22and R22’ are, independently of each other, an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R23is an hydrogen atom or a (C1-C3)alkyl; R23’ is -C(O)R24or a phenyl optionally substituted with halo preferably fluorine or chlorine, (C1-C6)alkyl or (C1-C6)alkoxy; and 15 R24is (C1-C6)alkyl or a phenyl; R25and R26are, independently of each other, an hydrogen atom or a (C1-C3)alkyl.

21. The compound for use according to any one of claims 15 to 20, wherein R5is a moiety selected in the group constituted of: 20wherein R13and R14are, independently of each other, an hydrogen atom or (C1-C6)alkyl; R18and R19are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or 25 a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl;131 R20and R21are, independently of each other, an hydrogen atom, halo, hydroxy, oxo, -NRR’, (C1-C6)alkyl, or a phenyl substituted with a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; R22and R22’ are, independently of each other, an hydrogen atom, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1-C3)alkyl; and 5 R23is an hydrogen atom or a (C1-C3)alkyl; R23’ is -C(O)R24or a phenyl optionally substituted with halo preferably fluorine or chlorine, (C1-C6)alkyl or (C1-C6)alkoxy; and R24is (C1-C6)alkyl or a phenyl. 10 22. The compound for use according to any one of claims 15 to 21, wherein R5is a moiety selected in the group constituted of:R13and R14are, independently of each other, an hydrogen atom or (C1-C6)alkyl; 15 R20and R21are, independently of each other, an hydrogen atom or halo, preferably hydrogen atom; R22is an hydrogen atom, halo, -NRR’, (C1-C3)alkyl, or a methoxy; R and R’ being an hydrogen atom or a (C1- C3)alkyl.

23. The compound for use according to claim 15, wherein V is -CH-; X, Y and Z represents -N-; R6is a 20 hydrogen atom; R5is as defined in claim 22; and R7is as defined in claim 15.

24. The compound for use according to claim 15, wherein V is -CH-; X, Y and Z represents -N-; R6is a hydrogen atom; R5is a moiety of formula (IX) as defined in claim 22; and R7is as defined in claim 15. 25 25. The compound for use according to claim 15, or a pharmaceutically acceptable salt, stereoisomer, selected in the group consisting of:132(A-41-rac) (A-41-ent-I) (A-41-ent-II)133134135 O N F FHF136137138139140141 N NH2H2NCl14214326. A method for treating a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, 5 cardiovascular diseases, and medication-induced weight gain, comprising administering to a subject in need thereof a therapeutically effective amount of the compound as defined in any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof as appetite suppressant.

27. Use of a compound as defined in any one of claims 1 to 12, or a pharmaceutically acceptable salt, 10 stereoisomer, tautomer or solvate thereof, for the manufacture of a medicine, in particular an appetite suppressant, for treating a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain. 15 28. A method for treating a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain, comprising administering to a subject in 20 need thereof a therapeutically effective amount of the compound as defined in any one of claims 15 to 25, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof as appetite suppressant.

29. Use of a compound as defined in any one of claims 15 to 25, or a pharmaceutically acceptable 25 salt, stereoisomer, tautomer or solvate thereof, for the manufacture of a medicine, in particular an appetite suppressant, for treating a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain. 30

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