N-PYRIDIN-3-YL OR N-PYRAZIN-2-YL CARBOXAMIDES

FIELD OF THE INVENTION

The present invention is concerned with N-pyridin-3-yl or N-pyrazin-2-yl carboxamide compounds being HDL-cholesterol raising agents, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances.

In particular, the invention relates to compounds of formula I

wherein A, R 1 to R 7 are as described below, and its isomeric forms and its pharmaceutically acceptable salts.

The compounds of the invention are HDL-cholesterol raising agents and can therefore be used in the therapeutic and/or prophylactic treatment of diseases and disorders such as dyslipidemia, atherosclerosis and cardiovascular diseases.

Atherosclerosis and its associated coronary heart disease is the leading cause of death in the industrialized world. Risk for development of coronary heart disease has been shown to be strongly correlated with certain plasma lipid levels. Lipids are transported in the blood by lipoproteins. The general structure of lipoproteins is a core of neutral lipids (triglyceride and cholesterol ester) and an envelope of polar lipids (phospholipids and non-esterified cholesterol). There are 3 different classes of plasma lipoproteins with different core lipid content: the low density lipoprotein (LDL) which is cholesteryl ester (CE) rich; high density lipoprotein (HDL) which is also cholesteryl ester (CE) rich; and the very low density lipoprotein (VLDL) which is triglyceride (TG) rich. The different lipoproteins can be separated based on their different flotation density or size. High LDL-cholesterol (LDL-C) and triglyceride levels are positively correlated, while high levels of HDL-cholesterol (HDL-C) are negatively correlated with the risk for developing cardiovascular diseases.

No wholly satisfactory HDL-elevating therapies exist. Niacin can significantly increase HDL, but has serious toleration issues which reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL-cholesterol only modestly (-10-12%). As a result, there is a significant unmet medical need for a well tolerated agent which can significantly elevate plasma HDL levels.

Thus, HDL-cholesterol raising agents can be useful as medicaments for the treatment and/or prophylaxis of atherosclerosis, peripheral vascular disease, dyslipidemia,

hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia,

hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia. In addition, HDL-cholesterol raising agents may be used in combination with another compound, said compound being an HMG-CoA reductase inhibitor, an microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor, a PPAR activator, a bile acid reuptake inhibitor, a cholesteryl ester transfer protein (CETP) inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, preparations containing niacin or other HM74a agonists, an ion-exchange resin, an antioxidant, an AC AT inhibitor or a bile acid sequestrant.

Object of the present invention is therefore to provide compounds that are potent HDL- cholesterol raising agents. It has been found that the compounds of formula I of the present invention are very useful for the treatment and/or prophylaxis of diseases and disorders which can be treated with HDL-cholesterol raising agents, i.e. the compounds of formula I are especially useful for the treatment and/or prevention of dyslipidemia, atherosclerosis and cardiovascular diseases. Object of the present invention is also to provide compounds which are, at therapeutically active concentrations that increase HDL-concentrations, not interacting with the CB 1 receptor. This is because CB 1 receptor ligands may compromise the therapeutic utility of HDL-cholesterol raising agents, as both agonists and antagonists of the CB l receptor have the potential to lead to side effects.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein. In this specification the term "lower" is used to mean a group consisting of one to seven, particularly of one to four carbon atom(s).

The term "alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, particularly one to sixteen carbon atoms, more particularly one to ten carbon atoms.

The term "lower alkyl" or "Ci_7-alkyl", alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 7 carbon atoms, in particular a straight or branched- chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight-chain and branched Ci_ ₇ alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyls and the isomeric heptyls, in particular ethyl, propyl, isopropyl and tert-butyl.

The term "lower alkoxy" or "Ci_ ₇ -alkoxy" refers to the group R'-O-, wherein R' is lower alkyl and the term "lower alkyl" has the previously given significance. Examples of lower alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy, in particular methoxy.

The term "lower alkoxyalkyl" or "Ci_ ₇ -alkoxy-Ci_ ₇ -alkyl" refers to a lower alkyl group as defined above which is mono- or multiply substituted with a lower alkoxy group as defined above. Examples of lower alkoxyalkyl groups are e.g. -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -O-CH ₃ ,

-CH ₂ -O-CH ₂ -CH ₃ and the groups specifically exemplified herein. More particularly, lower alkoxyalkyl is methoxyethyl.

The term "lower hydroxyalkyl" or "hydroxy-Ci_ ₇ -alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a hydroxy group. Of particular interest are C ₃ _ ₇ -hydroxyalkyl groups. Examples of lower hydroxyalkyl groups are 2-hydroxybutyl, 3-hydroxy-2,2-dimethylpropyl and the groups specifically exemplified therein.

The term "lower hydroxyimino-alkyl" or "hydroxyimino-Ci_ ₇ -alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a hydroxyimino group (=N-OH). Of particular interest is the 1-hydroxyiminoethyl group -C(=N-OH)-CH ₃ . The term "lower alkoxyimino-alkyl" or "Ci_ ₇ -alkoxyimino-Ci_ ₇ -alkyl" refers to a lower alkyl group as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a lower alkoxyimino group (=N-OR, R = lower alkyl). Examples of lower alkoxyimino-alkyl groups are 1-methoxyiminoethyl or 1-ethoxyiminoethyl. More particularly, lower alkoxyimino-alkyl is 1-methoxyiminoethyl (-C(=N-OCH ₃ )-CH ₃ ).The term "cycloalkyl" or "C ₃ _7-cycloalkyl" denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, more particularly cyclopropyl. The term "lower cycloalkylalkyl" or "C ₃ _7-cycloalkyl-Ci_7-alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a cycloalkyl group. Among the lower cycloalkylalkyl groups of particular interest resides cyclopropylmethyl.

The term "halogen" refers to fluoro, chloro, bromo and iodo, with fluoro, chloro and bromo being of particular interest. More particularly, halogen refers to fluoro and chloro.

The term "lower halogenalkyl" or "halogen-Ci_7-alkyl" refers to lower alkyl groups which are mono- or multiply substituted with halogen, preferably with fluoro or chloro, most preferably with fluoro. Examples of lower halogenalkyl groups are e.g. -CF ₃ , -CHF ₂ , -CH ₂ C1, -CH ₂ CF ₃ , -CH(CF ₃ ) ₂ , -CF ₂ -CF _3, -CH ₂ -CH ₂ -CF ₃ , -CH(CH ₃ )-CF ₃ and the groups specifically exemplified herein. Of particular interest are the groups trifluoromethyl (-CF ₃ ), 2,2,2-trifluoroethyl

(-CH ₂ CF ₃ ), and l,l,l-trifluoro-propan-2-yl (-CH(CH ₃ )-CF ₃ ).

The term "lower halogenalkoxy or "halogen-Ci_7-alkoxy" refers to lower alkoxy groups which are mono- or multiply substituted with halogen, preferably with fluoro or chloro, most preferably with fluoro. Examples of lower halogenalkyl groups are e.g. -OCF ₃ , -OCHF ₂ , -OCH ₂ Cl, -OCH ₂ CF ₃ , -OCH(CF ₃ ) ₂ , -OCF ₂ -CF ₃ and -OCH(CH ₃ )-CF ₃

The term "cyano" means to group -CN.

The term "amino" refers to the group -NH ₂ .

The term "azido" means the group -N=N ⁺ =N ^" .

The term "carbamoyl" or "aminocarbonyl" refers to the group -CO-NH ₂ . The term "lower carbamoylalkyl" or "carbamoyl-Ci_7-alkyl" refers to lower alkyl groups as defined above wherein one of the hydrogen atoms of the lower alkyl group is replaced by a carbamoyl group. Examples of lower carbamoylalkyl groups are 3-carbamoylpropyl, 4- carbamoylbutyl and 5-carbamoylpentyl, more particularly 4-carbamoylbutyl.

The term "lower alkylcarbonyl" refers to the group -CO-R", wherein R" is lower alkyl as defined herein before. "Lower alkylcarbonylamino" refers to the group -NH-CO-R", wherein R" is lower alkyl as defined herein before. The term "lower alkylcarbonylaminoalkyl" or "Ci_7-alkylcarbonylamino-Ci_7-alkyl" refers to lower alkyl groups as defined above wherein one of the hydrogen atoms of the lower alkyl group is replaced by a lower alkylcarbonylamino group. An example for a lower

alkylcarbonylaminoalkyl group is ethylcarbonylaminoethyl. The term "lower alkylaminocarbonyl" or "Ci_7-alkylaminocarbonyl" refers to the group

-CO-NH-R wherein R is a lower alkyl group as defined above. An example for a lower alkylaminocarbonyl group is methylaminocarbonyl.

The term "lower phenylalkyl" or "phenyl-Ci_7-alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a phenyl group. In particular, lower phenylalkyl means benzyl.

The term "heterocyclyl" refers to a saturated or partly unsaturated 3-, 4-, 5-, 6- or 7- membered ring which can comprise one, two or three heteroatoms selected from N, O and S. Examples of heterocyclyl rings include piperidinyl, piperazinyl, azetidinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, oxiranyl, thiadiazolylidinyl, oxetanyl, dioxolanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, and thiomorpholinyl. Of particular interest is the tetrahydrofuranyl group.

The term "lower heterocyclylalkyl" or "heterocyclyl-Ci_7-alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a heterocyclyl group as defined above.

The term "heteroaryl" refers to an aromatic 5- or 6-membered ring which can comprise one, two or three atoms selected from N, O and S. Examples of heteroaryl groups are e.g.

furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, oxatriazolyl, tetrazolyl, pentazolyl, or pyrrolyl. The term "heteroaryl" also includes bicyclic groups comprising two 5- or 6-membered rings, in which one or both rings are aromatic and can contain one, two or three atoms selected from nitrogen, oxygen or sulphur, such as quinolinyl, isoquinolinyl, cinnolinyl, pyrazolo[l,5-a]pyridyl, imidazo[l,2-a]pyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, and 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazinyl. The heteroaryl group can optionally be mono- or disubstituted by lower alkyl, hydroxy, cyano or halogen. Heteroaryl groups of particular interest are furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, [1,2,3] thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl.

The term "lower heteroarylalkyl" or "heteroaryl-Ci_7-alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a heteroaryl group as defined above.

"Isomeric forms" are all forms of a compound characterized by having an identical molecular formula but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Preferably, the isomeric forms differ in the arrangement of their atoms in space and can also be termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereoisomers", and stereoisomers that are non- superimpo sable mirror images are termed "enantiomers", or sometimes optical isomers. A carbon atom bonded to four non-identical substituents is termed a "chiral center". The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, and which do not possess any own properties that are undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,

methanesulfonic acid, ethanesulfonic acid, /?-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. Thus, preferred "pharmaceutically acceptable salts" include the acetate, bromide, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate and tosylate salt of compounds of formula I. In addition, pharmaceutically acceptable salts may be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethylamine, lysine, arginine, N-ethylpiperidine, piperidine, piperazine and the like. The compound of formula I can also be present in the form of zwitterions or in the form of hydrates. Particularly preferred pharmaceutically acceptable salts of compounds of formula I are the hydrochloride salts. The present invention relates to compounds of the formula

wherein

A is selected from CH or N;

R ¹ is selected from the group consisting of lower alkyl,

cycloalkyl,

lower cycloalkylalkyl,

lower hydroxyalkyl,

lower alkoxyalkyl,

lower halogenalkyl,

lower carbamoylalkyl,

lower alkylcarbonylaminoalkyl,

lower phenylalkyl,

lower heterocyclylalkyl wherein the heterocyclyl group is unsubstituted or substituted by oxo,

lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di- substituted by lower alkyl, and

phenyl which is unsubstituted or mono- or di-substituted by halogen; R ² and R ⁶ independently from each other are hydrogen or halogen;

R 3 and R 5 independently from each other are selected from the group consisting of

hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;

R ⁴ is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy, amino, azido and cyano; R ⁷ is selected from the group consisting of lower alkyl,

lower hydroxyalkyl, lower alkoxyalkyl, lower hydroxyimino-alkyl, lower alkoxyimino-alkyl,

lower cycloalkyl, said cycloalkyl being unsubstituted or substituted by hydroxy, lower heterocyclyl,

phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower

alkylaminocarbonyl and halogen,

heteroaryl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower

alkylaminocarbonyl and halogen; and pharmaceutically acceptable salts thereof.

Compounds of formula I of the present invention are those, wherein R is selected from the group consisting of lower alkyl, cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lower carbamoylalkyl, lower alkylcarbonylaminoalkyl, lower phenylalkyl, lower heterocyclylalkyl wherein the heterocyclyl group is unsubstituted or substituted by oxo, or lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di-substituted by lower alkyl.

The invention relates in particular to compounds of formula I, wherein R ¹ is selected from cycloalkyl, lower cycloalkylalkyl, lower alkoxyalkyl and lower halogenalkyl. More particularly, R ¹ is selected from cyclobutyl, cyclopropylmethyl, 2-methoxyethyl and lower halogenalkyl. Even more particularly, R ¹ is cyclopropylmethyl or lower halogenalkyl. Most particularly, R ¹ is 2,2,2-trifluoroethyl or l,l,l-trifluoro-propan-2-yl, with R ¹ being 2,2,2-trifluoroethyl being of most interest.

Compounds of formula I of the invention are those, wherein R ² and R ⁶ are independently from each other hydrogen or halogen. Compounds of formula I, wherein R ² and R ⁶ are hydrogen, are of particular interest.

The invention further relates to compounds of formula I, wherein R 3 and R 5 are

independently from each other selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano. In particular, the invention relates to compounds of formula I, wherein R 3 and R 5 are selected from hydrogen, halogen and lower alkyl, more particularly hydrogen, fluoro, chloro and methyl.

Furthermore, the invention is concerned with compounds of formula I, wherein R ⁴ is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy, amino, azido and cyano. More particularly, R ⁴ is lower alkyl or halogen. Most particularly, R ⁴ is halogen, more specifically chloro.

Compounds of formula I of the invention are further those, wherein R ⁷ is selected from the group consisting of lower alkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

lower hydroxyimino-alkyl, lower alkoxyimino-alkyl,

lower cycloalkyl, said cycloalkyl being unsubstituted or substituted by hydroxy,

lower heterocyclyl,

phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen, and

heteroaryl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen. One group of compounds of formula I of the invention are those, wherein R is lower alkyl, in particular methyl, propyl or butyl.

Another group of compounds of formula I of the present invention are those, wherein R is phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen, or heteroaryl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen.

Of particular interest are compounds of formula I according to the invention, wherein R is heteroaryl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen. In particular, the invention relates to compounds of formula I, wherein R is heteroaryl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, cyano, lower alkylaminocarbonyl and halogen. More particularly, the invention relates to compounds of formula I wherein R is heteroaryl selected from the group consisting of furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, [l,2,3]thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and 3,4-dihydro- 2H-pyrido[3,2-b][l,4]oxazinyl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen. Even more particularly, R is heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyridazinyl and pyrimidinyl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen. Most particularly, R is pyridyl, said pyridyl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen.

In particular, the invention relates to compounds of formula I, wherein R is selected from the group consisting of furan-2-yl, 5-methyl-furan-2-yl, furan-3-yl, 5-methyl-oxazol-4-yl, 2,4- dimethyl-oxazol-5-yl, isoxazol-5-yl, 3-methyl-isoxazol-4-yl, 3,5-dimethyl-isoxazol-4-yl, 5- methyl-isoxazol-3-yl, iH-pyrazol-3-yl, l-methyl-iH-pyrazol-3-yl, l,3-dimethyl-iH-pyrazol-4- yl, 2-methyl-2H-pyrazol-3-yl, 5-methyl-2H-pyrazol-3-yl, 2,5-dimethyl-2H-pyrazol-3-yl, thiazol-

2- yl, 5-methyl-thiazol-2-yl, isothiazol-5-yl, 4-methyl-[l,2,3]thiadiazol-5-yl, pyridin-2-yl, 3- methylpyridin-2-yl, pyridin-3-yl, 2,4-difluoro-pyridin-3-yl, 2-methyl-pyridin-3-yl, 5-methyl- pyridin-3-yl, 6-methyl-pyridin-3-yl, 5-cyano-pyridin-3-yl, 5-bromo-pyridin-3-yl, 5-iodo-pyridin-

3- yl, 5-methoxy-pyridin-3-yl, pyridin-4-yl, 2-methyl-pyridin-4-yl, 3-methyl-pyridin-4-yl, 2- hydroxy-pyridin-4-yl, 5-hydroxy-pyridin-2-yl, pyrazin-2-yl, pyridazin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl and 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl. More particularly, R is selected from pyridin-3-yl, 3-methyl-isoxazol-4-yl, pyridazin-3-yl, 1,3-dimethyl-iH- pyrazol-4-yl and 5-methyl-oxazol-4-yl. Most particularly, R is pyridin-3-yl.

In particular, the invention relates to compounds of formula I, wherein A is CH. These the pyridine derivatives of the formula

wherein

R ¹ is selected from the group consisting of lower alkyl,

cycloalkyl,

lower cycloalkylalkyl,

lower hydroxyalkyl,

lower alkoxyalkyl,

lower halogenalkyl, lower carbamoylalkyl,

lower alkylcarbonylaminoalkyl,

lower phenylalkyl,

lower heterocyclylalkyl wherein the heterocyclyl group is unsubstituted or substituted by oxo,

lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di- substituted by lower alkyl, and

phenyl which is unsubstituted or mono- or di-substituted by halogen; R ² and R ⁶ independently from each other are hydrogen or halogen; R 3 and R 5 independently from each other are selected from the group consisting of

hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;

R ⁴ is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy, amino, azido and cyano; R is selected from the group consisting of lower alkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

lower hydroxyimino-alkyl, lower alkoxyimino-alkyl,

lower cycloalkyl, said cycloalkyl being unsubstituted or substituted by hydroxy, lower heterocyclyl,

phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower

alkylaminocarbonyl and halogen,

heteroaryl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower

alkylaminocarbonyl and halogen; and pharmaceutically acceptable salts thereof. Particularly, the present invention relates to compounds of the formula

wherein

R is selected from the group consisting of lower alkyl,

cycloalkyl,

lower cycloalkylalkyl,

lower hydroxyalkyl,

lower alkoxyalkyl,

lower halogenalkyl,

lower carbamoylalkyl,

lower alkylcarbonylaminoalkyl,

lower phenylalkyl,

lower heterocyclylalkyl wherein the heterocyclyl group is unsubstituted or substituted by oxo,

lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di- substituted by lower alkyl, and

phenyl which is unsubstituted or mono- or di-substituted by halogen; R ² and R ⁶ independently from each other are hydrogen or halogen;

R 3 and R 5 independently from each other are selected from the group consisting of

hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;

R ⁴ is selected from the group consisting of hydrogen, lower alkoxy, halogen, lower

halogenalkyl, lower halogenalkoxy, amino, azido and cyano;

R is selected from the group consisting of lower alkyl,

lower hydroxyalkyl,

lower cycloalkyl, said cycloalkyl being unsubstituted or substituted by hydroxy, lower heterocyclyl, phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy and halogen,

heteroaryl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, cyano and halogen; and pharmaceutically acceptable salts thereof.

The invention also relates to compounds of formula I, wherein A is N. These are the pyrazine derivatives of the formula

wherein

R is selected from the group consisting of lower alkyl,

cycloalkyl,

lower cycloalkylalkyl,

lower hydroxyalkyl,

lower alkoxyalkyl,

lower halogenalkyl,

lower carbamoylalkyl,

lower alkylcarbonylaminoalkyl,

lower phenylalkyl,

lower heterocyclylalkyl wherein the heterocyclyl group is unsubstituted or substituted by oxo,

lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di- substituted by lower alkyl, and

phenyl which is unsubstituted or mono- or di-substituted by halogen;

R ² and R ⁶ independently from each other are hydrogen or halogen; R 3 and R 5 independently from each other are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;

R ⁴ is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy, amino, azido and cyano;

R is selected from the group consisting of lower alkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

lower hydroxyimino-alkyl, lower alkoxyimino-alkyl,

lower cycloalkyl, said cycloalkyl being unsubstituted or substituted by hydroxy, lower heterocyclyl,

phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower

alkylaminocarbonyl and halogen,

heteroaryl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower

alkylaminocarbonyl and halogen; and pharmaceutically acceptable salts thereof.

Particular compounds of formula I of the present invention are the following:

pentanoic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]-amide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin -3-yl]-benzamide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin -3-yl]-nicotinamide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin -3-yl]-isonicotinamide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin -3-yl]-acetamide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin -3-yl]-butyramide,

pyridine-2-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]-amide, N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-yl]-be nzamide,

N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-yl] -acetamide,

N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-yl] -nicotinamide,

N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-yl] -isonicotinamide,

pyrazine-2-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]-amide, 2,5-dimethyl-2H-pyrazole-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin-3-yl]-amide,

3-methyl-isoxazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl] -amide, 1- methyl-iH-pyrazole-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin- 3-yl]-amide,

5-methyl-isoxazole-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl] -amide,

pyridazine-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]-amide, N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-3-methyl-isonicotinamide, pyrimidine-5-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]- amide,

2- methyl-2H-pyrazole-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin- 3-yl]-amide,

2.4- dimethyl-oxazole-5-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-

3- yl] -amide,

isothiazole-5-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]- amide,

5-methyl-2H-pyrazole-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-

3- yl] -amide,

iH-pyrazole-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]- amide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-2-methyl-isonicotinamide, 5-methyl-thiazole-2-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl] -amide,

4- methyl-[l,2,3]thiadiazole-5-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin-3-yl]-amide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-6-methyl-nicotinamide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin -3-yl]-2-methyl-nicotinamide, isoxazole-5-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]-amide,

3.5- dimethyl-isoxazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin- 3 - yl] - amide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-2-hydroxy-isonicotinamide, l,3-dimethyl-iH-pyrazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin-3-yl]-amide,

pyrimidine-4-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]- amide,

thiazole-2-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]-amide, 3-methyl-pyridine-2-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl] -amide,

5- methyl-oxazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl] -amide, N-(5-(3,4-dimethylphenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)-nicotinamide,

N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)p yridin-3-yl)-nicotinamide,

and pharmaceutically acceptable salts thereof.

Further compounds of formula I of the present invention are the following:

5-hydroxy-pyridine-2-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl] -amide,

N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -5-methylnicotinamide,

(S)-N-(5-(4-chlorophenyl)-6-(l, l,l-trifluoropropan-2-yloxy)pyridin-3-yl)pyridazine-3- carboxamide,

(S)-N-(5-(4-chlorophenyl)-6-(l, l,l-trifluoropropan-2-yloxy)pyridin-3-yl)nicotinamide,

N-(5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)p yridin-3-yl)nicotinamide,

N-(5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)p yridin-3-yl)nicotinamide,

N-(5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)p yridin-3-yl)nicotinamide,

N-(5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-y l)nicotinamide,

(S)-N-(6-(4-chlorophenyl)-5-(l, l,l-trifluoropropan-2-yloxy)pyrazin-2-yl)nicotinamide,

N-(6-(4-chlorophenyl)-5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)nicotinamide,

N-(6-(4-chlorophenyl)-5-cyclobutoxypyrazin-2-yl)nicotinam ide,

N-(6-(4-chlorophenyl)-5-cyclobutoxypyrazin-2-yl)pyrimidin e-5-carboxamide,

N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)p yridin-3-yl)pyrimidine-5- carboxamide,

N-(5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyrimidine-5-carboxamide, N-(5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyrimidine-5-carboxamide, N-(5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyrimidine-5-carboxamide, N-(5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)p yrimidine-5-carboxamide,

N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)p yridin-3-yl)-2- hydroxyisonicotinamide,

N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)- l,3-dimethyl- lH- pyrazole-4-carboxamide,

N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-2,4-difluoronicotinamide, N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -2-hydroxybenzamide,

N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-5-cyanonicotinamide, N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyridazine-3-carboxamide, N-(5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyridazine-3-carboxamide, N-(5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyridazine-3-carboxamide, N-(5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)p yridazine-3-carboxamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)furan-2-carboxamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)furan-3-carboxamide, N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -5-methylfuran-2-carboxamide, N-(5-(4-chloro-3-methylphenyl)-6-(2-methoxyethoxy)pyridin-3- yl)benzamide,

(R)-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridi n-3-yl)tetrahydrofuran-2-carboxamide, (S)-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)tetrahydrofuran-3-carboxamide, N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -4-methyl-3,4-dihydro-2H- pyrido[3,2-b] [l,4]oxazine-7-carboxamide,

N-(5-(4-amino-3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyrid in-3-yl)-5-iodonicotinamide, N-(5-phenyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)nicotinami de,

N-(5-(4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)nicotinamide,

N-(5-(3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)nicotinamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -5-methoxynicotinamide,

N-(5-(4-chlorophenyl)-6-cyclobutoxypyridin-3-yl)pyrazine-2-c arboxamide,

N-(5-(4-chlorophenyl)-6-cyclobutoxypyridin-3-yl)nicotinamide ,

N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-4-methyl-3,4-dihydro- 2H-pyrido[3,2-b] [l,4]oxazine-7-carboxamide,

N-(5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-4-methyl-3,4-dihydro-2H- pyrido[3,2-b] [l,4]oxazine-7-carboxamide,

5-methyl-oxazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-cyclobutoxy-pyridin-3-yl]-amide N-[5-(4-Chloro-phenyl)-6-cyclobutoxy-pyridin-3-yl]-5-methyl- nicotinamide,

N5-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)-N2-methylpyridine-2,5- dicarboxamide,

5-bromo-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyrid in-3-yl)nicotinamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)-2-methoxypropanamide,

N3-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)-N5-methylpyridine-3,5- dicarboxamide,

(+)-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)-2-methoxypropanamide, (E)-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)-2-(methoxyimino)propanam and pharmaceutically acceptable salts thereof.

More particularly, compounds of formula I of the present invention are the following:

N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin -3-yl]-nicotinamide,

N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-yl] -nicotinamide,

3-methyl-isoxazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl] -amide,

pyridazine-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]-amide, l,3-dimethyl-iH-pyrazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin- 3 - yl] - amide, 5-methyl-oxazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-amide,

N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-nicotinamide,

N-(5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)p yridin-3-yl)nicotinamide,

(S)-N-(6-(4-chlorophenyl)-5-( 1 , 1,1 -trifluoropropan-2-yloxy)pyrazin-2-yl)nicotinamide,

N-(6-(4-chlorophenyl)-5-cyclobutoxypyrazin-2-yl)pyrimidin e-5-carboxamide,

N-(5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)p yridin-3-yl)pyrimidine-5-carboxam N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -2-hydroxybenzamide,

N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)p yridin-3-yl)-5-cyanonicotinamide, N-(5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyridazine-3-carboxamide, N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -5-methylfuran-2-carboxamide, N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -4-methyl-3,4-dihydro-2H- pyrido[3,2-b] [l,4]oxazine-7-carboxamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -5-methoxynicotinamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)-2-methoxypropanamide, and pharmaceutically acceptable salts thereof.

Even more particularly, the invention relates to a compound of formula I, which is N-[5-(4- chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nico tinamide, and pharmaceutically acceptable salts thereof.

Also more particularly, the invention relates to a compound of formula I, which is N-[5- chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-yl]-nicotinami de, and pharmaceutically acceptable salts thereof.

Also more particularly, the invention relates to a compound of formula I, which is N-(5-(4- chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-5-metho xynicotinamide, and

pharmaceutically acceptable salts thereof.

The compounds of formula I can be prepared by a process, which process comprises coupling a compound of formula

wherein A and R ¹ to R ⁶ are as defined herein before, with an acid of the formula wherein R is as defined herein before, with the help of a coupling agent under basic conditions, and, if desired, converting the resulting compound of formula I into a pharmaceutically acceptable salt thereof.

Coupling agents for the reaction of compounds of formula II with acids of formula III are for example N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), l-[bis(dimethylamino)- methylene]-iH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 1- hydroxy-l,2,3-benzotriazole (HOBT), 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), or 0-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate (HBTU). More particularly, the coupling agent is HBTU. Suitable bases include triethylamine, diisopropylethylamine and, particularly, N-methylmorpholine. The synthesis of the compounds with the general structure I- A can be accomplished according to scheme 1.

Following the procedure according to scheme 1, compound AA (3-bromo-2-chloro-5-nitro- pyridine, CAS RN 5470-17-7) can be used as starting material. AA is commercially available.

Compound AB can be prepared from AA by reaction with a suitably substituted primary or secondary alcohol R^OH in the presence of a base, for example sodium hydride, with or without an inert solvent, for example dimethylformamide, at temperatures from room temperature to reflux temperature of the solvent, preferably at room temperature.

Compound AC can be prepared from AB by reduction using the vast array of possibilities known in the art for reducing the aromatic nitro group. A convenient reduction method is the use of stannous chloride in a suitable solvent mixture, preferably in ethanol with added hydrochloric acid, at temperatures from room temperature to elevated temperatures, preferably at 25 °C. Scheme 1

Compound II can be prepared from AC by coupling a suitably substituted aryl metal species of formula AD, particularly an arylboronic acid or arylboronic acid ester in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly palladium(II) acetate/ triphenylphosphine mixtures or palladium(II)chloride-dppf (l, l'-bis(diphenyl- phosphino)ferrocene) complexes and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxye thane. Compounds of formula AD containing functional groups detrimental to palladium catalyzed Suzuki reactions can for the purpose of carrying out this reaction be protected with a suitable protecting group (P). Suitable amine protecting groups are for example benzyloxy- carbonyl (Z), t-butyloxycarbonyl (BOC), while suitable acid protecting groups are for example benzyl (Bn), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM) or allyl groups and silyl groups such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl esters (for more details see T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 edition). Protecting group removal can be carried out by suitable methods known in the art.

Compound I-A can be prepared from II and the corresponding acid of formula III by suitable amide bond forming reactions. These reactions are known in the art. For example coupling reagents like N,N'-carbonyl-diimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), l-[bis(dimethylamino)- methylene]-iH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 1- hydroxy-l,2,3-benzotriazole (HOBT), 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), and 0-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate (HBTU) can be employed to affect such transformation. A convenient method is to use for example HBTU and a base, for example N-methylmorpholine in an inert solvent such as for example dimethylformamide at room temperature.

Following the alternative procedure according to scheme 2, compound AC can be used as starting material. Compound BD can be prepared from AC and the corresponding acid of formula III by suitable amide bond forming reactions. These reactions are known in the art. For example coupling reagents like N,N'-carbonyl-diimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), l-[bis(dimethylamino)- methylene]-iH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 1- hydroxy- 1, 2,3 -benzotriazole (HOBT), 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), and 0-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate (HBTU) can be employed to affect such transformation. A convenient method is to use for example HBTU and a base, for example N-methylmorpholine in an inert solvent such as for example dimethylformamide at room temperature. Compound I-A can be prepared from BD by coupling a suitably substituted aryl metal species of formula AD, particularly an arylboronic acid or arylboronic acid ester in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly palladium(II) acetate/ triphenylphosphine mixtures or palladium(II)chloride-dppf (l,l'-bis(diphenyl- phosphino)ferrocene) complexes and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxye thane. Scheme 2

I-A

Compounds of formula AD containing functional groups detrimental to palladium catalyzed Suzuki reactions can for the purpose of carrying out this reaction be protected with a suitable protecting group (P). Suitable amine protecting groups are for example benzyloxy- carbonyl (Z), t-butyloxycarbonyl (BOC), while suitable acid protecting groups are for example benzyl (Bn), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM) or allyl groups and silyl groups such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl esters (for more details see T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 edition). Protecting group removal can be carried out by suitable methods known in the art.

Following the procedure according to scheme 3, compound CA (3-bromo-5-chloro-2- fluoro-pyridine, CAN 884484-87-5) can be used as starting material. CA is commercially available.

Compound CB can be prepared from CA by coupling a suitably substituted aryl metal species of formula AD, particularly an arylboronic acid or arylboronic acid ester in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly palladium(II) acetate / triphenylphosphine mixtures or palladium(II)chloride-dppf (l,l'-bis(diphenyl- phosphino)ferrocene) complexes and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxye thane.

Compounds of formula AD containing functional groups detrimental to palladium catalyzed Suzuki reactions can for the purpose of carrying out this reaction be protected with a suitable protecting group (P). Suitable amine protecting groups are for example benzyloxy- carbonyl (Z), t-butyloxycarbonyl (BOC), while suitable acid protecting groups are for example benzyl (Bn), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM) or allyl groups and silyl groups such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl esters (for more details see T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 edition). Protecting group removal can be carried out by suitable methods known in the art.

Compound CC can be prepared from CB by reaction with a suitably substituted primary or secondary alcohol R^-OH in the presence of a base, for example sodium hydride, with or without an inert solvent, for example dimethylformamide, at temperatures from room temperature to reflux temperature of the solvent, preferably at room temperature.

Compounds of the general formula CD can be obtained from compounds of the general formula CC by transition metal catalyzed, more specifically palladium catalyzed, preferentially palladium(II)chloride-dppf catalyzed reaction with carbon monoxide in a suitable solvent such as a primary alcohol, particularly methanol, at pressures of carbon monoxide of 1 to 200 bar, in particular 1 to 70 bar and temperatures of 0 to 150 °C, particularly 1 to 100 °C.

The saponification of the resulting ester CD by methods well known to the ones skilled in the art leads to acids of the general formula CE.

Compounds of general formula CF can be obtained from compounds of general formula CE by means of a Curtius rearrangement, preferentially by treatment with diphenylphosphoryl azide and a base, particularly triethylamine, in boiling i-butanol. The carbamates of the general formula CF can be deprotected by methods well known in the art to yield the amines of the general formula II. Alternatively the amines of general formula II can be prepared from the acids of general formula CE by synthesizing the corresponding primary amide followed by a Hoffmann rearrangement.

Compound I-A can be prepared from II and the corresponding acid of formula III by suitable amide bond forming reactions. These reactions are known in the art. For example coupling reagents like N,N'-carbonyl-diimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), l-[bis(dimethylamino)- methylene]-iH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 1- hydroxy-l,2,3-benzotriazole (HOBT), 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), and 0-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate (HBTU) can be employed to affect such transformation. A convenient method is to use for example HBTU and a base, for example N-methylmorpholine in an inert solvent such as for example dimethylformamide at room temperature.

Following the procedure according to scheme 4, compounds of general formula DA (the synthesis of which has been described for example in WO2008040651 and WO2008040649) can be used as starting materials to provide compounds of general formula I-B.

In particular compounds of general formula DB can be prepared from compounds of general formula DA by reaction with a suitably substituted primary or secondary alcohol R^-OH in the presence of a base, for example cesium carbonate, with or without an inert solvent, for example dimethylsulfoxide, at temperatures from room temperature to reflux temperature of the solvent, particularly at room temperature.

The saponification of the resulting ester of general formula DB by methods well known to the ones skilled in the art leads to acids of the general formula DC.

Compounds of general formula DD can be obtained from compounds of general formula DC by means of a Curtius rearrangement, preferentially by treatment with diphenylphosphoryl azide and a base, particularly triethylamine, in boiling i-butanol. The carbamates of the general formula DD can be deprotected by methods well known in the art to yield the amines of the general formula IV. Alternatively the amines of general formula IV can be prepared from the acids of general formula DC by synthesizing the corresponding primary amide followed by a Hoffmann rearrangement.

Compounds of general formula I-B can be prepared from IV and the corresponding acids of formula III by suitable amide bond forming reactions. These reactions are known in the art. For example coupling reagents like N,N'-carbonyl-diimidazole (CDI), N,N'-dicyclohexylcarbo- diimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1- [bis(dimethylamino)-methylene]-iH-l,2,3-triazolo[4,5-b]pyrid inium-3-oxide

hexafluorophosphate (HATU), l-hydroxy-l,2,3-benzotriazole (HOBT), O-benzotriazol-l-yl- N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), and 0-benzotriazole-N,N,N',N'- tetramethyl-uronium-hexafluoro-phosphate (HBTU) can be employed to affect such

transformation. A convenient method is to use for example HBTU and a base, for example N- methylmorpholine in an inert solvent such as for example dimethylformamide at room temperature.

Scheme 4

IV I B Compounds of general formula I-A or I-B can, if necessary, by methods known in the art, be processed further to other compounds of the same general formula. This could for example entail protective group removal by methods known in the art (for more details see T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 edition); or simple functional group transformations, for example the transformation of a keto group to a hydroxyimino or methoxyimino group.

As described above, the compounds of formula I of the present invention or

pharmaceutically acceptable salts thereof can be used as medicaments for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents. Examples of such diseases are atherosclerosis, peripheral vascular disease, dyslipidemia,

hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia,

hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia. The use as medicament for the treatment and/or prevention of dyslipidemia, atherosclerosis and cardiovascular diseases is of particular interest.

The invention therefore also relates to pharmaceutical compositions comprising a compound of formula I as defined above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and/or adjuvant. The pharmaceutical compositions are useful in the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents.

Thus, the invention relates to a pharmaceutical composition as defined above for use in the treatment and/or prophylaxis of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia,

hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia. In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, which method comprises administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof. Examples of such diseases are atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial

hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia. A method for the treatment and/or

prophylaxis of dyslipidemia, atherosclerosis and cardiovascular diseases is preferred. The invention also relates to the compounds of formula I or pharmaceutically acceptable salts thereof for use as medicaments. More specifically, the invention relates to compounds of formula I or pharmaceutically acceptable salts thereof for use as HDL-cholesterol raising agents. Thus, the invention is concerned with compounds of formula I or pharmaceutically acceptable salts thereof for use in the treatment and/or prophylaxis of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia, in particular for use in the treatment and/or prophylaxis of dyslipidemia, atherosclerosis and cardiovascular diseases.

In addition, the invention relates to the use of compounds of formula I as defined above or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment and/or prophylaxis of diseases can be treated with HDL raising agents. Examples of such diseases are atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial

hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia. The use of compounds of formula I as defined above or pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment and/or prophylaxis of dyslipidemia, atherosclerosis and cardiovascular diseases is of particular interest.

In addition, HDL raising agents of formula I are useful in combination or association with another compound, said compound being selected from the group consisting of an HMG-CoA reductase inhibitor, an microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor, a PPAR activator, a cholesteryl ester transfer protein (CETP) inhibitor, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, a preparation containing niacin or other HM74a agonists, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant.

The invention therefore also relates to pharmaceutical compositions comprising a compound of formula I as defined above or a pharmaceutically acceptable salt thereof in combination or association with a compound selected from the group consisting of an HMG- CoA reductase inhibitor, an microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor, a PPAR activator, a cholesteryl ester transfer protein (CETP) inhibitor, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, a preparation containing niacin or other HM74a agonists, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant, as well as a pharmaceutically acceptable carrier and/or adjuvant.

The invention further relates to compounds of formula I as defined above or

pharmaceutically acceptable salts thereof in combination or association with a compound selected from the group consisting of an HMG-CoA reductase inhibitor, an microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor, a PPAR activator, a cholesteryl ester transfer protein (CETP) inhibitor, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, a preparation containing niacin or other HM74a agonists, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant for use in the treatment and/or prophylaxis of diseases such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia.

The invention also relates to a method for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, which method comprises

administration of a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof in combination or association with a therapeutically effective amount of a compound selected from the group consisting of an HMG-CoA reductase inhibitor, an microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor, a PPAR activator, a cholesteryl ester transfer protein (CETP) inhibitor, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, a preparation containing niacin or other HM74a agonists, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant.

PHARMACEUTICAL COMPOSITIONS

The compounds of formula I and/or their pharmaceutically acceptable salts can be used in the form of pharmaceutical compositions for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, orally, e.g. in the form of buccal cavities, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions for intramuscular, intravenous or subcutaneous injection, or topically, e.g. in the form of ointments, creams or oils. Oral administration is of particular interest. The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other

therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi- synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavor-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.

The therapeutically effective amount or dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 to 100 mg, especially about 1 to 50 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units. The pharmaceutical compositions conveniently contain about 1-100 mg, preferably 5-

50 mg, of a compound of formula I.

The following examples CI to C3 illustrate typical compositions of the present invention, but serve merely as representative thereof. Example CI

Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat. Example C2

Capsules containing the following ingredients can be manufactured in a conventional manner:

The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

PHARMACOLOGICAL TESTS

The following tests were carried out in order to determine the activity of the compounds of formula I and their valuable pharmacological properties.

Detection of upregulation of ABCA1 protein in cells

The ability of compounds of the invention to increase the level of ABCA1 protein is determined in replicate cultures of THP-1 macrophage cells in 96-well microplates. Cells are plated at an initial density of 100,000 cells/well in 100 μΐ medium and differentiated to adherent macrophages with the addition of PMA (100 nM) for 68 hrs in 10% fetal bovine serum, 3 μΙ/L of b-mercaptoethanol, RPMI-1640 medium. Then, cells are incubated with RPMI-1640 medium containing 1% FCS, 25 μg/ml acetylated LDL, for 24 hours at 37 °. Following incubation with acetylated LDL, cells are washed twice with 50 μΐ PBS and incubated with 100 μΐ of RPMI-1640 medium containing the compound of interest solubilized in DMSO for an additional 24 hrs. The final DMSO concentration in presence of cells is maintained at 0.5%. ApoA-I binding assay using High Content Image Analysis is initiated by replacing with fresh medium, RPMI without Phenol Red, 0.2% BSA containing AlexaFluor®647 labeled ApoA-I for 2 h/37°C/5%C02. Then, cells are fixed with 4% Formaldehyde inPBS (15min, RT). Following Nuclei are stained with Hoechst solution (3μΜ PBS) and Cytoplasm with Cell Mask Blue ^g/ml PBS), 15min, RT. Finally the stained cells are fixed with a second round of formaldehyde treatment. Fixed stained cells are washed and kept in PBS at 4°C and can be read immediately until one month after preparation. That the binding of ApoA-I indeed reflected the level of ABCA1 in the cell, was demonstrated by loss of signal when ABCA1 expression was artificially reduced by transfection with small interfering RNA's.

The Alexa Fluor 647-labeled Apolipoprotein A-I (20nM) was prepared as follows: Human recombinant Apolipoprotein A-I (ApoA-I) was exchanged to a buffer of 0.02 M NaHC0 ₃ at pH 8.2 on an NAP desalting column (GE Healthcare) and brought to a concentration to 40 μΜ (1.13mg/ml) by adjustment with the same buffer. The ApoA-I was fluorescently labeled by incubation with Alexa Fluor carboxylic acid succimidyl ester. (Alexa Fluor 647, Invitrogen A- 20006) at a 2: 1 molar ratio (Alexa to ApoA-I) for 1 h under shaking at RT. The remaining unconjugated label was removed by buffer exchange to 0.02M NaHC0 ₃ at pH 8.2 .

Imaging and data collection were performed on an OPERA confocal microplate imaging reader using a 20x water immersion objective and UV360 or 405 laser to identify the cell nuclei and a 635 laser to identify the fluorescent ApoA-I. Eight fields of view are captured per well. Image capture and analysis was performed with the Acapella software. Background fluorescence detected in control wells without ApoA-I was subtracted.

Using XLfit3 program (ID Business Solutions Ltd. UK), the model 205 for Dose Response One Site is used to calculate the EC ₅ 0 values. The compounds of the present invention increase the level of ABCA1 protein by more than 45% at a concentration of 3 μΜ. Preferably the compounds exhibit EC ₅ 0 values in a range of 0.1 μΜ to 10 μΜ in the ABCA1 protein detection assay. Even more preferably, the compounds of the present invention have EC ₅ 0 values in a range of 0.1 μΜ to 3 μΜ. Table 1 ABCAl rotein increasing efficacy

Cholesterol efflux assay

The ability of compounds of the invention to stimulate cholesterol efflux is determined in replicate cultures of THP-1 cells in 96-well microplates. Cells are plated at an initial density of 150,000 cells/well and differentiated to macrophages with the addition of PMA (lOOng/ml) for 72 hrs in 10% fetal bovine serum, 3 μΙ/L of beta-mercaptoethanol, RPMI-1640 medium. Cells are washed once with RPMI-1640 and loaded with RPMI-1640 medium containing 2% FCS, 50 μg/ml acetylated LDL, and 10 μθ/ιηΐ [ H]cholesterol for 48 hours at 37 °C. After loading the cells are washed once with RPMI-1640 and incubated with the compound of interest from DMSO solutions for an additional 24 hrs in RPMI-1640 medium containing lmg/ml fatty acid free -bovine serum albumin (BSA). Upon incubation cells are washed once, and cholesterol efflux is induced by the addition of 10 μg/ml Apolipoprotein AI in RPMI-1640 containing 1 mg/ml BSA and in the presence of the compound for an additional 6 hrs. Following incubation radioactivity is determined in the supernatants and cholesterol efflux is expressed as the percent stimulation over replicate cultures treated only with DMSO. Sigmoidal curves were fitted using the XLfit3 program (ID Business Solutions Ltd. UK) and EC ₅ 0 values were determined.

The compounds of the present invention exhibit EC 50 values in a range of 0.1 μΜ to 3.0 μΜ in the cholesterol efflux assay. Preferably, the compounds of the present invention have EC ₅ 0 values in a range of 0.1 μΜ to 1.5 μΜ.

CB1 and CB2 receptor affinity The affinity of the compounds of the invention for cannabinoid receptors was determined using membrane preparations of human embryonic kidney (HEK) cells in which the human CB 1 receptor is transiently transfected using a Semliki Forest Virus system in conjunction with [3H]- CP-55,940 as radioligand. After incubation of freshly prepared cell membrane preparation with the [ H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glass fiber filters. Radioactivity on the filter was measured by scintillation counting.

The affinity of the compounds of the invention for cannabinoid CB2 receptors was determined using membrane preparations of human embryonic kidney (HEK) cells in which the human CB2 receptor is transiently transfected using a Semliki Forest Virus system in

conjunction with [ H]-CP-55,940 as radioligand. After incubation of freshly prepared cell membrane preparation with the [ H] -ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glass fiber filters. Radioactivity on the filter was measured by scintillation counting. The ability of the compounds to displace the radioligand [ H]-CP-55,940 was measured at a concentration of 10 μΜ and values provided as [% inhibition @ 10 μΜ] both for the CB l and CB2 receptor assay, The lower % inhibition is, the lower the likelihood of side effects based on CB 1 or CB2 receptor inhibition is. The compounds of the present invention exhibit values below 50% inhibition in both the

CB l and CB2 receptor assay at a concentration of 10 μΜ. Preferably, the compounds of the present invention exhibit values below 35% inhibition in both the CB l and CB2 receptor assays and even more preferably below 20% in both assays.

Table 2: CB l and CB2-receptor affinity

CBl receptor affinity CB2 receptor affinity

Example

[% inhibition @ 10 μΜ] [% inhibition @ 10 μΜ]

1 45 9.2

2 33 4.9

3 29 8.0

4 36 1.9

5 19 -5.4

6 47 11

7 13 1.2

8 52 15

9 24 9.6

10 36 28

11 25 -1.2

12 22 4

13 16 3

14 38 10

15 27 2

16 34 -1

17 16 -3

18 37 3

19 25 -10

20 34 9

21 29 1

22 45 8

23 12 -8

24 25 -1

25 25 -1

26 37 11

27 47 10

28 36 -6

29 41 19

30 27 -4

31 44 7 CB1 receptor affinity CB2 receptor affinity

Example

[% inhibition @ 10 μΜ] [% inhibition @ 10 μΜ]

32 21 0.9

33 22 -2

34 31 10

35 18 -3

36 18 2

37 27 8

38 12 15

39 19 16

40 19 -5

41 31 8

42 23 6

43 31 6

44 15 14

45 11 13

46 40 -1

47 34 5

48 40 -2

49 39 -3

50 39 -1

51 48 6

52 34 6

53 21 0

54 21 10

55 35 4

56 35 0

57 0 -18

58 3 -13

59 22 18

60 38 -2

61 17 12

62 -4 4

63 5 -1

64 9 2

65 19 5

66 30 5

67 33 9

68 26 4

69 35 18

70 49 15

71 41 4

72 25 -7

73 13 22

74 17 -7

75 31 5

76 1 5 CB1 receptor affinity CB2 receptor affinity

Example

[% inhibition @ 10 μΜ] [% inhibition @ 10 μΜ]

77 33 16

78 25 26

79 29 13

80 16 14

81 21 5

82 29 37

83 27 -5

84 23 3

85 38 5

86 48 5

87 19 -15

88 41 16

89 35 5

Further demonstration of biological activities of the compounds of the present invention may be accomplished through the following in vivo assays that are well known in the art.

Effects on plasma lipid levels in lean, chow fed rats The effects of compounds of compounds of formula I on plasma lipid levels were determined in lean, chow-fed Sprague-Dawley rats with compounds administered by p.o. gavage. After one week of acclimatisation, blood samples were collected from 4 hour-fasted animals for plasma lipid determination. Animals were then assigned to treatment groups based on HDL- cholesterol levels. Compounds of formula I were administered by gavage, once daily for five days. Control animals received vehicle alone. Blood was collected on day five from 4 hour- fasted rats, 2 hours after a final treatment, for plasma lipid analysis. Total cholesterol, HDL- cholesterol, and triglycerides were determined by measuring total cholesterol, HDL-cholesterol, and triglyceride using colorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). HDL-C was also quantified using size exclusion chromatography on superpose-6 column using a SMART system (Pharmacia). Lipoprotein distribution was calculated assuming a Gaussian distribution for each peak, using a nonlinear, least-squares curve-fitting procedure to calculate the area under the curve. Compound concentration was also determined in plasma.

Effects on plasma lipid levels in obese, high fat diet fed rats

Efficacy of compounds in modulating plasma lipid levels was determined also in obese male Sprague Dawley rats after 28-29 days administration of compounds. Male Sprague - Dawley rats of 10 weeks of age were fed a high fat diet during 3 weeks. Obese rats were distributed in groups according to homogeneous BW and FI evaluated a week before the start of the treatment. Treatment was administered as food-Admix. On day 29, blood was taken in the morning under slight anesthesia (retro-orbital method) in post-prandial conditions i.e. 4h after food was removed. Plasma was separated from blood by low speed centrifugation and selected organs were taken (e.g liver, fat). Total cholesterol, HDL-cholesterol, and triglycerides were determined by measuring total cholesterol, HDL-cholesterol, LDL-cholesterol and triglyceride using colorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). HDL-C was also quantified using size exclusion chromatography on superpose-6 column using a SMART system (Pharmacia). Lipoprotein distribution was calculated assuming a Gaussian distribution for each peak, using a nonlinear, least-squares curve-fitting procedure to calculate the area under the curve. Compound concentration was also determined in plasma.

Effects on plasma lipid levels in hamsters

Efficacy of compounds in modulating plasma lipid levels was determined in hamsters after 5 days of daily administration of compounds. Male hamsters of 6-8 weeks of age were used in the studies. After one week of acclimation, blood samples were collected from 4 hour-fasted animals for plasma lipid determination. Animals were then assigned to treatment groups based on HDL-cholesterol levels. Compounds were administered by gavage, once daily for five days. Control animals received vehicle alone. Blood was collected on day five from 4 hour-fasted hamsters, 2 hours after a final treatment, for plasma lipid analysis. Total cholesterol, HDL- cholesterol, LDL-cholesterol, and triglycerides were determined using colorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). HDL-cholesterol, LDL-cholesterol, and VLDL-cholesterol levels were also quantified using size exclusion chromatography on superpose-6 column using a SMART system (Pharmacia). Lipoprotein distribution was calculated assuming a Gaussian distribution for each peak, using a nonlinear, least-squares curve-fitting procedure to calculate the area under the curve. Compound concentration was also determined in plasma.

Effects on plasma lipid levels in cholesterol/fat fed hamsters

Efficacy of compounds in modulating plasma lipid levels was determined in hamsters after 5 days of daily administration of compounds. Male hamsters of 6-8 weeks of age were used in the studies. After one week of acclimatisation, blood samples were collected from 4 hour-fasted animals for plasma lipid determination. Animals were then assigned to treatment groups based on HDL-cholesterol levels. Compounds were administered by gavage, once daily for five days. Control animals received vehicle alone. Blood was collected on day five from 4 hour-fasted hamsters, 2 hours after a final treatment, for plasma lipid analysis. Total cholesterol, HDL- cholesterol, LDL-cholesterol, and triglycerides were determined using colorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). HDL-cholesterol was also determined after selective precipitation of HDL from plasma by standard procedures.

Examples

MS = mass spectrometry; EI = electron ionization; ESI = electrospray; NMR data are reported in parts per million (δ) relative to internal tetramethylsilane and are referenced to the deuterium lock signal from the sample solvent (d ₆ -DMSO unless otherwise stated); coupling constants (J) are in Hertz, mp = melting point; bp = boiling point; HPLC = LC = high performance liquid chromatography, Rt = retention time, TLC = thin layer chromatography, RT = room temperature, DIPEA = diisopropylethylamine, DPPA = phosphoric acid diphenyl ester azide, TBTU = 0-(benzotriazol-l-yl)-N,N',N'-tetramethyl-uronium-tetrafluor oborate; TEMPO = 2,2,6,6-tetra-methylpiperidine 1-oxyl radical, DMF = dimethylformamide, DMSO = dimethyl- sulfoxide, THF = tetrahydrofuran, CAN = CAS Registry Number.

Preparation of Intermediates

Example A

Preparation of 3-bromo-5-nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine

Sodium hydride (3.2 g, 80.02 mmol) was added carefully in small portions to 2, 2, 2- trifluroethanol (CAS Registry No. 75-89-8) (60 ml) at 0 °C under nitrogen atmosphere and stirred at 25 °C for 30 minutes. Then 3-bromo-2-chloro-5-nitropyridine (CAS Registry No. 5470-17-7) (2 g, 8.42 mmol) in trifluoroethanol was added, and the reaction mixture was refluxed for 16h. The solvent was evaporated in vacuo, and the residue was taken up in water and extracted with ethyl acetate (3x120 ml). The combined organic layers were washed with water and brine, dried over Na ₂ S0 ₄ and concentrated to get the crude residue (3g). The crude was purified by column chromatography (3% ethyl acetate/hexane) to give the desired product (2.4g, 95%) as yellow liquid. MS (LC/MS): not responding, NMR is in agreement with the structure: 1H-NMR (400 MHz, CDC1 ₃ ): δ 4.90 (m, 2H), 8.68 (d, 1H), 8.98 (d, 1H). Example B

Preparation of 3-bromo-2-cyclopropylmethoxy-5-nitro-pyridine

To a solution of sodium hydride (2.21 g, 55.34 mmol) in anhydrous DMF (20ml) was added cyclopropylmethanol (CAS Registry No. 2516-33-8) (12.45 ml, 153.2 mmol) under nitrogen at 0 °C and the reaction mixture was stirred at 25 °C for 30 minutes. Then 3-bromo-2- chloro-5-nitropyridine (CAS Registry No. 5470-17-7) (7.3 g, 30.74 mmol) was added drop wise at 0 °C and stirred for two hours at 25 °C. Water (60ml) was added to the reaction mixture and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with water and brine, dried over Na ₂ S0 ₄ and evaporated under reduced pressure to get the crude residue (12 g). The crude was purified by column chromatography (2% ethyl acetate/hexane) to get the desired product (2.06 g, 32%) as light yellow solid and 1.7g of unreacted 3-bromo-2-chloro-5- nitropyridine was recovered. MS (LC/MS): not responding, NMR is in agreement with the structure: 1H-NMR (400 MHz, CDC1 ₃ ): δ 0.41 (m, 2H), 0.65 (m, 2H), 1.32 (m, 1H), 4.34 (d, 2H), 8.60 (d, 1H), 8.96 (d, 1H).

Example C

Preparation of 5-bromo-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine

To a solution of 3-bromo-5-nitro-2-(2, 2, 2-trifluoro-ethoxy)-pyridine (2.4 g, 7.97 mmol) in ethanol (100 ml) were added HC1 (0.3 ml) and stannous chloride (10.5 g, 55.81 mmol) at 25 °C and the reaction mixture was stirred for 4 h at 25 °C. After total consumption of starting material (monitored by TLC), ethanol was evaporated under reduced pressure, diluted with ethyl acetate, neutralized with aqueous Na ₂ C0 ₃ solution, and filtered through a bed of celite. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2x120 ml). The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and evaporated in vacuo to get the desired compound (2.1 g, 97%) as brown liquid. This was used as such for the next step without further purification. MS (LC/MS): not responding, NMR is in agreement with the structure: 1H-NMR (400 MHz, CDC1 ₃ ): δ 4.70 (m, 2H), 7.30 (d, 1H), 7.54 (d, 1H).

Example D

Preparation of 5-bromo-6-cyclopropylmethoxy-pyridin-3-ylamine

To a solution of 3-bromo-2-cyclopropylmethoxy-5-nitro-pyridine (600 mg, 2.19 mmol) in methanol (30 ml) were added water (15 ml), zinc dust (1 g, 15.37 mmol) and ammonium chloride (1.28 g, 24.09 mmol) at 25 °C, and the reaction mixture was stirred for 45 min at 25 °C. After total consumption of starting material (monitored by TLC), the reaction mixture was filtered through a bed of celite, and the filtrate was evaporated under reduced pressure to get the crude residue. The residue was dissolved in dichloromethane and washed with water and brine. The organic part was dried over Na ₂ S0 ₄ and evaporated to get the compound (507 mg, 95 %). This compound was used in next step without further purification. MS (LC/MS): 244.0 (M+H).

Example E

Preparation of 5-(4-chloro-phenyl)-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine

To a solution of 5-bromo-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (2.1 g, 7.74 mmol) in DME, ethanol, water (3: 1: 1) (50 ml) in a sealed tube were added 4-chlorophenylboronic acid (CAS Registry No. 1679-18-1) (1.8 g, 11.62 mmol) and potassium phosphate (4.9 g, 23.22 mmol), and then the reaction mixture was purged with nitrogen for 15 min. Then Pd(dppf) ₂ Cl ₂ (651 mg, 0.93 mmol) was added to the reaction mixture and heated at 100 °C for 4h. The reaction mixture was filtered off and the filter cake was washed with ethyl acetate (3x20 ml). The organic layer was washed with water, brine, dried over Na ₂ S0 ₄ and evaporated in vacuo to get the crude (1.9 g). The crude was purified by column chromatography (20-25% ethyl acetate/hexane) to get the desired product (1.3 g, 56%) as brown liquid. MS (LC/MS): 303.0 (M+H). Example F

Preparation of 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-ylamine

The title compound was synthesized in analogy to Example E, using 5-bromo-6- cyclopropylmethoxy-pyridin-3-ylamine and 4-chlorophenylboronic acid (44 %). MS (LC/MS): 275.2 (M+H).

Example G

Preparation of N-[5-Bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotina mide

To a solution of nicotinic acid (454 mg, 3.69 mmol) in DMF (33 mL) were added successively TBTU (1.18 g, 3.69 mmol), N,N-diisopropylethylamine (3.16 mL, 18.4 mmol) and 5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-amine (1 g, 3.69 mmol). The brown mixture was stirred under argon for 3 h at room temperature. After evaporation of DMF, the brown oil was partitioned between ethyl acetate (50 mL) and 1M NaOH (30 mL). The aqueous layers were back-extracted with ethyl acetate (1 x 50 mL). The organic parts were washed with water (2 x 25 mL) and brine (25 mL), then dried over MgS0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 100% ethyl acetate in heptane) to deliver the desired product as a white solid (580 mg ; 42%); MS (EI): 376.1 ; 378.0 (M+H). Example 1

Preparation of pentanoic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl ]- amide To a solution of 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yla mine (50 mg,

0.165 mmol) and valeric acid (36 mg, 0.247 mmol) in DMF (5 ml) were added N-methyl morpholine (51mg, 0.5mmol) and HBTU (94mg, 0.247mmol), and the reaction mixture was stirred for 16 h at 25 °C. The reaction mixture was poured into water and extracted with ethyl acetate (3x20 ml). The combined ethyl acetate part was dried over Na ₂ S0 ₄ and evaporated to furnish the crude material (60 mg). The crude was purified by prep. HPLC and the desired product (30 mg, 47 %) was obtained as sticky white solid. MS (LC/MS): 387.2 (M+H).

Example 2

Preparation of N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-benzamide The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-

(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and benzoic acid as starting materials, MS (LC/MS): 407.2 (M+H). Example 3

Preparation of N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-nicotinamide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine and nicotinic acid as starting materials, MS (LC/MS): 408.0 (M+H).

Example 4

Preparation of N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-isonicotinamide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and isonicotinic acid as starting materials, MS (LC/MS): 408.0 (M+H).

Preparation of N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-acetamide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and acetic acid as starting materials, MS (LC/MS): 345.0 (M+H). Example 6

Preparation of N-[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-butyramide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and n-butyric acid as starting materials, MS

(LC/MS): 373.2 (M+H).

Example 7

Preparation of pyridine-2-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and pyridine-2-carboxylic acid as starting materials, MS (LC/MS): 408.0 (M+H).

Example 8

Preparation of N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-yl]-be nzamide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- cyclopropylmethoxy-pyridin-3-ylamine and benzoic acid as starting materials, MS (LC/MS): 379.2 (M+H).

Preparation of N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-yl]-ac etamide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- cyclopropylmethoxy-pyridin-3-ylamine and acetic acid as starting materials, MS (LC/MS): 317.2 (M+H).

Example 10

Preparation of N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-yl]-ni cotinamide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- cyclopropylmethoxy-pyridin-3-ylamine and nicotinic acid as starting materials, MS (LC/MS): 380.2 (M+H).

Example 11

Preparation of N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-yl]-is onicotinamide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- cyclopropylmethoxy-pyridin-3-ylamine and isonicotinic acid as starting materials, MS (LC/MS): 380.2 (M+H).

Example 12

Preparation of pyrazine-2-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin- 3 - yl] - amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6 (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-pyrazinecarboxylic acid as starting materials, MS (LC/MS): 409.6 (M+H).

Example 13

Preparation of 2,5-dimethyl-2H-pyrazole-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2- trifluoro-ethoxy)-pyridin-3-yl] -amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and l,3-dimethyl-lH-pyrazole-5-carboxylic acid as starting materials, MS (LC/MS): 425.6 (Μ+Η). Example 14

Preparation of 3-methyl-isoxazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-

(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-methyl-4-isoxazolecarboxylic acid as starting materials, MS (LC/MS): 412.2 (M+H).

Example 15

Preparation of l-methyl- lH-pyrazole-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and l-methyl- lH-Pyrazole-3-carboxylic acid as starting materials, MS (LC/MS): 411.0 (Μ+Η).

Preparation of 5-methyl-3-isoxazolecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-3-isoxazolecarboxylic acid as starting materials, MS (LC/MS): 412.2 (M+H).

Example 17

Preparation of 3-pyridazinecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin- 3 - yl] - amide The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-

(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-pyridazinecarboxylic acid as starting materials, MS (LC/MS): 409.0 (M+H).

Example 18

Preparation of N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-3-methyl-4- pyridinecarboxylic acid amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-methyl-4-pyridinecarboxylic acid as starting materials, MS (LC/MS): 422.0 (M+H). Example 19

Preparation of 5-pyrimidinecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin- 3 - yl] - amide The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-

(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-pyrimidinecarboxylic acid as starting materials, MS (LC/MS): 409.0 (M+H).

Example 20

Preparation of 1 -methyl- lH-pyrazole-5-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1 -methyl- lH-pyrazole-5-carboxylic acid, as starting materials, MS (LC/MS): 409.2 (Μ-Η).

Example 21

Preparation of 2,4-dimethyl-5-oxazolecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2,4-dimethyl-5-oxazolecarboxylic acid, as starting materials, MS (LC/MS): 426.2 (M+H).

Example 22

Preparation of 5-isothiazolecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin- 3 - yl] - amide The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-

(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-isothiazolecarboxylic acid as starting materials, MS (LC/MS): 414.0 (M+H).

Example 23

Preparation of 5-methyl- lH-pyrazole-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl- lH-pyrazole-3-carboxylic acid as starting materials, MS (LC/MS): 409.2 (Μ-Η). Example 24

Preparation of lH-pyrazole-3-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin- 3 - yl] - amide The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-

(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and lH-pyrazole-3-carboxylic acid as starting materials, MS (LC/MS): 395.2 (Μ-Η).

Example 25

Preparation of N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-2-methyl-4- pyridinecarboxylic acid amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-methyl-4-pyridinecarboxylic acid, as starting materials, MS (LC/MS): 422.0 (Μ+Η).

Example 26

Preparation of 5-methyl-2-thiazole-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-2-thiazolecarboxylic acid, as starting materials, MS (LC/MS): 428.2 (M+H).

Example 27

Preparation of 4-methyl- l,2,3-thiadiazole-5-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2- trifluoro-ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 4-methyl- l,2,3-thiadiazole-5-carboxylic acid, as starting materials, MS (LC/MS): 429.2 (M+H).

Preparation of N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-6-methyl-3- pyridinecarboxylic acid amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 6-methyl-3-pyridinecarboxylic acid as starting materials, MS (LC/MS): 420.4 (M-H). Example 29

Preparation of N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-2-methyl-3- pyridinecarboxylic acid amide The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-

(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-methyl-3-pyridinecarboxylic acid as starting materials, MS (LC/MS): 421.8 (M+H).

Example 30

Preparation of 5-isoxazolecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin- 3 - yl] - amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-isoxazolecarboxylic acid as starting materials, MS (LC/MS): 398.0 (M+H).

Example 31

Preparation of 3,5-dimethyl-4-isoxazolecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3,5-dimethyl-4-isoxazolecarboxylic acid, as starting materials, MS (LC/MS): 426.2 (M+H).

Example 32

Preparation of N-[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]- l,2-dihydro-2- oxo-4-pyridinecarboxylic acid amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and l,2-dihydro-2-oxo-4-pyridinecarboxylic acid, as starting materials, MS (LC/MS): 424.0 (M+H).

Example 33

Preparation of 1,3 -dimethyl- lH-pyrazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2- trifluoro-ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and l,3-dimethyl-lH-pyrazole-4-carboxylic acid as starting materials, MS (LC/MS): 425.0 (Μ+Η). Example 34

Preparation of 4-pyrimidinecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)- pyridin- 3 - yl] - amide The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-

(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 4-pyrimidinecarboxylic acid as starting materials, MS (LC/MS): 409.0 (M+H).

Example 35

Preparation of 2-thiazolecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin- 3 -yl]- amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-thiazolecarboxylic acid as starting materials, MS (LC/MS): 414.0 (M+H).

Example 36

Preparation of 3-methyl-2-pyridinecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-methyl-2-pyridinecarboxylic acid as starting materials, MS (LC/MS): 422.0 (M+H).

Example 37

Preparation of 5-methyl-4-oxazolecarboxylic acid [5-(4-chloro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-

(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-4-oxazolecarboxylic acid as starting materials, MS (LC/MS): 412.2 (M+H).

Example 38

Preparation of N-(5-(3,4-dimethylphenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)nicotinamide

In a 25 mL sealed tube N-(5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)nicotinamid e (200 mg, 532 μιηοΐ) was combined with toluene (11 mL). Under argon atmosphere, were added 3.4-dimethylbenzeneboronic acid (160 mg, 1.06 mmol), an aqueous solution of sodium carbonate (2M, 0.53 mL) and Pd(dppf) ₂ Cl ₂ (12 mg, 0.016 mmol). After two hours at 90 °C, the dark red suspension was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (10 mL) and brine (10 mL). The aqueous layer was back-extracted with ethyl acetate (15 mL). The organic layers were dried over MgS0 ₄ and concentrated in vacuo.

Crystallization from ethyl acetate / heptane (5 mL, 1 / 2) gave a white solid (96 mg), the filtrate was evaporated to dryness and purified by column chromatography (silica gel, 20 g, 10% to 100% ethyl acetate in heptane) to get a second part of the desired product as a white solid (139 mg). Overall yield was 65%; MS (EI): 402.3 (M+H).

Example 39

Preparation of N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)nicotin- amide

In a 25 ml sealed tube N-(5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)nicotinamid e (520 mg, 1.38 mmol) was combined with toluene (20 mL). Under argon atmosphere, were added 4- chloro-3-methylphenylboronic acid (471 mg, 2.77 mmol), an aqueous solution of sodium carbonate (2M, 1.38 mL) and Pd(dppf) ₂ Cl ₂ (30 mg, 0.041 mmol). After two hours at 90 °C, the dark red suspension was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (10 mL) and brine (10 mL). The aqueous layer was back-extracted with ethyl acetate (15 mL). The organic layers were dried over MgS0 ₄ and concentrated in vacuo. The crude material (760 mg) was purified by flash chromatography (silica gel, 20 g, 20% to 100% ethyl acetate in heptane) to give the title compound as a light brown solid (575 mg, 98%); MS (EI): 422.8 (M+H).

Example 40

Preparation of 5-hydroxy-pyridine-2-carboxylic acid [5-(4-cmoro-phenyl)-6-(2,2,2-trifluoro- ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6- (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-hydroxy-2-pyridinecarboxylic acid (CAN 15069-92-8) as starting materials; LC-MS (UV peak area/ESI) 96.3%, 422.0523 (M-H) ^" .

Example 41

Preparation of N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -5-methylnicotin- amide

The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6 (2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-3-pyridinecarboxylic acid (CAN 3222 49-9) as starting materials; MS (EI) 422.1 (M+H) ⁺ .

Example 42

Preparation of (S)-N-(5-(4-chlorophenyl)-6-(l,l, l-trifluoropropan-2-yloxy)pyridin-3- yl)pyridazine-3-carboxamide a) 5-Chloro-3-(4-chloro-phenyl)-2-fluoro-pyridine

A mixture of 3-bromo-5-chloro-2-fluoro-pyridine, (CAN 884494-87-5; 2.0 g, 9.50 mmol), 4-chlorophenylboronic acid (CAN 1679-18-1; 1.5 g, 9.50 mmol); tetrakis(triphenylphoshine)- palladium (0.55 g, 0.48 mmol) and potassium carbonate (2.6 g, 19 mmol) in water (50 mL) and THF (50 mL) was heated at reflux temperature for 18 h. The reaction mixture was cooled, diluted with ethyl acetate, phases were separated and the water phase was extracted with ethyl acetate. The organic phases were pooled, dried with MgS04 and the solvent was removed in vacuo. The residue was purified by column chromatography (on silica gel with a gradient of heptane to heptane : ethyl acetate = 9 : 1 to yield the title product (2.2 g, 95%) as white solid; MS (ESI): 241.0 (M) ⁺ . b) 5-Chloro-3-(4-chloro-phenyl)-2-((S)-2,2,2-trifluoro-l-methyl -ethoxy)-pyridine

To a mixture of 1.133g (S)-l,l,l-trifluoro-2-propanol in 10ml dry DMF 397mg sodium hydride (60%) was added and the mixture was stirred at room temperature for 30 minutes. The resulting solution was added dropwise at RT to a solution of 2.185g 5-chloro-3-(4-chloro- phenyl)-2-fluoro-pyridine in 20ml dry DMF. The reaction mixture was then stirred at room temperature for 2h. The resulting light yellow mixture was partitioned between water and ethyl acetate, the phases were separated. The organic phase was dried over MgS0 ₄ and purified by chromatography on silica gel with a gradient of heptane to heptane : ethyl acetate = 9 : 1 to yield 2.330g (76.80%) of the title compound as colourless liquid; MS (ESI) 336.1(M+H) ⁺ . c) (S)-Methyl 5-(4-chlorophenyl)-6-( 1 ,1,1 -trifluoropropan-2-yloxy)nicotinate

To a solution of 2.42 g 5-chloro-3-(4-chloro-phenyl)-2-((S)-2,2,2-trifluoro-l-methyl - ethoxy)-pyridine in 50 mL methanol was added 1.09 g triethylamine and 0.484 g

PdCl ₂ .dppf.CH ₂ Cl ₂ . The mixture was heated to 150 °C under an atmosphere of 70 bar carbon monoxide for 20 h. The reaction mixture was cooled to room temperature. The solids were removed by filtration and the mother liquor was evaporated and purified by chromatography on silica gel using a gradient of heptane to heptane : ethyl acetate 85 : 15 to yield 0.862g (33%) of the title compound as a light yellow oil; MS (ESI) 359 (M ⁺ ). d) (S)-5-(4-Chlorophenyl)-6-(l,l,l-trifluoropropan-2-yloxy)nico tinic acid

To a solution of 0.860 g (S)-methyl 5-(4-chlorophenyl)-6-( 1,1,1 -trifluoropropan-2- yloxy)nicotinate in 9 mL tetrahydrofuran was added 3 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was acidified by addition of 1M hydrochloric acid till pH=2. Ethyl acetate was added and the phases were separated. The organic phase was dried over MgS0 ₄ and the solvent was removed to yield 830 mg (100%) of the title compound as light yellow solid; MS (ESI) 344.1 (M-H) ^~ . e) [5-(4-Chloro-phenyl)-6-((S)-2,2,2-triiluoro-l-methyl-ethoxy) -pyridin-3-yl]-carbamic acid tert- butyl ester

(S)-5-(4-Chlorophenyl)-6-(l,l,l-trifluoropropan-2-yloxy)n icotinic acid (0.300 g, 868 μηιοΐ) was suspended in i-butanol (3.0 niL). DPPA (358 mg, 282 μΐ), and triethylamine (87.8 mg, 120 μΐ, 868 μηιοΐ) were added and the reaction mixture was stirred at 100°C overnight. The mixture was cooled to room temperature, extracted with ethyl acetate and sodium carbonate solution, the organic phase was dried with MgS0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20g, 5% to 25% ethyl acetate in heptane) to give 0.36 g (99%) of the title compound as white solid; MS (EI) 417.3 (M+H) ⁺ . f) 5-(4-Chloro-phenyl)-6-((S)-2,2,2-trifluoro-l-methyl-ethoxy)- pyridin-3-ylamine

Trifluoroacetic acid (2.74 g, 1.85 ml, 24.0 mmol) was added to (S)-tert-butyl 5-(4- chlorophenyl)-6-(l,l,l-trifluoropropan-2-yloxy)pyridin-3-ylc arbamate (0.350 g, 840 μιηοΐ). The resulting yellow solution was stirred at RT for 1 h. The solvent was evaporated. The residue was partitioned between ethyl acetate and 1M Na ₂ C0 ₃ solution, the organic phase was dried with MgS0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20g, 5 to 50% EtOAc in heptane) to give 0.22 g (82%) of the title compound as light brown oil; MS (EI) 317.1 (M+H) ⁺ . g) (S)-N-(5-(4-chlorophenyl)-6-(l,l, l-trifluoropropan-2-yloxy)pyridin-3-yl)pyridazine-3- carboxamide

Pyridazine-3-carboxylic acid (CAN 2164-61-6; 43.1 mg, 347 μιηοΐ) was suspended in DMF (1.0 mL) . TBTU (112 mg, 347 μιηοΐ), ethyldiisopropylamine (102 mg, 131 μΐ, 789 μιηοΐ,) and 5-(4-chloro-phenyl)-6-((S)-2,2,2-trifluoro-l-methyl-ethoxy)- pyridin-3-ylamine (0.100 g, 316 μιηοΐ) were added and the reaction mixture was stirred at room temperature for 1 h. The rection mixture was extracted with ethyl acetate and 1M citric acid solution; the organic phase was dried with MgS0 ₄ and concentrated in vacuo. The crude material was purified by flash

chromatography (silica gel, lOg, 10% to 50% ethyl acetate in heptane) to give 0.11 g (83%) of the title compound as white solid; MS (EI) 423.1 (M+H) ⁺ .

Example 43

Preparation of (S)-N-(5-(4-chlorophenyl)-6-( 1 , 1 , l-trifluoropropan-2-yloxy)pyridin-3- yl)nicotinamide

The title compound was synthesized in analogy to Example 42g, using 5-(4-chloro- phenyl)-6-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-pyridin-3-yl amine (example 42f) and 3-pyridine carboxylic acid (CAN 59-67-6) as starting materials; MS (EI) 422.0 (M+H) ⁺ . Example 44

Preparation of N-(5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)nicotin- amide The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2- trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-chloro-3-fluorophenyl)- boronic acid (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 96.4%, 424.0482 (M-H) ^~ .

Example 45

Preparation of N-(5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)nicotin- amide

The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2- trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(3-chloro-4-fluorophenyl)- boronic acid (CAN 144432-85-9) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 424.0483 (M-H) ^~ . Example 46

Preparation of N-(5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)nicotin- amide

The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2 trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-chloro-2-fluorophenyl)- boronic acid (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 97.2%, 424.0483 (M-H) ^~ .

Example 47

Preparation of N-(5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)n icotinamide

The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2 trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-ethylphenyl)-boronic acid (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 100%, 402.1409 (M+H) ⁺ .

Example 48

Preparation of (S)-N-(6-(4-chlorophenyl)-5-( 1,1, 1 -trifluoropropan-2-yloxy)pyrazin-2- yl)nicotinamide a) 6-(4-Chloro-phenyl)-5-((S)-2,2,2-trifluoro-l-methyl-ethoxy)- pyrazine-2-carboxylic acid methyl ester

5-Bromo-6-(4-chlorophenyl)-2-pyrazinecarboxylic acid methyl ester (CAN 960247-79-4, 2.420 g, 7.39 mmol) was dissolved in dry DMSO (25 mL). Cesium carbonate (4.41 g, 8.13 mmol) and (S)-l, l,l-trifluoropropan-2-ol (927 mg, 8.13 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The mixture was partitioned between water and ethyl acetate; the organic phase was dried with MgS0 ₄ and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, lOOg, 10% to 50% ethyl acetate in heptane) to yield 2.53 g (95%) of the title compound as yellow oil; MS (EI) 361.1 (M+H) ⁺ . b) 6-(4-Chloro-phenyl)-5-((S)-2,2,2-trifluoro- l-methyl-ethoxy)-pyrazine-2-carboxylic acid

The title compound was synthesized in analogy to Example 42d, using 6-(4-chloro- phenyl)-5-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-pyrazine-2-c arboxylic acid methyl ester as starting material; MS (ESI) 345.0 (M-H) ^~ . c) [6-(4-Chloro-phenyl)-5-((S)-2,2,2-trifluoro- l-methyl-ethoxy)-pyrazin-2-yl]-carbamic acid tert-butyl ester

The title compound was synthesized in analogy to Example 42e, using 6-(4-chloro- phenyl)-5-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-pyrazine-2-c arboxylic acid as starting material; MS (EI) 418.2 (M+H) ⁺ . d) 6-(4-Chloro-phenyl)-5-((S)-2,2,2-trifluoro-l-methyl-ethoxy)- pyrazin-2-ylamine

The title compound was synthesized in analogy to Example 42f, using [6-(4-chloro- phenyl)-5-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-pyrazin-2-yl ]-carbamic acid tert-butyl ester starting material; MS (EI) 318.0 (M+H) ⁺ . -(4-chlorophenyl)-5-( 1,1,1 -trifluoropropan-2-yloxy)pyrazin-2-yl)nicotinamide

6-(4-Chloro-phenyl)-5-((S)-2,2,2-trifluoro- l-methyl-ethoxy)-pyrazin-2-ylamine (0.100 g, 315 μιηοΐ) was dissolved in dried pyridine (1.0 mL), nicotinoyl chloride hydrochloride (61.6 mg, 346 μηιοΐ) was added and the suspension was stirred at 140 °C for 10 minutes in the microwave. The solvent was evaporated and the crude material was purified by flash chromatography (silica gel, lOg, 0% to 50% CH ₂ Cl ₂ /MeOH/NH ₃ 9/1/0.1) to give 0.121 g (91%) of the title compound as white solid; LC-MS (UV peak area/ESI) 100%, 423.0821 (M+H) ⁺ .

Example 49

Preparation of N-(6-(4-chlorophenyl)-5-(2,2,2-trif uoroethoxy)pyrazin-2-yl)nicotinamide a) 6-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-ca rboxylic acid methyl ester

The title compound was synthesized in analogy to Example 48a, using 5-bromo-6-(4- chlorophenyl)-2-pyrazinecarboxylic acid methyl ester (CAN 960247-79-4) and 2,2,2- trifluoroethanol as starting materials; MS (EI) 347.1 (M+H) ⁺ .

b) 6-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-ca rboxylic acid

The title compound was synthesized in analogy to Example 42d, using 6-(4-chloro- phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid methyl ester as starting material; MS (ESI) 331.1 (M-H) ^" . c) [6-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazin-2-yl ]-carbamic acid tert-butyl ester

The title compound was synthesized in analogy to Example 42e, using 6-(4-chloro- phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid as starting material; MS (EI) 404.3 (M+H) ⁺ . d) 6-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazin-2-yla mine

The title compound was synthesized in analogy to Example 42f, using [6-(4-chloro- phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazin-2-yl]-carbamic acid tert-butyl ester as starting material; MS (EI) 304.0 (M+H) ⁺ . -(4-Chlorophenyl)-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)nico tinamide

The title compound was synthesized in analogy to Example 48e, using 6-(4-chloro- phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazin-2-ylamine (example 49d) and nicotinoyl chloride hydrochloride as starting materials; LC-MS (UV peak area/ESI) 95.7%, 407.0532 (M-H) ^" .

Example 50

Preparation of N-(6-(4-chlorophenyl)-5-cyclobutoxypyrazin-2-yl)nicotinamide a) 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyrazine-2-carboxyl ic acid

Cyclopropylmethanol (1.54 g, 1.73 ml, 21.3 mmol) was diluted in dried DMF (15 mL); sodium hydride (512 mg, 21.3 mmol) was added in portions and the reaction mixture was stirred at room temperature for 15 minutes. The resulting solution was added slowly at <5°C to a solution of 5-bromo-6-(4-chlorophenyl)pyrazine-2-carboxylic acid (CAN 960247-80-7; 3.040 g, 9.7 mmol) in dried DMF (15 mL). The reaction mixture was stirred at room temperature for 30 minutes; water was added and the mixture was acidified with 1M HC1 solution to pH = 2. The mixture was extracted with ethyl acetate; organic phases were combined, dried with MgS0 ₄ and concentrated in vacuo. The crude did still contain starting material and was dissolved again in 15 mL DMF; a solution of cyclopropylmethanol (1.05 g, 1.18 ml, 14.5 mmol) and sodium hydride (582 mg, 14.5 mmol) in 15 mL DMF was added and the mixture was stirred at room temperature for 3 hours. Water was added and the reaction mixture was acidified with 1M HC1 solution to pH 2; the product precipitated to give 2.55 g (86%) of the title compound as light yellow solid; MS (ESI) 303.2 (M-H) ^~ . b) [6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyrazin-2-yl]-carb amic acid tert-butyl ester

The title compound was synthesized in analogy to Example 42e, using 6-(4-Chloro- phenyl)-5-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 50a) as starting material; MS (EI) 376.3 (M+H) ⁺ . c) 6-(4-Chloro-phenyl)-5-cyclobutoxy-pyrazin-2-ylamine

TFA (14.8 g, 10 mL, 130 mmol) was added to [6-(4-chloro-phenyl)-5- cyclopropylmethoxy-pyrazin-2-yl]-carbamic acid tert-butyl ester (example 50b, 1.365 g, 3.63 mmol). The resulting yellow solution was stirred at room temperature for 1 h. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1M Na ₂ C0 ₃ solution; the organic phases were combined, dried with MgS0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, lOOg, 10% to 50% ethyl acetate in heptane; then ethyl acetate/methanol 9/1 to give 0.133 g (13%) of the title compound (by rearrangement) as yellow oil; MS (EI) 276.1 (M+H) ⁺ . -(4-Chlorophenyl)-5-cyclobutoxypyrazin-2-yl)nicotinamide

The title compound was synthesized in analogy to Example 48 e, using 6-(4-chloro- phenyl)-5-cyclobutoxy-pyrazin-2-ylamine (example 50c) and nicotinoyl chloride hydrochloride as starting materials; LC-MS (UV peak area/ESI) 97.4%, 381.1096 (M+H) ⁺ .

Example 51

Preparation of N-(6-(4-chlorophenyl)-5-cyclobutoxypyrazin-2-yl)pyrimidine-5 -carboxamide

The title compound was synthesized in analogy to Example 42g, using 6-(4-chloro- phenyl)-5-cyclobutoxy-pyrazin-2-ylamine (example 50c) and 5-pyrimidinecarboxylic acid (CAN 4595-61-3) as starting materials; LC-MS (UV peak area/ESI) 96.3%, 482.1073 (M+H) ⁺ .

Example 52

Preparation of N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyrimidine- 5-carboxamide a) Pyrimidine-5-carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 42 g, using 5-bromo-6-(2, 2, 2- trifluoro-ethoxy)-pyridin-3-ylamine (example D) and 5-pyrimidinecarboxylic acid (CAN 4595- 61-3) as starting materials; MS (ESI) 375.2 (M-H) ^" . b) N-(5-(4-Chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyrimidine-5- carboxamide

The title compound was synthesized in analogy to Example 39, using pyrimidine-5- carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B- (4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; LC-MS (UV peak area/ESI) 100%, 421.0698 (M-H) ^" .

Example 53

Preparation of N-(5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyrimidine- 5-carboxamide

The title compound was synthesized in analogy to Example 39, using pyrimidine-5- carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B- (4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 425.0448 (M-H) ^" .

Preparation of N-(5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyrimidine- 5-carboxamide

The title compound was synthesized in analogy to Example 39, using pyrimidine-5- carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B- (3-chloro-4-fluorophenyl)-boronic acid (CAN 144432-85-9) as starting materials; LC-MS (UV peak area/ESI) 93.5%, 425.0449 (M-H) ^" .

Preparation of N-(5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyrimidine- 5-carboxamide

The title compound was synthesized in analogy to Example 39, using pyrimidine-5- carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B- (4-chloro-2-fluorophenyl)-boronic acid (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 92.2%, 425.0446 (M-H) ^" . Example 56

Preparation of N-(5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)p yrimidine-5- carboxamide

The title compound was synthesized in analogy to Example 39, using pyrimidine-5- carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B- (4-ethylphenyl)-boronic acid (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 100%, 403.1384 (M+H) ⁺ .

Example 57

Preparation of N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-2- hydroxyisonicotinamide a) 5-(4-Chloro-3-methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyri din-3-ylamine

The title compound was synthesized in analogy to Example 39, using 5-bromo-6-(2, 2, 2- trifluoro-ethoxy)-pyridin-3-ylamine (example D) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; MS (EI) 317.0 (M+H) ⁺ . b) N-(5-(4-Chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-2- hydroxyisonicotinamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-Chloro-3- methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 1,2-dihydro- oxo-4-pyridinecarboxylic acid (CAN 22282-72-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 436.0689 (M-H) ^" .

Example 58

Preparation of N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-l,3- dimethyl-lH-pyrazole-4-carboxamide a) l,3-Dimethyl- lH-pyrazole-4-carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-amid

The title compound was synthesized in analogy to Example 42 g, using 5-bromo-6-(2, 2, 2- trifluoro-ethoxy)-pyridin-3-ylamine (example D) and 1, 3 -dimethyl- lH-pyrazole-4-carboxylic acid (CAN 78703-53-4) as starting materials; LC-MS (UV peak area/ESI) 100%, 393.0063 (M- H)-. b) N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-l,3-dimethyl- lH- pyrazole-4-carboxamide

The title compound was synthesized in analogy to Example 39, using 1,3 -dimethyl- 1H- pyrazole-4-carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 58 a) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; LC- MS (UV peak area/ESI) 96.1%, 439.1154 (M+H) ⁺ .

Example 59

Preparation of N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-2,4- difluoronicotinamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3- methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 2,4-difluoro- 3- pyridinecarboxylic acid (CAN 849937-90-2) as starting materials; MS (EI) 458.2 (M+H) ⁺ . Example 60

Preparation of N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -2-hydroxy- benzamide The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-hydroxy-benzoic acid (CAN 69-72-7) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 421.5080 (M-H) ^" .

Example 61

Preparation of N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-5- cyanonicotinamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3- methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 5-cyano-3- pyridinecarboxylic acid, (CAN 887579-62-6) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 445.0693 (M-H) ^" . Example 62

Preparation of N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyridazine- 3-carboxamide a) Pyridazine-3-carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide

The title compound was synthesized in analogy to Example 42 g, using 5-bromo-6-(2, 2, 2- trifluoro-ethoxy)-pyridin-3-ylamine (example D) and 3-pyridazinecarboxylic acid (CAN 2164- 61-6) as starting materials; MS (ESI) 375.2 (M-H) ^" . b) N-(5-(4-Chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyridazine-3- carboxamide

The title compound was synthesized in analogy to Example 39, using pyridazine-3- carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B- (4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; LC-MS (UV peak area/ESI) 94.2%, 423.0828 (M+H) ⁺ . Example 63

Preparation of N-(5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyridazine- 3-carboxamide The title compound was synthesized in analogy to Example 39, using pyridazine-3- carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B- (4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 425.0438 (M-H) ^~ .

Example 64

Preparation of N-(5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)pyridazine- 3-carboxamide

The title compound was synthesized in analogy to Example 39, using pyridazine-3- carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B- (4-chloro-2-fluorophenyl)-boronic acid (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 427.0587 (M+H) ⁺ . Example 65

Preparation of N-(5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)p yridazine-3- carboxamide

The title compound was synthesized in analogy to Example 39, using pyridazine-3- carboxylic acid [5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B- (4-ethylphenyl)-boronic acid (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 98.9%, 403.1386 (M+H) ⁺ .

Example 66

Preparation of N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) furan-2-carboxamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-furancarboxylic acid (CAN 88-14-2) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 397.0566 (M+H) ⁺ .

Example 67

Preparation of N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) furan-3-carboxamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 3-furancarboxylic acid

(CAN 488-93-7) as starting materials; LC-MS (UV peak area/ESI) 98.2%, 395.0414 (M-H) ^" .

Example 68

Preparation of N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -5-methylfuran-2- carboxamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 5-methyl-2- furancarboxylic acid (CAN 1917-15-3) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 409.574 (M-H) ^" .

Example 69

Preparation of N-(5-(4-chloro-3-methylphenyl)-6-(2-methoxyethoxy)pyridin-3- yl)benzamide a) 3-Bromo-2-(2-methoxy-ethoxy)-5-nitro-pyridine

To a solution of 2-methoxyethanol (8.81 g, 9.13 ml, 116 mmol) in anhydrous THF (150ml) was added sodium hydride (4.63 g, 116 mmol) under nitrogen at 5 °C or below and the reaction mixture was stirred at 25 °C for 1 h. Then 3-bromo-2-chloro-5-nitropyridine (CAN 5470-17-7) (25 g, 105 mmol) was added drop wise at 25 °C and stirred at 25 °C for 1 h. Ice-water (150ml) was added to the reaction mixture and extracted with ethyl acetate (500 mL). The combined organic layers was washed with water and brine, dried over Na ₂ S0 ₄ and evaporated under reduced pressure to get the crude residue (25.7 g). The crude was purified by column

chromatography (15% ethyl acetate/hexane) to get the desired product (21.6 g, 74%) as light yellow solid; GC/MS (FID/EI): 100%, 276.0 (M) ⁺ . b) 5-Bromo-6-(2-methoxy-ethoxy)-pyridin-3-ylamine The title compound was synthesized in analogy to Example C, using 3-bromo-2-(2- methoxy-ethoxy)-5-nitro-pyridine (example 69 a) as starting material; LC-MS (UV peak area/ESI) 100%, 247.0084 (M+H) ⁺ . c) 5-(4-Chloro-3-methyl-phenyl)-6-(2-methoxy-ethoxy)-pyridin-3- ylamine

The title compound was synthesized in analogy to Example E, using 5-bromo-6-(2- methoxy-ethoxy)-pyridin-3-ylamine (example 69 b) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; GC/MS (FID/EI): 100%, 292 (M) ⁺ . d) N-(5-(4-chloro-3-methylphenyl)-6-(2-methoxyethoxy)pyridin-3- yl)benzamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3- methyl-phenyl)-6-(2-methoxy-ethoxy)-pyridin-3-ylamine (example 69 c) and benzoic acid as starting materials; LC-MS (UV peak area/ESI) 100%, 397.1307 (M+H) ⁺ .

Example 70

Preparation of (RS)-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin- 3- yl)tetrahydrofuran-2-carboxamide The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and tetrahydro-2- furancarboxylic acid, (CAN 16874-33-2) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 30% ethanol/ n-heptane (-) enantiomer isolated; LC-MS (UV peak area/ESI) 100%, 401.0868 (M+H) ⁺ ; a™(MeOH) = -16.8°

Example 71

Preparation of (SR)-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin- 3-yl)- tetrahydrofuran-3 -carboxamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and tetrahydro-3- furancarboxylic acid, (CAN 89364-31-8) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 30% ethanol/ n-heptane (+) enantiomer isolated; LC-MS (UV peak area/ESI) 98.1%, 401.0869 (M+H) ⁺ ; a {MeOH) = +10.1°

Example 72

Preparation of N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -4-methyl-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazine-7-carboxamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 3,4-dihydro-4-methyl- 2H-pyrido[3,2-b]-l,4-oxazine-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 479.2 (M+H) ⁺ .

Example 73

Preparation of N-(5-(4-amino-3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyrid in-3-yl)-5- iodonicotinamide a) {4-[5-Amino-2-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-2-chlor o-phenyl}-carbamic acid benzyl ester

The title compound was synthesized in analogy to Example E, using 5-bromo-6-(2, 2, 2- trifluoro-ethoxy)-pyridin-3-ylamine (example C) and N-[2-chloro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-carbamic acid phenylmethyl ester (CAN 1218791-42-4) as starting materials; MS (EI) 452.1 (M+H) ⁺ . b) {2-Chloro-4-[5-[(5-iodo-pyridine-3-carbonyl)-amino]-2-(2,2,2 -trifluoro-ethoxy)-pyridin-3- yl] -phenyl }-carbamic acid benzyl ester

The title compound was synthesized in analogy to Example 42 g, using {4-[5-amino-2- (2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-2-chloro-phenyl}-carb amic acid benzyl ester (example 73 a) and 5-iodo-3-pyridinecarboxylic acid (CAN 15366-65-1) as starting materials; LC-MS (UV peak area/ESI) 68.6%, 683.4 (M+H) ⁺ . -amino-3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl )-5-iodonicotinamide

{2-Chloro-4-[5-[(5-iodo-pyridine-3-carbonyl)-amino]-2-(2, 2,2-trifluoro-ethoxy)-pyridin-3- yl] -phenyl }-carbamic acid benzyl ester (87 mg, 127 μηιοΐ) was, with cooling, combined with trifluoroacetic acid (3 mL) to give a brown solution. The reaction mixture was warmed to room temperature and stirred for 72 h. The crude reaction mixture was concentrated in vacuo, poured into 50 mL ethyl acetate and extracted with 1 M NaOH (1 x 25 mL). The aqueous layer was washed with ethyl acetate (1 x 50 mL). The organic layers were combined, dried with Na ₂ S0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20g, 0% to 40% EtOAc in heptane) to give the title compound (59 mg, 84%); LC-MS (UV peak area/ESI) 98.1%, 548.9795 (M+H) ⁺ .

Example 74

Preparation of N-(5-phenyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)nicotinami de The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2- trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-phenyl-boronic acid (CAN 98- 80-6) as starting materials; LC-MS (UV peak area/ESI) 100%, 374.1107 (M+H) ⁺ . Example 75

Preparation of N-(5-(4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) nicotinamide

The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2 trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-fluorophenyl)-boronic acid (CAN 1765-93-1) as starting materials; LC-MS (UV peak area/ESI) 100%, 392.1005 (M+H) ⁺ .

Example 76

Preparation of N-(5-(3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) nicotinamide

The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2 trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(3-chlorophenyl)-boronic acid (CAN 63503-60-6) as starting materials; LC-MS (UV peak area/ESI) 100%, 408.0719 (M+H) ⁺ .

Example 77

Preparation of N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -5- methoxynicotinamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 5-methoxy- 3- pyridinecarboxylic acid (CAN 20826-03-3) as starting materials; LC-MS (UV peak area/ESI) 97.8%, 438.0812 (M+H) ⁺ .

Example 78

Preparation of N-(5-(4-chlorophenyl)-6-cyclobutoxypyridin-3-yl)pyrazine-2-c arboxamide a) 5-Bromo-6-cyclobutoxy-nicotinic acid

5-Bromo-6-chloronicotinic acid (CAN 29241-62-1; 3 g, 12.7 mmol) was dissolved in DMSO (30 mL); cyclobutanol (1.19 g, 1.29 ml, 16.5 mmol) and potassium hydroxide (powder) (2.14 g, 38.1 mmol) were added and the reaction mixture was stirred at room temperature for 5 h. More cyclobutanol (0.5 mL) and KOH (1 g) was added and the reaction mixture was stirred at room temperature for another 2 days. Water (30 mL) was added and the mixture was acidified (cooling) with 5 mL 37% HC1 in water (pH = 2). The suspension was filtered and washed with water. The cake was dried in vacuo to obtain the title compound (3.1 g, 88.7%) as white solid; MS (ESI) 270.2 (M-H) ^~ . b) 5-(4-Chloro-phenyl)-6-cyclobutoxy-nicotinic acid

5-Bromo-6-cyclobutoxy-nicotinic acid (example 78 a; 1.531 g, 5.63 mmol), 4-chloro- phenylboronic acid (968 mg, 6.19 mmol), potassium carbonate (1.56 g, 11.3 mmol) and tetrakis(triphenylphosphine)palladium (325 mg, 281 μιηοΐ) were suspended in THF (38 mL) and water (38 mL). The reaction mixture was stirred at reflux temperature (100°C) over the weekend. THF was removed and the residue was partitioned between water (pH = 2) and ethyl acetate; the organic phases were combined, dried with MgS0 ₄ and concentrated in vacuo to obtain the title compound (quant.) as off-white solid; MS (ESI) 302.2 (M-H) ^~ . c) [5-(4-Chloro-phenyl)-6-cyclobutoxy-pyridin-3-yl]-carbamic acid tert-butyl ester

The title compound was synthesized in analogy to Example 42e, using 5-(4-chloro- phenyl)-6-cyclobutoxy-nicotinic acid (example 78 b) as starting material; LC-MS (UV peak area/ESI) 92.9%, 375.1456 (M+H) ⁺ .

d) 5-(4-Chloro-phenyl)-6-cyclobutoxy-pyridin-3-ylamine

[5-(4-Chloro-phenyl)-6-cyclobutoxy-pyridin-3-yl]-carbamic acid tert-butyl ester (1.042 g, 2.78 mmol) was dissolved in 4M HCl in dioxane (10.4 ml, 41.7 mmol). The reaction mixture was a light yellow solution and was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and 1M Na ₂ C0 ₃ solution. The organic phases were combined, dried with MgS0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, lOOg, 5% to 75% ethyl acetate in heptane) to give 0.358g (46.9%) of the title compound as light red oil; LC-MS (UV peak area/ESI) 94.3%, 275.0950 (M+H) ⁺ . e) N-(5-(4-chlorophenyl)-6-cyclobutoxypyridin-3-yl)pyrazine-2-c arboxamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and 2-pyrazinecarboxylic acid (CAN 98-97-5) as starting materials; MS (EI) 381.2(M+H) ⁺ .

Example 79

Preparation of N-(5-(4-chlorophenyl)-6-cyclobutoxypyridin-3-yl)nicotinamide

The title compound was synthesized in analogy to Example 48e, using 5-(4-chloro- phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and nicotinoyl chloride hydrochloride as starting materials; MS (EI) 380.2(M+H) ⁺ .

Example 80

Preparation of N-(5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-4-methyl- 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-7-carboxamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3- methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 3,4-dihydro-4- methyl-2H-pyrido[3,2-b]-l,4-oxazine-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 493.1(M+H) ⁺ . Example 81

Preparation of N-(5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-4-methyl- 3,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]oxazine-7-carboxamide a) 5-(4-Chloro-3-fluoro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyri din-3-ylamine

The title compound was synthesized in analogy to Example E, using 5-bromo-6-(2, 2, 2- trifluoro-ethoxy)-pyridin-3-ylamine (example C) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; MS (EI) 379.3 (M+OAc) ⁺ . b) N-(5-(4-Chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyri din-3-yl)-4-methyl-3,4-dihydro 2H-pyrido[3,2-b][l,4]oxazine-7-carboxamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3- fluoro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 81 a) and 3,4-dihydro-4- methyl-2H-pyrido[3,2-b]-l,4-oxazine-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 497.2(M+H) ⁺ . Example 82

Preparation of 5-Methyl-oxazole-4-carboxylic acid [5-(4-chloro-phenyl)-6-cyclobutoxy-pyridin- 3-yl] -amide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and 5-methyl-4-oxazolecarboxylic acid (CAN 103879-58-9) as starting materials; LC-MS (UV peak area/ESI) 100%, 384.1102 (M+H) ⁺ .

Example 83

Preparation of N-[5-(4-Chloro-phenyl)-6-cyclobutoxy-pyridin-3-yl]-5-methyl- nicotinamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and 5-methyl-3-pyridinecarboxylic acid (CAN 40473-04-9) as starting materials; MS (EI) 394.1 (M+H) ⁺ . Example 84

Preparation of N5-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl )-N2- methylpyridine-2,5-dicarboxamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 6-[(methylamino)- carbonyl]-3-pyridinecarboxylic acid (CAN 170464-32- 1) as starting materials; MS (EI) 465.2(M+H) ⁺ .

Example 85

Preparation of 5-bromo-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyrid in-3- yl)nicotinamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 5-bromo-3- pyridinecarboxylic acid (CAN 20826-04-4) as starting materials; LC-MS (UV peak area/ESI) 92.7%, 485.9662 (M-H) ^~ .

Preparation of N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl) -2-methoxy- propanamide The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-methoxy-propanoic acid (CAN 4324-37-2) as starting materials; MS (EI) 389.2 (M+H) ⁺ .

Example 87

Preparation of N3-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl )-N5- methylpyridine-3,5-dicarboxamide a) 5-[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- ylcarbamoyl]-nicotinic acid ethyl ester

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 3,5-pyridinedicarboxylic acid 3-ethyl ester (CAN 84254-37-5) as starting materials; MS (EI) 480.1(M+H) ⁺ . b) 5-[5-(4-Chloro-phenyl)-6-(2,2,2-trinuoro-ethoxy)-pyridin-3-y lcarbamoyl]-nicotinic acid

5- [5-(4-Chloro-phenyl)-6-(2,2,2-trif uoro-ethoxy)-pyridin-3-ylcarbamoyl] -nicotinic acid ethyl ester (510 mg, 1.06 mmol) was combined with THF (25 mL), methanol (5 mL) and water (5 mL) to give a light yellow suspension. The reaction mixture was stirred for 4 h, and concentrated in vacuo. The reaction mixture was poured into 100 mL ethyl acetate and extracted with 1 M HCl (1 x 25 mL) and brine (1 x 25 mL). The aqueous layer phases were extracted with ethyl acetate (1 x 50 mL). The organic layers were combined, dried with Na ₂ S0 ₄ and

concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% ethyl acetate in heptane) to deliver 0.17 g (48.7%) of the title compound as white solid; MS (ESI) 450.0(M-H) ^~ . c) N3-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl )-N5-methylpyridine-3,5- dicarboxamide

5- [5-(4-Chloro-phenyl)-6-(2,2,2-trif uoro-ethoxy)-pyridin-3-ylcarbamoyl] -nicotinic acid

(120 mg, 260 μιηοΐ) and methylamine hydrochloride (140 mg, 2.6 mmol) were dissolved in DMF (3 mL). TBTU (125 mg, 390 μπιοΐ) and DIPEA (672 mg, 908 μΐ, 5.2 mmol) were added. The reaction mixture was stirred at room temperature for 20 h. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, 0% to 100% ethyl acetate in heptane) to deliver 34 mg (28%) of the title compound as white solid; LC-MS (UV peak area/ESI) 99.5%, 465.0928 (M+H) ⁺ .

Preparation of (+)-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)-2- methoxyprop anamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-methoxy-propanoic acid (CAN 4324-37-2) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 10% ethanol / n-heptane); (+) enantiomer isolated; LC-MS (UV peak area/ESI) 100%, 389.0874 (M+H) ⁺ ; ² ° (MeOH) = +37.5° .

Preparation of (E)-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)-2- (methoxyimino)propanamide a) N-[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-2-oxo-propionamide

The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro- phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-oxo-propanoic acid (127-17-3) as starting materials; MS (EI) 373.0(M+H) ⁺ . b) (E)-N-(5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)-2-(methoxyimino)- propanamide

N-[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin -3-yl]-2-oxo-propionamide (0.063 g, 169 μιηοΐ) was dissolved in methanol (1.00 mL). O-Methyl hydroxylamine hydrochloride (70.6 mg, 845 μιηοΐ) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate; the organic phase was dried with MgS0 ₄ and concentrated in vacuo to deliver 67 mg (89%) of the title compound as white solid; LC-MS (UV peak area/ESI) 99.0%, 402.0825 (M+H) ⁺ .