HK1193598A - 5-cycloalkyl-or 5-heterocyclyl-nicotinamides - Google Patents

Description

5-cycloalkyl-or 5-heterocyclyl-nicotinamide

Technical Field

The present invention relates to 5-cycloalkyl-or 5-heterocyclyl-nicotinamide as HDL-cholesterol raising agent, their preparation, pharmaceutical compositions containing them and their use as therapeutically active substances.

The compounds of the present invention are HDL-cholesterol raising agents and therefore may 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 are the leading causes of death in the industrialized world. The risk of developing coronary heart disease has been shown to be strongly correlated with certain plasma lipid levels. Lipids are transported in the blood by lipoproteins. The overall structure of lipoproteins is a core of neutral lipids (triglycerides and cholesterol esters) and a shell of polar lipids (phospholipids and non-esterified cholesterol). There are 3 different classes of plasma lipoproteins, which differ in their core lipid content: cholesterol Ester (CE) -rich low-density lipoproteins (LDL); high Density Lipoprotein (HDL) also rich in Cholesterol Esters (CE); and Very Low Density Lipoprotein (VLDL) rich in Triglycerides (TG). Different lipoproteins can be separated based on their different floating densities or sizes.

High LDL-cholesterol (LDL-C) and triglyceride levels are positively correlated with the risk of developing cardiovascular disease, while high levels of HDL-cholesterol (HDL-C) are negatively correlated with the risk of developing cardiovascular disease.

There is no entirely satisfactory HDL-raising therapy. Niacin can significantly increase HDL, but has serious tolerability issues that reduce compliance. Fibric acid and HMG CoA reductase inhibitors only marginally (10-12%) raise HDL-cholesterol. As a result, there is a significant unmet medical need for well-tolerated agents that can significantly elevate plasma HDL levels.

Thus, HDL-cholesterol raising agents may be used as medicaments for the treatment and/or prevention of atherosclerosis (atheroclerosis), peripheral vascular disease (peripheral vascular disease), dyslipidemia (dyslipidemia), hyperbetalipoproteinemia (hyperbetalipoproteinemia), hypoalphalipoproteinemia (hypoalphalipoproteinemia), hypercholesterolemia (hypercholesterolaemia), hypertriglyceridemia (hypertriglyceridemia), familial hypercholesterolemia (hypercholesterolaemia), cardiovascular disease (cardiovascular disorders), angina (angina), ischemia (ischemic), cardiac ischemia (cardiac ischemia), stroke (stroke), myocardial infarction (myocardial perfusion), reperfusion injury (reperfusion injury), vascular restenosis (restenosis), hypertension (hypertension), hypertension complications, obesity, hypertension complications, diabetes mellitus, hypertension complications, hypertension complications of diabetes, hypertension.

In addition, the HDL-cholesterol raising agent may be used in combination with another compound which is 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, fibric acid, nicotinic acid, a preparation containing nicotinic acid or other HM74a agonist, an ion exchange resin, an antioxidant, an ACAT inhibitor, or a bile acid sequestrant.

Accordingly, it is an object of the present invention to provide compounds which are potent HDL-cholesterol raising agents. The compounds of formula I according to the invention have been found to be very useful for the treatment and/or prophylaxis of diseases and conditions which can be treated with HDL-cholesterol raising agents, i.e. the compounds of formula I can be used in particular for the treatment and/or prophylaxis of dyslipidemia, atherosclerosis and cardiovascular diseases. It is also an object of the present invention to provide compounds that do not interact with the CB1 receptor at therapeutically active concentrations that increase HDL-concentration. This is because CB1 receptor ligands may counteract the therapeutic utility of HDL-cholesterol raising agents, as both agonists and antagonists of the CB1 receptor have the potential to cause side effects.

Detailed Description

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used herein to describe the invention.

In the present specification, the term "lower" is used to indicate a group consisting of 1 to 7, especially 1 to 4, carbon atoms.

The term "alkyl", alone or in combination with other groups, refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms, particularly 1 to 16 carbon atoms, more particularly 1 to 10 carbon atoms.

The term "lower alkyl" or "C_1-7-alkyl ", alone or in combination, denotes a linear or branched alkyl group having from 1 to 7 carbon atoms, in particular a linear or branched alkyl group having from 1 to 6 carbon atoms, and more particularly a linear or branched alkyl group having from 1 to 4 carbon atoms. Straight and branched C_-7-Examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomericPentyl, the isomeric hexyl and the isomeric heptyl radicals, in particular ethyl, propyl, isopropyl and tert-butyl.

The term "lower alkoxy" or "C_1-7-alkoxy "refers to the group R '-O-, wherein R' is lower alkyl and the term" lower alkyl "has the previously given meaning. Examples of lower alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, especially methoxy.

The term "lower alkoxyalkyl" or "C_1-7-alkoxy-C_1-7-alkyl "means a lower alkyl group as defined above, which is mono-or polysubstituted with a lower alkoxy group as defined above. Examples of lower alkoxyalkyl are, for example, -CH₂-O-CH₃、-CH₂-CH₂-O-CH₃、-CH₂-O-CH₂-CH₃And groups specifically exemplified herein. More particularly, lower alkoxyalkyl is methoxyethyl.

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-C_1-7-alkyl "refers to lower alkyl as defined above, wherein at least one of the hydrogen atoms of the lower alkyl is replaced by cycloalkyl. Among the lower cycloalkylalkyl groups of particular interest is cyclopropylmethyl.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, of which fluorine, chlorine and bromine are of particular interest. More particularly, halogen refers to fluorine and chlorine.

The term "lower haloalkyl" or "halogen-C_1-7-alkyl "means lower alkyl mono-or polysubstituted with halogen, in particular with fluorine or chlorine, most particularly with fluorine. Examples of lower haloalkyl are, for example, -CF₃、-CHF₂、-CH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂-CF₃、-CH₂-CH₂-CF₃、-CH(CH₃)-CF₃And groups specifically exemplified herein. Of particular interest is the group trifluoromethyl (-CF)₃) And 2, 2, 2-trifluoroethyl (-CH)₂CF₃)。

The term "cyano" refers to the group-CN.

The term "heterocyclyl" refers to a saturated or partially unsaturated 3-, 4-, 5-, 6-, or 7-membered ring, which may include one, two, or three heteroatoms selected from N, O and S. Examples of heterocyclyl rings include piperidinyl, piperazinyl, azetidinyl, azaA pyrrolidinyl group, a pyrazolidinyl group, an imidazolinyl group, an imidazolidinyl group, a,Oxazolidinyl, isoOxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, oxiranyl, thiadiazolidinyl, oxetanyl, dioxolanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl and thiomorpholinyl. Of particular interest are dihydropyranyl groups.

The term "heteroaryl" refers to an aromatic 5-or 6-membered ring which may contain one, two or three atoms selected from N, O and S. Examples of heteroaryl groups are, for example, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isofurylOxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,Azolyl, imidazolyl, pyrazolyl, triazolyl,A diazolyl group,Triazolyl, tetrazolyl, pentazolyl or pyrrolyl. The term "heteroaryl" also includes bicyclic radicals comprising two 5-or 6-membered rings, wherein one or both rings are aromatic and may contain one, two or three atoms selected from nitrogen, oxygen or sulfur, such as quinolinyl, isoquinolinyl, cinnolinyl, pyrazolo [1, 5-a ]]Pyridyl, imidazo [1, 2-a ]]Pyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl and 3, 4-dihydro-2H-pyrido [3, 2-b ]][1，4]An oxazine group. Heteroaryl of particular interest is isoAzolyl, pyrazolyl, and,Oxadiazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

"isomeric forms" are all forms of a compound characterized by the same molecular formula but differing in the nature or order of their atomic attachment or in the spatial arrangement of their atoms. In particular, isomeric forms differ in the spatial arrangement of their atoms and may also be referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", and stereoisomers that are non-superimposable mirror images are referred to as "enantiomers", or sometimes optical isomers. The carbon atom to which the four non-equivalent substituents are attached is referred to as a "chiral center".

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, and which do not possess any undesirable properties of their own. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, particularly 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, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. Thus, preferred "pharmaceutically acceptable salts" include the acetate, bromide, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate and tosylate salts of the compounds of formula I. In addition, pharmaceutically acceptable salts can be prepared by adding the free acid with an inorganic or organic base. Salts derived from inorganic bases include, but are not limited to, 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 compounds of formula I may also exist in zwitterionic form or in the form of hydrates. A particularly preferred pharmaceutically acceptable salt of a compound of formula I is the hydrochloride salt.

The invention relates to compounds of formula I

Wherein

R¹Selected from the group consisting of: c_1-7-an alkyl group,

C_3-7-a cycloalkyl group,

C_3-7-cycloalkyl-C_1-7-an alkyl group,

hydroxy-C_1-7-an alkyl group,

C_1-7-alkoxy-C_1-7-alkyl, and

halogen-C_1-7-an alkyl group;

R²selected from the group consisting of:

C_3-7-a cycloalkyl group,

C_4-7-cycloalkenyl group, and

(ii) heterocyclyl, having 3 to 7 ring atoms, containing one, two or three heteroatoms selected from N, O and S and being saturated or partially unsaturated;

R³selected from the group consisting of: c_1-7-an alkyl group,

C_3-7-cycloalkyl, unsubstituted or substituted by hydroxy,

lower heterocyclyl having 3 to 7 ring atoms, containing one, two or three heteroatoms selected from N, O and S and being unsubstituted or substituted by hydroxy or oxo,

-(CH₂)_m-phenyl, wherein phenyl is unsubstituted or substituted with one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl and m is selected from 0 or 1, and

-(CH₂)_n-heteroaryl, wherein heteroaryl is unsubstituted or substituted by one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl and n is selected from 0 or 1;

R⁴is hydrogen or C_1-7-an alkyl group;

and pharmaceutically acceptable salts thereof.

The compounds of the formula I according to the invention are especially those in which R is¹Is C_3-7-cycloalkyl-C_1-7-alkyl or halogen-C_1-7-an alkyl group. More particularly, R¹Is halogen-C_1-7-an alkyl group.

The compounds of the formula I according to the invention are also those in which R²Is C_3-7-cycloalkyl or C_4-7-cycloalkenyl groups. In particular, R²Selected from the group consisting of cyclopentyl, cyclohexyl, cyclopenten-1-yl and cyclohexen-1-yl. More particularly, R²Is cyclopentyl or cyclopentenyl.

Another group of compounds of the formula I according to the invention are those in which R is²Is a heterocyclic group having 3 to 7 ring atoms, contains one, two or three heteroatoms selected from N, O and S and is saturated or partially unsaturated. More particularly, R²Is 3, 6-dihydro-2H-pyran-4-yl.

The compounds of the formula I according to the invention are also those in which R³Is that

-(CH₂)_m-phenyl, wherein phenyl is unsubstituted or substituted with one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl and m is selected from 0 or 1, or

-(CH₂)_n-heteroaryl, wherein heteroaryl is unsubstituted or substituted by one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl and n is selected from 0 or 1.

In particular, the invention relates to compounds of formula I wherein R³Is that

-(CH₂)_n-heteroaryl, wherein heteroaryl is unsubstituted or substituted by one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl and n is selected from 0 or 1.

In particular, the heteroaryl group is selected from the group consisting of: a furyl group, a thienyl group,azolyl radical, isoAn azole group, a pyrazole group,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, in particular selected from the group consisting of: different from each otherAn azole group, a pyrazole group,(ii) oxadiazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-an alkyl group. More particularly, the heteroaryl group is selected from pyridyl, pyridazinyl, pyrimidinylPyridyl and pyrazinyl.

The integer n is selected from 0 or 1. In particular, n is 0.

In particular, the invention relates to compounds of formula I wherein R³Selected from the group consisting of: 1-cyclopropylmethyl-1H-pyrazol-3-ylmethyl, 2-cyclopropyl-thiazol-4-ylmethyl, 3-methoxy-iso-methylAzol-5-ylmethyl, 3-methyl- [1, 2, 4 ]]Oxadiazol-5-ylmethyl, 3-trifluoromethyl- [1, 2, 4 ]]Oxadiazol-5-ylmethyl, pyridin-2-yl, pyridin-3-yl, pyridazin-4-yl, pyrimidin-5-yl and pyrazin-2-yl. More particularly, R³Selected from the group consisting of pyridin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyridazin-4-yl.

Another group of compounds of formula I are those wherein R is³Is- (CH)₂)_m-phenyl, wherein phenyl is unsubstituted or substituted with one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl and m is selected from 0 or 1. In particular, m is 0. More particularly, R³Is a 4-cyanophenyl group.

Another group of compounds of the formula I according to the invention are those in which R is³Is C_1-7-alkyl, especially ethyl or isopropyl.

The compounds of the formula I according to the invention are those in which R⁴Is hydrogen or C_1-7-an alkyl group. More particularly, R⁴Selected from hydrogen, methyl and ethyl. Most particularly, R⁴Is hydrogen.

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

5-cyclohex-1-enyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohex-1-enyl-N-ethyl-N-isopropyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohex-1-enyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide,

5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide,

5- (3, 6-dihydro-2H-pyran-4-yl) -6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide,

5-cyclohexyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopent-1-enyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridazin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridin-2-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoro-ethoxy)Methyl- [1, 2, 4 ]]Oxadiazol-5-ylmethyl) -nicotinamide,

5-cyclopentyl-N- (3-methoxy-iso)Oxazol-5-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N- (3-methoxy-iso)Oxazol-5-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N- (3-methyl- [1, 2, 4 ]]Oxadiazol-5-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N- (1-cyclopropylmethyl-1H-pyrazol-3-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N- (2-cyclopropyl-thiazol-4-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N- (1-cyclopropylmethyl-1H-pyrazol-3-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N- (2-cyclopropyl-thiazol-4-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N-pyrimidin-5-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N-pyridazin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N-pyrimidin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyrimidin-5-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyrimidin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

n- (4-cyano-phenyl) -5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

n- (4-cyano-phenyl) -5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridazin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N-pyrazin-2-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyrazin-2-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

or a pharmaceutically acceptable salt thereof.

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

5-cyclopent-1-enyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyrimidin-5-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyrimidin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridazin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

or a pharmaceutically acceptable salt thereof.

The compounds of formula I may be prepared by a process comprising

a) Coupling a compound of formula II with an amine of formula III in the presence of a coupling agent under basic conditions

Wherein R is¹And R²As defined herein above in connection with the above,

wherein R is³And R⁴As defined herein above in connection with the above,

and, if desired, converting the resulting compound of formula I into a pharmaceutically acceptable salt thereof; or, alternatively,

b) coupling a halide of formula IV with a compound of formula V in the presence of a suitable catalyst

Wherein R is¹，R³And R⁴As defined herein above, and X is Br or I,

wherein A is selected from the group consisting of: CH (CH)₂NH, O and S, S are selected from 0, 1, 2 and 3 and M is a metal species, to obtain a compound of formula I-b

The compound of formula I-b may be hydrogenated to obtain the compound of formula I-a

Wherein A, s, R¹、R³And R⁴As defined herein above in connection with the above,

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

The amine of formula III may contain functional groups that would interfere with the coupling procedure described for coupling steps (II to I). In this case, it will be appreciated that the amine III needs to be suitably protected by methods known in the art before the coupling procedure is carried out, and that the compound needs to be deprotected by methods known in the art after the coupling step to give the compound of formula I.

Coupling agents for the reaction of compounds of the formula II with amines of the formula III are, for example, N '-Carbonyldiimidazole (CDI), N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] hexafluorophosphate]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT), O-benzotriazole-N, N '-tetramethyl-urehan Hexafluorophosphate (HBTU) or O-benzotriazole-1-yl-N, N' -tetramethylurehan tetrafluoroborate (TBTU). In particular, the coupling agent is TBTU. Suitable bases include triethylamine, N-methylmorpholine, and especially diisopropylethylamine.

In alternative b), the substituent R of the compound of the formula I²By employing a metal species of formula V. M is, for example, a boronic acid or boronic ester species, especially a cyclopentylborane species, more especially 4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl. Suitable catalysts are in particular palladium catalysts, for example palladium (II) chloride-dppf (1, 1' -bis (diphenylphosphino) ferrocene) complexes. More specifically, a palladium (II) -dppf (1, 1' -bis (diphenylphosphino) ferrocene) chloride complex is used in the presence of a base such as potassium carbonate.

The compounds of formula I-B are hydrogenated by methods known in the art. More particularly, it is hydrogenated with hydrogen in the presence of a palladium catalyst, more particularly in the presence of palladium on carbon.

An alternative method known in the art may be started by: the acid chloride is prepared from II and coupled with an amine of formula III in the presence of a suitable base.

Following the procedure according to scheme 1, compound AA (5-bromo-6-chloro-3-pyridinecarboxylic acid, CAN29241-62-1) CAN be used as starting material. AA is commercially available or can alternatively be prepared from 6-hydroxy-3-pyridinecarboxylic acid by a multistep sequence following literature procedures.

Scheme 1

Compound AB can be prepared from AA by: with an appropriately substituted primary or secondary alcohol R in the presence of a base such as potassium hydroxide in an inert solvent such as dimethyl sulfoxide at a temperature from room temperature to the reflux temperature of the solvent, in particular at room temperature¹-OH (AC) reaction.

Compound AD can be obtained from compound AB by a number of carboxylate formation methods known in the art, for example by formation of carboxylic acid chloride with thionyl chloride in the presence of catalytic amounts of DMF at elevated temperatures followed by methanolysis of the acid chloride at temperatures from 0 ℃ to reflux temperature.

Compound AG can be prepared from AD by: in the presence of a suitable catalyst, especially a palladium catalyst and more especiallyA suitably substituted alkenyl metal species of formula AF, in particular a cycloalkenyl borate, is coupled with AD in the presence of a palladium (II) chloride) -dppf (1, 1' -bis (diphenylphosphino) ferrocene) complex and a base, in particular potassium carbonate, in an inert solvent such as dimethylformamide, wherein s is an integer selected from 0, 1, 2 and 3 and a is selected from the group consisting of: CH (CH)₂NH, O and S.

Compound AH can be obtained by hydrogenation of compound AG by methods known in the art, for example by hydrogenation with hydrogen in the presence of a palladium catalyst, for example palladium on carbon, in an inert solvent, for example ethanol, at suitable temperatures and pressures, in particular at ambient temperature and pressure.

Compound AI (II-a) can be obtained by saponification of compound AH by methods known in the art, for example by saponification using an alkali metal hydroxide, for example lithium hydroxide, in a mixture of a suitable solvent, for example THF and water.

Compound I-a can be prepared from II-a and the corresponding amine of formula III by a suitable amide bond formation reaction. These reactions are known in the art. For example, coupling reagents such as N, N '-carbonyl-diimidazole (CDI), N, N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] hexafluorophosphate]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT) and tetrafluoroboric acid O-benzotriazol-1-yl-N, N' -tetramethylurea (TBTU) can be used to effect such conversions. A convenient method is to use, for example, TBTU and a base, for example Hunig's base (N-ethyldiisopropylamine), in an inert solvent such as, for example, dimethylformamide at room temperature.

Following an alternative route according to scheme 2, compound AG can be used as starting material.

Compound BA (II-b) can be obtained by saponification of compound AG by methods known in the art, for example by saponification using an alkali metal hydroxide, for example lithium hydroxide, in a mixture of a suitable solvent, for example THF and water.

Scheme 2

Compounds I-b can be prepared from II-b and the corresponding amine of formula III by a suitable amide bond formation reaction. These reactions are known in the art. For example, coupling reagents such as N, N 'carbonyl-diimidazole (CDI), N, N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] hexafluorophosphate]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT) and tetrafluoroboric acid O-benzotriazol-1-yl-N, N' -tetramethylurea(TBTU) may be used to effect such transformations. A convenient method is to use, for example, TBTU and a base, for example Hunig's base (N-ethyldiisopropylamine), in an inert solvent such as, for example, dimethylformamide at room temperature.

Compound I-a can be obtained by hydrogenation of compound I-b by methods known in the art, for example by hydrogenation with hydrogen in the presence of a palladium catalyst, for example palladium on carbon, in an inert solvent, for example ethanol, at suitable temperatures and pressures, in particular at ambient temperature and pressure.

Compound CA (5-iodo-6-chloro-3-pyridinecarboxylic acid, CAN59782-87-5) CAN be used as starting material following the procedure according to scheme 3. CA is commercially available.

The compound CB may be passed through by CAThe preparation method comprises the following steps: with an appropriately substituted primary or secondary alcohol R in the presence of a base such as potassium hydroxide in an inert solvent such as dimethyl sulfoxide at a temperature from room temperature to the reflux temperature of the solvent, in particular at room temperature¹-OH (AC) reaction.

Scheme 3

Compound CD can be prepared from CB and the corresponding amine of formula III by a suitable amide bond formation reaction. These reactions are known in the art. For example, coupling reagents such as N, N '-carbonyl-diimidazole (CDI), N, N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] hexafluorophosphate]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT) and tetrafluoroboric acid O-benzotriazol-1-yl-N, N' -tetramethylurea(TBTU) may be used to effect such transformations. A convenient method is to use, for example, TBTU and a base, for example Huinig base (N-ethyldiisopropylamine), in an inert solvent such as, for example, dimethylformamide at room temperature.

Compound I-b can be prepared from CD by: a suitably substituted alkenyl metal species of formula AF, particularly a cycloalkenyl borate, is coupled with CD in the presence of a suitable catalyst, particularly a palladium catalyst and more particularly a palladium (II) chloride-dppf (1, 1' -bis (diphenylphosphino) ferrocene) complex and a base, particularly potassium carbonate, in an inert solvent such as dimethylformamide.

Compound I-a can be obtained by hydrogenation of compound I-b by methods known in the art, for example by hydrogenation with hydrogen in the presence of a palladium catalyst, for example palladium on carbon, in an inert solvent, for example ethanol, at suitable temperatures and pressures, in particular at ambient temperature and pressure.

As mentioned above, the compounds of formula I according to the invention 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, improvement in glycemic control, obesity or endotoxemia. Of particular interest is the use as a medicament for the treatment and/or prevention of dyslipidemia, atherosclerosis and cardiovascular diseases.

The present invention therefore also relates to pharmaceutical compositions comprising a compound of formula I as described above and a pharmaceutically acceptable carrier and/or adjuvant. The pharmaceutical compositions can be used for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents.

Accordingly, the present invention relates to a pharmaceutical composition as described above for the treatment and/or prevention 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, improvement of glycemic control, obesity or endotoxemia.

In another embodiment, the present invention relates to a method of treating and/or preventing diseases which can be treated with HDL-cholesterol raising agents, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. 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, improvement in glycemic control, obesity or endotoxemia. Methods for treating and/or preventing dyslipidemia, atherosclerosis and cardiovascular diseases are preferred.

The invention also relates to compounds of formula I for use as medicaments. More particularly, the present invention relates to compounds of formula I useful as HDL-cholesterol raising agents. The present invention therefore relates to compounds of formula I for the treatment and/or prophylaxis of atherosclerosis, peripheral vascular diseases, 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, improvement of glycemic control, obesity or endotoxemia, in particular for the treatment and/or prophylaxis of dyslipidemia, atherosclerosis and cardiovascular diseases.

Furthermore, the invention relates to the use of compounds of the formula I as described above for the preparation of medicaments for the treatment and/or prophylaxis of diseases which 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, improvement in glycemic control, obesity or endotoxemia. The use of compounds of formula I as described above for the preparation of medicaments for the treatment and/or prophylaxis of dyslipidemia, atherosclerosis and cardiovascular diseases is of particular interest.

In addition, the HDL-raising agent of formula I may be used in combination or association with another compound selected from the group consisting of: HMG-CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors, PPAR activators, Cholesteryl Ester Transfer Protein (CETP) inhibitors, bile acid reuptake inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, fibric acid, nicotinic acid, formulations containing nicotinic acid or other HM74a agonists, ion exchange resins, antioxidants, ACAT inhibitors or bile acid sequestrants.

The present invention therefore also relates to pharmaceutical compositions comprising a compound of formula I as defined above in combination or association with a compound selected from the group consisting of: HMG-CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors, PPAR activators, Cholesteryl Ester Transfer Protein (CETP) inhibitors, bile acid reuptake inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, fibric acid, nicotinic acid, formulations containing nicotinic acid or other HM74a agonists, ion exchange resins, antioxidants, ACAT inhibitors or bile acid sequestrants.

The present invention also relates to a compound of formula I as defined above in combination or association with a compound selected from the group consisting of: HMG-CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors, PPAR activators, Cholesteryl Ester Transfer Protein (CETP) inhibitors, bile acid reuptake inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, fibric acid, nicotinic acid, formulations containing nicotinic acid or other HM74a agonists, ion exchange resins, antioxidants, ACAT inhibitors or bile acid sequestrants for the treatment and/or prophylaxis of diseases such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disease, angina, ischemia, myocardial ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, improvement in glycemic control, obesity or endotoxemia.

The present invention also relates to a method for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, said method comprising administering a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount of a compound selected from the group consisting of: HMG-CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors, PPAR activators, Cholesteryl Ester Transfer Protein (CETP) inhibitors, bile acid reuptake inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, fibric acid, nicotinic acid, formulations containing nicotinic acid or other HM74a agonists, ion exchange resins, antioxidants, ACAT inhibitors or bile acid sequestrants.

Pharmacological testing

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

Detection of ABCA1 protein up-regulation in cells

The ability of the compounds of the invention to increase the levels of ABCA1 protein was determined in replica-plated THP-1 macrophages in 96-well microplates. Cells were plated at an initial density of 100,000 cells/well in 100. mu.l of medium and PMA (100nM) was added to 10% fetal bovine serum, 3. mu.l/L of b-mercaptoethanol, RPMI-1640 medium for 68 hours to differentiate into attached macrophages. Thereafter, the cells were incubated with RPMI-1640 medium containing 1% FCS, 25. mu.g/ml acetylated LDL for 24 hours at 37 ℃. After incubation with acetylated LDL, cells were washed twice with 50. mu.l PBS and incubated for another 24 hours with 100. mu.l RPMI-1640 medium containing the compound of interest dissolved in DMSO. The final DMSO concentration in the presence of cells was maintained at 0.5%. By using fresh medium, RPMI without phenol red, containing0.2% BSA replacement of labeled ApoA-I initiates ApoA-I binding assays using High Content Image Analysis (2 h/37 deg.C/5% CO 2). After this time, the cells were fixed with 4% formaldehyde in PBS (15 min, RT). The nuclei were then stained with Hoechst solution (3. mu.M PBS) and the cytoplasm with Cell Mask Blue (2. mu.g/ml PBS), 15min, RT. Finally, stained cells were fixed with a second round of formaldehyde treatment. Fixed stained cells were washed and kept in PBS at 4 ℃ and can be read immediately until one month after preparation. Binding of ApoA-I, which truly reflects ABCA1 levels in cells, is demonstrated by loss of signal when ABCA1 expression is artificially reduced by transfection with small amounts of interfering RNA.

Alexa Fluor647 labeled apolipoprotein A-I (20nM) was prepared as follows: human recombinant apolipoprotein A-I (ApoA-I) was exchanged on a NAP desalting column (GE Healthcare) to 0.02M NaHCO at pH8.2₃And the concentration was adjusted to 40. mu.M (1.13 mg/ml) by using the same buffer. ApoA-I was fluorescently labeled by incubation with Alexa Fluor carboxysuccinimidyl ester (Alexa Fluor647, Invitrogen A-20006) at a 2: 1 molar ratio (Alexa to ApoA-I) for 1h at RT with shaking. By changing the buffer to 0.02M NaHCO, pH8.2₃The remaining unbound label is removed.

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 nuclei and 635 laser to identify fluorescent ApoA-I. Each hole captures eight fields of view. Image capture and analysis was performed using Acapella software. The background fluorescence detected in the control wells without ApoA-I was subtracted.

EC is calculated using a module 205 for Dose Response single points (Dose Response One Site) using the XLFit3 program (ID Business Solutions Ltd. UK)₅₀The value is obtained. The compounds of the invention showed EC in the range of 0.1. mu.M to 10. mu.M in the ABCA1 protein detection assay₅₀The value is obtained. In particular, the compounds of the present invention haveEC in the range of 0.1. mu.M to 3. mu.M₅₀The value is obtained.

TABLE 1ABCA1 protein to improve potency

Examples	% increase in ABCA1 at 3. mu.M	EC50[μM]
			1		0.51
2	＞45％3μM
			3	＞45％3μM
4		0.15
			5		2.92
6		3.39
			7	＞45％3μM
8	＞45％3μM

Examples	% increase in ABCA1 at 3. mu.M	EC50[μM]
			9		10
10		1.01
			11	＞45％3μM
12	＞45％3μM
			13	＞45％3μM
14	＞45％3μM
			15	＞45％3μM
16	＞45％3μM
			17	＞45％3μM
18	＞45％3μM
			19	＞45％3μM
20	＞45％3μM
			21	＞45％3μM
22	＞45％3μM
			23	＞45％3μM
24	＞45％3μM
			25	＞45％3μM
26	＞45％3μM
			27	＞45％3μM
28	＞45％3μM

Cholesterol efflux assay

Determination of Compounds of the invention in replica cultures of THP-1 cells on 96-well microplatesThe ability of the substance to stimulate cholesterol efflux. Cells were seeded on a plate at an initial density of 150,000 cells/well and differentiated into macrophages with addition of PMA (100 ng/ml) in 10% fetal bovine serum, 3. mu.l/L beta-mercaptoethanol, RPMI-1640 medium for 72 hours. The cells were washed once with RPMI-1640 and loaded with 2% FCS, 50. mu.g/ml acetylated LDL and 10. mu. Ci/ml 2 [ ]³H]Cholesterol in RPMI-1640 medium at 37 ℃ for 48 hours. After loading, the cells were washed once with RPMI-1640 and incubated for a further 24 hours with a DMSO solution of the compound of interest in RPMI-1640 medium containing 1 mg/ml of Bovine Serum Albumin (BSA) without fatty acids. After incubation, the cells were washed once and cholesterol efflux was induced for an additional 6 hours by addition of 10 μ g/ml apolipoprotein AI in RPMI-1640 with 1 mg/ml BSA and in the presence of the compound. After incubation, radioactivity in the supernatant was determined and cholesterol efflux was expressed as a percentage stimulation relative to replicate cultures treated with DMSO alone. Sigmoidal curves were fitted using the XLfit3 program (IDBusiness Solutions ltd. uk) and EC was determined₅₀The value is obtained.

In the cholesterol efflux assay, the compounds of the invention show an EC in the range of 0.1. mu.M to 3.0. mu.M₅₀The value is obtained. In particular, the compounds of the invention have an EC in the range of 0.1 μ M to 1.5 μ M₅₀The value is obtained.

Affinity for CB1 and CB2 receptors

Determination of the affinity of the compounds of the invention for cannabinoid receptors using membrane preparations of Human Embryonic Kidney (HEK) cells, in which the human CB1 receptor is bound using the Semliki Forest Virus System [3H]Transient transfection with CP-55, 940 as a radioligand. Having a value of [ 2 ], [ 2 ] in a freshly prepared form, with or without the addition of a compound of the invention³H]-separation of bound and free ligand by filtration on a glass fiber filter after incubation of the cell membrane preparation of the ligand. Radioactivity on the filter was measured by scintillation counting.

Assay of chemometrics of the invention Using Membrane preparations of Human Embryonic Kidney (HEK) cellsAffinity of a compound for the cannabinoid CB2 receptor, wherein the human CB2 receptor is bound using the Semliki Forest Virus system [ 2 ]³H]CP-55, 940 was transiently transfected as a radioligand. The newly prepared alpha-olefin copolymer having the formula [ 2 ] with or without the addition of the compound of the present invention³H]-separation of bound and free ligand by filtration on a glass fiber filter after incubation of the cell membrane preparation of ligand. Radioactivity on the filter was measured by scintillation counting.

Measurement of Compound-substituted radioligand [ 2 ] at a concentration of 10. mu.M³H]Capacity of CP-55, 940, and as [% inhibition 10. mu.M for both CB1 and CB2 receptor assays]Given the values, the lower the% inhibition, the lower the propensity for side effects based on CB1 or CB2 receptor inhibition.

Compounds of the invention exhibited values of less than 50% inhibition at a concentration of 10 μ M in both the CB1 and CB2 receptor assays. In particular, the compounds of the invention exhibit values of less than 35% inhibition in both CB1 and CB2 receptor assays and even more particularly less than 20% in both assays.

Table 2: affinity for CB1 and CB 2-receptors

Further demonstration of the biological activity of the compounds of the invention can be accomplished by the following in vivo assays well known in the art.

Effect on plasma lipid levels in lean fed rats

The effect of a compound of formula I on plasma lipid levels was determined in lean-fed Sprague-Dawley rats dosed with compound via oral gavage. After one week of acclimation, blood samples were collected from 4 hour fasted animals for plasma lipid assay. Animals were then divided into treatment groups based on HDL-cholesterol levels. The compound of formula I is administered by gavage once a day for 5 days. Control animals received vehicle only. On day 5, blood was collected from 4-hour fasted rats for plasma lipid analysis after 2 hours of the last treatment. Total cholesterol, HDL-cholesterol and triglycerides were determined by measuring total cholesterol, HDL-cholesterol and triglycerides using a colorimetric enzyme assay (Roche diagnostic GmbH, Mannheim, Germany). HDL-C was also quantified by size exclusion chromatography on a superpose-6 column (Pharmacia) using a SMART system. Lipoprotein distribution was calculated by the following method: assuming each peak is gaussian, the area under the curve is calculated using a non-linear least squares curve fitting program. The concentration of the compound in plasma was also determined.

Effect on plasma lipid levels in obese high fat diet-fed rats

The efficacy of the compounds in the modulation of plasma lipid levels was also determined in obese male Sprague Dawley rats 28-29 days after compound administration. Male Sprague-Dawley rats, 10 weeks old, were fed with high fat chow for 3 weeks. Obese rats were grouped according to uniform BW and FI assessed one week prior to starting treatment. The treatment is carried out by administering the composition in the form of a food mix. Blood was taken under light anesthesia (retro-orbital) on the morning of day 29 under postprandial conditions, i.e., 4h after removal of food. Plasma is separated from the blood by low speed centrifugation and selected organs (e.g. liver, fat) are removed. Total cholesterol, HDL-cholesterol and triglycerides were determined by measuring total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides using a colorimetric enzyme assay (Roche Diagnostic GmbH, Mannheim, Germany). HDL-C was also quantified by size exclusion chromatography on a superpose-6 column (Pharmacia) using a SMART system. Lipoprotein distribution was calculated by the following method: assuming each peak is gaussian, the area under the curve is calculated using a non-linear least squares curve fitting program. The concentration of the compound in plasma was also determined.

Effect on hamster plasma lipid levels

The efficacy of the compounds in modulating plasma lipid levels was determined in hamsters 5 days after administration of the compounds daily. Male hamsters 6-8 weeks old were used in the study. After one week of acclimation, blood samples were collected from 4 hour fasted animals for plasma lipid assay. Animals were then divided into treatment groups based on HDL-cholesterol levels. The compounds were administered by gavage once a day for 5 days. Control animals received vehicle only. On day 5, blood was collected from 4-hour fasted hamsters 2 hours after the last treatment for plasma lipid analysis. Total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides were determined using a colorimetric enzyme assay (Roche diagnostic GmbH, Mannheim, Germany). HDL-cholesterol, LDL-cholesterol and VLDL-cholesterol levels were also quantified by size exclusion chromatography on a superpose-6 column (Pharmacia) using the SMART system. Lipoprotein distribution was calculated by the following method: assuming each peak is gaussian, the area under the curve is calculated using a non-linear least squares curve fitting program. The concentration of the compound in plasma was also determined.

Effect on plasma lipid levels of Cholesterol/fat fed hamsters

The utility of a compound to modulate plasma lipid levels was determined after 5 days of daily administration of the compound in hamsters. Male hamsters of 6-8 weeks of age were used in the study. After one week of acclimation, blood samples were collected from 4 hour fasted animals for plasma lipid assay. Animals were then divided into treatment groups based on HDL-cholesterol levels. The compounds were administered by gavage once daily for five days. Control animals received only vehicle. On the fifth day, after 2 hours of the last treatment, blood was collected from 4-hour fasted hamsters for plasma lipid analysis. Total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides were determined using a colorimetric enzyme assay (Roche diagnostic GmbH, Mannheim, Germany). HDL-cholesterol was also determined after selective precipitation of HDL from plasma by standard procedures.

Pharmaceutical composition

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, orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions; oral, e.g. in the form of buccal tablets; rectal administration, for example in the form of suppositories; parenteral administration, for example in the form of injection or infusion solutions for intramuscular, intravenous or subcutaneous injection; or topically, e.g., in the form of an ointment, cream, or oil. Oral administration is of particular interest.

The production of pharmaceutical compositions can be carried out in any manner familiar to the person skilled in the art by bringing the compounds of the formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, nontoxic, inert, therapeutically compatible solid or liquid carrier substances and, if desired, customary 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, however, no carrier may be required in the case of soft gelatine capsules). Suitable carrier substances 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 formulations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Conventional 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 are contemplated as pharmaceutical adjuvants.

The therapeutically effective amount or dose of the compound of formula I may 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 dose of about 1-100mg, especially about 1-50mg, is contemplated. Depending on the severity of the disease and the precise pharmacokinetic profile, the compounds may be administered in 1 or several daily dosage units, e.g. 1-3 dosage units.

The pharmaceutical composition conveniently contains from about 1 to 100mg, especially 5 to 50mg, of a compound of formula I.

The following examples C1 to C3 illustrate typical compositions of the invention, but serve only as representatives thereof.

Example C1

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

composition (I)	Each tablet
			And (3) nucleus:
a compound of formula (I)	10.0mg	200.0mg
			Microcrystalline cellulose	23.5mg	43.5mg
Hydrous lactose	60.0mg	70.0mg
			Polyvinylpyrrolidone K30	12.5mg	15.0mg
Sodium starch glycolate	12.5mg	17.0mg
			Magnesium stearate	1.5mg	4.5mg
(core weight)	120.0mg	350.0mg
			Film coating:
hydroxypropyl methylcellulose	3.5mg	7.0mg
			Polyethylene glycol 6000	0.8mg	1.6mg
Talc	1.3mg	2.6mg
			Iron oxide (yellow)	0.8mg	1.6mg
Titanium dioxide	0.8mg	1.6mg

The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granules were then mixed with sodium starch glycolate and magnesium stearate and compressed to produce 120 or 350mg cores, respectively. The core is coated with an aqueous solution/suspension of the film coat described above.

Example C2

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

composition (I)	Per capsule
		A compound of formula (I)	25.0mg
Lactose	150.0mg
		Corn starch	20.0mg
Talc	5.0mg

The components were sieved and mixed and filled into size 2 capsules.

Example C3

The injection solution may have the following composition:

a compound of formula (I)	3.0mg
		Polyethylene glycol 400	150.0mg
Acetic acid	Adding into pH5.0
		Water for injection	Adding into the mixture to 1.0ml

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 by the addition of acetic acid. The volume was adjusted to 1.0ml by adding the balance of water. The solution was filtered, filled into vials with the appropriate excess and sterilized.

Examples

MS = mass spectrum; EI = electron ionization; ESI = electrospray; NMR data relative to internal tetramethylsilane and referenced from sample solvent (d)₆-DMSO, unless otherwise stated) deuterium lock signal is reported in parts per million (δ); coupling constant (J) in hertz, mp = melting point; bp = boiling point; HPLC = LC = high performance liquid chromatography, Rt = retention time, TLC = thin layer chromatography, TBTU = O- (benzotriazol-1-yl) -N, N' -tetramethyl-urea-a tetrafluoroborate salt; TEMPO =2, 2, 6, 6-tetra-methylpiperidine 1-oxyl radical, DMF = dimethylformamide, DIPEA: n, N-diisopropylethylamine, DMSO = dimethyl sulfoxide, THF = tetrahydrofuran, CAN = CAS registry number.

Example 1

Preparation of 5-cyclohex-1-enyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

a) 5-iodo-6- (2, 2, 2-trifluoroethoxy) nicotinic acid

6-chloro-5-iodo-3-pyridinecarboxylic acid (CAN59782-87-5, 4.7g, 16.6mmol) was dissolved in DMSO (49.5 ml). Potassium hydroxide pellets (2.79g, 49.7mmol) and 2, 2, 2-trifluoroethanol (2.16g, 1.55ml, 21.6mmol) were added slowly at room temperature under argon. The reaction mixture was stirred at room temperature for 2 h; water (35mL) was added and the mixture was cooled to 0-5 ℃. Concentrated HCl solution (8mL) was added dropwise and the precipitated solid was collected, washed with cold water and dried. The crude material was purified by flash chromatography (silica gel, 150g, 0% to 20% isopropyl acetate in n-heptane + 10% acetic acid) to yield the title compound (1.6g, 28%) as a colorless solid; MS (ESI)345.7(M-H) -.

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

5-iodo-6- (2, 2, 2-trifluoroethoxy) nicotinic acid (1g, 2.88mmol) was dissolved in DMF (10.0 mL); 3-amino-pyridine (285mg, 3.03mmol), TBTU (981mg, 3.05mmol) and N, N-diisopropylethylamine (1.8g, 14.4mmol) were added and the reaction mixture was stirred for 20 h. The mixture was poured into 5mL of 1M NaOH solution and extracted with isopropyl acetate (2 × 50 mL). The organic layers were combined and washed with Na₂SO₄Dried and concentrated in vacuo to yield a pale yellow solid. Crystallization from dichloromethane yielded the title compound (0.78g, 64%) as a white solid; MS (ESI)423.9(M + H)⁺。

c) 5-cyclohex-1-enyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

5-iodo-N- (pyridin-3-yl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide (0.05g, 118. mu. mol), 2-cyclohexenyl-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxanBorolane (CAN141091-37-4, 22.1mg, 22.9. mu.l, 106. mu. mol) and potassium phosphate (75.2mg, 355. mu. mol) were combined in degassed DMF (1.1 ml)/THF (367. mu.l) to give a yellow solution which was heated to 80 ℃ and stirred for 2 days. After cooling, the mixture was poured into 5mL of saturated NaHCO₃To the solution and extracted with isopropyl acetate (2 × 50 mL). The organic layers were combined and washed with Na₂SO₄Dried and concentrated in vacuo to give a brown oil which was purified by preparative TLC (silica gel, 2.0mm, 1: 2 n-heptane/isopropyl acetate) to give the title compound (19mg, 42%) as a light yellow solid; MS (ESI)378.2(M + H)⁺。

Example 2

Preparation of 5-cyclohex-1-enyl-N-ethyl-N-isopropyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

a) 5-cyclohex-1-enyl-6- (2, 2, 2-trifluoroethoxy) nicotinic acid methyl ester

Methyl 5-bromo-6- (2, 2, 2-trifluoroethoxy) -3-pyridinecarboxylate (CAN1211589-51-3), 200mg, 637. mu. mol), 2-cyclohexenyl-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan (CAN141091-37-4, 119mg, 123. mu.l, 574. mu. mol), K₃PO₄(409mg, 1.91mmol) and PdCl₂(dppf)-CH₂Cl₂The adduct (26.0mg, 31.8. mu. mol) was combined in degassed DMF (4.38 mL)/THF (1.46mL) to give a yellow suspension. The mixture was heated to 70 ℃ and shaken overnight. After cooling, the mixture was poured into 100mL of saturated NaHCO₃In ice water and extracted with isopropyl acetate (2 × 100 mL). The organic layers were washed with ice/brine (1X150mL), combined, and Na₂SO₄Dried and concentrated in vacuo to yield 283mg of a brown oil. The crude material was purified by preparative TLC (silica gel, 2X2.0mm, n-heptane/iPrOAc 9: 1) to give the title compound (129mg, 64%) As a colorless solid; MS (ESI)316.2(M + H)⁺。

b) 5-cyclohex-1-enyl-6- (2, 2, 2-trifluoroethoxy) nicotinic acid

Methyl 5-cyclohex-1-enyl-6- (2, 2, 2-trifluoroethoxy) nicotinate (0.03g, 95.2 μmol) was combined with THF (0.3mL) and water (0.15mL) to give a light yellow solution. Lithium hydroxide hydrate (7.99mg, 190. mu. mol) was added under argon. The reaction mixture was stirred at room temperature overnight, poured into 2mL of 2M HCl and extracted with isopropyl acetate (2 × 20 mL). The organic layers were combined and washed with Na₂SO₄Dried and concentrated in vacuo to yield the title compound (30mg, quantitative) as a white solid, which was used in the subsequent reaction without further purification; MS (ESI)300.2(M-H) -.

c) 5-cyclohex-1-enyl-N-ethyl-N-isopropyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

5-cyclohex-1-enyl-6- (2, 2, 2-trifluoroethoxy) nicotinic acid (15ng, 49.8. mu. mol) was dissolved in DMF (5mL) to give a pale yellow solution. 3-amino-pyridine (5.15mg, 54.8. mu. mol), TBTU (24.0mg, 74.7. mu. mol) and N, N-diisopropylethylamine (32.2mg, 43.5. mu.l, 249. mu. mol) were added successively with stirring and under argon to give a light brown solution. The reaction mixture was stirred for 18 h; poured into 5mL of 1N NaOH/ice water and extracted with isopropyl acetate (2X20 mL). The organic layers were combined, washed with brine (1 × 10mL), and Na₂SO₄Dried and concentrated in vacuo to yield a brown oil. The crude material was purified by preparative TLC (silica gel, 1.0mm, n-heptane/isopropyl acetate 1: 1) to yield the title compound as a by-product(5mg, 27%) as a colorless oil; LC-MS (UV peak area/ESI) 94%, 371.1936(M + H)⁺。

Example 3

Preparation of 5-cyclohex-1-enyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide

In analogy to example 1b, 5-cyclohex-1-enyl-6- (2, 2, 2-trifluoroethoxy) nicotinic acid (example 2b) and 3- (trifluoromethyl) -1, 2, 4-Oxadiazole-5-methylamine (944905-93-5) as a starting material to synthesize the title compound; MS (ESI)451.2(M + H)⁺。

Example 4

Preparation of 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide

a) 5-cyclohexyl-6- (2, 2, 2-trifluoroethoxy) nicotinic acid methyl ester

Methyl 5-cyclohex-1-enyl-6- (2, 2, 2-trifluoroethoxy) nicotinate (example 2a, 163mg, 517. mu. mol) was dissolved in ethanol (5 mL). Palladium (10% on carbon, 16.3mg, 517 μmol) was added; the suspension is evacuated and the suspension is,flushed 3 times with hydrogen and stirred at ambient temperature for 1.5 h. Passing the reaction mixture throughFiltration and concentration in vacuo gave the title compound (95mg, quantitative) as a grey solid, which was used in the subsequent reaction without further purification; MS (ESI)318.1(M + H)⁺。

b) 5-cyclohexyl-6- (2, 2, 2-trifluoroethoxy) nicotinic acid

Methyl 5-cyclohexyl-6- (2, 2, 2-trifluoroethoxy) nicotinate (95mg, 299 μmol) was combined with THF (4mL) and water (2mL) to give a pale yellow solution. Lithium hydroxide hydrate (25.1mg, 599. mu. mol) was added under argon. The reaction mixture was stirred at ambient temperature overnight; poured into 6mL of 2m hcl solution and extracted with isopropyl acetate (2 × 60 mL). The organic layers were combined and washed with Na₂SO₄Dried and concentrated in vacuo to give the title compound (92mg, quantitative) as a white solid, which was used in the subsequent reaction without further purification; MS (ESI)302.0(M-H) -.

c) 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide

In analogy to example 1b, 5-cyclohexyl-6- (2, 2, 2-trifluoroethoxy) nicotinic acid (example 4b) and C- (3-trifluoromethyl-1, 2, 4-Oxadiazol-5-yl) -methylamine (CAN944905-93-5) as starting material the title compound was synthesized; MS (ESI)453.1(M + H)⁺。

Example 5

Preparation of 5- (3, 6-dihydro-2H-pyran-4-yl) -6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide

a) 5-iodo-6- (2, 2, 2-trifluoroethoxy) -N- ((3- (trifluoromethyl) -1, 2, 4-Oxadiazol-5-yl) methyl) nicotinamide

5-iodo-6- (2, 2, 2-trifluoroethoxy) nicotinic acid (example 1a, 1g, 2.88mmol) was dissolved in DMF (10 mL). Adding C- (3-trifluoromethyl-1, 2, 4-Oxadiazol-5-yl) -methylamine hydrochloride (616mg, 3.03mmol), TBTU (981mg, 3.05mmol) and N, N-diisopropylethylamine (1.86g, 2.45ml, 14.4 mmol). The reaction mixture was stirred overnight, poured into 75mL of 1M NaOH solution and extracted with isopropyl acetate (2x200 mL). The organic layers were combined and washed with Na₂SO₄Dried and concentrated in vacuo to yield a brown oil. The crude material was purified by flash chromatography (silica gel, 50g, 25% isopropyl acetate in n-heptane) to yield the title compound (1.2g, 84%) as a light yellow solid; MS (ESI)497.0(M + H)⁺。

b)5- (3, 6-dihydro-2H-pyran-4-yl) -6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide

Reacting 5-iodo-6- (2, 2, 2-trifluoroethoxy) -N- ((3- (trifluoromethyl) -1, 2, 4-Oxadiazol-5-yl) methyl) nicotinamide (49.6mg, 100. mu. mol), potassium carbonate (39.5mg, 286. mu. mol) and PdCl₂(dppf) (3.89mg, 4.76. mu. mol) were combined to give a pale red solid. To this solid was added a solution of 3, 6-dihydro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2H-pyran (CAN287944-16-5, 0.02g, 95.2. mu. mol) in degassed DMF (2 mL). The reaction mixture was stirred at 80 ℃ overnight, extracted with isopropyl acetate (2x75mL) after cooling and washed with water (1x10mL) to pH 7. The organic layers were combined and washed with Na₂SO₄Dried and concentrated in vacuo to yield a brown oil. The crude material was purified by flash chromatography (silica gel, 10g, 0% to 10% isopropyl acetate in n-heptane) followed by preparative TLC (silica gel, 1.0mm, 1: 1 n-heptane/isopropyl acetate) to give the title compound (4mg, 9%) as a light brown solid; MS (ESI)453.1(M + H)⁺。

Example 6

Preparation of 5-cyclohexyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

Reacting 5-cyclohex-1-enyl-N- (pyridin-3-yl) -6- (2, 2, 2-trifluoroethoxy) ethylNicotinamide (example 1c, 0.012g, 31.8. mu. mol) was dissolved in ethyl acetate (1 mL). Palladium (10% on carbon, 3.4mg, 32 μmol) was added; the suspension was degassed and aerated with argon (5 ×). It was then degassed and gassed with hydrogen (3 ×) and stirred under hydrogen for 20 h. The reaction mixture was degassed and again aerated with argon (3 ×). It was then filtered through dicalite, washed with isopropyl acetate and concentrated in vacuo to give the title compound (11mg, 91%) as a white solid; MS (ESI)380.3(M + H)⁺。

Example 7

Preparation of 5-cyclopent-1-enyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

The title compound was synthesized in analogy to example 1c, using 5-iodo-N- (pyridin-3-yl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide (example 1b) and 2- (1-cyclopent-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan (CAN287944-10-9) as starting materials; MS (ESI)364.4(M + H)⁺。

Example 8

Preparation of 5-cyclopentyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

The title compound was synthesized in analogy to example 6, using 5-cyclopent-1-enyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide (example 7) as starting material; MS (ESI)366.4(M + H)⁺。

Example 9

Preparation of 5-cyclopentyl-N-pyridazin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

a) 5-Cyclopent-1-enyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid methyl ester

The title compound was synthesized in analogy to example 2a, using 5-bromo-6- (2, 2, 2-trifluoroethoxy) -3-pyridinecarboxylic acid methyl ester (CAN1211589-51-3) and 2- (1-cyclopenten-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (CAN287944-10-9) as starting materials; MS (ESI)302.0(M + H)⁺。

b) 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid methyl ester

The title compound was synthesized in analogy to example 4a, using 5-cyclopent-1-enyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid methyl ester as starting material; MS (ESI)303.9(M + H)⁺。

c) 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid

The title compound was synthesized in analogy to example 4b, using 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid methyl ester as starting material; MS (ESI)287.8(M-H) -.

d) 5-cyclopentyl-N-pyridazin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

The title compound was synthesized in analogy to example 1b, using 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) and 3-pyridazinamine (CAN5469-70-5) as starting materials; MS (ESI)367.2(M + H)⁺。

Example 10

Preparation of 5-cyclopentyl-N-pyridin-2-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

The title compound was synthesized in analogy to example 1b, using 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) and 2-pyridylamine (CAN504-29-0) as starting materials; MS (ESI)366.2(M + H)⁺。

Example 11

Preparation of 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide

To a solution of 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) (124mg, 0.43mmol) in DMF (4mL) at 25 deg.C were added DIPEA (0.1mL, 1.08mmol) and HATU (204mg, 0.54 mmol). The reaction mixture was stirred at 25 ℃ for 30 min. To which C- (3-trifluoromethyl-1, 2, 4-Diazoles-5-yl) -methylamine (CAN944905-93-5) (60mg, 0.36mmol) and the reaction mixture was stirred at 25 ℃ for 12 h. The volatiles were removed in vacuo and the resulting residue was purified by preparative HPLC to give 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl-1, 2, 4-Oxadiazol-5-ylmethyl) -nicotinamide (61mg, 38.7%) as an off-white solid; ms (esi): 439(M + H)]⁺。

Example 12

Preparation of 5-cyclopentyl-N- (3-methoxy-iso-methyl)Azol-5-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

The same procedure as described in example 11 was followed using 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) (135mg, 0.47mmol) and 3-methoxy-5-iso-cyclo-ethoxyOxazole methylamine (CAN2763-94-2) (60.16mg, 0.47mmol) as the starting material to prepare the compound; off-white solid (59mg, 37.8%). Ms (esi): 400(M + H)⁺。

Example 13

Preparation of 5-cyclohexyl-N- (3-methoxy-iso)Azol-5-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

The same procedure as described in example 11 was followed using 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 4b) (120mg, 0.4mmol) and 3-methoxy-5-iso-cyclo-4Oxazole methylamine (CAN2763-94-2) (60.16mg, 0.47mmol) as the starting material to prepare the compound; off-white solid (32mg, 19.6%). Ms (esi): 414(M + H)⁺。

Example 14

Preparation of 5-cyclohexyl-N- (3-methyl- [1, 2, 4 ]]Oxadiazol-5-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

The same procedure as described in example 11 was followed using 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 4b) (100mg, 0.33mmol) and 3-methyl-1, 2, 4-Oxadiazole-5-methylamine (CAN90928-92-0) (37mg, 0.33mmol) as the starting material to prepare the compound; off-white solid (30mg, 22.9%). Ms (esi): 399(M + H)⁺。

Example 15

Preparation of 5-cyclohexyl-N- (1-cyclopropylmethyl-1H-pyrazol-3-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

a)2- ((1- (cyclopropylmethyl) -1H-pyrazol-3-yl) methyl) isoindoline-1, 3-dione

To a colorless solution of 2- (1H-pyrazol-3-ylmethyl) -1H-isoindole-1, 3(2H) -dione (CAN 95533-75-8; 3.66g, 16.1mmol) in DMF (80mL) was added sodium hydride (1.29g, 32.2mmol) in four portions at 0 ℃ over 15 min. After warming to room temperature, the mixture was stirred for 30min and cyclopropylmethyl bromide (21.7g, 15.6mL, 161mmol) in DMF (20mL) was added over 30 min. The mixture was stirred at room temperature for 22h, poured into ethyl acetate (200mL) and extracted with water (3 × 100 mL). The aqueous phase was washed with ethyl acetate (200mL), the organic phases were combined and MgSO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80g, 0% to 100% EtOAc in heptane) and finally by preparative HPLC to yield 1.63g (36%) of the title compound as a white solid; ms (esi): 282.2(M + H)⁺。

b) C- (1-cyclopropylmethyl-1H-pyrazol-3-yl) -methylamine

To a colorless solution of 2- ((1- (cyclopropylmethyl) -1H-pyrazol-3-yl) methyl) isoindoline-1, 3-dione (400mg, 1.42mmol) in THF (10mL) and ethanol (5mL) was added hydrazine hydrate (0.62g, 0.60mL, 12.3 mmol). The white suspension was stirred at room temperature for 20h, diluted with tert-butyl methyl ether (50mL) and phthalhydrazide removed by filtration. The filtrate was concentrated in vacuo and the crude material was purified by flash chromatography (amino phase, 12g, 0% to 100% ethyl acetate in heptane) to yield 197mg (92%) of the title compound as a pale yellow oil; ms (esi): 152.1(M + H)⁺。

c) 5-cyclohexyl-N- (1-cyclopropylmethyl-1H-pyrazol-3-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

This compound was prepared following the same method as described in example 11, using 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 4b) (100mg, 0.33mmol) and C- (1-cyclopropylmethyl-1H-pyrazol-3-yl) -methylamine (51mg, 0.33mmol) as starting materials; off-white solid (48mg, 33.3%). Ms (esi): 437(M + H)⁺。

Example 16

Preparation of 5-cyclohexyl-N- (2-cyclopropyl-thiazol-4-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

This compound was prepared following the same method as described in example 11, using 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 4b) (100mg, 0.33mmol) and 2-cyclopropyl-4-thiazolemethanamine (CAN1083299-53-9, 54mg, 0.35mmol) as starting materials; off-white solid (66mg, 45.4%). Ms (esi): 440(M + H)⁺。

Example 17

Preparation of 5-cyclopentyl-N- (1-cyclopropylmethyl-iH-pyrazol-3-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

The same procedure as described in example 11 was followed using 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) (100mg, 0.35mmol) andc- (1-cyclopropylmethyl-1H-pyrazol-3-yl) -methylamine (53mg, 0.35mmol) as a starting material, to prepare the compound; off-white solid (60mg, 41.1%). Ms (esi): 423(M + H)⁺。

Example 18

Preparation of 5-cyclopentyl-N- (2-cyclopropyl-thiazol-4-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

This compound was prepared following the same method as described in example 11, using 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) (100mg, 0.35mmol) and 2-cyclopropyl-4-thiazolemethanamine (CAN1083299-53-9, 54mg, 0.35mmol) as starting materials; off-white solid (67mg, 45.6%). Ms (esi): 426(M + H)⁺。

Example 19

Preparation of 5-cyclohexyl-N-piperidin-5-yl-6- (2, 22-trifluoro-ethoxy) -nicotinamide

This compound was prepared following the same method as described in example 11 using 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 4b) (100mg, 0.33mmol) and 5-pyrimidinamine (CAN591-55-9, 31.4mg, 0.33mmol) as starting materials; off-white solid (64mg, 51.0%). Ms (esi): 381.4(M + H)⁺。

Example 20

Preparation of 5-cyclohexyl-N-pyridazin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

This compound was prepared following the same method as described in example 11, using 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 4b) (100mg, 0.33mmol) and 4-pyridazinamine (CAN20744-39-2, 31.4mg, 0.33mmol) as starting materials; off-white solid (60mg, 47.8%). Ms (esi): 381.4(M + H)⁺。

Example 21

Preparation of 5-cyclohexyl-N-pyrimidin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

This compound was prepared following the same method as described in example 11 using 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 4b) (100mg, 0.33mmol) and 4-pyrimidinamine (CAN591-54-8, 31.4mg, 0.33mmol) as starting materials; off-white solid (50mg, 39.8%). Ms (esi): 381.4(M + H)⁺。

Example 22

Preparation of 5-cyclopentyl-N-pyrimidin-5-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

This compound was prepared following the same method as described in example 11, using 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) (100mg, 0.35mmol) and 5-pyrimidinamine (CAN591-55-9, 39.5mg, 0.41mmol) as starting materials; off-white solid (61mg, 48.2%). Ms (esi): 367.2(M + H)⁺。

Example 23

Preparation of 5-cyclopentyl-N-pyrimidin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

This compound was prepared following the same method as described in example 11, using 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) (100mg, 0.35mmol) and 4-pyrimidinamine (CAN591-54-8, 39.5mg, 0.41mmol) as starting materials; off-white solid (63mg, 49.7%). Ms (esi): 367.2(M + H)⁺。

Example 24

Preparation of N- (4-cyano-phenyl) -5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

This compound was prepared according to the same method as described in example 11, using 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 4b) (100mg, 0.33mmol) and 4-aminobenzonitrile (CAN873-74-5, 39.0mg, 0.33mmol) as starting materials; off-white solid (24mg, 18.0%). Ms (esi): 402.2(M + H)⁺。

Example 25

Preparation of N- (4-cyano-phenyl) -5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

The same procedure as described in example 11 was followed using5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) (100mg, 0.35mmol) and 4-aminobenzonitrile (CAN873-74-5, 49.0mg, 0.41mmol) as starting materials this compound was prepared; off-white solid (10mg, 7.4%). Ms (esi): 388.2(M + H)⁺。

Example 26

Preparation of 5-cyclopentyl-N-pyridazin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

This compound was prepared following the same method as described in example 11, using 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) (100mg, 0.35mmol) and 4-pyridazinamine (CAN20744-39-2, 39.5mg, 0.41mmol) as starting materials; off-white solid (12mg, 9.5%). Ms (esi): 367.2(M + H)⁺。

Example 27

Preparation of 5-cyclohexyl-N-pyrazin-2-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

To a solution of 5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 4b) (50mg, 0.16mmol) in dichloromethane (5mL) at 0 ℃ was added oxalyl chloride (0.02mL, 0.25mmol) and the reaction mixture was stirred at 25 ℃ for 3 h. The solvent was removed in vacuo and the residue was dissolved in anhydrous dichloromethane, DIPEA (0.2mL, 0.99mmol) was added thereto at 25 ℃ followed by 2-pyrazinamine (CAN5049-61-6, 19mg, 0.21mmol) and the reaction mixture was stirred at said temperature for 12 hours. The solvent was removed in vacuo and the crude residue was purified by preparative HPLC to give 5-cyclohexyl-N-pyrazin-2-yl-6- (2, 2, 2-trifluoro-ethyl esterOxy) -nicotinamide as an off-white solid (10mg, 15.9%); ms (esi): 381.4[ M + H]⁺。

Example 28

Preparation of 5-cyclopentyl-N-pyrazin-2-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

This compound was prepared following the same method as described in example 11, using 5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (example 9c) (50mg, 0.17mmol) and 2-pyrazinamine (CAN5049-61-6, 20mg, 0.21mmol) as starting materials; off-white solid (15mg, 23.7%). Ms (esi): 365.2(M + H)⁺。

Claims (20)

1. A compound of formula I

Wherein

R¹Selected from the group consisting of: c_1-7-an alkyl group,

C_3-7-a cycloalkyl group,

C_3-7-cycloalkyl-C_1-7-an alkyl group,

hydroxy-C_1-7-an alkyl group,

C_1-7-alkoxy-C_1-7-alkyl, and

halogen-C_1-7-an alkyl group;

R²selected from the group consisting of:

C_3-7-a cycloalkyl group,

C_4-7-cycloalkenyl group, and

(ii) heterocyclyl, having 3 to 7 ring atoms, containing one, two or three heteroatoms selected from N, O and S and being saturated or partially unsaturated;

R³selected from the group consisting of: c_1-7-an alkyl group,

C_3-7-cycloalkyl, unsubstituted or substituted by hydroxy,

lower heterocyclyl, said heterocyclyl having 3 to 7 ring atoms, containing one, two or three heteroatoms selected from N, O and S and being unsubstituted or substituted by hydroxy or oxo, - (CH)₂)_m-phenyl, wherein phenyl is unsubstituted or substituted with one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl, and m is selected from 0 or 1, and

-(CH₂)_n-heteroaryl, wherein heteroaryl is unsubstituted or substituted by one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl, and n is selected from 0 or 1;

R⁴is hydrogen or C_1-7-an alkyl group;

and pharmaceutically acceptable salts thereof.

2. A compound of formula I according to claim 1, wherein R¹Is C_3-7-cycloalkyl-C_1-7-alkyl or halogen-C_1-7-an alkyl group.

3. A compound of formula I according to claim 1 or 2, wherein R¹Is halogen-C_1-7-an alkyl group.

4. A compound of formula I according to any one of claims 1 to 3, wherein R²Is C_3-7-cycloalkyl or C_4-7-cycloalkenyl groups.

5. Compounds of formula I according to any one of claims 1 to 4, wherein R²Is cyclopentyl or cyclopentenyl.

6. A compound of formula I according to any one of claims 1 to 3, wherein R²Is a heterocyclic group having 3 to 7 ring atoms, contains one, two or three heteroatoms selected from N, O and S and is saturated or partially unsaturated.

7. Compounds of formula I according to any one of claims 1 to 6, wherein R³Is that

-(CH₂)_m-phenyl, wherein phenyl is unsubstituted or substituted with one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl, and m is selected from 0 or 1, or

-(CH₂)_n-heteroaryl, wherein heteroaryl is unsubstituted or substituted by one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl, and n is selected from 0 or 1.

8. Compounds of formula I according to any one of claims 1 to 7, wherein R³Is that

-(CH₂)_n-heteroaryl, wherein heteroaryl is unsubstituted or substituted by one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl, and n is selected from 0 or 1.

9. Compounds of formula I according to any one of claims 1 to 8, wherein R³Is that

-(CH₂)_n-a heteroaryl group selected from the group consisting of: different from each otherAn azole group, a pyrazole group,(ii) oxadiazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, and is unsubstituted or substituted with one or two groups selected from the group consisting of: c_1-7Alkyl, hydroxy, C_1-7Alkoxy, cyano, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-7Alkyl, halogen and halogen-C_1-7-alkyl, and n is selected from 0 or 1.

10. Compounds of formula I according to any one of claims 1 to 6, wherein R³Is C_1-7-an alkyl group.

11. Compounds of formula I according to any one of claims 1 to 10, wherein R⁴Is hydrogen.

12. A compound of formula I according to claim 1, selected from the group consisting of:

5-cyclohex-1-enyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohex-1-enyl-N-ethyl-N-isopropyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohex-1-enyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide,

5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide,

5- (3, 6-dihydro-2H-pyran-4-yl) -6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide,

5-cyclohexyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopent-1-enyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridazin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridin-2-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -N- (3-trifluoromethyl- [1, 2, 4)]Oxadiazol-5-ylmethyl) -nicotinamide,

5-cyclopentyl-N- (3-methoxy-iso)Oxazol-5-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N- (3-methoxy-iso)Oxazol-5-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N- (3-methyl- [1, 2, 4 ]]Oxadiazol-5-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N- (1-cyclopropylmethyl-1H-pyrazol-3-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N- (2-cyclopropyl-thiazol-4-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N- (1-cyclopropylmethyl-1H-pyrazol-3-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N- (2-cyclopropyl-thiazol-4-ylmethyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N-pyrimidin-5-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N-pyridazin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N-pyrimidin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyrimidin-5-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyrimidin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

n- (4-cyano-phenyl) -5-cyclohexyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

n- (4-cyano-phenyl) -5-cyclopentyl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridazin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclohexyl-N-pyrazin-2-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyrazin-2-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

and pharmaceutically acceptable salts thereof.

13. A compound of formula I according to claim 1, selected from the group consisting of:

5-cyclopent-1-enyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridin-3-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyrimidin-5-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyrimidin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

5-cyclopentyl-N-pyridazin-4-yl-6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide,

and pharmaceutically acceptable salts thereof.

14. Pharmaceutical compositions comprising a compound of formula I according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier and/or adjuvant.

15. Pharmaceutical compositions according to claim 14 for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, in particular 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, improvement of glycemic control, obesity or endotoxemia.

16. A compound of formula I according to any one of claims 1 to 13 for use as a medicament.

17. A compound of formula I according to any one of claims 1 to 14 for the treatment and/or prophylaxis of atherosclerosis, peripheral vascular diseases, 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, improvement of glycemic control, obesity or endotoxemia.

18. A method for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, which method comprises administering a compound of formula I according to any one of claims 1 to 14 to a human being or animal.

19. The use of a compound of formula I according to any one of claims 1 to 14 for the preparation of medicaments for the treatment and/or prophylaxis of atherosclerosis, peripheral vascular diseases, 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, improvement of glycemic control, obesity or endotoxemia, in particular for the treatment and/or prophylaxis of dyslipidemia, atherosclerosis and cardiovascular diseases.

20. A process for the preparation of a compound of formula I according to any one of claims 1 to 14, which process comprises

a) Coupling a compound of formula II with an amine of formula III in the presence of a coupling agent under basic conditions

Wherein R is¹And R²As defined in claim 1, the method further comprising,

wherein R is³And R⁴As defined in claim 1, the method further comprising,

and, if desired, converting the resulting compound of formula I into a pharmaceutically acceptable salt thereof; or, alternatively,

b) coupling a halide of formula IV with a compound of formula V in the presence of a suitable catalyst

Wherein R is¹，R³And R⁴As defined in claim 1, and X is Br or I,

wherein A is selected from the group consisting of: CH (CH)₂NH, O and S, S are selected from 0, 1, 2 and 3And M is a metal species,

to obtain a compound of formula I-b

The compound of formula I-b may be hydrogenated to obtain the compound of formula I-a

Wherein A, s is as defined above and R¹，R³And R⁴As defined in claim 1, and, if desired, converting the resulting compound of formula I into a pharmaceutically acceptable salt thereof.