HK1136823B - Piperidine or piperazine substituted tetrahydro-naphthalene-1-carboxylic acid mtp inhibiting compounds - Google Patents

Description

MTP-INHIBITING COMPOUNDS OF PIPERIDINE OR PIPERAZINE SUBSTITUTED TETRAHYDRO-NAPHTHALENE-1-CARBOXYLIC ACIDS

The present invention relates to novel piperidine or piperazine substituted tetrahydronaphthalene-1-carboxylic acid derivatives having apo B secretion/MTP inhibitory activity with concomitant lipid lowering activity. The invention also relates to processes for the preparation of such compounds, pharmaceutical compositions comprising said compounds and the use of said compounds as a medicament for the treatment of atherosclerosis, pancreatitis, obesity, hypertriglyceridemia, hypercholesterolemia, hyperlipidemia, diabetes and type II diabetes.

Obesity is the cause of a myriad of serious health problems such as adult diabetes and heart disease. In addition, weight loss has become a nuisance in increasing population rates.

Hypercholesterolemia, particularly that associated with increased plasma concentrations of low density lipoproteins (hereinafter LDL) and very low density lipoproteins (hereinafter VLDL), and the etiologic relationship of early stage atherosclerosis and/or cardiovascular disease are now generally recognized. However, the number of drugs currently available for the treatment of hyperlipidemia is limited.

Drugs mainly used for the treatment of hyperlipidemia include bile acid chelate resins such as cholestyramine and colestipol, fibric acid derivatives such as bezafibrate, clofibrate, fenofibrate, ciprofibrate, and gemfibrate, nicotinic acid, and cholesterol synthesis inhibitors such as HMG coenzyme a reductase inhibitors. There remains a need for new lipid lowering agents with improved efficacy and/or by mechanisms other than those described above.

Plasma lipoproteins are water-soluble complexes of lipids (cholesterol, triglycerides, phospholipids) and apolipoproteins with high molecular weight. There are five major classes of lipoproteins that differ in the ratio of lipid to apolipoprotein types, all of which are located in the liver and or small intestine, and have been defined in terms of their density (measured by ultracentrifugation). They include LDL, VLDL, intermediate density lipoprotein (hereinafter referred to as IDL), high density lipoprotein (hereinafter referred to as HDL) and chylomicron. Ten major human plasma apolipoproteins have been identified. VLDL is secreted by the liver and contains apolipoprotein B (hereinafter Apo-B), which is broken down into LDL capable of transporting 60 to 70% of total serum cholesterol. Apo-B is also the major protein component of LDL. Increased plasma LDL-cholesterol due to over-synthesis or reduced metabolism is associated with the etiology of atherosclerosis. In contrast, high density lipoprotein (hereinafter referred to as HDL) containing apolipoprotein a1 has a protective effect and is negatively associated with coronary heart disease. The ratio of HDL/LDL is thus a routine method to assess the likelihood of arteriosclerotic activation of the personal plasma lipid profile.

Two isoforms of apolipoprotein (apo) B, apo B-48 and apo B-100, are important proteins in human lipoprotein metabolism. In the sodium dodecyl sulfate-polyacrylamide gel, Apo B-48 is about 48% of the size of Apo B-100, which is synthesized in the human small intestine. ApoB-48 is essential for the assembly of chylomicron and thus plays an essential role in the absorption of dietary fat in the small intestine. Apo B-100 produced in the human liver is essential for the synthesis and secretion of VLDL. LDL contains about 2/3 cholesterol in human plasma, a metabolite of VLDL. Apo B-100 is essentially the only protein component of LDL. Elevated plasma concentrations of apoB-100 and LDL are considered risk factors for the development of atherosclerotic coronary artery disease.

A number of inherited and acquired diseases can cause hyperlipidemia. It can be classified into primary and secondary hyperlipidemic states. The most common causes of secondary hyperlipidemia are diabetes, ethanol abuse, drugs, hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasis and binge eating. Primary hyperlipidemia has also been classified into common hypercholesterolemia, familial combined hyperlipidemia, familial hypercholesterolemia, remnant (remnants) hyperlipidemia, chylomicronemia syndrome, and familial hypertriglyceridemia.

Microsomal triglyceride transfer protein (hereinafter referred to as MTP) is known to catalyze the transfer of triglycerides, cholesterol esters and phospholipids such as phosphatidylcholine. This indicates that MTP is necessary for the synthesis of Apo B-containing lipoproteins such as chylomicrons and VLDL (a precursor of LDL). Thus, it is known that MTP inhibitors inhibit the synthesis of VLDL and LDL, thereby lowering the levels of VLDL, LDL, cholesterol and triglycerides in humans. Compounds that inhibit MTP are believed to be useful in treating diseases such as obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, type II diabetes, atherosclerosis and lowering plasma levels of serum triglycerides after meals.

The present invention is based on the unexpected discovery that: a group of tetrahydronaphthalene-1-carboxylic acid derivatives have apoB secretion/MTP inhibitory activity. These compounds of formula (I) may act systemically and/or as selective MTP inhibitors, i.e. MTP capable of selectively blocking the levels of the intestinal wall in mammals.

The present invention relates to a novel family of compounds of formula (I)

The pharmaceutically acceptable acid addition salts thereof, the N-oxides thereof, and the stereochemically isomeric forms thereof, wherein

X is N or CH;

A¹is-CH₂-or- (C ═ O) -;

A²is absent or represents-CH₂- (when X represents N), or

A²is-NR⁶- (when X represents CH), wherein R⁶Is hydrogen or C_1-4An alkyl group;

R¹is-NR⁷R⁸OR-OR⁹；

Wherein each R is⁷Or R⁸Is independently selected from

The presence of hydrogen in the presence of hydrogen,

C_1-8an alkyl group, a carboxyl group,

c substituted by one, two or three substituents_1-8Alkyl, each substituent being independently selected from halo, cyano, C_3-8Cycloalkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, polyhaloC_1-4Alkyl, hydroxycarbonyl, -OR¹⁰、-NR¹⁰R¹¹、-CONR¹²R¹³Aryl, polycyclic aryl or heteroaryl;

C_3-8a cycloalkyl group;

C_3-8a cycloalkenyl group;

C_3-8an alkenyl group;

C_3-8an alkynyl group;

an aryl group;

a polycyclic aryl group;

a heteroaryl group;

or R⁷And R⁸And with R⁷And R⁸May form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl or azocinyl ring, wherein each of these rings may optionally be substituted by one or two substituents independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, hydroxycarbonyl, C_1-4Alkoxycarbonyl or C_1-4Alkoxycarbonyl radical C_1-4Alkyl substituent substitution;

wherein R is¹⁰Is hydrogen, C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, R¹²-NH-carbonyl, aryl C_1-4Alkyl, polycyclic aryl, heteroaryl;

R¹¹is hydrogen or C_1-4An alkyl group;

R¹²is hydrogen, C_1-4Alkyl, phenyl or phenyl C_1-4An alkyl group;

R¹³is hydrogen, C_1-4Alkyl, phenyl or phenyl C_1-4An alkyl group;

R⁹is C_1-8Alkyl, aryl, heteroaryl, and heteroaryl,

C substituted by one, two or three substituents_1-8Alkyl, each substituent being independently selected from halo, cyano, C_3-8Cycloalkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, polyhaloC_1-4Alkyl, hydroxycarbonyl, -OR¹⁰、-NR¹⁰R¹¹、-CONR¹²R¹³Aryl, polycyclic aryl or heteroaryl;

C_3-8a cycloalkyl group;

C_3-8a cycloalkenyl group;

C_3-8an alkenyl group;

C_3-8an alkynyl group;

an aryl group;

a polycyclic aryl group;

a heteroaryl group;

wherein

Aryl is phenyl; phenyl substituted with 1-5 substituents, each substituent independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, halo, hydroxy, trifluoromethyl, cyano, C_1-4Alkoxycarbonyl group, C_1-4alkoxycarbonyl-C_1-4Alkyl, methylsulfonylamino, methylsulfonyl, NR¹⁰R¹¹、 C_1-4Alkyl radical NR¹⁰R¹¹、CONR¹²R¹³Or C_1-4Alkyl CONR¹²R¹³；

Polycyclic aryl is naphthyl, indanyl, fluorenyl or 1, 2, 3, 4-tetrahydronaphthyl, and the polycyclic aryl isThe cyclic aryl group is optionally substituted with one or two substituents, each substituent being independently selected from C_1-6Alkyl radical, C_1-6Alkoxy, phenyl, halo, cyano, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl radical C_1-4Alkyl, NR¹⁰R¹¹、C_1-4Alkyl radical NR¹⁰R¹¹、CO NR¹²R¹³、C_1-4Alkyl CONR¹²R¹³Or C_1-4An alkoxycarbonylamino group, and

heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl, thienyl, quinolinyl, isoquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, benzothiazolyl, benzo [1, 3]Dioxolyl, 2, 3-dihydro-benzo [1, 4 ]]Dioxinyl (dioxinyl), indolyl, 2, 3-dihydro-1H-indolyl, 1H-benzimidazolyl, and said heteroaryl is optionally substituted with one or two substituents, each substituent being independently selected from C_1-6Alkyl radical, C_1-6Alkoxy, phenyl, halo, cyano, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl radical C_1-4Alkyl, NR¹⁰R¹¹、C_1-4Alkyl radical NR¹⁰R¹¹、CONR¹²R¹³Or C_1-4Alkyl CONR¹²R¹³；

R^2a、R^2bAnd R^2cIndependently of one another, from hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, halo, hydroxy, cyano, nitro, polyhaloC_1-4Alkyl, polyhalo C_1-4Alkoxy or C_1-4An alkoxycarbonyl group;

R^3a、R^3band R^3cIndependently of one another, from hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, halo, hydroxy, cyano, nitro, polyhaloC_1-4Alkyl, polyhalo C_1-4Alkoxy or C_1-4An alkoxycarbonyl group;

R⁴is phenyl; phenyl substituted with 1-5 substituents, each substituent independently selected from C_1-4Alkyl, halo, hydroxy, C_1-4Alkoxy, amino, cyano, nitro, polyhaloC_1-4Alkyl, polyhalo C_1-4Alkoxy radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, sulfamoyl, heterocyclyl or phenyl optionally substituted with one, two or three substituents, each substituent being independently selected from C_1-4Alkyl, halo, C_1-4Alkoxy, or trifluoromethyl; or a heteroaryl selected from: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furyl and thienyl, wherein each of these heteroaryl groups may be optionally substituted with one or two substituents, each substituent being independently selected from C_1-4Alkyl, halo, hydroxy, C_1-4Alkoxy, oxo, cyano, polyhalo C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl or heterocyclyl;

wherein the content of the first and second substances,

heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl or azacyclooctyl, which may optionally be substituted with one or two substituents each independently selected from C_1-4Alkyl or halogenated substituents; and

R⁵is hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy or halo.

As used in the previous definition:

halo generally refers to fluoro, chloro, bromo and iodo;

-C_1-4alkyl defines straight and branched chain saturated hydrocarbon groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, and the like;

-C_1-6alkyl is intended to include C_1-4Alkyl and its utensilHigher homologs having 5 to 6 carbon atoms, such as 2-methylbutyl, pentyl, hexyl, and the like;

-C_1-8alkyl is intended to include C_1-6Alkyl groups and their higher homologs having 7 to 8 carbon atoms such as heptyl, ethylhexyl, octyl, and the like;

-polyhalo C_1-4Alkyl is defined as C substituted by polyhalo_1-4Alkyl, especially C, substituted by 1-4 halogen atoms_1-4Alkyl (as defined herein above) such as fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, and the like;

-C_3-8cycloalkyl is typically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;

-C_3-8cycloalkenyl is typically intended to mean cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl;

-C_3-8alkenyl is defined as straight and branched chain hydrocarbon radicals containing one double bond and having 3 to 8 carbon atoms, such as: 2-propenyl, 3-butenyl, 2-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-pentenyl, 2-octenyl and the like;

-C_3-8alkynyl is defined as straight and branched chain hydrocarbon radicals containing one triple bond and having 3 to 8 carbon atoms, such as: 2-propynyl, 3-butynyl, 2-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-pentynyl, 2-octynyl and the like.

The pharmaceutically acceptable acid addition salts which the compounds of formula (I) mentioned above in this specification are capable of forming are intended to include non-toxic acid addition salt forms which are therapeutically active. These pharmaceutically acceptable acid addition salts are conveniently obtained by treating the base form with such an appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, for example: hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as: acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid (pamoic acid), and the like.

Instead, the salt form can be converted to the free base form by treatment with a suitable base.

The compounds of formula (I) may exist in unsolvated as well as solvated forms. The term "solvate" as used in this specification is intended to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water.

The N-oxide forms of the compounds according to formula (I) are intended to include compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxides, especially those wherein one or more tertiary nitrogens (e.g. piperazinyl or piperidinyl) are N-oxidized. Such N-oxides are readily available to the skilled artisan without any inventive innovations, and they are obvious alternatives to compounds according to formula (I) since these compounds are metabolites that are formed by oxidation in the human body when ingested. As is well known, oxidation is usually the first step involved in drug metabolism (organic medicine and pharmaceutical chemistry education, 1977, pages 70-75). As is also well known, the metabolite form of a compound can also be administered to the human body in place of the compound itself with very similar effects.

The compounds of formula (I) may be converted to their N-oxide form by converting the trivalent nitrogen to its N-oxide form according to methods known in the art. The N-oxidation reaction may generally be carried out by reacting a compound of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, such as sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids, such as peroxybenzoic acid, or halo-substituted peroxybenzoic acids, such as: trichloroperoxybenzoic acids, peroxyalkanoic acids, such as: peracetic acid, alkyl hydroperoxides, such as: tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, such as: ethanol, etc., hydrocarbons, such as: toluene, ketones, for example: 2-butanone, halogenated hydrocarbons, such as: dichloromethane, and mixtures of such solvents.

The term "stereochemically isomeric forms" as used hereinbefore in the present specification is defined as all possible isomeric forms which the formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound refers to the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More particularly the stereogenic center may have the R-or S-configuration and the substituents on the bivalent cyclic (partially) saturated radicals may have either the cis-or trans-configuration. Compounds encompassing a double bond may have E-or Z-stereochemistry at the double bond. The stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of the present invention.

The absolute stereochemical configuration of the compounds of formula (I) and the intermediates used to prepare them can be readily determined by those skilled in the art using well-known methods such as X-ray diffraction.

The compounds of formula (I) have at least two asymmetric carbon atoms as illustrated below, wherein the asymmetric carbon atoms are defined by a^*To be identified.

Since at least two asymmetric carbon atoms are present, in general, the term "compound of formula (I)" covers a mixture of four stereoisomers. Most of the compounds of the present invention have been prepared with either the trans-configuration or the cis-configuration:

the "cis" or "trans" compounds described above each comprise a racemic mixture of two enantiomers, and bold or dashed bonds are used to indicate this relative stereochemical configuration.

If a "cis" or "trans" compound separates into two individual enantiomers, the bold and dashed bonds are replaced by wedge bonds to indicate that the compound is a single enantiomer. If the absolute stereochemistry of a particular chiral carbon atom in a single enantiomer is not determined, its stereochemical configuration is as R^*Or S^*Labeled to indicate relative stereochemistry.

Furthermore, certain compounds of formula (I) and certain intermediates used in their preparation may exhibit polymorphism. It is to be understood that the present invention encompasses any polymorphic form having properties useful in the treatment of the above-mentioned conditions.

Certain compounds of formula (I) may exist in their tautomeric form. Such forms, while not specifically indicated in the above formulae, are intended to be included within the scope of the present invention. For example, when an aromatic heterocycle is substituted with a hydroxyl group, then the keto form can be a tautomer of the predominant mode.

In the framework of the present application, the expression "compound according to the invention" is also intended to include compounds according to general formula (I) and prodrugs thereof, or isotopically labelled compounds thereof.

Also encompassed within the scope of the present invention are so-called "prodrugs" of the compounds of formula (I). Prodrugs are certain derivatives of pharmaceutically active compounds which may themselves have little or no pharmacological activity and which, when administered into or onto the body, are converted to compounds of formula (I) having the desired pharmaceutical activity, for example by hydrolytic cleavage. Such derivatives are referred to as "prodrugs".

In the framework of the present invention, the compounds according to the invention are intended to include all isotopic combinations of their chemical elements. Within the framework of the present application, a chemical element, especially when mentioned in relation to compounds according to formula (I), comprises all isotopes and isotopic mixtures of such elements, whether naturally occurring or synthetically produced, whether in naturally enriched or isotopically enriched form. In particular, when hydrogen is mentioned, it is understood to mean¹H、 ²H、³H and mixtures thereof; when carbon is mentioned, it is understood to mean¹¹C、¹²C、¹³C、¹⁴C and mixtures thereof; when and nitrogen, it is understood to mean¹³N、¹⁴N、¹⁵N and mixtures thereof; when referring to oxygen, it is understood to mean containing¹⁴O、¹⁵O、¹⁶O、¹⁷O、¹⁸O and mixtures thereof; and when fluorine is mentioned it is understood to mean¹⁸F、¹⁹F and mixtures thereof.

The compounds according to the invention therefore inherently include compounds bearing one or more isotopes of one or more elements, and mixtures thereof, including radioactive compounds, also known as radiolabeled compounds, in which one or more non-radioactive atoms are replaced by 1 of its radioactive isotopes. The term "radiolabeled compound" means any compound according to formula (I), a pharmaceutically acceptable acid or base addition salt thereof, an N-oxide form thereof, or a quaternary ammonium salt thereof, which comprises at least one radioactive atom. For example, a compound may be labelled with an positron or a radioisotope capable of emitting gamma radiation. For radioligand binding techniques (cell membrane receptor assays),³h atom or¹²⁵I atom is selected forA displaced atom. For imaging purposes, the most commonly used Positron Emitting (PET) radioisotope is¹¹C、¹⁸F、¹⁵O and¹³n, all produced by the accelerator and having half-lives (half-lives) of 20, 100, 2 and 10 minutes, respectively. Because the half-life of these radioisotopes is so short, they can only be practically used by a mechanism that has an accelerator at its production site, thus limiting their usefulness. The most widely used of these isotopes is¹⁸F、^99mTc、²⁰¹Tl and¹²³I. the handling of these radioisotopes, their production, isolation and incorporation into molecules are known to those skilled in the art.

In particular, the radioactive atoms are selected from hydrogen, carbon, nitrogen, sulfur, oxygen and halogens. Preferably the radioactive atom is selected from hydrogen, carbon and halogen.

In particular, the radioisotope is selected from³H、¹¹C、¹⁸F、¹²²I、¹²³I、¹²⁵I、¹³¹I、 ⁷⁵Br、⁷⁶Br and⁸²br is added. Preferably the radioisotope is selected from³H、¹¹C and¹⁸F。

important compounds of formula (I) are compounds of formula (I) wherein one or more of the following limitations apply:

a) x is CH; or

b) X is N; or

c)R^2a＝R^3a，R^2b＝R^3bAnd R is^2c＝R^3c(ii) a Especially R^2a＝R^3a＝H，R^2b＝R^3bIs H and R^2c＝R^3cH, or

d)A¹Is- (C ═ O) -; or

e)A¹is-CH₂-; or

f)R¹Is NR⁷R⁸Wherein each R is⁷And R⁸Independently selected from hydrogen; c_1-8An alkyl group; c substituted by one or two substituents_1-8Alkyl, each substituent being independently of the others selected from hydroxy, C_1-4Alkoxy radical, C_1-4Alkoxycarbonyl, hydroxycarbonyl, NR¹⁰R¹¹、CONR¹²R¹³Aryl or heteroaryl; or an aryl group; or

g)R¹Is NR⁷R⁸Wherein R is⁷And R⁸And with R⁷And R⁸Wherein each of these rings may be optionally substituted with one or two substituents, each substituent being independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, hydroxycarbonyl or C_1-4An alkoxycarbonyl group; or

h)R¹Is OR⁹Wherein R is⁹Is C_1-6Alkyl or C_3-8An alkenyl group; or

i)R⁴Is phenyl; phenyl substituted with 1, 2 or 3 substituents, each substituent independently selected from C_1-4Alkyl, halo, hydroxy, C_1-4Alkoxy, polyhalo C_1-4Alkoxy, sulfamoyl, phenyl substituted by trifluoromethyl, or heterocyclyl, wherein the heterocyclyl is substituted by C_1-4Alkyl-substituted morpholinyl or piperazinyl, or

j)R⁴Is heteroaryl, wherein the heteroaryl is pyridyl or pyridazinyl optionally substituted with one or two substituents, each substituent independently selected from C_1-4Alkyl, hydroxy, C_1-4Alkoxy or oxo; or

k) Aryl is phenyl; or phenyl substituted with 1-2 substituents, each substituent being selected from C_1-4Alkyl radical, C_1-4Alkoxy, halo or hydroxy; or

l)R⁹Is a heteroaryl group; wherein heteroaryl is indolyl;

m)R⁵is hydrogen or C_1-4An alkoxy group;

in one embodiment, the present invention relates to those compounds of formula (I) wherein X is CH or N; when X represents CH, then A₂is-NR⁶-, wherein R⁶Is hydrogen or C_1-4Alkyl, or when X represents N, then A₂Is absent; a. the₁Is- (C ═ O) -or-CH₂-；R^2a＝R^3a＝H，R^2b＝R^3bIs H and R^2c＝R^3c＝H；R¹Is NR⁷R⁸Wherein each R is⁷And R⁸Independently selected from hydrogen; c_1-8An alkyl group; c substituted by one or two substituents_1-8Alkyl, each substituent being independently of the others selected from hydroxy, C_1-4Alkoxy radical, C_1-4Alkoxycarbonyl, hydroxycarbonyl, NR¹⁰R¹¹、CONR¹²R¹³Aryl or heteroaryl; or an aryl group; or R¹Is NR⁷R⁸Wherein R is⁷And R⁸And with R⁷And R⁸Wherein each of these rings may be optionally substituted with one or two substituents, each substituent being independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, hydroxycarbonyl or C_1-4An alkoxycarbonyl group; or R¹Is OR⁹Wherein R is⁹Is hydrogen, C_1-6Alkyl or C_3-8An alkenyl group; r⁴Is phenyl; or phenyl substituted with 1, 2 or 3 substituents each independently selected from C_1-4Alkyl, halo, hydroxy, C_1-4Alkoxy, polyhalo C_1-4Alkoxy, sulfamoyl, phenyl substituted by trifluoromethyl, or heterocyclyl, wherein the heterocyclyl is substituted by C_1-4Alkyl-substituted morpholinyl or piperazinyl; or R⁴Is heteroaryl, wherein the heteroaryl is pyridyl or pyridazinyl optionally substituted with one or two substituents, each substituent independently selected from C_1-4Alkyl, hydroxy, C_1-4Alkoxy or oxo; r⁵Is hydrogen or C_1-4An alkoxy group; aryl is phenyl;or phenyl substituted with 1-2 substituents, each substituent being selected from C_1-4Alkyl radical, C_1-4Alkoxy, halo or hydroxy; and heteroaryl is indolyl.

In another embodiment, the invention relates to

a) A compound of formula (I) wherein R^2a＝R^3a＝H，R^2b＝R^3bIs H and R^2c＝R^3c＝H；

b) A compound of formula (I) wherein R⁴Is phenyl substituted by a heterocyclic group, wherein the heterocyclic group is substituted by C_1-4Alkyl (especially methyl or isopropyl) substituted piperazinyl;

c) a compound of formula (I) wherein the substituents at the 1, 2, 3, 4-tetrahydronaphthyl moiety have the trans configuration;

d) a compound of formula (I) wherein the substituent at the 1, 2, 3, 4-tetrahydronaphthyl moiety has the (1R, 4S) configuration;

particular compounds of formula (I) are compounds (34), (39), (47), (129), (199), (208), (246), (247), (248), (249), (252) and (276).

In general, compounds of formula (1-a) (which are defined as wherein A₁represents-CH₂The compounds of formula (I) of (a) can be prepared by N-alkylating an intermediate of formula (III) with an intermediate of formula (II), wherein W is a suitable leaving group, for example halo such as chloro, bromo, iodo or in some instances W may also be a sulfonyloxy group, for example methanesulfonyloxy, arylsulfonyloxy such as benzenesulfonyloxy or p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and similar active leaving groups. The reaction can be carried out in a reaction-inert solvent such as acetonitrile, 2-pentanol, isobutanol, dimethylacetamide, dichloromethane, chloroform, 1, 2-dichloroethane or DMF and optionally in the presence of a suitable base such as sodium carbonate, potassium carbonate or triethylamine. Agitation may facilitate the rate of the reaction. The reaction is conveniently carried out at a temperature between room temperature and the reflux temperature of the reaction mixtureAt room temperature. The reaction rate and yield can be increased by microwave assisted heating.

A compound of formula (1-b) (which is defined as wherein A¹Compounds of formula (I) representing- (C ═ O) -) can be prepared by reaction of an intermediate of formula (V) with an intermediate of formula (IV) in at least one reaction-inert solvent in at least one "solid state synthesis" as in s.kates and f.albericio: the handbook of practical application "(ISBN 0-8247-0359-6), Marcel Dekker, Inc, 2000, page 275-330) in the presence of suitable coupling agents and/or suitable bases, such as sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine or N-methylmorpholine, which optionally also comprises converting the compounds of the formula (I-b) into their addition salts and/or preparing stereochemically isomeric forms thereof. . The reaction rate and yield can be increased by microwave assisted heating.

The intermediate of formula (IV) may be conveniently converted to the acid halide derivative by reaction with, for example, thionyl chloride, oxalyl bromide, oxalyl chloride, phosgene, phosphorus trichloride or phosphorus tribromide, prior to addition of the intermediate of formula (V) and the appropriate base.

The carboxylic acid of formula (IV) may conveniently be activated by the addition of an effective amount of a reaction promoter. Non-limiting examples of such reaction promoters include carbonyldiimidazole, diimides such as N, N' -dicyclohexyl-carbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, and functional derivatives thereof. If a chirally pure reactant of formula (IV) is used, the reaction of the intermediate of formula (IV) with the intermediate of formula (V) is rapid and without enantiomeric isomerization can be carried out in an effective amount of a compound such as Hydroxybenzotriazole (HOBT), benzotriazolyloxytris (dimethylamino) -phosphonium hexafluorophosphate, tetrapyrrolidinophosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate, or a functional derivative thereof as described in D.Hudson, "journal of organic chemistry", (1988), 53: 617. page.3 of the derivatives disclosed. Or the intermediate of formula (IV) may be conveniently converted to the acid halide derivative by reacting it with thionyl chloride, oxalyl bromide, oxalyl chloride, phosgene, phosphorus trichloride or phosphorus tribromide, before addition of the intermediate of formula (V) and the appropriate base.

An intermediate of formula (XVII) wherein the substituent R^2a、R^2b、R^2c、R^3a、R^3b、R^3c、R⁴、R⁵、A¹、A²And X is as defined for compounds of formula (I), by N-acylation as known in the art, using H-NR⁷R⁸As reagents converted to compounds of formula (I-c) defined as R therein¹Represents NR⁷R⁸A compound of formula (I).

Wherein R is¹Is OR⁹And R is⁹Is C_1-6Alkyl compounds of formula (I) may also be converted to compounds in which R is¹Is OR⁹And R is⁹A compound of formula (I) which is hydrogen. Wherein R is¹Is OR⁹And R is⁹Is C_3-8The alkenyl compounds of formula (I) may be converted to R wherein R is by reduction as known in the art, for example with sodium borohydride in the presence of tetrakis (triphenylphosphine) palladium in a suitable solvent such as THF¹Is OR⁹And R is⁹A compound of formula (I) which is hydrogen. Protection groups in "organic synthesis" by t.w.greene and p.g.m.wuts, Wiley-Interscience; third edition (19)5.5.15) (ISBN 0471160199), wherein R may be¹Is OR⁹And R is⁹Is a protecting group such as allyl; conversion of a benzyl or tert-butyl compound of formula (I) into a compound of formula (I) wherein R¹Is OR⁹And R is⁹A compound of formula (I) which is hydrogen.

Is defined as wherein R¹Represents OR⁹，R^2a＝R^3a，R^2b＝R^3bAnd R is^2c＝R^3cThe intermediates of formula (XIII) of formula (IV) can be prepared as outlined below.

The intermediate of formula (XV) can be prepared as follows. The intermediate of formula (XV) is wherein R¹Represents NR⁷R⁸An intermediate of formula (IV).

The intermediate of formula (II) may be prepared as follows. The intermediate of formula (II-a) is defined as wherein R¹Represents NR⁷R⁸And intermediates of formula (II-b) are defined wherein R¹Represents OR⁹Intermediate of formula (II)

The compounds of formula (I) prepared in the above-described processes can be synthesized as racemic mixtures of enantiomers, which can be separated from each other according to resolution methods known in the art. The compounds of formula (I) obtained in racemic form can be converted into the corresponding diastereomers by reaction with an appropriate chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom with a base. Another method for separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs in a stereospecific manner. Preferably, if a particular enantiomer is desired, the compound can be synthesized by stereospecific methods of preparation. These processes will advantageously employ enantiomerically pure starting materials.

The compounds of formula (I), their N-oxide forms, pharmaceutically acceptable salts and stereoisomeric forms have advantageous apoB secretion and MTP inhibitory activity and concomitant lipid lowering activity. The compounds of formula (I) according to the invention are therefore useful as medicaments, especially in methods for treating patients suffering from hyperlipidemia, obesity, atherosclerosis or type II diabetes. The invention is then useful for the manufacture of a medicament for the treatment of diseases caused by an excess of Very Low Density Lipoprotein (VLDL) or Low Density Lipoprotein (LDL), and in particular diseases caused by cholesterol associated with said VLDL and LDL. In particular, the compounds of the present invention are useful for the preparation of a medicament for the treatment of hyperlipidemia, obesity, atherosclerosis, or type II diabetes.

The main mechanism of action of the compounds of formula (I) appears to inhibit MTP (microsomal triglyceride transfer protein) activity in hepatocytes and small intestinal epithelial cells, leading to a decrease in VLDL and chylomicron production, respectively. This is a novel and inventive method for hyperlipidemia, and is expected to lower LDL-cholesterol and triglycerides by decreasing VLDL production in the liver and chylomicron production in the small intestine.

There are many genetic and acquired diseases that cause hyperlipidemia. They can be classified into primary and secondary hyperlipidemic states. The most common causes of secondary hyperlipidemia are diabetes, ethanol abuse, drugs, hypothyroidism, chronic renal failure, nephrotic syndrome, bile obstruction, and binge eating. Primary hyperlipidemia is common hypercholesterolemia, familial combined hyperlipidemia, familial hypercholesterolemia, remnant hyperlipidemia, chylomicronemia syndrome, and familial hypertriglyceridemia. The compounds are also useful in the prevention or treatment of patients suffering from obesity or atherosclerosis, especially coronary atherosclerosis and more generally diseases associated with atherosclerosis such as ischemic heart disease, peripheral vascular disease, cerebrovascular disease. The compounds of the invention cause a reduction in atherosclerosis and inhibit the clinical consequences of atherosclerosis, especially morbidity and mortality.

In view of the utility of the compounds of formula (I), the present invention also provides a method for treating warm-blooded animals, including humans (collectively referred to as patients in this specification), suffering from diseases caused by an excess of Very Low Density Lipoproteins (VLDL) or Low Density Lipoproteins (LDL), especially diseases caused by cholesterol associated with said VLDL and LDL. Accordingly, a method of treatment is provided to alleviate a patient suffering from a condition such as hyperlipidemia, obesity, atherosclerosis, or type II diabetes.

Apo B-48 synthesized by the small intestine is essential for the assembly of chylomicrons and therefore plays a mandatory role in the absorption of dietary lipids by the small intestine. The present invention provides compounds that are useful as selective MTP inhibitors at the level of the intestinal wall.

The present invention further provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with at least one pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in the form of a single dose, preferably suitable for oral, rectal, transdermal or parenteral administration.

For example, in preparing the compositions in oral dosage form, any of the usual liquid pharmaceutical carriers may be employed, such as water, glycerol, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or in the case of powders, pills, capsules and tablets, solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, dispersants and the like. Because tablets and capsules are easy to administer, they represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the pharmaceutical carrier will consist essentially of sterile water, although other ingredients may be included to enhance the solubility of the active ingredient. Solutions for injection may be prepared using, for example, a pharmaceutically acceptable carrier comprising saline solution, dextrose solution, or a mixture of the two. Injectable suspensions may also be prepared using suitable liquid carriers, suspending agents and the like. In compositions suitable for transdermal administration, the pharmaceutically acceptable carrier may optionally contain a penetration enhancer and/or a suitable humectant, optionally in combination with a small proportion of a suitable additive that does not cause significant damage to the skin. The additives may be selected to aid in the application of the active ingredient to the skin and/or to aid in the preparation of the desired composition. These topical compositions can be administered in a number of ways, such as transdermal patches, topically applied salves (spot-on), or ointments. The addition salts of the compounds of formula (I) are obviously more suitable for the preparation of aqueous compositions due to their increased water solubility over the corresponding base forms.

It is particularly advantageous to formulate the pharmaceutical compositions of the present invention in unit dosage form to provide ease of administration and uniformity of dosage. As used herein, "unit dosage form" refers to physically discrete units suitable as unitary dosage forms, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with a desired pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls, and the like, and segregated multiples thereof.

For oral administration, the pharmaceutical compositions of the present invention may take the form of solid dosage forms, for example, tablets (both swallowable and chewable forms), capsules or caplets (gelcaps), prepared by conventional methods using pharmaceutically acceptable excipients and carriers such as binding agents (pregelatinized corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), fillers (e.g., lactose, microcrystalline cellulose, calcium phosphate and the like), lubricants (e.g., magnesium stearate, talc, colloidal silica and the like), disintegrants (e.g., potato starch, sodium starch glycolate and the like), wetting agents (e.g., sodium lauryl sulfate) and the like. Such tablets may also be coated by methods known in the art.

Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be formulated as a dry product for admixture with water and/or another suitable liquid carrier before use. Such liquid preparations may be prepared by conventional means, optionally together with other pharmaceutically acceptable additives such as suspending agents (for example sorbitol syrup, methyl cellulose, hydroxypropylmethyl cellulose or hydrogenated edible fats and oils), emulsifying agents (for example lecithin or acacia), non-aqueous vehicles (for example almond oil, oily esters or ethyl alcohol), sweetening agents, flavouring agents, masking agents and preservatives (for example methyl or propyl p-hydroxybenzoates or sorbic acid).

The pharmaceutically acceptable sweeteners used in the pharmaceutical compositions of the present invention preferably include at least one intense sweetener such as aspartame, acesulfame potassium (acesulfame potassium), cyclamate sodium, alitame, dihydrochalcone sweeteners, vegetable monellin (monellin), stevioside, sucralose (4, 1 ', 6' -trichloro-4, 1 ', 6' -trideoxygalactosucrose) or preferably saccharin, sodium saccharin or calcium saccharin, and optionally at least one bulk (bulk) sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt (isomalt), glucose, hydrogenated glucose syrup, xylitol, caramel or honey. Intense sweeteners are conveniently used at low concentrations. In the case of sodium saccharin, for example, the concentration may range from about 0.04% to 0.1% (weight/volume) of the final formulation. Bulk sweeteners can be effectively used at greater concentrations ranging from about 10% to about 35%, preferably from about 10% to about 15% (weight/volume).

The pharmaceutically acceptable flavoring agent which can mask bitter ingredients in low dose formulations is preferably a fruit flavor such as cherry, raspberry, blackcurrant or strawberry flavor. Combining the two flavors can produce very good results. In high dose formulations, a strong pharmaceutically acceptable taste may be required, such as caramel chocolate, super-cooled mint, Fantasy taste (Fantasy), etc. The concentration of flavoring agent for each flavor in the final composition ranges from about 0.05% to 1% (weight/volume). This combination of strong flavors is advantageously used. Preferably, a flavoring agent is used which does not produce any change or loss of taste and/or color in the environment of the formulation.

The compounds of formula (I) may be formulated for parenteral administration by injection, for example by bolus injection or continuous intravascular infusion, conveniently by intravenous, intramuscular or subcutaneous injection. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, including an added preservative. They may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as isotonic, suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be presented in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter and/or other glycerides.

The compounds of formula (I) may also be used in combination with other drugs, in particular the pharmaceutical compositions of the invention may further comprise at least one additional lipid lowering agent, leading to so-called combination lipid lowering therapy. The additional lipid lowering agent may be, for example, a known drug which may be conventionally used for the treatment of hyperlipidaemia, such as a resin which chelates bile acids, a fibric acid derivative or nicotinic acid as mentioned previously in the background of the invention. Suitable additional lipid lowering agents also include other cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors, especially HMG-CoA reductase inhibitors and HMG-CoA synthetase inhibitors, HMG-CoA reductase gene expression inhibitors, CETP inhibitors, ACAT inhibitors, squalene synthetase inhibitors, CB-1 antagonists, cholesterol absorption inhibitors such as ezetimibe and the like.

Any HMG-CoA reductase inhibitor may be used as the second compound in the combination therapy of the present invention. As used herein, the term "HMG-CoA reductase inhibitor" refers to a compound that inhibits the biotransformation of hydroxymethylglutaryl-CoA, catalyzed by the enzyme HMG-CoA reductase, to mevalonate, unless otherwise indicated. Such "HMG-CoA reductase inhibitors" are, for example, lovastatin, simvastatin, fluvastatin, pravastatin, rivastatin and atorvastatin.

Any HMG-CoA synthase inhibitor may be used as the second compound in the combination therapy aspect of the present invention. The term "HMG-CoA synthase inhibitor" as used herein, unless otherwise indicated, refers to a compound that inhibits the biosynthesis of hydroxymethylglutaryl-CoA from acetyl-CoA and acetoacetyl-CoA catalyzed by the enzyme HMG-CoA synthase.

Any HMG-CoA reductase gene expression inhibitor may be used as the second compound in the combination therapy aspect of the invention. These drugs may be HMG-CoA reductase transcription inhibitors that block DNA transcription or translation inhibitors that prevent translation of mRNA encoding HMG-CoA reductase into protein. Such inhibitors may directly affect transcription or translation, or may be bioconverted by one or more than one enzyme in the cholesterol biosynthesis cascade to a compound having the above-described properties, or capable of causing aggregation of metabolites having the above-described activities.

Any CETP inhibitor may be used as the second compound in the combination therapy aspect of the invention. As used herein, the term "CETP inhibitor" refers to a compound that inhibits the transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL, which is regulated by Cholesteryl Ester Transfer Protein (CETP), unless otherwise indicated.

Any ACAT inhibitor may be used as the second compound in the combination therapy aspect of the invention. As used herein, the term "ACAT inhibitor" refers to a compound that inhibits the intracellular esterification of dietary cholesterol by the enzyme acyl CoA cholesterol acyltransferase, unless otherwise indicated.

Any squalene synthetase inhibitor can be used as the second compound in the combination therapy aspect of the invention. As used herein, the term "squalene synthetase inhibitor" refers to a compound that, unless otherwise indicated, inhibits the condensation of two farnesyl pyrophosphate molecules catalyzed by the enzyme squalene synthetase to form squalene.

A person skilled in the art of treatment of hyperlipidaemia will readily be able to determine a therapeutically effective amount of a compound of formula (I) from the test results presented below. In general, a therapeutically effective dose is considered to be from about 0.001mg/kg to about 50mg/kg body weight, more preferably from about 0.01mg/kg to about 5mg/kg body weight of the patient to be treated. Suitable administration is by administering a therapeutically effective dose in the form of two or more sub-doses at appropriate intervals during the day. The sub-doses may be formulated in unit dosage forms, for example, each unit dosage form containing from about 0.1mg to about 350mg, more preferably from about 1mg to about 200mg, of the active ingredient.

The precise dosage and frequency of administration will depend upon the particular compound of formula (I) employed, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient, and other drugs which may be employed by the patient, including the additional lipid lowering agents mentioned above, and are well known to those skilled in the art. Furthermore, the effective daily amount may be decreased or increased based on the response of the patient being treated and/or based on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily dosage ranges set forth in this specification are therefore only used as a guide.

Experimental part

The following abbreviations are used in the methods described below: "DCM" represents dichloromethane; "DMA" means N, N-dimethylacetamide; "DMF" means N, N-dimethylformamide; "TFA" represents trifluoroacetic acid; "THF" represents tetrahydrofuran; "EtOH" represents ethanol; "MeOH" represents methanol and "DIPE" represents diisopropyl ether.

N-cyclohexylcarbodiimide N-methyl polystyrene HL resin (1.90mmol/g) is a Novabiochem 01-64-021 resin; polymer supported carbonate matrix [ polystyrylmethyl]Trimethylammonium dicarbonate resin (5.8mmol/g) is Novabiochem's 01-64-041 resin; the polystyrene-carbodiimide resin (1.90mmol/g) is Novabiochem's 01-64-024 resin; polystyrene-N-methylmorpholine HL resin (3.80mmol/g) is Novabiochem's 01-64-0211 resin; polystyrene-dicarbonate (5.8mmol/g) is Novabiochem's 01-064-. Novabiochem resins are available from Calbiochem-Novabiochem AG, Weidenmattweg 4, CH-4448In sweden.

PS-carbodiimide resin (polystyrene resin bound N-cyclohexylcarbodiimide) and PS-isocyanate resin (1% crosslinked polystyrene-divinylbenzene resin copolymer with benzylic isocyanate functionality) were obtained from argonaut (biotage), New Road, Hengoed, Mid Glamorgan, uk.

Extrelut^TMIs a product of Merck KgaA, Darmstadt, Germany, and is a short column containing diatomaceous earth. Chiralcel OD, OJ, and AD are chiral stationary phase column materials, available from daicel chemical Industries, ltd.

Prochrom The Dynamic Axial Compression column was obtained from Novasep S.A.S., Boulevard de la Moselle, B.P.50F-54340 Pompey, France.

The absolute stereochemical configuration of certain compounds was determined using vibronic circular dichroism polarization (VCD). Description of VCD for determining absolute configuration can be found in Chirality, 14: 215, 219 (2002).

A. Synthesis of intermediates

Example A.1

Preparation ofIntermediate (1)

2-hydroxy-2-phenyl-propionic acid methyl ester (0.1mol) was added to a solution of sulfuric acid (300ml) in water (250ml) and the reaction mixture was stirred at 100 ℃ for 20 hours. The precipitate was filtered off and dissolved in DCM (600ml), washed with water and brine. The organic layer was separated, dried, filtered and the solvent was evaporated to a volume of 100 ml. The precipitate was filtered off and dried to yield 9g of intermediate (1).

Example A.2

Preparation of

A mixture of intermediate (1) (1.327mol) dissolved in absolute ethanol (2360ml) was stirred and concentrated sulfuric acid (4ml) was added. The reaction mixture was refluxed for 22 hours under nitrogen and then allowed to cool to room temperature overnight. The resulting precipitate was filtered off, washed with absolute ethanol and dried to give 120g of intermediate (2) (mp.186-187 ℃ C.).

The ethanol layers were combined and evaporated, the resulting residue was dissolved in DCM (1450ml) and NaHCO₃The aqueous solution was washed (twice with 500ml), dried and the solvent was evaporated. The residue was stirred in DIPE (680ml) at a temperature of 50-55 ℃ and the remaining DCM was distilled off and the concentrate was left at room temperature for more than 2 hours. Filtering to obtainWashed with DIPE (120ml) and pentane and then dried at 40 ℃ to give a further 103.2g of intermediate (2) (mp.187-188 ℃).

Preparation of

The previous DIPE/pentane layer was evaporated and the residue was dissolved in dry acetonitrile (200ml), then the solvent was evaporated again to give 166.3g of intermediate (3) (mp.75 ℃ C.)

Example A.3

Preparation ofIntermediate (4)

Intermediate (2) (0.03mol) was stirred in chloroform (50 ml). Thionyl chloride (0.06mol) was added and the reaction mixture was stirred and refluxed for 4 hours until gas evolution ceased. The reaction mixture was concentrated by evaporation of the solvent. Chloroform (200ml) was added and the solvent was evaporated again to give a residue, which was slowly added to anhydrous ethanol (100ml) cooled on an ice water bath at. + -. 5 ℃. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 4 hours. Evaporation of the solvent gave intermediate (4) (mp.78-80 ℃ C.).

Intermediate (5) was prepared in a similar manner but starting from intermediate (3).

Preparation ofIntermediate (5)

Example A.4

Preparation ofIntermediate (6)

A mixture of intermediate (4) (0.0567mol) and p-toluenesulfonic acid (1g) was stirred and refluxed in a mixture of formic acid (500ml) and concentrated hydrochloric acid (125ml) for 3 hours. The reaction mixture was concentrated by evaporation of the solvent, the residue was dissolved in DCM and NaHCO was used₃The aqueous solution is washed and dried. The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1/9) to give intermediate (6) (mp.115-118 ℃ C.).

Intermediate (7) (mp.133-135 ℃) was prepared in a similar manner but starting from intermediate (5).

Preparation ofIntermediate (7)

Example A.5

a) Preparation ofIntermediate (8)

Intermediate (1) (0.1mol) was dissolved in ethanol (500ml), sulfuric acid (5ml) was added and the reaction mixture was stirred and refluxed overnight, then cooled and ethanol was evaporated off. The residue was dissolved in DCM and washed with water (2 × 200ml) and brine (100 ml). The organic layer was dried, the solvent was concentrated and the residue triturated with DIPE, filtered and dried to yield 18g of intermediate (8).

b) Preparation ofIntermediate (9)

Thionyl chloride (0.255mol) was added to a solution of intermediate (8) (0.03409mol) in chloroform (200 ml). The mixture was stirred and refluxed for 4 hours.The solvent was evaporated. The residue was dissolved in DCM (125ml) under a stream of nitrogen. The mixture was cooled to-10 ℃. A solution of benzylamine (benzzenamine) (0.230mol) in DCM (75ml) was added dropwise at-10 ℃ under a stream of nitrogen. The mixture was stirred at room temperature overnight. The precipitate was filtered off, washed with 1M HCl (until pH < 7), washed with water (until pH 7), washed with saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue obtained is purified by column chromatography over silica gel (eluent: (hexane/ethyl acetate (2/1)/CH)₂Cl₂). The pure fractions were collected and the solvent was evaporated, yielding 10.244g of intermediate (9).

c) Preparation ofIntermediate (10)

A solution of intermediate (9) (0.01985mol) in anhydrous THF (400ml) was cooled to 0 ℃ under a stream of nitrogen. LiBH is added dropwise at 0 ℃ under a nitrogen stream₄(2M in THF) (0.1 mol). The mixture was stirred for 15 minutes. Ethanol (100ml) was added. The mixture was stirred at room temperature overnight. HCl solution 1M (200ml) was added. The mixture was extracted with ethyl acetate (500 ml). The organic layer was separated, washed with water (until pH 7), washed with saturated NaCl solution, dried, filtered and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate 1/2). The pure fractions were collected and the solvent was evaporated. The remaining fraction (6.62g, 90%) was dried in vacuo at 60 ℃ over the weekend to give intermediate (10).

d) Preparation ofIntermediate (11)

4-Methylbenzenesulfonyl chloride (0.024mol) was added portionwise under a nitrogen stream to a solution of intermediate (10) (0.00782mol) in pyridine (75 ml). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated. The residue was dissolved in DCM (300ml) and washed with water and brine. The organic layer was separated, washed with HCl (0.1M), washed with water (until pH 7), washed with saturated NaCl solution, dried and the solvent evaporated. The residue was dissolved in toluene, the solvent was evaporated twice and the resulting residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate 2/1). The pure fractions were collected and the solvent was evaporated, yielding 3.57g of intermediate (11).

Example A.6

a) Preparation ofIntermediate (12)

Thionyl chloride (0.01551mol) was added to a solution of intermediate (8) (0.0031mol) in chloroform (20 ml). The mixture was stirred at 80 ℃ for 4 hours. The solvent was evaporated. The residue was dissolved in DCM (20 ml). The mixture was cooled to-10 ℃. A solution of benzylamine (0.05487mol) in DCM (20ml) was added dropwise at-10 ℃ under a stream of nitrogen. The reaction mixture was stirred at room temperature for 15 hours. The precipitate was filtered off. The filtrate was washed three times with water (20ml), washed with saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was dissolved in 1MHCl (100 ml). The mixture was extracted with DCM, washed several times with water and with saturated NaCl solution. The organic layer was dried, filtered and the solvent was evaporated. The resulting fraction was treated with DIPE. The precipitate was filtered off and dried to yield 0.6355g of intermediate (12).

b) Preparation ofIntermediate (13)

A mixture of intermediate (12) (0.00439mol) in 36% HCl solution (50ml) was stirred and refluxed overnight. The precipitate was filtered off. The residue was stirred in DCM (several ml) for one hour. Hexane was added and the mixture was stirred. The precipitate was filtered off and dried to yield 1.2g of intermediate (13).

Example A.7

Preparation ofIntermediate (14)

A mixture of intermediate (9) (0.00469mol) in 36% HCl solution (40ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was dried and then stirred in 1M NaOH. The mixture was extracted twice with DCM (2 × 20ml) and separated into its layers. The aqueous layer was acidified with HCl solution and extracted with DCM. The combined organic layers were washed with saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was dried in vacuo to give 1.07g of intermediate (14).

Example A.8

a) Preparation ofIntermediate (15)

Thionyl chloride (0.0426mol) was added to a solution of intermediate (8) (0.00852mol) in chloroform (50 ml). The mixture was stirred at 80 ℃ for 4 hours. The solvent was evaporated. The residue was dissolved in anhydrous DCM (60 ml). The mixture was cooled to-10 ℃. A solution of 1-propylamine (0.1338mol) in dry DCM (50ml) was added dropwise at-10 ℃ under a stream of nitrogen. The mixture was stirred overnight while the temperature was brought to room temperature, then washed with water, 0.5M HCl (20ml) and water. The organic layer was separated, washed with saturated NaCl solution, dried, filtered and the solvent was evaporated. The resulting fraction was purified by column chromatography over silica gel (eluent: DCM 100%). The pure fractions were collected and the solvent was evaporated. The residue was suspended in DIPE. The precipitate was filtered off and dried to yield 2.694g of intermediate (15).

b) Preparation ofIntermediate (16)

A mixture of intermediate (15) (0.00548mol) in HCl solution (36%, 50ml) was stirred and refluxed for 3 hours. More HCl solution (36%, 20ml) was added. The mixture was stirred and refluxed overnight. The precipitate was filtered off and dried to yield 0.516g of intermediate (16).

Example A.9

a) Preparation ofIntermediate (17)

The reaction was carried out under nitrogen atmosphere. Intermediate (15) (0.00478mol) was dissolved in dry THF (150ml) and cooled to 0 ℃. Addition of LiBH at 0 deg.C₄(2M in THF) (0.028 mol). The mixture was stirred for 15 minutes. Ethanol (20ml) was added and the reaction mixture was stirred at room temperature overnight. 1M HCl (100ml) was added. Ethyl acetate (125ml) was added and the layers were separated. The organic layer was washed with water, once with brine, dried, filtered and the solvent was evaporated, yielding 1.5g of intermediate (17).

b) Preparation ofIntermediate (18)

4-Methylbenzenesulfonyl chloride (0.0418mol) was added portionwise to a solution of intermediate (17) (0.00836mol) in pyridine (75 ml). The mixture was stirred at room temperature for 20 hours. The solvent was evaporated. The residue was dissolved in DCM (250 ml). The organic layer was separated, washed with HCl (0.1M), washed with water (until pH 7), washed with saturated NaCl solution, dried and the solvent was evaporated. The residue was dissolved in toluene (2X 20 ml). The solvent was evaporated and the fraction of the residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate 2: 1). The pure fractions were collected and the solvent was evaporated. The resulting fractions were suspended in DIPE. The precipitate was filtered off and dried to yield 3.305g of intermediate (18).

Example A.10

a) Preparation of

And

and

a solution of intermediate (8) (0.14mol) in DCM (600ml) and chloroform (600ml) was stirred under nitrogen at 20 ℃ and thionyl chloride (79ml) was added over a period of 5 minutes. The reaction mixture was stirred and refluxed for 4 minutes. The mixture was cooled to 20 ℃ and the solvent was evaporated. The residue was dissolved in THF (1000ml) and the solution was cooled to-5 ℃ under nitrogen, then a solution of ethylamine (1.4mol, 70% in water) in THF (100ml) was added dropwise while maintaining the temperature below 0 ℃. The mixture was then allowed to warm to 20 ℃ and stirred for 2 hours. Diethyl ether (1000ml) was added and the organic layer was separated, then washed with water (400ml three times) and brine (400 ml). The mixture was dried and the solvent was evaporated to give intermediate (21), which was chromatographically separated into trans isomer intermediate (19) and cis isomer intermediate (20).

b) Preparation of

And

a suspension of intermediate (21) (0.043mol) in 37% concentrated hydrochloric acid solution (200ml) was stirred and refluxed overnight, then the HCl solution (+ -100 ml) was evaporated and the residue was diluted with water (400 ml). The resulting mixture was extracted with DCM (200ml twice) and the combined extracts were dried. The solvent was evaporated and the solid residue was purified by flash column chromatography (eluent: first ether/hexane 1/1 and then ether/hexane 1/0). The fractions of the product were collected to give a mixture of cis/trans isomers which was purified by flash column chromatography (eluent 1: ether; eluent 2: ethyl acetate/petroleum ether 80/20; eluent 3: ethyl acetate). The desired product fractions were collected and the solvent was evaporated. The residue was washed with diethyl ether (100ml twice) to give a solid residue (I) and a diethyl ether wash (II).

The residue (I) (9.8g) was crystallized from ethyl acetate and the resulting crystals were collected to give residue (Ia) (4.6g of the "trans" isomer, mp.182-187 ℃).

The ethereal washing (II) is purified by flash column chromatography (eluent: DCM/EtOAc 70/30) and then by flash column chromatography (eluent: DCM/EtOAc 80/20). Two product fractions were collected and the solvent was evaporated. Both residual fractions were crystallized from ethyl acetate and collected. The resulting fraction, 4.9g of residue (IIa), was combined with residue (Ia) to give 9.5g of intermediate (23) (mp.182-187 ℃ C.). The other resulting fraction, 2.7g of residue (IIb), was collected to give intermediate (22) (mp.179-182 ℃ C.).

Example A.11

a) Preparation ofIntermediate (24)

Intermediate (8) (0.15mol) was stirred in 0.15M NaHCO dissolved in water (200ml)₃And trioctylmethylammonium chloride (Aliquat 336) in DCM (200ml) was added) (0.15mol) and 3-bromo-1-propane (0.75mol), the reaction mixture was then stirred at 20 ℃ for four days and the organic layer was separated. The aqueous layer was washed with DCM (300ml)The combined organic layers were extracted and dried. The solvent was evaporated and the residue was stirred in hexane (500ml) and then cooled to 0 ℃. The resulting precipitate was filtered off, washed with hexane and dried overnight at 60 ℃ to give 46g of intermediate (24).

b) Preparation of

And

a28% concentrated hydrochloric acid solution (100ml) and 4-methylbenzenesulfonic acid (0.7g) were added to a solution of intermediate (24) (0.13mol) in formic acid (400ml), and the reaction mixture was stirred and refluxed for 6 hours. The solvent was evaporated and the residue was taken up in DCM (300ml) and saturated NaHCO₃The mixture was partitioned in an aqueous solution (200 ml). The DCM layer was separated, dried and the solvent was evaporated. The residue was triturated under ether to give solid (I) and the mother liquor was concentrated then crystallized from ethyl acetate/hexane to give solid (II). The solid (I) and the solid (II) are combined and subjected to flash column chromatography (eluent: DCM/CH)₃OH 95/5). Fractions of the product were collected, the solvent was evaporated and the residue was triturated under hexane. The recovered residue (9.5g) was then triturated under ether and filtered off, collecting a solid portion to give 7g of intermediate (25) ("trans" isomer, mp.: 138-139 ℃) and concentrating the collected mother liquor layer to give 2g of intermediate (26) ("cis/trans" mixture 25/75).

Example A.12

a) Preparation of

Intermediate (3) (0.0031mol) and NaHCO₃(0.0031mol) solution in water (10ml) was reacted with trioctylmethylammonium chloride (Aliquat 336)) A mixture of (0.0031mol) and 3-bromo-1-propene (0.0031mol) in DCM (10ml) was stirred vigorously for three days. The reaction mixture was extracted with DCM, dried, concentrated and subjected to flash column chromatography (eluent: CH)₃OH/CHCl₃10/90) is purified. The pure product fractions were collected and the solvent was evaporated to yield intermediate (27).

b) Preparation of

A mixture of intermediate (27) (0.0165mol) in formic acid (100ml) was stirred and refluxed with concentrated hydrochloric acid solution (50ml) and methanesulfonic acid (catalytic amount) overnight, then the reaction mixture was cooled and the solvent was evaporated. The residue was dissolved in DCM and taken up with saturated NaHCO₃The solution was washed, dried and the solvent was evaporated to yield 1.81g of intermediate (28).

Example A.13

a) Preparation of

A solution of intermediate (19) (0.0568mol) in THF (800ml) was cooled to 0 ℃ under nitrogen, then lithium bromide (0.17mol) and sodium borohydride (0.17mol) were added in one portion and the mixture was stirred at 0 ℃ for 1 hour. Ethanol (300ml) was added and the mixture was stirred at 20 ℃ overnight. HCl (1N, 100ml) was added and the organic layer was separated, washed with brine and dried. The solvent was evaporated and the resulting residue was triturated under ether. The solid residue is then filtered off and crystallized from diethyl ether to give 16.3g of intermediate (29) (mp.122-129 ℃ C.).

b) Preparation of

A solution of intermediate (29) (0.0038mol) and tosyl chloride (0.019mol) in pyridine (35ml) was stirred at room temperature (16 ℃ C.) for 20 hours, then the reaction mixture was poured into ice-water (100ml) and the mixture was stirred for one hour. The aqueous solution was extracted with DCM (50ml three times) and the organic layers were combined, washed with brine, dried and the solvent evaporated, yielding 0.9g of intermediate (30) (mp.130-132 ℃ C.).

Example A.14

a) Preparation of

Thionyl chloride (15ml) was added to a suspension of intermediate (2) (0.05mol) in DCM. The reaction mixture was stirred and refluxed for 1 hour. The solvent was evaporated. DCM (100ml) was added. The solvent was evaporated. The residue was dissolved in DCM. Adding concentrated ammonia NH₄OH/H₂O (100ml) and the reaction mixture was stirred overnight. The organic layer was separated, dried, filtered and the solvent was evaporated to give intermediate (31).

b) Preparation of

A mixture of intermediate (31) (0.05mol) in concentrated hydrochloric acid (60ml) and dioxane (60ml) was stirred and refluxed for 2 hours. The mixture was allowed to cool to room temperature. Water (200ml) was added and stirring was continued for 1 hour. The precipitate was filtered off, washed with water and 2-propanol and then dried to yield 13.1g of intermediate (32).

Example A.15

a) Preparation of

The reaction was carried out under nitrogen. A mixture of 4- (tert-butoxycarbonylamino) -piperidine (0.0345mol), intermediate (25) (0.0345mol), 1-hydroxy-1H-benzotriazole (HOBT) (0.0517mol) and N' - (ethylcarbamimidoyl) -N, N-dimethyl-1, 3-propanediamine (0.0517mol) in DCM (1000ml) was stirred at room temperature for 4 hours. The solvent was evaporated and ethyl acetate (400ml) was added to the residue. The organic solution was washed with water, 1N HCl (300ml), aqueous NaHCO3 (300ml), brine (300ml), then dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate 2/1). Fractions of the product were collected and the solvent was evaporated to give 5.16g of intermediate (33).

b) Preparation of

A solution of intermediate (33) (4.5g, 0.0087mol) and triphenylphosphine (2.28g, 0.0087mol) in dry acetonitrile (60ml) was stirred at room temperature under nitrogen. Pyrrolidine (0.75ml) and tetrakis (triphenylphosphine) palladium (0.5g, 5 mol%) were added and the reaction mixture was stirred at room temperature for 18 h. Ethyl acetate (80ml) was added and the mixture was washed with saturated NaHCO₃The mixture was extracted with solution (4X 100 ml). The combined alkaline extracts were acidified with 1N HCl and then extracted with DCM (3X 150 ml). The combined organic layers were dried, filtered, and the solvent was evaporated to give 2.82g of intermediate (34).

c) Preparation of

A mixture of intermediate (34) (0.001mol), potassium carbonate (0.003mol) and iodomethane (0.065ml) in DMF (6ml) was stirred at room temperature for 92 hours. The reaction mixture was poured into water (15ml) and the resulting solid was filtered off and purified by Biotage flash chromatography (eluent 1: DCM; eluent 2: hexane/ethyl acetate 4/1 → 3/1 → 2/1 → 1/1 → 1/2). The pure fractions were collected and the solvent was evaporated. The residue was stirred in hexane overnight to give intermediate 35 (mp.: 190 ℃; trans).

Example A.16

a) Preparation of

Intermediate (3) (0.05mol) was dissolved in DCM (100 ml). Thionyl chloride (0.2mol) was added and the mixture was stirred. Several drops of DMF were added and the reaction mixture was stirred and refluxed for 1 hour. The solvent was evaporated. DCM was added and then evaporated again. The residue was dissolved in DCM, stirred and concentrated aqueous ammonia NH added₄OH/H₂O1/1(50 ml; 1/1). The reaction mixture was stirred for 2 hours. The layers were separated. The organic layer was dried, filtered and the solvent was evaporated to give 16g of intermediate (36).

b) Preparation of

A mixture of intermediate (36) (0.05mol) in concentrated hydrochloric acid (60ml) and dioxane (60ml) was stirred and refluxed for 2 hours. Water (200ml) was added. The mixture was cooled. The precipitate was filtered off, washed with water and 2-propane and then dried to yield 13.2g of intermediate (37).

Example A.17

Preparation of

Intermediate (6) (0.154mol) was stirred in DCM (200ml) and DMF (5 drops) was added followed by thionyl chloride (37 ml). The mixture was stirred and refluxed for 1 hour, then the solvent was evaporated. Fresh DCM (100ml) was added and the solvent was evaporated twice to give intermediate (38).

Example A.18

a) Preparation ofIntermediate (41)

The 2-methoxy 3-pyridinecarboxylic acid was first converted to its thionyl chloride by refluxing the carboxylic acid in DCM (100ml, p.a) and thionyl chloride (7 ml). The solvent was evaporated. To this residue (0.024mol) was added saturated NaHCO₃To a mixture in aqueous solution (75ml) was added a mixture of 1- (phenylmethyl) -4-piperidinamine (0.024mol) in DCM (150 ml). The reaction mixture was stirred for 2 hours. The layers were separated. The separated organic layer was dried (MgSO)₄) The solvent was filtered and evaporated. By column Chromatography (CH)₃OH/CH₂Cl₂1/99) the residue was purified. The fractions to be obtained were collected and the solvent was evaporated. The residue was triturated from diisopropyl ether to give 7.38g of intermediate (41).

b) Preparation ofIntermediate (42)

A mixture of intermediate (41) (7g, 0.021mol) in methanol (50ml) was hydrogenated using 10% palladium on carbon (1g) as a catalyst at room temperature. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. Addition of a small amount of HCl in 2-propanol gave a white solid, yielding 4.08g of intermediate (42).

Example A.19

a) Preparation ofIntermediate (43)

A mixture of 1- (ethoxycarbonyl) -4-aminopiperidine (0.065mol), triethylamine (0.09mol) and toluene (160ml) was stirred on an ice bath. A solution of 2-methoxy-5-chlorobenzoyl chloride (0.072mol) dissolved in toluene (40ml) was added dropwise. The reaction mixture was stirred overnight and water was added. The organic layer was separated, washed twice with water, dried and evaporated. The solid residue was crystallized from DIPE to give 16.2g of intermediate (43) (mp.113.2 ℃ C.).

b) Preparation of

A mixture of intermediate (43) (0.044mol), potassium hydroxide (12g), isopropanol (150ml) and water (1ml) was stirred and heated back for 3 hours. The reaction mixture was evaporated and the residue was dissolved in a mixture of water and chloroform. The organic layer was separated, washed twice with water, dried and evaporated. The residue was dissolved in methyl isobutyl ketone and acidified by addition of isopropanol saturated with HCl. The resulting precipitate was filtered off and dried to yield 9.1g of intermediate (44).

Intermediate (45) was prepared in a similar manner but starting from ethyl cis-4-amino-3-methoxypiperidine 1-carboxylate and 2-methoxybenzoic acid.

Example A.20

Preparation ofIntermediate (46)

6-amino-n-hexanoic acid (0.01mol) was dissolved in propanol (30ml) and sulfuric acid (1ml) was added and the reaction mixture was refluxed for 48 hours. Evaporation of the solvent gave 2.1g of intermediate (46).

Example A.21

Preparation ofIntermediate (47)

A mixture of (S) -2-aminoglutaric acid (0.0068mol) and sulfuric acid (0.00816mol) in propanol (40ml) was refluxed for 48 hours. The solvent was evaporated and the residue was dried to give intermediate (47).

Example A.22

Preparation ofIntermediate (48)

Sulfuric acid (0.00816mol) was added to a solution of (S) -2-aminoglutaric acid (0.0136mol) in isopropanol (40ml) and refluxed for 48 hours. Evaporation of the solvent afforded intermediate (48).

Example A.23

Preparation ofIntermediate (49)

Sulfuric acid (0.012mol) was added to a solution of 4-aminobutyric acid (0.01mol) in isopropanol (30ml) and refluxed for 48 hours. Evaporation of the solvent afforded intermediate (49).

Example A.24

a) Preparation ofIntermediate (50)

Will N⁶- [ (1.1-Dimethylethoxy) carbonyl]-N²- [ (9H-fluoren-9-ylmethoxy) carbonyl]-L-lysine (5g) was dissolved in methanol (100ml, anhydrous) and cesium carbonate (17g, 0.5 equiv.) was added. The solution was stirred for 10 minutes. The solvent was evaporated and the residue was co-evaporated with toluene. The residue was dissolved in acetonitrile (30ml, anhydrous) and 1-iodopropane (18g, 10 equivalents) was added in portions. The reaction mixture was stirred. The solvent was evaporated at a temperature as low as possible under reduced pressure. The residue was dissolved in water and extracted with ether. The organic layer was separated and the solvent was evaporated. The residue was purified by column chromatography (eluent: ethyl acetate/hexane 1/4). The desired fractions were collected and the solvent was evaporated. The residue was stirred in water and filtered to give 2g of intermediate (50).

b) Preparation ofIntermediate (51)

Intermediate (50) (4g, 0.0078mol) was dissolved in DCM (30ml) and TFA (10ml) was added. The reaction mixture was stirred at room temperature until TLC indicated completion of the reaction. The solvent was evaporated under reduced pressure while keeping the temperature as low as possible to give intermediate (51).

c) Preparation ofIntermediate (52)

Intermediate (51) (0.0078mol) was dissolved in DCM (200 ml). Adding saturated NaHCO₃Aqueous solution (200ml) and the reaction mixture was stirred under nitrogen for 20 minutes. 1-methylethyl chloroformate (1-methyleth-carbonochloridic acid, ester) (11.4ml) was then added in portions. The reaction was stirred and the layers were separated. The separated organic layer was washed with water, dried and the solvent was evaporated to give 3.5g of intermediate (52).

d) Preparation ofIntermediate (53)

Intermediate (52) (3.5g, 0.007mol) was dissolved in acetonitrile (40ml) followed by the addition of piperidine (10 ml). The reaction mixture was stirred for 10 minutes. The solvent was evaporated to dryness. The crude residue was used in the next reaction to give intermediate (53).

Example A.25

a) Preparation ofIntermediate (54)

Thionyl chloride (0.0965mol) was added dropwise to a solution of 2- (4-morpholinyl) -benzoic acid (0.029mol) dissolved in DCM (150 ml). A few drops of DMF were added and the reaction mixture was refluxed for 2 hours. The solvent was evaporated, some DCM was added and the solvent was evaporated again. DCM was added again. 1- (Phenylmethyl) -4-piperidinamine (0.029mol) was added to the reaction mixture. Then saturated NaHCO₃An aqueous solution (75ml) was added to the reaction mixture and stirred for 2 hours. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was triturated under DIPE. The precipitate was filtered off and dried to yield 10.06g of intermediate (54).

b) Preparation ofIntermediate (55)

A mixture of intermediate (54) (0.026mol) in DCM (150ml) and THF (10ml) was hydrogenated using 10% palladium on carbon (2g) as catalyst. The catalyst was filtered off. A little more 10% (2g) of palladium on carbon was then added to the filtrate. This mixture was again hydrogenated with hydrogen (1 equivalent was used for the whole process). The catalyst was filtered off and the solvent was evaporated, yielding 5.3g of intermediate (55).

Example A.26

a) Preparation ofIntermediate (56)

Andintermediate (57)

The intermediate (2) was purified by supercritical fluid chromatography using an AD-H column (20X 250mm) at a flow rate of 50 ml/min (eluent: CO)₂/(methanol with 0.1% 2-propanol) 85/15). The column oven was set at 40 ℃ and the nozzle pressure at 100 bar. Two different product fractions were collected and the solvent was evaporated, yielding intermediate (56) and intermediate (57) OR: 7.46 ° (c: 0.7502 w/v%, MeOH, 20 ℃, 365 nm).

b) Preparation ofIntermediate (58)

Intermediate (57) (0.000308mol, 0.1g) was dissolved in DCM (3 ml). Thionyl chloride (0.045) and DMF (one drop) were added and the mixture was refluxed. The reaction mixture was concentrated and DCM (3ml) was added again. The solvent was evaporated. The residue was slowly added to ethanol (6ml) and cooled to 0 ℃ in an ice bath. The ice bath was removed and the reaction mixture was allowed to reach room temperature. The reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated. The residue was dissolved in DCM and taken up with saturated NaHCO₃And (4) washing with an aqueous solution. It was then purified by column chromatography (from 100% CH)₂Cl₂Start until 2% MeOH/CH₂Cl₂). A product fraction was collected and the solvent was evaporated to afford intermediate (58).

c) Preparation ofIntermediate (59))

Andintermediate (60)

Intermediate (58) (0.00284mol, 1g) was dissolved in p-toluenesulfonic acid (0.050g), formic acid (25ml) and concentrated hydrochloric acid (6 ml). The reaction mixture was refluxed. The reaction mixture was concentrated in vacuo. The residue was then dissolved in DCM and taken up with saturated NaHCO₃The aqueous solution was washed, dried and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate/hexane 1/9). Fractions of the product were collected and the solvent was evaporated, yielding 0.74g of intermediate (59) and 0.75g of intermediate (60).

Example A.27

a) Preparation ofIntermediate (61)

2- (4-methyl-1-piperazinyl) benzoic acid (6.33g, 0.0287mol) was dissolved in DCM (150ml) and DMF (one drop) was added. Thionyl chloride (8.34ml, 0.1148mol, 4 eq) was then added and the mixture refluxed for 2 hours 30 minutes. The solvent was evaporated and DCM (150ml) was added again. The solvent was evaporated and DCM (150ml) was added a third time. 1- (Phenylmethyl) -4-piperidinamine (5.46g, 0.0287mol) and saturated NaHCO were then added₃The solution (75ml) was stirred at room temperature. The layers were separated and the separated organic layer was dried (MgSO)₄) The solvent was filtered and evaporated. The residue is purified by column chromatography (eluent: CH)₃OH/CH₂Cl₂1/9). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from DCM and isopropyl ether to give 10.03g of intermediate (61).

b) Preparation ofIntermediate (62)

A mixture of intermediate (61) (7g, 0.017mol) in methanol (100ml) was hydrogenated using 10% (2g) palladium on carbon as a catalyst. After absorption of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated to give intermediate (62).

Example A.28

Preparation ofIntermediate (63)

Andintermediate (64)

Intermediate (25) was subjected to supercritical fluid chromatography and purified by using AD-H column (20X 250mm) at a flow rate of 50 ml/min (eluent: CO)₂/(methanol with 0.1% 2-propanol) 85/15). The column oven was set at 40 ℃ and the nozzle pressure at 100 bar. Two different product fractions were collected and the solvent was evaporated, yielding 7.23g of intermediate (63) (1R, 4S) and 7.55g of intermediate (64) (1S, 4R).

Example A.29

a) Preparation ofIntermediate (65)

2-Methoxybenzoic acid (10.665g, 0.0699mol) was dissolved in DCM (100 ml). Thionyl chloride (10.09ml, 0.1398mol, 2 eq) and DMF (1 drop) were added and the mixture was refluxed for 2 hours. The solvent was evaporated and DCM (100ml) was added again. The solvent was evaporated and DCM (100ml) was added again. 1-benzyl-4- (methylamino) piperidine (14.2g, 0.0699mol) and saturated NaHCO were then added₃Aqueous solution (50 ml). Stirring the two-layer system andthe layers were separated. The separated organic layer was dried (MgSO)₄) Filtration and evaporation of the solvent gave 22.83g of intermediate (65).

b) Preparation ofIntermediate (66)

A mixture of intermediate (65) (0.067mol) in methanol (250ml) was hydrogenated at 50 ℃ using 10% (2g) palladium on carbon as catalyst. After absorption of hydrogen (1686ml), the catalyst was filtered off and the filtrate was evaporated to yield 16g of intermediate (66).

Example A.30

a) Preparation ofIntermediate (67)

Trimethylsilylcyanide (48ml, 0.36mol) and zinc iodide (0.114g, 0.00036mol) were added to 3-acetyl-1-fluorobenzene (44.6ml, 0.36 mol). The reaction mixture was slowly heated to 50 ℃ (the temperature was increased by 10 ℃ every 15 minutes). The mixture was stirred at 50 ℃ for 3 hours and then at room temperature for 20 hours. The solvent was evaporated and co-evaporated with toluene to give intermediate (67).

b) Preparation ofIntermediate (68)

Methanol (400ml) was cooled to 0 ℃ and the solvent was saturated with hydrogen chloride gas. Cooled intermediate (67) (85.4g, 0.36mol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then heated to 60 ℃ overnight. Adding NaHCO₃The solution was taken up to pH7 and the mixture was extracted twice with DCM. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. By column Chromatography (CH)₂Cl₂) The residue was purified. The desired fractions were collected and the solvent was evaporated, yielding 55.3g of intermediate (68).

c) Preparation ofIntermediate (69)

Intermediate (68) (5.8g, 0.02g) was dissolved in methanesulfonic acid (36ml) and the solution was heated to 80 ℃ and stirred overnight. The reaction was then quenched with water and ethyl acetate was added. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. By column Chromatography (CH)₂Cl₂) The residue was purified. Two different product fractions were collected and the solvent was evaporated. The first fraction was identified as 3-fluoro- α -methylene-phenylacetic acid methyl ester. The second fraction was dissolved in ethyl acetate and the solution was washed with NaOH solution and then with sulfuric acid solution. The organic layer was dried (MgSO₄) Filtration and evaporation of the solvent gave 1.2g of intermediate (69).

d) Preparation ofIntermediate (70)

Andintermediate (71)

Intermediate (69) (10g, 0.06mol) was dissolved in B (80ml) and the solution was heated to 100 ℃ overnight. The precipitate was filtered off and washed with DCM. The mixture was again allowed to react overnight, and the precipitate was again filtered, washed with DCM and purified by reverse phase high performance liquid chromatography (shandonHyperprep)C18BDS (base-deactivated silica gel) 8 μm, 250g, i.d.5 cm). A gradient of buffer and organic solvent is applied. Two different product fractions were collected and the solvent was evaporated. Each residue was dissolved in a small amount of methanol. Then DCM is added andthe solution was washed with HCl (1N). The solvent of the two fractions was evaporated to yield 1.8g of intermediate (70) and 2.67g of intermediate (71).

e) Preparation ofIntermediate (72)

Intermediate (70) (0.2g, 0.000602mol) was dissolved in DCM (6ml) and thionyl chloride (10g, 0.0015mol, 2.5 eq) was added. The reaction mixture was refluxed for 2 hours. The mixture was cooled to room temperature and absolute ethanol (2ml) was added. The mixture was stirred for 2 hours. The solvent was evaporated. The residue was purified by column chromatography. The desired fractions were collected and the solvent was evaporated to yield intermediate (72).

f) Preparation ofIntermediate (73)

Intermediate (72) was dissolved in a mixture of formic acid (2ml) and concentrated hydrochloric acid (2 ml). The mixture was heated for 3 hours. By column Chromatography (CH)₃OH/CH₂Cl₂1/9) purifying the mixture. The desired fractions were collected and the solvent was evaporated to yield intermediate (73).

Example A.31

a) Preparation ofIntermediate (74)

A mixture of 1- (phenylmethyl) -4-piperidinamine (7g, 0.037mol) in DCM (100ml) was added to a mixture of 2-methoxybenzoyl chloride (6.4g, 0.037mol) in DCM (100 ml). Sodium bicarbonate solution (100ml) was then added and the mixture was stirred at room temperature for 2 hours. The layers were separated. The separated organic layer was dried and the solvent was evaporated. The residue was triturated in DIPE, filtered and dried to yield 10.6g of intermediate (74).

b) Preparation ofIntermediate (75)

A mixture of intermediate (74) (10.7g, 0.033mol) in methanol (150ml) was hydrogenated using 10% palladium on carbon (1g) as a catalyst. After absorption of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 2-propanol and the solution was acidified with a solution of hydrochloric acid in 2-propanol. The product was crystallized from this solution. The precipitate was filtered off and dried to yield 8.3g of intermediate (75).

Example A.32

a) Preparation ofIntermediate (76)

2-bromo-1- (2-methoxyphenyl) ethanone (0.1g, 0.000436mol) was dissolved in anhydrous DCM (4ml) and 1- (phenylmethyl) piperazine (0.077g) and triethylamine (0.061ml, 1.2 eq) were added. The mixture was stirred at room temperature for 2 hours. The mixture was washed with water and the aqueous layer was extracted with DCM to give intermediate (76).

b) Preparation ofIntermediate (77)

A mixture of intermediate (76) (0.00308mol) in methanol (100ml) was hydrogenated using 10% palladium on carbon (0.050g) as catalyst in the presence of saturated 2-propanol with HCl (5 ml). After the reaction, the catalyst was filtered off and the filtrate was evaporated to give 0.46g of intermediate (77).

Example A.33

a) Preparation ofIntermediate (84)

2- (4-methyl-1-piperazinyl) -3-pyridinecarboxylic acid (11.9g, 0.0538mol) was dissolved in DCM (10ml) and thionyl chloride (12.7g) and 1 drop of DMF were added. The reaction mixture was stirred and refluxed for 90 minutes. The solvent was evaporated. Additional DCM (10ml) was added and evaporated. More DCM (10ml) was added and evaporated. 1- (Phenylmethyl) -4-piperidinamine (10.20g) and saturated NaHCO were added₃Aqueous solution (5ml) and the reaction mixture was stirred at room temperature until the reaction was complete. Additional DCM and saturated NaHCO were added₃The aqueous solution was repeated several times and the organic layer was separated and dried (MgSO₄) Filtration and evaporation of the solvent gave 4.24g of intermediate (84).

b) Preparation ofIntermediate (85)

A mixture of intermediate (84) (4.24g, 0.0107mol) in methanol was hydrogenated using palladium on activated carbon (2g) as a catalyst. After absorption of hydrogen (1 equivalent), the catalyst was filtered off over Celite (Celite) and the filtrate was evaporated to give intermediate (85).

Example A.34

a) Preparation ofIntermediate (87)

Intermediate (71) (0.2g, 0.00052mol) was dissolved in ethanol (5ml) and sulfuric acid (0.5ml) was added. The reaction mixture was stirred in advance in a microwave oven for 10 seconds, then heated at 100 ℃ for 2 hours, and then at 140 ℃ for 2 hours. The solution was evaporated to give intermediate (87).

b) Preparation ofIntermediate (88)

Intermediate (87) (0.00052mol) was dissolved in formic acid (2ml) and concentrated hydrochloric acid (1ml) and p-toluenesulfonic acid (catalytic amount) were added. The solution was heated for 3 hours. The solvent was then evaporated and reverse phase high performance liquid chromatography (Shandon Hyperprep)C18BDS (base-deactivated silica gel) 8 μm, 250g, i.d.5 cm). A gradient containing buffer and organic solvent was used. The desired fractions were collected and recovered to yield intermediate (88).

Example A.35

a) Preparation ofIntermediate (89)

Trimethylsilyl cyanide (0.05mol) and zinc iodide (50mg) were added to 1-acetyl-4-bromobenzene (5g, 0.05 mol). The mixture was stirred at 50 ℃ for 5.5 hours and then at room temperature for 12 hours. The precipitate was filtered off, washed with toluene and the filtrate was evaporated, yielding 15g of intermediate (89).

b) Preparation ofIntermediate (90)

Intermediate (89) (0.05mol) was added to a cooled methanol solution (150ml) saturated with hydrochloric acid. The mixture was stirred and refluxed for 20 hours, with saturated NaHCO₃The solution (220ml) was neutralized and extracted three times with DCM (100 ml). The combined organic layers were washed with a saturated solution of NaCl and dried (MgSO)₄) Filtration and evaporation of the solvent gave 15g of intermediate (90).

c) Preparation ofIntermediate (91)

A solution of intermediate (90) (0.05mol) in sulphuric acid (50%) (300ml) was stirred at 100 ℃ for 20 hours. The precipitate was filtered off and dissolved in DCM and 2-propanone. The mixture was separated into its layers. The aqueous layer was extracted with DCM (200 ml). The combined organic layers were dried (MgSO)₄) The solvent was filtered and evaporated. The residue was dissolved in DCM. Hexane was added. The precipitate was filtered off and dried to give 4g of residue. The residue was triturated with 2-propanone and the precipitate was filtered off and dried. The residue was triturated with ether. The precipitate was filtered off and dried to yield 1g of intermediate (91).

d) Preparation ofIntermediate (92)

Intermediate (94) (0.1g, 0.0002mol) was dissolved in acetonitrile (2ml) and intermediate (91) (0.09g, 0.0002mol) and triethylamine (0.033ml) were added. The mixture was stirred for 6 days. By reverse phase high performance liquid chromatography (Shandon Hyperprep)C18BDS (base-deactivated silica gel) 8 μm, 250g, i.d.5 cm). Using a gradient of two or three mobile phases (phase A: 0.25% NH)₄HCO₃The solution is in water; phase B: CH (CH)₃OH (optional); and C phase: CH (CH)₃CN). The desired fractions were collected and the solvent was evaporated, yielding 0.031g of intermediate (92).

Example A.36

Preparation ofIntermediate (93)

Intermediate (42) (0.0043mol) was dissolved in 2-propanol (10 ml). Potassium hydroxide (2.38g) was added and the reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature. Excess solvent was removed under vacuum. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried and the solvent was evaporated to give intermediate (93).

Example A.37

Preparation ofIntermediate (94)

2-methoxy-N-4-piperidinylbenzamide monohydrochloride (0.1g, 0.000426mol) was dissolved in DCM. First, 1' -carbonyldiimidazole (0.083g, 1.2 equivalents) was added, followed by triethylamine (0.120ml) and the reaction mixture was stirred overnight. The mixture was then washed with water, filtered through Isolute and the solvent was evaporated. The residue was dissolved in acetonitrile. Methyl iodide was added and the mixture was shaken. The solvent and excess methyl iodide were then evaporated in vacuo to yield 0.127g of intermediate (94).

Other intermediate compounds which may be used for the preparation of the final compound are those known in the art such as 4- (phenylcarboxamido) piperidine, 4- (2-methoxybenzamido) piperidine, 2-methyl-N-4-piperidinyl-benzamide, 4-amino-5-chloro-2-methoxy-N- (3-methoxy-4-piperidinyl) benzamide, N-4-piperidinyl-4' - (trifluoromethyl) - [1, 1-biphenyl ] -2-carboxamido, 3-hydroxy-6-methoxybenzoic acid, methyl acetate, ethyl acetate, and, 1-benzoyl-piperazine, 1- (2-methoxybenzoyl) piperazine, piperazin-1-yl- (4' -trifluoromethyl-biphenyl-2-yl) -methanone, glycine methyl ester, glycine ethyl ester hydrochloride, glycine tert-butyl ester, N6-acetyl-L-lysine methyl ester, N6-acetyl-L-lysine ethyl ester, glycine ethyl ester, (R) -alanine ethyl ester hydrochloride, (S) -alanine ethyl ester hydrochloride, N-methylglycine ethyl ester hydrochloride, beta-alanine methyl ester hydrochloride, (R) -valine ethyl ester, D-valine ethyl ester hydrochloride, L-leucine ethyl ester hydrochloride, L-serine ethyl ester hydrochloride, L-arginine, (S) -aspartic acid diethyl ester hydrochloride, 2-ethoxycarbonyl-piperidine, 3-ethoxycarbonyl-piperidine, L-glutamine methyl ester hydrochloride, L-glutamic acid diethyl ester hydrochloride, (R) -proline ethyl ester hydrochloride, (S) -proline ethyl ester hydrochloride, (2S, 4R) -4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride, (R) -phenylglycine ethyl ester hydrochloride, (S) -phenylglycine ethyl ester hydrochloride, (R) -phenylalanine ethyl ester, (S) -phenylalanine ethyl ester, tyrosine ethyl ester hydrochloride, tryptophan ethyl ester hydrochloride, glycine tert-butyl ester, L-alanine tert-butyl ester hydrochloride, D-alanine tert-butyl ester hydrochloride, N-methylglycine tert-butyl ester hydrochloride, L-glutamic acid diethyl ester hydrochloride, L, Beta-alanine tert-butyl ester hydrochloride, L-valine tert-butyl ester hydrochloride, L-leucine tert-butyl ester hydrochloride, O-tert-butyl-L-serine tert-butyl ester hydrochloride, L-aspartic acid di (tert-butyl ester) hydrochloride, L-glutamine tert-butyl ester hydrochloride, L-glutamic acid di (tert-butyl ester) hydrochloride, lysine, N6-carboxyl-, di- (tert-butyl) ester, hydrochloride; l-proline tert-butyl ester, D-proline tert-butyl ester, (4R) -4- (1, 1-dimethyl-ethoxy) -L-proline, 1-dimethylethyl ester, R-amino-phenyl-acetic acid tert-butyl ester hydrochloride, S-amino-phenyl-acetic acid tert-butyl ester hydrochloride, L-phenyl-alanine tert-butyl ester hydrochloride, D-phenylalanine tert-butyl ester hydrochloride, L-tyrosine tert-butyl ester, L-tryptophan tert-butyl ester, L-asparagine tert-butyl ester, 4-propalanine propyl ester, 4-amino isopropyl butyrate.

B. Preparation of the Final Compounds

Example B.1

A mixture of intermediate (30) (0.0017mol), 4- (phenylcarboxamido) piperidine (0.0034mol) and diisopropylethylamine (0.0051mol) in acetonitrile (30ml) was stirred and refluxed for 8 days, then the solvent was evaporated. The residue was dissolved in DCM (10ml) and purified by column chromatography (eluent: ethyl acetate) to give compound (17).

Example B.2

PS-carbodiimide resin (0.170g) was added to DCM (2ml) and a solution of intermediate (13) (0.000135mol) in DCM (0.5ml) was added. The reaction mixture was shaken at room temperature for 30 minutes. A solution of 4- (phenylcarboxamido) piperidine (0.00095mol) in DCM (0.5ml) was added and the reaction mixture shaken overnight. The reaction mixture was filtered and the resin was washed with DCM (3X 3 ml). The filtrate was evaporated and the residue was dissolved in DCM (1ml) and this solution was added to PS-isocyanate resin (100mg) and shaken overnight. The mixture was filtered and the resin was washed with DCM (3X 3ml) and the filtrate was evaporated to give compound (2).

Example B.3

A mixture of intermediate (25) (0.004mol), N-4-piperidinyl-benzamide (0.004mol), N' - (ethylformylimino) -N, N-dimethyl-1, 3-propanediamine (0.006mol), 1-hydroxy-1H-benzotriazole (HOBT) (0.006mol) and tetramethylmorpholine (0.016mol) in DCM (100ml) was stirred under nitrogen at 20 ℃ for 24H. The mixture was diluted with ethyl acetate (300ml) and then with HCl (0.5N, 100ml), saturated NaHCO₃The aqueous solution (100ml) and brine (100ml) were washed sequentially. The resulting mixture was dried and the solvent was evaporated. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexane 75/25). Fractions of the product were collected and the solvent was evaporated, yielding 1.2g of compound (13) (mp.103-107 ℃).

Example B.4

Intermediate (6) (0.0001mol) was dissolved in DCM (3 ml). Thionyl chloride (0.001mol) was added. The tube was capped and shaken for 2 hours. The solvent was evaporated under a gentle stream of nitrogen. DCM (3ml) was added and evaporated again. 4-amino-5-chloro-2-methoxy-N-4-piperidinyl-benzamide (0.0002mol) and polystyrene-N-methylmorpholine HL resin (0.0002mol) were added. DCM (4ml) was added. The reaction mixture was shaken overnight (16 hours) at room temperature. The resin was removed by filtration. The resin was washed once with DCM (3 ml). PS-isocyanate resin (0.0004mol) was then added and the reaction mixture shaken at room temperature for 3 hours. The resin was filtered off, washed with DCM and the solvent of the filtrate was evaporated. The residue was purified by reverse phase high performance liquid chromatography. A gradient containing buffer and organic solvent was used. The desired fractions were collected and worked up to give 0.027g of compound (24).

Example B.5

A mixture of 1- (2-methoxybenzoyl) -piperazine monohydrochloride (0.0001mol), polystyrene-carbodiimide (1.90mmol/g) resin (0.0002mol, 0.105g), polystyrene-N-methylmorpholine HL (3.80mmol/g) resin (0.0005mol, 0.132g), intermediate (6) (0.00015mol) in DCM (1ml) and 1-Hydroxybenzotriazole (HOBT) (0.0015mol, 0.020g) in THF (1ml) was shaken overnight at room temperature. Polystyrene-dicarbonate (5.8mmol/g) resin (0.0005mol, 0.086g) was added as a scavenger to remove excess HOBT. The reaction mixture was shaken for 2 hours, filtered and the filtrate was evaporated off. The residue was purified by reverse phase high performance liquid chromatography. A gradient containing buffer and organic solvent was used. The desired fractions were collected and worked up to give compound (27).

Example B.6

A mixture of intermediate (38) (0.0175mol) in DCM was added to a stirred mixture of N-4-piperidinyl-benzamide (0.0175mol) and 4-methylmorpholine (0.0175mol) in DCM (50ml) and the reaction mixture was stirred for 2 hours. The mixture was washed with water, 10% NaHCO₃The solution, HCl (1N) and brine were washed, then the mixture was dried and filtered. The crude product is purified by column chromatography (eluent 1: diethyl ether; wash)Removing agent 2: ethyl acetate/hexane 1/1). Fractions of the product were collected and the solvent was evaporated, yielding 5.1g of compound (25) (mp.112-115 ℃).

Example B.7

Compound (25) (0.0137mol) was separated into its enantiomers by high performance liquid chromatography (stationary phase: OD Chiralcel) (eluent: hexane/ethanol 50/50). Fractions of both products were collected and the solvent was evaporated. The residues were each triturated in 2-propanol/DIPE and the desired product was collected to give 2.66g of compound (32) and 2.71g of compound (33).

Example B.8

Compound (26) (0.0159mol) was separated into its enantiomers by high performance liquid chromatography (stationary phase: OJ Chiralcel) (eluent: hexane/ethanol 50/50). Fractions of both products were collected and the solvent was evaporated. Each residue was triturated with a small amount of 2-propanol under DIPE and the desired product was collected to give 3.23g of compound (34) and 3.18g of compound (35).

Example B.9

A mixture of intermediate (32) (0.029mol), 2-methoxy-N-4-piperidinylbenzamide (0.029mol) and 1-hydroxy-1H-benzotriazole (HOBT) (0.035mol) was stirred in DCM (300ml) and N '- (ethylformylimino (carbonimidoyl)) -N, N' -dimethyl-1, 3-propanediamine (0.035mol) was added. The reaction mixture was stirred at room temperature for 20 hours and diisopropylethylamine (10ml) was added. The resulting mixture was stirred for 24 hours and then with diluted HCl solution for 1 hour. The layers were separated and the organic layer was washed with NaHCO₃The solution was washed 3 times. The solvent was evaporated and the residue was crystallized from 2-propanol. The precipitate was filtered, dried and purified by column chromatography over silica gel (eluent: DCM/MeOH 99/1, 95/5). Collecting the pure product fractionAnd the solvent was evaporated. The residue was triturated under DIPE, then the desired product was filtered and dried (1.51 g). A portion (0.150g) of this residue was separated by hand chromatography into its enantiomers (Prochrom)Dynamic Axial Compression column, 5cm internal diameter, loaded with 500g ADChiral phase) (isocratic elution with a mixture of hexane/ethanol 50/50 at a flow rate of 110 ml/min). The two product fractions were collected and the solvent was evaporated, yielding 67mg of compound (43) and 69mg of compound (44).

Example B.10

Intermediate (37) (0.027mol) was stirred in dioxane (100ml) at room temperature. Thionyl chloride (0.2mol) was added and the reaction mixture was stirred and refluxed for 1 hour. The solvent was evaporated. DCM (100ml) was added to the residue, which was then evaporated again. The residue was dissolved in DCM (100 ml). A solution of 2-methoxy-N-4-piperidinyl-benzamide (0.027mol) in DCM (50ml) was added. Adding NaHCO₃Solution (50ml) and the resulting reaction mixture was stirred for an additional 4 hours. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/methanol 99/1 to 97/3). Fractions of the product were collected and the solvent was evaporated. The residue was crystallized from 2-propanol (over four days while stirring). The precipitate was filtered and dried to obtain 6.9g of compound (37).

Compound (37) was purified and separated into its enantiomers by high performance liquid chromatography over Chiracel OD (250g, 20 μm, column radius 50mm, column length 21cm) with methanol as eluent (flow rate: 80 ml/min). Fractions of both products were collected and the solvent was evaporated. Each residue was stirred in DIPE for 20 hours, followed by filtration and drying, to give 3.02g of compound (40) and 2.72g of compound (41).

Example B.11

a) A mixture of compound (35) (0.00092mol) in HCl 12N (30ml) and dioxane (3ml) was shaken at 100 ℃ for 16 h. The solvent was evaporated. The residue was purified by reverse phase high performance liquid chromatography. A gradient containing buffer and organic solvent was used. Fractions of the product were collected and the solvent was evaporated. The residue was dissolved in DCM and washed with dilute hydrochloric acid. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated under DIPE, filtered and dried to give 0.024g 4- [4- (2-methoxy-benzoylamino) piperidine-1-carbonyl ] -1-phenyl-1, 2, 3, 4-tetrahydro-naphthalene-1-carboxylic acid (intermediate (78)) (1S, 4R); OR +23 ° (c 0.4000 w/v%, EtOH, 20 ℃, 589 nm).

b) Thionyl chloride (0.02mol) and DMF (3 drops) were added to a solution of intermediate (78) (0.0058mol) in DCM (100ml) and the reaction mixture was stirred and refluxed for 1 hour. The solvent was evaporated and the residue was dissolved in DCM. The resulting solution was stirred at room temperature, then glycine ethyl ester (0.01mol) was added followed by NaHCO₃Aqueous solution (50 ml). The reaction mixture was stirred for a further 1 hour and the layers were separated. The organic layer was washed with 1N hydrochloric acid, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/methanol 99/1 up to 90/10). Fractions of the product were collected and the solvent was evaporated. The residue was crystallized from 2-propanol/DIPE, and the desired product was collected to give 2.78g of compound (48) (1S, 4R).

Example B.12

Intermediate (35) (0.000061mol) was dissolved in DCM (19ml) and DCM/TFA (9/1) (1ml) was added, then the reaction mixture was stirred at room temperature for 16 h and the solvent was evaporated. The residue was dissolved in DCM (9ml) and washed with 10% Na₂CO₃The solution was washed with an aqueous solution and then passed through an ExtreltFilter and wash filter with DCM (2 × 3 ml). Collecting filterAnd the solvent was evaporated. The resulting residue was dissolved in DCM (14ml) to give a solution (I).

Solution (I) (1ml) was added to a stirring solution of 2, 3-dimethoxybenzoic acid (0.000091mol) and N' - (ethylformylimino) -N, N-dimethyl-1, 3-propanediamine (0.000122mol) in DMF (1ml) and diisopropylethylamine (0.000134mol) at room temperature, and the reaction mixture was stirred at room temperature for 70 hours. N, N-dimethyl-4-pyridylamine was added and the resulting mixture was shaken at room temperature for 80 hours, then the solvent was evaporated and the residue was dissolved in methanol (2ml) and water (0.5 ml). The resulting solution was purified by reverse phase high performance liquid chromatography. A gradient containing buffer and organic solvent was used. The desired fractions were collected and worked up to give compound (49).

Example B.13

Compound (62) was dissolved in DCM (1 ml). TFA (0.4ml) was added. The mixture was shaken at room temperature for 1 hour (500rpm) and then over the weekend at room temperature (400 rpm). The reaction mixture was evaporated and subjected to reverse phase high performance liquid chromatography (column: Xterra Prep MS C18, particle size: 5 μm, length: 10 cm; inner diameter: 19 mm; eluent (0.2% NH)₄HCO₃In H₂In O)/CH₃OH/acetonitrile gradient) was purified. Fractions of the product were combined and the solvent was evaporated. DCM (3ml) was added to the residue, which was then evaporated again to give 0.031g of compound (63).

Example B.14

Compound (243) (0.0215mol) was separated into its enantiomers by reverse phase HPLC via Daicel Chiralpak AD (2kg, 1000. ANG., radius: 20 μm; eluent: ethanol 100%, flow rate: 750 ml/min). Fractions of both products were collected and the solvent was evaporated. Each residue was stirred in DIPE, filtered and dried to obtain compound (245) (OR: +32.8 °)(at 589nm, CH₃OH, 20 ℃)) and compound (244) (OR: 37.55 ° (at 589nm, 26.1mg/5ml, CH)₃OH，20℃))。

Example B.15

a) A solution of compound (45) (0.0186mol) and tetrakis (triphenylphosphine) -palladium (0.00037mol) in THF (100ml) was stirred and cooled on an ice bath. Sodium borohydride (0.0186mol) was added and the reaction mixture was stirred for an additional 4 hours while cooling on an ice bath. Additional sodium borohydride (0.22g) was added and the reaction mixture was stirred at room temperature over the weekend. The reaction was quenched with 1N HCl solution. The mixture was extracted with DCM. The separated organic layer was dried (MgSO)₄) The solvent was filtered and evaporated. Subjecting the residue to reverse phase high performance liquid chromatography (Shandon Hyperprep)8 micron, 250g, i.d.5cm C18BDS (base-deactivated silica gel). Using a gradient of two or three mobile phases (phase A: (0.5% NH)₄OAc in Water/CH₃CN 90/10; phase B: CH (CH)₃OH (optional); and C phase: CH (CH)₃CN). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in DCM, washed with water, separated, dried (MgSO)₄) Filtered and the solvent evaporated. The residue was triturated under DIPE, filtered and dried to give 5.65g of (1R, 4S) -4- [4- (2-methoxy-benzoylamino) -piperidine-1-carbonyl]-1-phenyl-1, 2, 3, 4-tetrahydro-naphthalene-1-carboxylic acid [ intermediate (79)](OR: -25.38 ° (at 589nm, 0.532 w/v%, 20 ℃, ethanol)).

b) Intermediate (79) (0.007mol) and 4-methyl-morpholine (3ml) were dissolved in DCM (40 ml). 1-hydroxy-1H-benzotriazole (HOBT) (0.0075mol), 1- (3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride (0.010mol) and intermediate (46) (0.0075mol) were added to the reaction mixture in that order and stirred overnight. The reaction mixture was washed with water. The separated organic layer solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate from 1/1 to 1/2). Fractions of the product were collected and the solvent was evaporated to give 3.1g of compound (246) (1R, 4S).

Example B.16

Intermediate (25) (10g, 0.0297mol) was dissolved in DCM (150ml, p.a.). A small amount of DMF was then added together with thionyl chloride (20 ml). The reaction mixture was refluxed for 1 hour, and then the solvent was evaporated. Intermediate (42) (6.99 g; 1 eq.) and saturated NaHCO were added₃Aqueous solution (150ml) and DCM (150ml) and the reaction mixture was stirred at room temperature for 2 hours. The organic layer was then separated. The separated organic layer was dried and the solvent was evaporated. The residue was crystallized from isopropanol and isopropyl ether. Purifying the precipitate by column chromatography (reversed phase; NH)₄HCO₃The solution is used as a buffer together with an organic solvent). The desired fractions were collected and the solvent was removed. The residue was separated into its enantiomers by supercritical liquid chromatography on an AD-H column (60% methanol and 0.1% isopropanol; flow rate 50 ml/min). Fractions of the product were collected and the solvent was evaporated to give 2.0g of compound (265) and 2.3g of compound (266).

Example B.17

a) Compound (265) (2g, 0.0036mol) was dissolved in THF (18ml, anhydrous). Nitrogen was bubbled through the reaction, followed by the addition of tetrakis (triphenylphosphine) palladium (0.083g, 2 mol%). The reaction was cooled to 0 ℃ with an ice bath, and then sodium borohydride (0.0036mol) was added. Cooling was continued for four hours and the mixture was allowed to react at room temperature overnight. Acetone (0.5ml) was then added and the solvent was evaporated. The residue was dissolved in DCM and HCl (1N) was added. The separated organic layer was dried (MgSO)₄) The solvent was filtered and evaporated. By column chromatography (eluent: CH)₂Cl₂/CH₃OH from 1/99 to 10/90). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in CH₃OH/CH₂Cl₂Neutralizing and treating the solution with activated carbon Norit. The mixture was filtered through celite (decalite) and the solvent was evaporated to give intermediate (80).

b) Intermediate (80) (0.00194mol, 1g) was dissolved in DCM (10 ml). Thionyl chloride (0.00388mol, 0.282ml) and several drops of DMF were added. The reaction mixture was refluxed for 90 minutes. The solvent was evaporated and DCM (10ml) was added. The solvent was again evaporated. The crude product was dissolved in DCM (10ml) and methyl 3-aminopropionate hydrochloride (0.00194mol, 0.272g) was added. To this mixture was added saturated NaHCO₃Solution (10ml) and the reaction mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried (MgSO)₄) The solvent was filtered and evaporated. By high performance liquid chromatography (Shandon Hyperprep)C18BDS (base-deactivated silica gel) 8 μm, 250g, i.d.5 cm). Using a gradient of two or three mobile phases (phase A: 0.25% NH)₄HCO₃In water; phase B: CH (CH)₃OH (optional); and C phase: CH (CH)₃CN). Two different product fractions were collected and the solvent was evaporated, yielding a first fraction of 0.160g of compound (254) and a second fraction of 0.244g of compound (255) intermediate.

Example B.18

a) A solution of compound (46) (0.0139mol) and tetrakis (triphenylphosphine) palladium (0.00083mol) in THF (80ml) was stirred and cooled on ice. Sodium borohydride (0.0139mol) was added and the reaction mixture was stirred for 4 hours while cooling on ice and then stirred at room temperature for 20 hours. The reaction was quenched with 1N aqueous HCl. The mixture was extracted twice with DCM. The separated organic layer was dried (MgSO)₄) The solvent was filtered and evaporated. The residue is purified over silica gel on a glass filter (eluent: CH)₂Cl₂/CH₃OH 97/3, then 95/5). The product fractions were collected and the solvent was evaporated. The residue was purified by reverse phase high performance liquid chromatography (Shandon Hyperprep)C18BDS (base-deactivated silica gel) 8 μm, 250g, i.d.5 cm). Using a gradient of two or three mobile phases (phase A: (0.5% NH)₄OAc in Water/CH₃CN 90/10; phase B: CH (CH)₃OH (optional); and C phase: CH (CH)₃CN). Fractions of the product were collected and the solvent was evaporated. The residue was triturated under DIPE, filtered and dried to give 4.50g of intermediate (81) (63%; (1S, 4R): OR: +21.03 ° (c ═ 0.504 w/v%, MeOH, 20 ℃, 589 nm)).

b) Intermediate (81) (0.000194mol, 0.1g) was dissolved in dry DCM (10ml) and 1-hydroxy-1H-benzotriazole (HOBT) (1.2 eq, 0.031g), 1-ethyl-3- (3' -dimethyl-aminopropyl) carbodiimide hydrochloride (EDCI) (1.2 eq, 0.045g) and 3-amino-propionic acid methyl ester hydrochloride (3 eq, 0.081g) and diisopropylethylamine (10 eq, 0.320ml) were added to the mixture. The reaction mixture was stirred at room temperature overnight. Additional methyl 3-amino-propionate hydrochloride (3 eq, 0.081g) was added and the mixture was taken up with saturated NaHCO₃The aqueous solution was washed 3 times. The separated organic layer was dried (MgSO)₄) The solvent was filtered and evaporated. The residue was then purified by column chromatography (from 100% CH)₂Cl₂To 2% CH₃OH/CH₂Cl₂) To obtain 0.060g of compound (256).

Example B.19

Intermediate (25) (0.00297mol, 1g) was dissolved in DCM (5 ml). Thionyl chloride (0.00742mol, 0.539ml) and several drops of DMF were added. The reaction mixture was refluxed for 90 minutes. The solvent was evaporated and DCM (5ml) was added. The solvent was then evaporated. The crude product was dissolved in DCM (5ml) and intermediate (55) (0.00297mol, 0.859g) was added. To this mixture was added saturated NaHCO₃Aqueous solution (5ml) and the reaction mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and steamingSolvent extraction gave 1.80g of Compound (264).

Example B.20

a) Compound (264) (0.00297mol) was dissolved in THF (20 ml). Nitrogen was bubbled through the reaction, followed by addition of tetrakis (triphenylphosphine) palladium (0.070 g). The mixture was cooled to 0 ℃ on an ice bath, and then sodium borohydride (0.00297mol) was added. Cooling was continued for 4 hours and the reaction was allowed to react overnight at room temperature. The reaction was then quenched with HCl (1N) and extracted with DCM. The separated organic layer was dried (MgSO)₄) The solvent was filtered and evaporated. By column chromatography (eluent: CH)₂Cl₂/CH₃OH from 99/1 to 90/10). The product fractions were collected and the solvent was evaporated in vacuo. Redissolving the residue in CH₂Cl₂/CH₃OH and treated with activated carbon. The mixture was filtered through celite (decalite) and the solvent was evaporated, and the residue was purified by reverse phase high performance liquid chromatography (Shandon Hyperprep)8 micron, 250g, i.d.5cm C18BDS (base-deactivated silica gel). Using a gradient of two or three mobile phases (phase A: (0.25% NH)₄OAc in water; phase B: CH (CH)₃OH (optional); and C phase: CH (CH)₃CN). Two different fractions were collected and the solvent was evaporated. The residue was redissolved in DCM and the two solutions were added to diisopropyl ether. In both cases, the precipitate was filtered off and the solid was dried to yield intermediate (82) (31%; mp.: 257 ℃) and compound (260) (36%).

b) Intermediate (82) (0.000176mol, 0.100g) was dissolved in anhydrous DCM and 1-hydroxy-1H-benzotriazole (HOBT) (1.2 eq, 0.028g), 1-ethyl-3- (3' -dimethyl-aminopropyl) carbodiimide hydrochloride (EDCI) (1.2 eq, 0.04052g) and methyl 3-aminopropionate hydrochloride (3 eq, 0.073g) and diisopropylethylamine (10 eq, 0.290ml) were added to the mixture. The reaction mixture was stirred at room temperatureOvernight. Additional diisopropylethyl ester (3 eq, 0.073g) was added and the mixture was taken up with saturated NaHCO₃The aqueous solution was washed three times. The separated organic layer was dried (MgSO)₄) The solvent was filtered and evaporated. The residue was then purified by column chromatography (from 100% CH)₂Cl₂To 20% CH₃OH/CH₂Cl₂) The desired fractions were collected and the solvent was evaporated to give compound (263).

Example B.21

a) Compound (269) (0.00359mol) was dissolved in THF (18 ml). The solution was allowed to cool to 0 ℃. Tetrakis (triphenylphosphine) palladium (0.083g, 2 mol%) and sodium borohydride (0.136g, 1 eq) were then added and the mixture was stirred at 0 ℃ for 4 h. Quench the reaction with HCl (1N), add DCM and dry the organic layer (MgSO)₄) The solvent was filtered and evaporated. HCl (1N) was added to the residue and the mixture was stirred for 2 hours. The aqueous layer was evaporated and co-evaporated with toluene to give intermediate (83) as the hydrochloric acid addition salt.

b) Intermediate (83) (1g, 0.0017mol) was dissolved in DCM (15ml) and 1-ethyl-3- (3' -dimethyl-aminopropyl) carbodiimide hydrochloride (EDCI) (0.397g, 0.002mol) was added to the solution. DIPEA (2.8ml, 0.017mol), 1-hydroxy-1H-benzotriazole (HOBT) (0.276g, 0.002mol) and isopropyl 3-aminopropionate hydrochloride (0.851g) in a small amount of DCM were then added to the reaction mixture. The reaction mixture was stirred at room temperature. The mixture was washed four times with water. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. By reverse phase high performance liquid chromatography (Shandon Hyperprep)C18BDS (base-deactivated silica gel) 8 μm, 250g, i.d.5em) purification of the residue. Using a gradient of two or three mobile phases (phase A: (0.25% NH)₄HCO₃The solution is in water; phase B: CH (CH)₃OH (optional); and C phase: CH (CH)₃CN). Collecting fractions of the productAnd the solvent was evaporated. The product was dissolved in ethyl acetate and the solution was taken up with saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried and the solvent was evaporated to give 0.324g of compound (276).

Compound (272) was prepared in a similar manner by reacting intermediate (83) in the presence of methyl 3-aminopropionate hydrochloride instead of isopropyl 3-aminopropionate hydrochloride.

Example B.22

Intermediate (63) (2.49g, 0.00739mol) was dissolved in DCM (6 ml). Thionyl chloride (1.07ml) and one drop of DMF were added to the solution. The reaction mixture was refluxed for one hour and the solvent was evaporated. DCM (6ml) was added and the solvent evaporated and added further (6 ml). Intermediate (85) (2.24g, 0.00739mol) and saturated NaHCO were then added₃Aqueous solution (3ml) and the two layer system was stirred at room temperature. The layers were separated and the organic layer was dried (MgSO₄). The crude compound was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 20/1). The compound was purified again by flash column chromatography (eluent: DCM/MeOH from 100/0 to 99/1). The desired fractions were collected and the solvent was evaporated to yield compound (278).

Example B.23

a) Compound (278) (1.52g, 0.00244mol) was dissolved in THF (12ml) and nitrogen bubbled through at 0 deg.C for 10 minutes. Tetrakis (triphenylphosphine) palladium (0.056g, 2 mol%) and sodium borohydride (0.092g) were added and the reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was treated with 1N HCl and stirred overnight. After extraction with ethyl acetate, the product was in the aqueous layer. The pure product was extracted from the aqueous layer by adding ammonia until the pH was 7. The separated organic layer was dried, filtered and the solvent was evaporated to give intermediate (86).

b) Intermediate (86) (0.3g, 0.000515mol) was dissolved in DCM and EDCI (0.395g) was added to the solution. To this mixture was added diisopropylethylamine (0.850ml) and isopropyl 3-aminopropionate hydrochloride (0.259g, 3 equivalents) in a small amount of DCM. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was washed four times with water and dried (MgSO)₄) Filtered and the solvent evaporated. By reverse phase high performance liquid chromatography (ShandonHyperprep)C18BDS (base-deactivated silica gel) 8 μm, 250g, i.d.5 cm). Using a gradient of two or three mobile phases (phase A: (0.25% NH)₄HCO₃The solution is in water; phase B: CH (CH)₃OH (optional); and C phase: CH (CH)₃CN). Fractions of the product were collected and the solvent was evaporated to give 0.324g of compound (277).

Example B.24

Intermediate (88) (0.000602mol) was dissolved in DCM (6 ml). Thionyl chloride (87ml, 0.001204mol) was then added and the reaction mixture refluxed for 2 hours. The solvent was evaporated and DCM (6ml) was added again. The solvent was evaporated once more and DCM (6ml) was added again. Intermediate (75) (0.000602mol) and saturated NaHCO were then added₃Aqueous solution (3 ml). The mixture was stirred. The mixture was then washed with water and the separated organic layer was dried (MgSO₄) Filtration and evaporation of the solvent gave compound (273).

Example B.25

Intermediate (92) was dissolved in DCM (4ml) and EDCI (0.011g) in a small amount of DCM was added. To this mixture were added DIPEA (0.076ml), 1-hydroxy-1H-benzotriazole (0.008g) and isopropyl 3-aminopropionate hydrochloride (0.023g), and DMF. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (three times), dried (MgSO)₄) And purified by column chromatography (Isolute) from DCM to DCM/MeOH (1/9) to give 14mg of compound (275).

Example B.26

Intermediate (80) (0.0040mol) was dissolved in DCM (20ml) and 1-ethyl-3- (N, N-dimethylamino) propylcarbodiimide (0.920g) was added to the mixture, to which was added DIPEA (0.659ml), 1-hydroxy-1H-benzotriazole (0.648g) and isopropyl 3-aminopropionate hydrochloride (2.00g), and DMF in a small amount of DCM (20 ml). The reaction mixture was stirred at room temperature. The reaction mixture is worked up. Additional DCM was added and the reaction mixture was washed with water (three times), dried (MgSO)₄) And the organic layer was evaporated. The residue was purified by column chromatography (heptane/ethyl acetate; 1/1-MeOH/DCM; 1/10). The product was further subjected to reverse phase high performance liquid chromatography (Shandon Hyperprep)C18BDS (base-deactivated silica gel) 8 μm, 250g, i.d.5 cm). A gradient of buffer and organic solvent was used to give 850mg of compound (280).

Tables F-1 and F-1a list the compounds prepared according to the above examples. The stereochemical configuration of certain compounds has been designated as R^*Or S^*Although the compound itself has been isolated as a single enantiomer, and is enantiomerically pure, it is used to indicate relative stereochemistry where absolute stereochemistry has not been determined. Melting points (m.p.) have been included for some compounds.

TABLE F-1

TABLE F-1a：

Table 2: intermediates of formula (XVII) prepared according to the procedures of the experimental section

Compound identification

General procedure

HPLC measurements were performed using an Alliance HT 2790(Waters) system comprising a quaternary pump (quaternary pump) with degasser, autosampler, a column thermostat (set at 40 ℃ C., unless otherwise specified), diode matrix detector (DAD) and the top column in each of the following methods. The flow from the column will be split to the MS mass spectrometer. The MS detector was equipped with an electrospray ionization source.

Mass spectra were acquired by scanning from 100 to 1000 in one second with a retention time of 0.1 second. The capillary tip voltage was 3kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the gas for the nebulizer. Data acquisition was performed using a Waters-Micromass MassLynx-Openlynx data system.

General procedure B

LC measurements were performed using the Acquity UPLC (Waters) system, which contains a binary pump, sample manager, column heater (set at 55 ℃), diode matrix detector (DAD) and column as specified in the methods below. The flow from the column will be split to the MS mass spectrometer. The MS detector was equipped with an electrospray ionization source. Mass spectra were obtained by scanning from 100 to 1000 in 0.18 seconds using a retention time of 0.02 seconds. The capillary tip voltage was 3.5kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the gas for the nebulizer. Data acquisition was performed using a Waters-Micromass MassLynx-Openlynx data system.

General procedure C

HPLC measurements were performed using a Shimadzu 2010 LCMS system, which included a pump, a diode matrix detector (DAD) (set at 200-. The flow from the column will be split to the MS mass spectrometer.

APCI (gas pressure chemical ionization) source was used as a standard for both positive and negative ionization regimes (both performed separately). Mass spectra were obtained by scanning, for example, 150 to 500 (other ranges are possible) in 0.7 seconds using a retention time of 0.3 seconds. A typical parameter set is probe current using 6.80 μ A for positive ionization and-13.50 μ A for negative ionization. The probe bias was 4.5kV for positive ionization and-4.00 kV for negative ionization. The APCI probe temperature was 400 ℃. The CDL (curved desolvation line using a heated capillary) temperature was 250 ℃. The CDL voltage is-5V for positive ionization and +5V for negative ionization. The temperature of the heating block was 200 ℃. Nitrogen was used as the gas for the nebulizer (2.50 l/min).

Occasionally (depending on the compound type), electrospray ionization is used in both positive and negative ionization modes. The flow rate of the atomizing gas was 4.5 l/min. Typical parameter settings for positive ionization were to use a probe current of 4.20 μ A, a probe deviation of 4.50kV, a CDL voltage of 25V and a CDL temperature of 250 ℃. The temperature of the heating block was 200 ℃. Typical parameter settings for negative ionization were probe current of-3.50 μ A, probe deviation of-3.50 kV, CDL voltage of-25V and CDL temperature of 250 ℃.

Method 1

In addition to general procedure a: reverse phase HPLC was performed on a Xterra MS C18 column (3.5 microns, 4.6X 100mm) at a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to perform a gradient condition: from 100% a to 1% a, 49% B and 50% C completed in 6.5 minutes to 1% a and 99% B completed in one minute and these conditions were maintained for one minute and equilibrated with 100% a for an additional 1.5 minutes. An injection volume of 10 microliters was used. The cone voltage was 10V for positive ionization and 20V for negative ionization.

Method 2

Except for general method B: reverse phase UPLC (ultra performance liquid chromatography) was performed on a bridged ethylsiloxane/silica gel hybrid (BEH) C18 column (1.7 microns, 2.1 x 50mm, Waters Acquity) at a flow rate of 0.8 ml/min. Two mobile phases (mobile phase a: 0.1% formic acid in water/methanol 95/5; mobile phase B: methanol) were used to perform a gradient condition: from 95% a and 5% B to 5% a and 95% B was completed in 1.3 minutes and maintained for 0.2 minutes. An injection volume of 0.5 microliters was used. The cone voltage was 10V for positive ionization and 20V for negative ionization.

Method 3

In addition to general procedure a: reverse phase HPLC was carried out on Chromolith (4.6X 25mm) at a flow rate of 3 ml/min. Three mobile phases (mobile phase A: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to perform a gradient condition: from 96% a, 2% B and 2% C to 49% B and 49% C completed in 0.9 minutes to 100% B completed in 0.3 minutes and held at this condition for 0.2 minutes. An injection volume of 2 microliters was used. The cone voltage was 10V for positive ionization and 20V for negative ionization.

Method 4

In addition to general procedure a: reverse phase HPLC was carried out on Chromolith (4.6X 25mm) at a flow rate of 3 ml/min. Three mobile phases (mobile phase A: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to perform a gradient condition: from 100% a to 50% B and 50% C completed in 0.9 minutes to 100% B completed in 0.3 minutes and held at this condition for 0.2 minutes. An injection volume of 2 microliters was used. The cone voltage was 10V for positive ionization and 20V for negative ionization.

Method 5

In addition to general procedure a: reverse phase HPLC was performed on a Xterra MS C18 column (3.5 microns, 4.6X 100mm) at a flow rate of 1.2 ml/min. Three mobile phases (mobile phase A: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to perform a gradient condition: from 100% a to 50% B and 50% C in 10 minutes to 100% B in 1 minute, 100% B over 3 minutes and equilibrate with 100% a for an additional 1.5 minutes. An injection volume of 10 microliters was used.

Method 6

In addition to general procedure a: reverse phase HPLC was performed on a Xterra MS C18 column (3.5 microns, 4.6X 100mm) at a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to perform a gradient condition: from 100% A to 50% B and 50% C in 6.5 minutes to 100% B in 1 minute, 100% B over 1 minute and equilibrate with 100% A for an additional 1.5 minutes. An injection volume of 10 microliters was used. The cone voltage was 10V for positive ionization and 20V for negative ionization.

Method 7

In addition to general procedure a: reverse phase HPLC on a Xterra MS C18 column (3.5 micron, 4.6X 100mm) with a flow rate of 1.2 ml/min. Three mobile phases (mobile phase A: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to perform a gradient condition: from 100% a to 2% a, 49% B and 49% C completed in 10 minutes to 1% a and 99% B completed in 1 minute and held in this condition for 3 minutes and equilibrated with 100% a for an additional 2.5 minutes. An injection volume of 10 microliters was used. The cone voltage is 10V for positive ionization mode and 20V for negative ionization mode. The column temperature was 45 ℃.

Method 8

In addition to general procedure C: reverse phase HPLC was performed on a Phenomenex column (Gemini 5. mu.C 18) (50 mm. times.4.6 mm) at a flow rate of 1 ml/min. Two mobile phases (mobile phase A: 10mM ammonium acetate in water; mobile phase B: acetonitrile) were used. First 80% A and 20% B for 30 seconds. A linear gradient was then applied to reach 10% a and 90% B over 3.5 minutes. 10% A and 90% B for 1 minute, then 80% A and 20% B for 2 minutes. Typical injection volumes of 1-5 microliters are used.

Method 9

In addition to general procedure a: reverse phase HPLC was performed on a Xterra MS C18 column (3.5 microns, 4.6X 100mm) at a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to perform a gradient condition: from 100% A to 30% A, 35% B and 35% C in 3 minutes to 50% B and 50% C in 3.5 minutes, 100% B

This was done in 0.5 min. An injection volume of 10 microliters was used. The cone voltage is 10V for positive ionization mode.

Table 3:analyzing data

When a compound is in a mixture of isomers and different peaks are obtained in the LCMS process, only the retention time of the major component is provided in the LCMS table (Rt: retention time in minutes).

Co. No.	Rt	(MH)+	Method of producing a composite material
				2	1.36	558	2
3	1.38	572	2
				4	1.34	524	2
5	1.01	510	2
				6	1.20	654	2
7	1.25	540	2
				8	1.38	553	2
9	1.32	540	2
				10	1.39	654	2
11	1.44	654	2
				12	1.40	523	2
13	1.36	523	2
				14	1.22	510	2
15	0.96	526	2
				16	1.16	640	2
17	6.05	496	1
				18	5.72	510	1
19	6.75	667	1
				20	5.76	570	1
21	5.98	574	1

Co. No.	Rt	(MH)+	Method of producing a composite material
				22	5.48	524	1
23	5.55	619	1
				24	6.16	590	1
26	5.95	541	1
				27	6.09	527	1
28	6.78	641	1
				29	6.22	497	1
30	6.19	527	1
				31	6.86	641	1
32	5.61	511	1
				33	5.61	511	1
34	5.78	541	1
				34	1.36	541	2
35	5.78	541	1
				36	5.91	527	1
37	5.21	512	1
				38	5.11	540	1
39	5.10	540	1
				40	1.25	512	2
41	1.25	512	2

Co. No.	Rt	(MH)+	Method of producing a composite material
				42	5.92	527	1
43	1.15	512	2
				44	1.15	512	2
45	5.85	553	1
				46	5.85	553	1
46	1.38	553	2
				47	0.96	598	4
48	5.28	598	1
				49	7.79	557	5
50	7.91	557	5
				51	8.22	541	7
52	6.89	606	7
				53	8.28	625	7
54	7.81	563	7
				55	8.56	543	7
56	7.66	528	7
				57	8.06	542	7
58	7.44	556	7
				59	7.47	559	7
60	1.32	527	2

[0488]

Co. No.	Rt	(MH)+	Method of producing a composite material
				61	7.33	543	7
62	5.86	626	1
				63	1.15	570	2
64	1.15	584	2
				65	0.96	598	3
66	5.96	612	1
				67	5.96	612	1
68	6.46	640	1
				69	6.41	640	1
70	6.6	654	1
				71	5.38	628	1
72	6.05	684	1
				73	5.88	670	1
74	6.15	698	1
				75	6.22	755	1
76	6.15	638	1
				77	6.12	638	1
78	5.2	640	1
				79	6.38	674	1
80	6.43	674	1
				81	6.48	688	1
82	6.45	688	1
				83	6.45	652	1
84	6.16	652	1
				85	5.89	704	1
86	6.31	727	1
				87	6.32	640	1
88	6.26	640	1
				89	4.38	584	1
90	1.11	584	2
				91	6.28	738	6
92	3.57	626	6
				93	6.39	640	1
94	6.52	666	1
				95	6.73	702	1
96	6.15	716	6
				97	4.35	584	1
98	4.59	610	1

Co. No.	Rt	(MH)+	Method of producing a composite material
				99	4.23	646	6
100	4.93	660	1
				101	6.43	640	1
102	6.79	668	1
				103	6.76	668	1
104	6.26	682	6
				105	6.91	712	1
106	6.79	740	1
				107	5.03	697	6
108	6.19	754	6
				109	6.69	798	1
110	5.89	666	6
				111	6.75	702	1
112	6.78	716	1
				113	5.63	732	6
114	6.60	755	1
				115	4.94	683	6
116	4.49	584	1
				117	4.92	612	1
118	4.66	612	1
				119	5.19	626	1
120	4.71	656	6
				121	3.66	628	1
122	3.69	642	1
				123	4.56	610	1
124	4.99	646	1
				125	5.19	660	1
126	4.49	676	1
				127	4.99	699	1
128	3.57	627	6
				129	1.22	612	2
130	1.16	697	2
				131	1.19	711	2
132	0.94	641	2
				133	5.05	599	1
135	5.46	613	1
				136	5.39	613	1
138	4.82	599	1

Co. No.	Rt	(MH)+	Method of producing a composite material
				139	6.08	641	1
140	5.99	641	1
				141	6.23	655	1
142	4.68	629	1
				143	5.58	685	1
144	6.02	653	1
				146	5.69	699	1
147	5.66	653	1
				148	5.79	756	1
149	5.59	639	1
				150	5.58	639	1
152	5.99	675	1
				153	6.06	675	1
154	6.12	689	1
				155	6.05	689	1
157	5.93	728	1
				158	4.73	585	1
159	5.16	613	1
				160	5.65	627	1
161	6.02	641	1
				162	5.99	641	1
163	5.86	641	1
				169	1.36	741	2
179	6.49	717	1
				181	4.89	684	1
182	5.05	571	9
				183	5.12	585	9
184	4.83	585	9
				185	4.80	585	9
186	5.05	585	9
				187	5.51	613	9
188	5.06	613	9
				189	5.35	627	9
190	5.00	642	9
				191	5.24	611	9
192	4.69	627	9
				193	5.01	647	9
194	5.60	647	9

[0491]

Co. No.	Rt	(MH)+	Method of producing a composite material
				195	5.74	661	9
196	5.24	661	9
				197	4.9	677	9
198	4.89	628	9
				199	1.27	626	2
200	6.82	626	9
				201	6.24	612	9
202	6.44	626	9
				203	7.2	654	9
204	6.61	626	9
				205	6.63	640	9
206	6.85	654	9
				207	6.83	640	9
208	7.29	668	9
				209	7.34	682	9
210	7.03	769	9
				211	6.84	741	9
212	6.81	755	9
				213	7.26	769	9
214	6.22	697	9
				215	6.88	755	9
216	7.05	769	9
				217	6.65	741	9
218	7.15	755	9
				219	6.87	741	9
220	7.09	755	9
				221	7.05	769	9
222	6.38	627	9

Co. No.	Rt	(MH)+	Method of producing a composite material
				223	6.34	627	9
224	5.80	613	9
				225	6.02	627	9
226	6.71	655	9
				227	6.45	655	9
228	6.32	641	9
				229	6.59	669	9
230	6.83	683	9
				231	6.85	770	9
232	6.18	742	9
				233	6.36	756	9
234	6.37	756	9
				235	6.77	770	9
236	5.59	698	9
				237	6.41	756	9
238	6.05	728	9
				239	6.3	742	9
240	6.41	742	9
				241	6.41	756	9
242	6.64	770	9
				244	5.30	554	6
245	5.31	554	6
				246	1.35	668	2
247	1.36	726	2
				248	1.35	726	2
249	1.29	640	2
				250	1.28	640	2
251	4.70	769	8

Co. No.	Rt	(MH)+	Method of producing a composite material
				252	6.24	596	1
253	6.20	542	1
				254	5.35	599	1
255	4.54	585	1
				256	0.90	598	3
257	5.97	626	1
				258	0.78	585	3
259	1.09	541	2
				260	1.37	610	2
261	1.26	627	2
				262	1.16	599	2
263	1.18	653	2
				264	6.32	608	1
265	6.30	554	1
				266	6.29	554	1
267	1.08	641	3
				268	1.06	609	2
269	1.08	621	2
				270	1.30	555	2
271	1.34	577	2
				272	5.19	666	1
273	1.38	577	2
				274	1.42	570	2
275	1.46	782	2
				276	1.03	694	2
277	1.00	695	2
				279	5.77	626	1
280	1.29	627	2

Optical rotation action

Optical rotation was measured using a Perkin Elmer 341 polarimeter. [ alpha ] to]_D ²⁰The optical rotation measured with light of the D-line wavelength of sodium (589nm) at a temperature of 20 ℃ is indicated. The path length of the sample container (cell) was 1 dm. The concentration and solvent of the solution used to measure the optical rotation will be mentioned after the exact values.

Co.No.	[α]D 20	Concentration of	Solvent(s)
				32	-30.79°	25.17mg/5ml	EtOH

[0497]

Co.No.	[α]D 20	Concentration of	Solvent(s)
				33	+29.84°	24.46mg/5ml	EtOH
34	-28.21°	25.35mg/5ml	EtOH
				35	+27.70°	25.27mg/5ml	EtOH
36	-26.91°	24.90mg/5ml	DMF
				38	+13.82°	25.68mg/5ml	EtOH
39	-13.80°	25.36mg/5ml	EtOH
				40	+68.8°	24.20mg/5ml	EtOH
41	-67.30°	24.07mg/5ml	EtOH
				42	+27.24°	24.96mg/5ml	DMF
45	-31.12°	14.62mg/5ml	MeOH
				46	+31.63°	9.80mg/5ml	EtOH
47	-12.85°	22.96mg/5ml	DMF
				48	+12.26°	23.65mg/5ml	DMF
62	-14.13°	20.52mg/5ml	DMF
				65	-15.29°	7.52mg/5ml	MeOH
90	-12.66°	10.67mg/5ml	MeOH
				199	-16.30°	8.28mg/5ml	MeOH
208	-19.29°	19.96mg/5ml	MeOH
				213	-28.33°	12.00mg/5ml	MeOH
244	-37.55°	26.10mg/5ml	MeOH
				246	-20.81°	10.57mg/5ml	MeOH
247	-33.40°	10.78mg/5ml	MeOH
				248	-33.89°	13.28mg/5ml	MeOH
249	-21.64°	11.32mg/5ml	MeOH
				250	-20.72°	14.24mg/5ml	MeOH
253	-27.74°	6.67mg/5ml	EtOH
				254	-64.08°	6.32mg/5ml	MeOH
255	-20.18°	5.45mg/5ml	MeOH
				256	+14.93°	19.09mg/5ml	MeOH
257	+14.89°	7.05mg/5ml	MeOH
				258	-7.40°	58.10mg/5ml	CHCl3
261	+15.60°	14.74mg/5ml	MeOH
				262	+12.55°	10.76mg/5ml	MeOH
265	+31.68°	12.94mg/5ml	MeOH
				266	-34.09°	8.80mg/5ml	MeOH
269	-25.49°	46.10mg/5ml	MeOH
				276	-11.82°	12.27mg/5ml	MeOH
277	-13.12°	10.67mg/5ml	MeOH
				279	-15.70°	23.25mg/5ml	DMF

[0498]

Co.No.	[α]D 20	Concentration of	Solvent(s)
				280	-16.36°	6.42mg/5ml	MeOH

SFC-MS：

SFC-MS (supercritical liquid chromatography-mass spectrometry) assays were performed on certain compounds using an analytical SFC system from Berger Instruments (Newar, U.S.A., DE) containing a system for delivering carbon dioxide (CO)₂) And a binary pump control module for modifiers (FCM-1200), a temperature control module for column heating (TCM2100) with temperature control in the range of 1-150 ℃, and column selection valves for six different columns (Valco, VICI, houston, texas, usa). A photodiode matrix detector (align 100, Waldbronn, germany) was equipped with a high pressure flow cell (pressures up to 400 bar) and was constructed with a CTC LC Mini PAL autosampler (Leap Technologies, karborro, north carolina, usa). The ZQ mass spectrometer (Waters, Milford, Mass.) was equipped with an orthogonal Z-electrospray interface coupled to an SFC system. Instrument control, data collection and processing were performed using an integrated platform containing SFC ProNTo software and Masslynx software.

For compound No. 44, a very small amount (0.01%) of the second isomer was detected when SFC-MS was performed on a Chiralpak AD-H column (500X 4.6mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min, using two mobile phases (mobile phase A: CO: mobile phase A)₂: mobile phase B: 2-propanol containing 0.2% 2-propylamine) was conducted under conditions ranging from 40% B (for 19.5 minutes) to 50% B completed in 1 minute and maintained for 4.10 minutes. The column temperature was set at 50 ℃.

For Compound No. 279, on a Chiralcel OJ-H column (500X 4.6mm) (Daicel Chemical Industries Ltd) at a flow rate of 3 ml/minIn line SFC-MS, a very small amount (0.1%) of the second isomer was detected, using two mobile phases (mobile phase A: CO)₂: mobile phase B: methanol containing 0.2% 2-propylamine) to proceed from 10% B to 40% B completed in 18.75 minutes, then from 40% B to 50% B completed in 2 minutes and maintained for 3.6 minutes.

For compound (No. 280), 100% enantiomeric excess was found when scanning was performed using four different columns (Chiralcel OJ-H, Chiralpak AD-H, Chiralcel OD-H, Chiralpak AS-H; 500X 4.6 mm; Daicel Chemical Industries Ltd) and three different solvents (MeOH, EtOH, 2-propanol; the solvent contained 0.2% 2-propylamine). SFC-MS was performed using one of the above mentioned columns at a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO) are used₂: mobile phase B: one of the above solvents containing 0.2% 2-propylamine) to proceed to conditions from 10% B to 40% B completed in 18.75 minutes. A gradient from 40% B to 50% B (over 2 min) was then applied and maintained for 3.6 min. The column temperature was set at 50 ℃.

C. Pharmacological examples

C.1 quantification of Apo B secretion

HepG2 cells were cultured in 24-well plates of MEM Rega3 containing 10% fetal bovine serum. At 70% confluence, the medium was changed and test compound or vehicle (DMSO, 0.4% final concentration) was added. After 24 hours of incubation, the medium was transferred to Eppendorf tubes and clarified by centrifugation. A goat antibody to either apo B was added to the supernatant and the mixture was held at 8 ℃ for 24 hours. Rabbit anti-sheep antibodies were then added and the immune complexes were allowed to precipitate for 24 hours at 8 ℃. The immunoprecipitates were pelleted by centrifugation at 1320g for 25 min and containing 40mM Mops, 40mM NaH₂PO₄100mM NaF, 0.2M DTT, 5mM EDTA, 5mM EGTA, 1% Triton-X-100, 0.5% sodium Deoxycholate (DOC), 0.1% SDS, 0.2. mu.M leupeptin, and 0.2. mu.M PMSF. Radioactivity in the precipitate was measured by liquid scintillation counting. IC (integrated circuit)₅₀The values are usually converted into pIC₅₀Value (═ logIC)₅₀Value) for ease of use.

TABLE 4：pIC₅₀Value of

C.2.MTP assay

MTP activity was determined using a method similar to that described in J.R.Wetterau and D.B.Zilversmit, in "chemistry and Physics of lipids", 38 th, 205 th-222 th (1985). To prepare the donor and acceptor vesicles, the appropriate lipids dissolved in chloroform were placed in a glass tube and dried under a stream of nitrogen. The mixture containing 15mM Tris-HCl pH7.5, 1mM EDTA, 40mM NaCl, 0.02% NaN₃To the dried lipid (assay buffer) was added. After a brief vigorous vortex of the mixture, the lipids were hydrated on ice for 20 minutes. Vesicles were then prepared by bath sonication (Branson 2200) at room temperature for up to 15 minutes. Butylated hydroxytoluene was included in all vesicle preparations at a concentration of 0.1%. The lipid transfer assay mixture contained donor vesicles (40nmol phosphatidylcholine, 7.5 mol% cardiolipin, and 0.25 mol% tris [1-¹⁴C]Glyceryl oleate), receptor vesicles (240nmol phosphatidylcholine) and 5mg BSA (total volume 675 microliters). Test compounds (0.13% final concentration) dissolved in DMSO were added. After a 5 min pre-incubation at 37 ℃ the reaction was started in 100. mu.l dialysis buffer by adding MTP. By adding 400. mu.l of a solution of the active ingredient in 15mM Tris-HCl pH7.5, 1mM EDTA, 0.02% NaN₃The reaction was terminated by pre-equilibration of DEAE-52 cellulose in (1: 1 v/v). The reaction mixture was stirred for 4 minutes at maximum speedThe DEAE-52 bound donor vesicles were pelleted by centrifugation in Eppendorf centrifuge tubes for 2 minutes (4 ℃). Measuring an aliquot of the radioactivity of the supernatant containing the acceptor liposomes and using¹⁴C]Counts to calculate the percent transfer of triglycerides from donor to recipient.

TABLE 5：pIC₅₀Value of

Claims (11)

1. A compound of formula (I)

Pharmaceutically acceptable acid addition salts thereof and stereochemically isomeric forms thereof, wherein

X is N or CH;

A¹is-CH₂-or- (C ═ O) -;

A²when X represents N, is not storedIn or represents-CH₂-, or

A²When X represents CH, is-NR⁶-, wherein R⁶Is hydrogen or C_1-4An alkyl group;

R¹is-NR⁷R⁸OR-OR⁹；

Wherein each R is⁷And R⁸Is independently selected from

The presence of hydrogen in the presence of hydrogen,

C_1-8an alkyl group, a carboxyl group,

c substituted by one, two or three substituents_1-8Alkyl, each substituent being independently selected from halo, cyano, C_3-8Cycloalkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, polyhaloC_1-4Alkyl, hydroxycarbonyl, -OR¹⁰、-NR¹⁰R¹¹、-CONR¹²R¹³Aryl, polycyclic aryl or heteroaryl;

C_3-8a cycloalkyl group;

C_3-8a cycloalkenyl group;

C_3-8an alkenyl group;

C_3-8an alkynyl group;

an aryl group;

a polycyclic aryl group;

a heteroaryl group;

or R⁷And R⁸And carry R⁷And R⁸Can form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl or azoctanyl ring, wherein each of these rings can optionally be substituted with one or two substituents independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, hydroxycarbonyl, C_1-4Alkoxycarbonyl or C_1-4Alkoxycarbonyl radical C_1-4Alkyl substituent substitution;

wherein R is¹⁰Is hydrogen, C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, R¹²-NH-carbonyl, aryl C_1-4Alkyl, polycyclic aryl, heteroaryl;

R¹¹is hydrogen or C_1-4An alkyl group;

R¹²is hydrogen, C_1-4Alkyl, phenyl C_1-4An alkyl group;

R¹³is hydrogen, C_1-4Alkyl, phenyl C_1-4An alkyl group;

R⁹is C_1-8An alkyl group, a carboxyl group,

c substituted by one, two or three substituents_1-8Alkyl, each substituent being independently selected from halo, cyano, C_3-8Cycloalkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, polyhaloC_1-4Alkyl, hydroxycarbonyl, -OR¹⁰、-NR¹⁰R¹¹、-CONR¹²R¹³Aryl, polycyclic aryl or heteroaryl;

C_3-8a cycloalkyl group;

C_3-8a cycloalkenyl group;

C_3-8an alkenyl group;

C_3-8an alkynyl group;

an aryl group;

a polycyclic aryl group;

a heteroaryl group;

wherein

Aryl is phenyl; phenyl substituted with 1-5 substituents, each substituent independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, halo, hydroxy, trifluoromethyl, cyano, C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl radical C_1-4Alkyl, methylsulfonylamino, methylsulfonyl, NR¹⁰R¹¹、C_1-4Alkyl radical NR¹⁰R¹¹、CONR¹²R¹³Or C_1-4Alkyl CONR¹²R¹³；

Polycyclic aryl is naphthyl, indanyl, fluorenyl or 1, 2, 3, 4-tetrahydronaphthyl, and the polycyclic aryl is optionally substituted with one or two substituents, each substituent independently selected from C_1-6Alkyl radical, C_1-6Alkoxy, phenyl, halo, cyano, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl radical C_1-4Alkyl, NR¹⁰R¹¹、C_1-4Alkyl radical NR¹⁰R¹¹、CONR¹²R¹³、C_1-4Alkyl CONR¹²R¹³Or C_1-4Alkoxycarbonylamino group, and

heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,Azolyl, pyrrolyl, furanyl, thienyl, quinolinyl, isoquinolinyl, 1, 2, 3, 4-tetrahydro-isoquinolinyl, benzothiazolyl, benzo [1, 3 ]]Dioxolyl, 2, 3-dihydro-benzo [1, 4 ]]Dioxinyl, indolyl, 2, 3-dihydro-1H-indolyl, 1H-benzimidazolyl, and said heteroaryl is optionally substituted with one or two substituents, each substituent independently selected from C_1-6Alkyl radical, C_1-6Alkoxy, phenyl, halo, cyano, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl radical C_1-4Alkyl, NR¹⁰R¹¹、C_1-4Alkyl radical NR¹⁰R¹¹、CONR¹²R¹³Or C_1-4Alkyl CONR¹²R¹³；

R^2a、R^2bAnd R^2cIndependently of one another, from hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, halo, hydroxy, cyano, nitro, polyhaloC_1-4Alkyl, polyhalo C_1-4Alkoxy or C_1-4An alkoxycarbonyl group;

R^3a、R^3band R^3cIndependently of one another, from hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, halo, hydroxy, cyano, nitro, polyhaloC_1-4Alkyl, polyhalo C_1-4Alkoxy or C_1-4An alkoxycarbonyl group;

R⁴is phenyl; phenyl substituted with 1-5 substituents, each substituent independently selected from C_1-4Alkyl, halo, hydroxy, C_1-4Alkoxy, amino, cyano, nitro, polyhaloC_1-4Alkyl, polyhaloGeneration C_1-4Alkoxy radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, sulfamoyl, heterocyclyl or phenyl optionally substituted with one, two or three substituents, each substituent being independently selected from C_1-4Alkyl, halo, C_1-4Alkoxy or trifluoromethyl; or a heteroaryl selected from: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furyl and thienyl, wherein each of these heteroaryl groups may be optionally substituted with one or two substituents, each substituent being independently selected from C_1-4Alkyl, halo, hydroxy, C_1-4Alkoxy, oxo, cyano, polyhalo C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl or heterocyclyl;

wherein the content of the first and second substances,

heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl and azacyclooctyl, which may optionally be substituted with one or two substituents independently selected from C_1-4Alkyl or halogenated substituents; and

R⁵is hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy or halo.

2. A compound as claimed in claim 1, wherein A¹Is- (C ═ O) -.

3. A compound as claimed in claim 1, wherein A¹is-CH₂-。

4. A compound as claimed in claim 1 wherein R¹Is NR⁷R⁸。

5. A compound as claimed in claim 1 wherein R¹Is OR⁹。

6. A compound as claimed in claim 1 wherein R^2a＝R^3a，R^2b＝R^3bAnd R is^2c＝R^3c。

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as claimed in any one of claims 1 to 6.

8. A process for preparing a pharmaceutical composition as claimed in claim 7, wherein a therapeutically effective amount of a compound as claimed in any one of claims 1 to 6 is intimately mixed with a pharmaceutically acceptable carrier.

9. The use of a compound as claimed in any of claims 1 to 6 for the manufacture of a medicament.

10. An intermediate compound of formula (XVII),

wherein the substituent R^2a、R^2b、R^2c、R^3a、R^3b、R^3c、R⁴、R⁵、A¹、A²And X is as defined in claim 1.

11. A process for the preparation of a compound of formula (I),

wherein the substituent R^2a、R^2b、R^2c、R^3a、R^3b、R^3c、R¹、R⁴、R⁵、A¹、A²

And X is as defined in claim 1;

wherein

a) General formula (II)An intermediate, wherein W is a suitable leaving group selected from halo and sulfonyloxy, with an intermediate of formula (III) in a reaction-inert solvent and optionally in the presence of a suitable base selected from sodium carbonate, potassium carbonate and triethylamine, to give a compound of formula (I-a), defined as wherein A is¹represents-CH₂A compound of formula (I);

b) alternatively, the intermediate of formula (IV) is reacted with the intermediate of formula (V) in a reaction-inert solvent and optionally in the presence of a suitable coupling reagent and/or a suitable base selected from sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine and N-methylmorpholine to give a compound of formula (I-b), defined as wherein A is¹A compound of formula (I) representing- (C ═ O) -;

c) alternatively, by N-alkylation methods known in the art, with H-NR⁷R⁸As reagents, compounds of formula (I-c), defined as wherein R¹Represents OR⁹And R is⁹A compound of formula (I) being hydrogen, to a compound of formula (I-d), which is defined wherein R¹Represents NR⁷R⁸A compound of formula (I);

d) or, converting the compounds of formula (I) with each other according to art-known conversion reactions; or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable acid addition salt, or conversely, converting an acid addition salt of a compound of formula (I) with a base into the form of the free base and, if desired, preparing stereochemically isomeric forms thereof.