HK1135392B - Substituted acetophenones useful as pde4 inhibitors - Google Patents

Description

Substituted acetophenones useful as PDE4 inhibitors

Technical Field

The present invention relates to novel substituted acetophenones and derivatives thereof, to processes for preparing them, to the compounds for use in therapy, to pharmaceutical compositions comprising the compounds, to methods of treating diseases with the compounds, and to the use of the compounds in the preparation of medicaments.

Background

Phosphodiesterases are enzymes that catalyze the hydrolysis of cyclic AMP and/or cyclic GMP in cells to 5-AMP and 5-GMP, respectively, and thus are important for the cellular regulation of cAMP or cGMP levels. Of the 11 phosphodiesterases currently identified, Phosphodiesterase (PDE)4, PDE7 and PDE8 are selective for cAMP. PDE4 is the most important regulator of cAMP expressed by immune and inflammatory cells such as neutrophils, macrophages and T-lymphocytes (z.huang and j.a.mannini, Current med.chem.13, 2006, 3253-. Since cAMP is a key second messenger in the modulation of inflammatory responses, PDE4 has been found to modulate the inflammatory response of inflammatory cells by modulating pro-inflammatory cytokines such as TNF α, IL-2, IFN- γ, GM-CSF, and LTB 4. Therefore, inhibition of PDE4 is an attractive target for the treatment of inflammatory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), rheumatoid arthritis, atopic dermatitis, Crohn's disease, etc. (M.D. Houslay et al, Drug Discovery Today 10(22), 2005, page 1503-1519). Inhibition of PDE4 would also be a viable treatment for Atopic Dermatitis (AD) due to its elevated PDE activity in AD patients (Journal of Investigative Dermatology (1986), 87(3), 372-6). The PDE4 gene family consists of at least 4 genes A, B, C and D, which have a high degree of homology (v. boswell Smith and D. spinoa, curr. opinion investig. drugs 6(11), 2006, 1136-. These four PDE4 subtypes are differentially expressed in different tissues and cell types. Thus, PDE4B is expressed predominantly in monocytes and neutrophils but not in cortical and epithelial cells, whereas PDE4D is expressed in lung, cortex, cerebellum and T cells (c.kroegel and m.foerster, exp. opinion investig. drugs 16(1), 2007, page 109-. Inhibition of PDE4D in the brain is presumed to be associated with side effects found in clinical administration of PDE4 inhibitors, mainly nausea and vomiting, whereas inhibition of PDE4B is associated with anti-inflammatory effects (b.lipworth, Lancet 365, 2005, page 167-. However, PDE inhibitors that have been developed to date cannot be considered specific for any of the four PDE4 subtypes. A number of PDE4 inhibitors have been investigated for their therapeutic effect on inflammatory diseases, mainly asthma and COPD.

Among them, theophylline, the first to be mentioned, is a weak, non-selective phosphodiesterase inhibitor used for the treatment of respiratory diseases such as asthma and COPD. However, treatment with theophylline may cause moderate and severe side effects such as arrhythmias and convulsions, thereby limiting the clinical use of theophylline (Kroegel and Foerster, supra). Since phosphodiesterases are attractive targets for anti-inflammatory therapy, several other more selective inhibitors of PDE4 have been developed and studied in a clinical setting. Clinical development of many first generation PDE4 inhibitors (e.g., rolipram) has been discontinued due to dose-limiting side effects, mainly nausea and vomiting. Second generation PDE4 inhibitors have significantly lower side effects and are undergoing clinical trials (Houslay, supra). PDE-4 inhibitors are disclosed, for example, in EP 0771794 and EP 0943613.

WO95/20578 and WO 96/31476 disclose structurally different 4-substituted-3, 5-dichloropyridines which are inhibitors of cyclic AMP phosphodiesterase. There is a continuing need to develop new PDE4 inhibitors that have a better therapeutic window (i.e., fewer side effects) while maintaining their therapeutic anti-inflammatory effects. A summary of preclinical and clinical trials for selective PDE4 inhibitors, including those directed at treating psoriasis, recently identified by Inflammation & Allergy: DrugTargets, 2007, 6(1), 17-26.

Summary of The Invention

The inventors have surprisingly found that novel compounds of the invention have selective PDE4 inhibitory activity (with > 10-fold reduced activity on PDE 1, 2, 3, 5, 7, 8, 9, 10 or 11) which are useful as therapeutic agents for the following diseases: inflammatory allergic diseases such as bronchial asthma, allergic rhinitis and nephritis; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, crohn's disease, and systemic lupus erythematosus; central nervous system diseases such as depression, amnesia, and dementia; organ diseases associated with ischemia caused by heart failure, stroke, cerebrovascular disease, and the like; insulin-resistant diabetes; trauma; AIDS, and the like.

The compounds of the invention may also be advantageously used for the prevention, treatment or alleviation of a variety of diseases, for example, skin diseases or disorders, such as proliferative and inflammatory skin diseases, in particular psoriasis, epidermal inflammation, alopecia, skin atrophy, steroid-induced skin atrophy, skin ageing, skin photoaging, acne, dermatitis, allergic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritis and eczema.

The compounds of the invention may also have advantageous properties, such as low cytotoxicity, reduced HERG inhibition, low genotoxicity, reduced skin irritation, improved metabolic stability and metabolic elimination, skin delivery properties, systemic administration properties after skin delivery, all of which make them particularly suitable as pharmaceutical active ingredients in pharmaceutical preparations for the treatment of skin diseases.

The present invention therefore relates to compounds of formula I, and pharmaceutically and physiologically cleavable esters, pharmaceutically acceptable salts, hydrates, N-oxides, or solvates thereof

Wherein X₁、X₂、X₃、X₄And X₅Each independently represents-CH-or N;

or X₃、X₄And X₅Each independently represents-CH-or N, and X₁And X₂Each independently represents C and forms part of another 6-membered aromatic ring;

wherein R is₁Represents alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or alkylcarbonyl, all of which are optionally substituted by one or more, identical or different radicals selected from R₄Is substituted by a substituent of (A), or R₁Represents hydrogen;

R₂represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, arylalkyl, alkylalkoxycarbonyl, alkylcarbonyloxy or alkoxyalkyl, all optionally substituted by one or more, identical or different substituents selected from R₅Substituted with the substituent(s); or R₂Represents hydrogen or-CH₂-C(O)NR₉-R₁₂；

R₃Represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, arylalkyl, alkylalkoxycarbonyl, alkylcarbonyloxy or alkoxyalkyl, all optionally substituted by one or more, identical or different substituents selected from R₆Substituted with the substituent(s); or R₃Represents hydrogen, -CH₂-C (O) -heterocycloalkyl or-CH₂-C(O)NR₉-R₁₂；

R₄Represents hydrogen, alkyl, alkenyl, alkynyl, halogen, oxo, alkoxy, hydroxy or haloalkyl;

R₅represents alkylaryl, carboxy, alkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, carbamoyl, hydroxyalkyl, aryloxy, alkoxycarbonyloxy, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, heterocycle, aminocarbonyl, alkylthio, alkylcarbonylamino, hydroxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy or amino, all optionally substituted by one or more, identical or different groups selected from R₇Substituted with the substituent(s); or R₅Represents hydrogen, oxo, halogen, cyano or nitro;

R₆represents alkylaryl, carboxy, alkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, carbamoyl, hydroxyalkyl, aryloxy, alkoxycarbonyloxy, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, heterocycle, aminocarbonyl, alkylthio, alkylcarbonylamino, arylcarbonyl, hydroxy, alkylcarbonyl, alkylcarbonyloxy or amino, all optionally substituted by one or more, identical or different groups selected from R₈Substituted with the substituent(s); or R₆Represents hydrogen, oxo, halogen, cyano or nitro;

R₇represents alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkynyl, alkoxy, haloalkyl, alkylthio, heterocycloalkenyl, heterocycloalkyl, aryl, alkylcarbonyl, heteroaryl, aryloxy, alkoxycarbonyl, hydroxyalkyl, amino, hydroxyl or carboxyl; all of which are optionally substituted by one or more, identical or different substituents selected from R₁₀Substituted with the substituent(s); or R₇Represents hydrogen, halogen or oxo;

R₈represents alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkynyl, alkoxy, haloalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, heterocycloalkenyl, heterocycloalkyl, aryl, alkylcarbonyl, heteroaryl, arylcarbonylOxy, alkoxycarbonyl, hydroxyalkyl, amino, hydroxy or carboxy; all of which are optionally substituted by one or more, identical or different substituents selected from R₁₀Substituted with the substituent(s); or R₈Represents hydrogen, halogen or oxo;

R₉represents hydrogen, alkyl, haloalkyl or hydroxyalkyl;

R₁₀represents hydrogen, alkyl, oxo, hydroxy, halogen, carboxy, amino, alkoxy, haloalkyl or hydroxyalkyl;

R₁₁represents one or more, identical or different substituents selected from: hydrogen, halogen, cyano, amino, alkyl, methylsulfinyl, methylsulfonyl, amino, cyano or alkoxy;

R₁₂represents alkylaryl, arylalkyl, carboxy, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, carbamoyl, hydroxyalkyl, aryloxy, alkoxycarbonyloxy, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, heterocycle, aminocarbonyl, alkylthio, alkylcarbonylamino, hydroxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy or amino, all of which are optionally substituted by one or more, identical or different groups selected from R₈Is substituted by a substituent of (A), or R₁₂Represents hydrogen;

provided that R is₁、R₂And R₃Not all are methyl;

with the proviso that when R₂And R₃When both are hydrogen, R₁Cannot be methyl or hydrogen;

with the proviso that when R₁Is methyl or hydrogen, R₂Is methyl and R₃When hydrogen, ring B cannot be phenyl.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of general formula I as defined herein and a pharmaceutically acceptable vehicle or excipient or a pharmaceutically acceptable carrier and optionally one or more other therapeutically active compounds.

In another aspect, the present invention relates to the use of a compound of formula I as defined herein and pharmaceutically acceptable and physiologically cleavable esters, pharmaceutically acceptable salts, hydrates, N-oxides or solvates thereof in the manufacture of a medicament for the prevention, treatment or alleviation of a skin disease or condition, or an acute or chronic skin trauma condition.

In another aspect, the present invention relates to a method of preventing, treating or ameliorating a skin disease or condition, or an acute or chronic skin wound condition, which comprises administering to a person suffering from at least one of said diseases an effective amount of one or more compounds of formula I as defined herein and pharmaceutically and physiologically cleavable esters, pharmaceutically acceptable salts, hydrates, N-oxides, or solvates thereof; and optionally a pharmaceutically acceptable carrier or one or more excipients, and optionally other therapeutically active compounds.

In another aspect, the invention relates to a method of preparing or making a compound of formula I, the method comprising a method as described anywhere herein, e.g. method a), b), c), d), or any one of the general methods or procedures as described in the examples or preparations herein, and optionally further processing the resulting compound to obtain a compound of formula I as defined anywhere herein.

Detailed Description

The term "hydrocarbon group" is used to denote a group containing only hydrogen and carbon atoms, which may contain one or more carbon-carbon double and/or triple bonds, and which may contain cyclic groups as well as branched or straight chain groups. The hydrocarbon comprises from 1 to 20 carbon atoms, preferably from 1 to 12, such as from 1 to 6, such as from 1 to 4, such as from 1 to 3, such as from 1 to 2 carbon atoms. The term includes alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkynyl and aryl groups as described below.

The term "aryl" is used to denote an aromatic carbocyclic group, especially a 5 or 6 membered ring, comprising 6 to 20 carbon atoms, such as 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, including fused carbocyclic rings having at least one aromatic ring, such as phenyl, naphthyl, indenyl and indanyl.

The term "heteroaryl" is used to denote a heteroaromatic ring group comprising 1-6 heteroatoms (selected from O, S and N) and 1-20 carbon atoms, such as 1-5 heteroatoms and 1-10 carbon atoms, such as 1-5 heteroatoms and 1-6 carbon atoms, such as 1-5 heteroatoms and 1-3 carbon atoms, in particular a 5-or 6-membered ring having 1-4 heteroatoms selected from O, S and N, including fused bicyclic rings having 1-4 heteroatoms, and wherein at least one ring is aromatic, such as pyridyl, quinolyl, isoquinolyl, indolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, furanyl, pyridyl, thiazolyl, benzoxazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolyl, indolyl, etc, Benzimidazolyl and benzofuranyl.

In this context, the term "alkyl" is used to denote a group that results when one hydrogen atom is removed from a hydrocarbon. The alkyl group comprises 1 to 20, preferably 1 to 12, such as 1 to 6, such as 1 to 4 or such as 1 to 3 carbon atoms. The term includes the following subclasses: primary (n-alkyl), secondary and tertiary alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.

The term "cycloalkyl" is used to denote a saturated cycloalkane group containing 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, especially 3 to 8 carbon atoms, for example 3 to 6 carbon atoms, including fused bicyclic rings, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "heterocycloalkyl" is used to denote a cycloalkyl group as described above in which one or more carbon atoms are replaced by a heteroatom, containing from 1 to 20 carbon atoms, for example from 2 to 5 or from 2 to 4 carbon atoms, and also containing from 1 to 6 heteroatoms, preferably 1, 2 or 3 heteroatoms, selected from O, N or S, such as piperidinyl, pyrrolidinyl, morpholinyl, [1, 3] dioxolanyl and [1, 3] dioxolyl, or including fused bicyclic rings having from 1 to 4 heteroatoms, in which at least one ring contains a heteroatom, and in which the other ring may be, for example, a carbocyclic ring, such as isoindolyl.

The term "alkenyl" is used to denote a mono-, di-, tri-, tetra-or pentaunsaturated hydrocarbon group comprising 2 to 10 carbon atoms, in particular 2 to 6 carbon atoms, for example 2 to 4 carbon atoms, such as vinyl, propenyl (allyl), methylbutenyl, butenyl, pentenyl or hexenyl.

The term "cycloalkenyl" is used to denote a mono-, di-, tri-or tetra-unsaturated non-aromatic cyclic hydrocarbon group containing 3 to 20 carbon atoms, including fused bicyclic rings, typically containing 3 to 10 carbon atoms, such as 3, 4 or 6 carbon atoms, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl.

The term "heterocycloalkenyl" is used to denote a cycloalkenyl group as described above, wherein one or more carbon atoms are replaced by a heteroatom, comprising 1 to 20 carbon atoms, for example 2 to 4 carbon atoms, and further comprising 1 to 6 heteroatoms, preferably 1, 2 or 3 heteroatoms selected from O, N or S, including fused bicyclic rings having 1 to 4 heteroatoms, wherein at least one ring comprises a heteroatom, and wherein the other ring may be, for example, a carbocyclic ring, such as dihydrofuranyl or 2, 5-dihydro-1H-pyrrolyl.

The term "alkynyl" is used to denote a hydrocarbon group containing 1-5C-C triple bonds and 2-20 carbon atoms, typically 2-10 carbon atoms, especially 2-6 carbon atoms, for example 2-4 carbon atoms, e.g. ethynyl, propynyl, butynyl, pentynyl or hexynyl.

The term "halogen" is used to denote substituents from main group 7 of the periodic table, such as fluorine, chlorine and bromine.

The term "haloalkyl" is used to denote an alkyl group as defined above, e.g. difluoromethyl or trifluoromethyl, substituted with one or more halogen atoms as defined above, e.g. fluorine or chlorine.

The term "alkoxy" is used to denote a group of formula-OR ', wherein R' is alkyl as defined above, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, and the like.

The term "hydroxyalkyl" is used to denote an alkyl group as defined above substituted with one or more hydroxyl groups, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl.

The term "amino" is used to denote the formula-NR₂Wherein each R' independently represents hydrogen or a hydrocarbon group as defined above, for example-NH₂Dimethylamino, -NHMe, -NHEt, tert-butylamino.

The term "alkylthio" is used to denote a group of formula-S-R ', wherein R' is alkyl as defined above, e.g. -SMe.

The term "alkoxycarbonyl" is used to denote a group of formula-c (O) -O-R ', wherein R' is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and the like.

The term "aminocarbonyl" is used to denote a compound of the formula-C (O) -NR₂Wherein each R' is as described above.

The term "alkylcarbonylamino" is used to denote a group of formula-NR "-c (o) -R ', wherein R' is alkyl as defined above and each R" is as described above.

The term "alkylcarbonyl" is used to denote a group of formula-c (o) -R ', wherein R' is alkyl as defined above, e.g. acetyl.

The term "alkylcarbonyloxy" is used to denote a group of formula-O-c (O) -R ', wherein R' is alkyl as defined above.

The term "alkoxycarbonyloxy" is used to denote a group of formula-O-c (O) -O-R ', wherein R' is alkyl as defined above.

The term "heterocycle" includes the definitions of heteroaryl, heterocycloalkyl and heterocycloalkenyl as defined above, including ring systems kneaded with each other or with a cyclic hydrocarbon, such as 2, 5-dihydrobenzo (b) dioxaoctatriene, 2, 3, 5, 8-tetrahydro- [1, 4] dioxaoctatriene, 5, 8-dihydro- [1, 4] dioxaoctatriene, 2, 3-dihydro-1H-isoindole.

The term "alkylaryl" is used to denote an aryl group as defined above substituted with an alkyl group as defined above, for example tolyl, ethylbenzene and the like.

The term "arylalkyl" is used to denote an alkyl group as defined above substituted with an aryl group as defined above, e.g., benzyl, phenylethyl, naphthylmethyl, and the like.

The term "alkoxyalkyl" is intended to denote an alkyl group as defined above substituted with an alkoxy group as defined above, i.e., -R ' -O-R ', wherein each R ' is the same or different alkyl group as defined above, e.g., methoxymethyl, ethoxymethyl.

The term "aryloxy" is used to denote-O-R '", wherein R'" is aryl as defined above, e.g., phenoxy.

The term "arylcarbonyl" is used to denote-C (O) -R "", wherein R "" is an aryl group as defined above, e.g., benzoyl, naphthylcarbonyl.

The term "alkylalkoxycarbonyl" is used to denote-R ' -C (O) -O-R ', wherein each R ' is the same or different alkyl group as described above, e.g., tert-butoxycarbonylmethyl, methoxycarbonylmethyl.

The term "pharmaceutically acceptable salt" is used to indicate a salt prepared by reacting a compound of formula I with a suitable inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, 2-dichloroacetic acid, adipic acid, ascorbic acid, L-aspartic acid, L-glutamic acid, galactaric acid, lactic acid, maleic acid, L-malic acid, phthalic acid, citric acid, propionic acid, benzoic acid, glutaric acid, gluconic acid, D-glucuronic acid, methanesulfonic acid, salicylic acid, succinic acid, malonic acid, tartaric acid, benzenesulfonic acid, ethane-1, 2-disulfonic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfamic acid or fumaric acid. Pharmaceutically acceptable salts of the compounds of formula I may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, ammonia and the like, or a suitable non-toxic amine such as a lower alkylamine, for example triethylamine, a hydroxy-lower alkylamine, for example 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine, a cycloalkylamine, for example dicyclohexylamine, or a benzylamine, for example N, N' -dibenzylethylenediamine and dibenzylamine, or L-arginine or L-lysine. Salts obtained by reaction with a suitable base include, but are not limited to, sodium, choline, 2- (dimethylamino) -ethoxide, 4- (2-hydroxyethyl) -morpholine, L-lysine, N- (2-hydroxyethyl) -pyrrolidine, ethanolamine, potassium, tetrabutylammonium, benzyltrimethylammonium, hexadecyltrimethylammonium, tetramethylammonium, tetrapropylammonium, tris (hydroxymethyl) aminomethane, N-methyl-D-glucamine, silver, benzethonium, and triethanolamine.

The term "solvate" is used to denote a class of substances formed by the interaction between a compound (e.g. a compound of formula I) and a solvent (e.g. alcohol, glycerol or water), wherein said class is in solid form. When water is the solvent, this class is referred to as hydrates.

The compounds of the invention containing free hydroxyl groups or free carboxylic acid groups may also be present in the form of pharmaceutically acceptable, physiologically cleavable esters and are also included within the scope of the invention. Such pharmaceutically acceptable esters are preferably prodrug ester derivatives which can be converted by solvolysis or cleavage under physiological conditions to the corresponding compounds of the invention containing a free hydroxyl group or a free carboxylic acid group, respectively, for example by in vivo hydrolysis.

Embodiments of the invention

In one or more embodiments of the invention, ring B represents pyridyl, pyrazinyl, quinolinyl, pyrimidinyl or pyridazinyl, optionally mono-or di-substitutedOne or more, the same or different substituents selected from the group consisting of: fluorine, chlorine, bromine, cyano, methoxy, -NH₂Or C_1-4An amino group.

In one or more embodiments of the invention, optionally substituted with R₁₁Substituted ring B represents 2- (6-chloro-pyrazinyl), 2-pyrazinyl, 4- (3-bromo-pyridyl), 4- (3, 5-dibromo-pyridyl), 4- (6-chloro-pyrimidinyl), 2- (4-chloro-pyridyl), 3- (2-chloro-pyridyl), 4- (2-methoxy-pyridyl), 4- (2-cyano-pyridyl), 3-pyridazinyl, 4- (2-tert-butylamino-3, 5-dichloro-pyridyl), 4- (2-amino-3, 5-dichloro-pyridyl), 4- (3, 5-dichloro-pyridyl); optionally substituted phenyl, 2- (3-bromo-pyrazinyl), 4-pyridyl, 4-quinolyl or 4- (3, 5-dichloro-1-oxy-pyridyl).

In one or more embodiments of the invention, formula I represents general formula Iz,

wherein X₃represents-CH-or N, and wherein R₁、R₂And R₃As defined anywhere herein.

In one or more preferred embodiments of the invention, R₁Represents alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or alkylcarbonyl, all of which are optionally substituted by one or more, identical or different radicals selected from R₄Is substituted by a substituent of (a), and/or

R₂Represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, alkylalkoxycarbonyl, arylalkyl, alkylcarbonyloxy or alkoxyalkyl, all optionally substituted by one or more, identical or different substituents selected from R₅Substituted with the substituent(s); or R₂represents-CH₂-C(O)NR₉-R₁₂。

In one or more preferred embodiments of the invention, R₁Represents methyl or ethyl.

In one or more embodiments of the invention, R₂Represents C₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, halo C₁-C₆Alkyl radical, C₁-C₆Alkynyl, C₁-C₆Cycloalkyl radical, C₁-C₆Alkyl radical C₆-C₁₀Aryl radical, C₁-C₆Alkyl radical C_1-6Alkoxycarbonyl or C₁-C₆Alkylcarbonyloxy, all of which are optionally substituted by one or more, identical or different radicals selected from R₅Substituted with the substituent(s).

In one or more embodiments of the invention, R₂Represents methyl, ethyl, propyl, tert-butoxycarbonylmethyl, allyl, difluoromethyl, ethylbenzene, methylbenzene, butenyl, hydroxyethyl, ethylphenyl, tolyl, pentenyl, methoxyethyl, butynyl, propynyl, cyclopentyl, all of which are optionally substituted by one or more, the same or different substituents selected from R₅Substituted with the substituent(s).

In one or more embodiments of the invention, R₂Represents cyclopropyl, methylcyclopropyl, cyclopentyl, methyl, ethyl, propyl or allyl, all of which are optionally substituted by one or more, the same or different substituents selected from hydroxy, fluoro or alkoxy.

In one or more embodiments of the invention, R₃Represents methyl, ethyl, propyl, butyl, pentyl, hydroxyethyl, hexyl, butenyl, pentenyl, allyl, butynyl, methylbenzene, ethylbenzene, tolyl, toluyl, propylbenzene, methylnaphthyl, ethylnaphthyl, methylcarbonylmethoxy, methylcarbonylethoxy, methoxyethyl, methoxypropyl, all optionally substituted by one or more,Identical or different from R₆Are optionally substituted by one or more, the same or different substituents selected from R₈Is substituted by a substituent of (A), or R₃Represents hydrogen, -CH₂-C (O) -heterocycloalkyl or-CH₂-C(O)NR₉-R₁₂。

In one or more embodiments of the invention, R₃Represents methyl, ethyl, propyl or allyl, all of which are optionally substituted by one or more, identical or different substituents selected from hydroxyl, fluorine or alkoxy.

In one or more embodiments of the invention, R₅Represents methyl, tert-butoxy, vinyl, cyclopropyl, propenyl, phenyl, butenyl, propynyl, ethylhydroxy, ethynyl, allyl, ethyl or methoxy, all of which are optionally substituted by one or more, the same or different substituents selected from R₇Is substituted by a substituent of (A), or R₅Represents hydrogen, oxo, chloro, fluoro or hydroxy.

In one or more embodiments of the invention, R₆Represents vinyl, methyl, tert-butoxy, isoxazolyl, methoxy, propynyl, butenyl, phenyl, pyridyl, benzoxazolyl, thiazolyl, [1, 3, 4]Thiadiazolyl, [1, 2, 4]]Oxadiazolyl, 2, 3-dihydro-1H-isoindolyl, ethoxy, thienyl, propyl, ethyl, butyl, pentyl, allyl, isopropoxy, isopropyl, naphthyl, cyclohexyl, hydroxy, cyclopentyl, phenoxy, tolyl, toluyl, benzoyl, carbonylnaphthalene, ethylbenzene, quinolinyl, -NH₂Ethoxycarbonyl, methoxycarbonyl, carbamoyl, isoindole, methylamine, pyrrolidinyl, morpholinyl, methylsulfonyl, methylsulfinyl, butylamine, propylamine, ethylamine, cycloheptyl, hydroxyethyl, hydroxypropyl, indanyl or ethoxyethyl, all of which are optionally substituted by one or more, the same or different groups selected from R₈Is substituted by a substituent of (A), or R₆Represents hydrogen, oxo, fluoro, chloro or cyano.

In one or more embodiments of the invention, R₈Represents methyl, ethyl, propyl, butyl, phenyl, cyclopropyl, ethoxy, methoxy, allyl, vinyl, ethoxycarbonyl, hydroxy, naphthyl, cyclohexyl, methoxycarbonyl, phenoxy, isopropoxy, -NH₂Methylamine, pyrrolidinyl, morpholinyl, methylsulfonyl, methylsulfinyl, cycloheptyl, cyclopentyl, hydroxymethyl, hydroxyethyl, dimethylamino, furanyl, pyridinyl, tolyl, piperidinyl, acetyl, thienyl, cycloheptyl, all of which are optionally substituted with one or more, the same or different groups selected from R₁₀Is substituted by a substituent of (A), or R₈Represents hydrogen, oxo, chloro, bromo, fluoro, cyano or trifluoromethyl.

In one or more embodiments of the invention, R₉Represents hydrogen, methyl or ethyl.

In one or more embodiments of the invention, R₁₀Represents hydrogen, oxo, methyl, hydroxy, fluoro, cyano, chloro or methoxy.

In one or more embodiments of the invention, R₂Represents a methyl group.

In one or more embodiments of the invention, R₁And R₂Both represent methyl.

In one or more embodiments of the invention, R₁And R₃Represents methyl and/or difluoromethyl.

In one or more embodiments of the invention, R₃represents-CH₂-C(O)NH-R₁₂、-CH₂-C (O) NH-heterocycloalkyl, -CH₂CH₂-phenyl-R₆or-CH₂-phenyl-R₆。

In one or more embodiments of the invention, R₂And/or R₃represents-CH₂COOH, methyl, hydrogen, allyl, ethyl, tert-butoxycarbonylmethyl, difluoromethyl, 3-methyl-5-methylisoxazole, 2-methoxy-ethane, 2-butyne, 2-methyl-2-butene, 2-phenylethane, benzyl, 2-methyl-1, 3-benzoxazole, 4-methyl-2-methylthiazole, 2-methyl-5-cyclopropyl- [1, 3, 4]Thiadiazole, 3-methyl- [1, 2, 4]]Oxadiazole, ethyl acetate, 4-chlorobenzyl, 5-chloro-2-methyl-thiophene, phenoxyethane, (4-methylphenyl) ethane, 3-phenylpropane, (3-methoxyphenyl) ethane, (4-methoxyphenyl) ethane, (3-bromophenyl) ethane, (2-methoxyphenyl) ethane, (4-fluorophenyl) ethane, (2-fluorophenyl) ethane, (3, 4-dimethoxyphenyl) ethane, benzyl acetate, isopropyl acetate, methyl 3-methylbenzoate, 3-methyl-butane, 1-hexyl, but-1-ene, pent-1-ene, 1-propyl, 1-butyl, 2-methyl-propane, ethyl butyrate, 4-methyl-benzyl, 5-chloro-2-methyl-thiophene, 3-chloro-benzyl, propoxybenzene, 1- (4-methoxy-phenyl) -ethanone, 4-methyl-benzonitrile, 2-methyl-naphthalene, 1-pentyl, methyl-cyclohexane, 3-methyl-benzonitrile, 1-ethoxy-4-chloro-benzene, 2-ethyl-butane, 2-hydroxy-ethane, methyl 4-methylbenzoate, 1-naphthalen-2-yl-ethanone, 2, 5-dimethoxy-phenyl-ethanone, 1-p-tolyl-ethanone, 4-fluoro-benzyl, 2-fluoro-benzyl, 5-trifluoromethyl-benzyl, 5-trifluoromethoxy-benzyl, 3-fluoro-5-trifluoromethyl-benzyl, 1- (2-methoxy-phenyl) -ethanone, 1- (2, 4-dimethyl-phenyl) -ethanone, 4-chloro-benzyl, 2-difluoromethoxy-benzyl, 4-isopropyl-benzyl, 2-fluoro-6-trifluoromethyl-benzyl, 2, 3-difluoro-4-methyl-benzyl, 2-methyl-benzyl, 3-methyl-benzyl, pent-2-ene, 6-methyl-2-methyl-quinoline, 2-chloro-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, (3-chloro-phenyl) -ethane, 5-methyl-hexane, ethyl-cyclohexane, methyl-ethyl-benzyl, methyl-benzyl-2-methyl-quinoline, methyl-benzyl-3-methoxy-benzyl, methyl-benzyl-4-methoxy-benzyl, methyl-3-phenyl-ethane, ethyl valerate, (propoxymethyl) -benzene, acetamide, 2-ethyl-isoindole-1, 3-dione, 2-propyl-isoindole-1, 3-dione, N-methyl-acetamide, methyl-cyclopropane, but-1-ene, 4-yl-but-1-ene, 2-methyl-pent-2-ene, ethanol, benzyl, pent-2-ene, 2-methoxy-ethane, but-2-yne, propyne, acetate, 1-pyrrolidin-1-yl-ethanone, N-benzylacetamide, 1-morpholin-4-yl-ethanone, N-phenyl-acetamide, N-methyl-N-phenyl-acetamide, N-ethyl-isoindole, N-methyl-1, 3-pentanone, 2-methyl-isoindole-1, 3-dione, 2-methyl-2-penten-ene, 2-methyl-, N- (3-hydroxy-3-methyl-butyl) -acetamide, N-N-propyl-acetamide, N-ethyl-acetamide, N-isopropyl-acetamide,N-butyl-acetamide, N-cyclopentyl-acetamide, N- (3-methyl-butyl) -acetamide, N- (4-methoxy-benzyl) -acetamide, N- (2, 2-dimethyl-propyl) -acetamide, N-cyclohexyl-acetamide, N- (3-methoxy-benzyl) -acetamide, N-cycloheptyl-acetamide, N- (2-methoxy-benzyl) -acetamide, N-cyclohexylmethyl-acetamide, N- (2-hydroxy-ethyl) -acetamide, N- (1-phenyl-ethyl) -acetamide, N- (3-hydroxy-propyl) -acetamide, N-butyl-acetamide, N- (2-dimethyl-propyl) -acetamide, N- (3-methoxy-benzyl) -acetamide, N- (2-methoxy-benzyl) -acetamide, N-cyclohexylmethyl-acetamide, N- (2-hydroxy-ethyl) -acetamide, N- (2-methoxy-ethyl) -acetamide, N- (2-dimethylamino-ethyl) -acetamide, N- (3-dimethylamino-propyl) -acetamide, N- (1-phenyl-ethyl) -acetamide, N- (3-isopropoxy-propyl) -acetamide, N-furan-2-ylmethyl-acetamide, N-pyridin-3-ylmethyl-acetamide, N- (2-phenoxy-ethyl) -acetamide, N-pyridin-4-ylmethyl-acetamide, N- (4-ethyl-benzyl) -acetamide, N- (2-methoxy-ethyl) -acetamide, N- (2-dimethylamino-ethyl) -acetamide, N- (3-dimethylamino-propyl) -acetamide, N- (1-phenyl-ethyl) -acetamide, N- (2-isopropoxy-propyl) -acetamide, N-furan-2-, N- (3, 5-difluoro-benzyl) -acetamide, N- (2, 3-difluoro-benzyl) -acetamide, N- (2-pyridin-2-yl-ethyl) -acetamide, N- (2-methyl-benzyl) -acetamide, N- (3-fluoro-benzyl) -acetamide, N- (3-methyl-benzyl) -acetamide, N- (4-methyl-benzyl) -acetamide, N-phenethyl-acetamide, N- (2-pyridin-4-yl-ethyl) -acetamide, N- (3-phenyl-propyl) -acetamide, N- (2-chloro-benzyl) -acetamide, N- (2-fluoro-benzyl) -acetamide, N-acetyl-methyl-acetamide, N- (2-pyridin-2-yl-ethyl) -acetamide, N- (2-fluoro-benzyl) -acetamide, N- (2-methyl-benzyl) -acetamide, N- (2-piperidin-1-yl-ethyl) -acetamide, N- (3-chloro-benzyl) -acetamide, N- (2-morpholin-4-yl-ethyl) -acetamide, N- (4-chloro-benzyl) -acetamide, N- (2-pyridin-3-yl-ethyl) -acetamide, N- (2-pyrrolidin-1-yl-ethyl) -acetamide, N- (2-acetylamino-ethyl) -acetamide, (R) -N- (2-hydroxy-2-phenyl-ethyl) -acetamide, (S) -N- (2-hydroxy-2-phenyl-ethyl) -acetamide, salts thereof, and solvates thereof, N-thiophen-2-ylmethyl-acetamide, N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]-acetamide, N- (2-hydroxy-indan-1-yl) -acetamide, N-cycloheptylmethyl-acetamide, N- [2- (2-hydroxy-ethoxy) -ethyl]-acetamide, N- (4-dimethylamino-butyl) -acetamide, cyclopentane, cyclopropylmethyl, ethyl, phenyl-ethane, benzyl acetate, 2-methyl-benzonitrile, (1-oxy-pyridin-4-yl) ethane, (4-pyridyl) ethane, (3-pyridyl) ethane, (2-pyridyl) ethane, (4-benzonitrile) ethane, (4-methylsulfinyl-phenyl) ethane, (4-methylsulfonyl-phenyl) ethane, 1-phenyl-propane, 2-phenyl-propane or 1-methyl-2-Phenyl-ethane.

In one or more embodiments of the invention, R₁₂Represents alkyl, cycloalkyl, hydroxyalkyl, aryl, arylalkyl, alkylcarbonylamino, all optionally substituted by one or more, identical or different substituents selected from the group consisting of: alkyl, cycloalkyl, alkoxy, heterocycloalkyl, heteroaryl, aryloxy, amino, hydroxy, halogen, oxy, all optionally substituted by oxo or hydroxy, or R₁₂Represents hydrogen.

In one or more embodiments of the invention, R₁₂Represents methyl, ethyl, 1-propyl or 2-propyl, optionally substituted by one or more, identical or different substituents selected from fluorine, chlorine, bromine or methyl; or R₁₂Represents hydrogen.

In another embodiment, the invention relates to compounds of formula Iz wherein X₃Represents CH, R₁And R₂Are all methyl, and R₃As described anywhere herein.

In one or more embodiments of the invention, R₁And R₂Not all can be hydrogen.

In one or more embodiments of the invention, R₂And/or R₃As described anywhere in the compounds specifically exemplified below.

The invention includes wherein R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁And R₁₂All embodiments combined in any combination described anywhere herein.

In one or more embodiments of the invention, the compound of general structure I has a molecular weight of less than 800 daltons, such as less than 750 daltons, such as less than 700 daltons, or less than 650, 600, 550 or 500 daltons.

In particular, the compound of formula I may be selected from:

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hydroxy-3, 4-dimethoxy-phenyl) -ethanone (compound 101),

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-hydroxy-2, 4-dimethoxy-phenyl) -ethanone (compound 102),

1- (2-allyloxy-3-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 103),

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-diethoxy-4-methoxy-phenyl) -ethanone (compound 104),

{ 2-tert-Butoxycarbonylmethoxy-6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -3-methoxy-phenoxy } -acetic acid tert-butyl ester (compound 105),

1- (2, 3-di-allyloxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 106),

1- (2, 3-bis-difluoromethoxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 107),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (5-methyl-isoxazol-3-ylmethoxy) -phenyl ] -ethanone (compound 108),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methoxy-ethoxy) -phenyl ] -ethanone (compound 109),

1- (2-but-2-ynyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 110),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methyl-but-2-enyloxy) -phenyl ] -ethanone (Compound 111),

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-phenethyloxy-phenyl) -ethanone (compound 112),

1- (2-benzyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 113),

1- (2-allyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 114),

1- [2- (benzoxazol-2-ylmethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 115),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methyl-thiazol-4-ylmethoxy) -phenyl ] -ethanone (compound 116),

1- [2- (5-cyclopropyl- [1, 3, 4] thiadiazol-2-ylmethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (Compound 117),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- ([1, 2, 4] oxadiazol-3-ylmethoxy) -phenyl ] -ethanone (compound 118),

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid ethyl ester (compound 119),

1- {2- [2- (4-chloro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 120),

1- [2- (5-chloro-thiophen-2-ylmethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 121),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-phenoxy-ethoxy) -phenyl ] -ethanone (compound 122),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-p-tolyl-ethoxy) -phenyl ] -ethanone (compound 123),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-phenyl-propoxy) -phenyl ] -ethanone (compound 124),

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (3-methoxy-phenyl) -ethoxy ] -phenyl } -ethanone (Compound 125),

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (4-methoxy-phenyl) -ethoxy ] -phenyl } -ethanone (compound 126),

1- {2- [2- (3-bromo-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 127),

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (2-methoxy-phenyl) -ethoxy ] -phenyl } -ethanone (compound 128),

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone (compound 129),

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (2-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone (compound 130),

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (3, 4-dimethoxy-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone (compound 131),

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid benzyl ester (compound 132),

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid isopropyl ester (compound 133),

3- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzoic acid methyl ester (Compound 134),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methyl-butoxy) -phenyl ] -ethanone (Compound 135),

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hexyloxy-3, 4-dimethoxy-phenyl) -ethanone (compound 136),

1- (2-but-3-enyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 137),

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-pent-4-enyloxy-phenyl) -ethanone (compound 138),

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-propoxy-phenyl) -ethanone (compound 139),

1- (2-butoxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 140),

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-isobutoxy-3, 4-dimethoxy-phenyl) -ethanone (compound 141),

4- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -butyric acid ethyl ester (compound 142),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (4-methyl-benzyloxy) -phenyl ] -ethanone (compound 143),

1- [2- (3-chloro-benzyloxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 144),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-phenoxy-propoxy) -phenyl ] -ethanone (Compound 145),

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (4-methoxy-phenyl) -2-oxo-ethoxy ] -phenyl } -ethanone (compound 146),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzonitrile (compound 147),

4- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzonitrile (compound 148),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (naphthalen-2-ylmethoxy) -phenyl ] -ethanone (compound 149),

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-pentoxy-phenyl) -ethanone (compound 150),

1- (2-Cyclohexylmethoxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (Compound 151),

3- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzonitrile (compound 152),

1- {2- [2- (4-chloro-phenoxy) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 153),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-ethyl-butoxy) -3, 4-dimethoxy-phenyl ] -ethanone (compound 154),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-hydroxy-ethoxy) -3, 4-dimethoxy-phenyl ] -ethanone (compound 155),

4- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzoic acid methyl ester (Compound 156),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-naphthalen-2-yl-2-oxo-ethoxy) -phenyl ] -ethanone (compound 157),

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (2, 5-dimethoxy-phenyl) -2-oxo-ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone (compound 158),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-oxo-2-p-tolyl-ethoxy) -phenyl ] -ethanone (compound 159),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (4-fluoro-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone (compound 160),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-fluoro-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone (compound 161),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-trifluoromethyl-benzyloxy) -phenyl ] -ethanone (compound 162),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-trifluoromethoxy-benzyloxy) -phenyl ] -ethanone (compound 163),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (3-fluoro-5-trifluoromethyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone (compound 164),

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (2-methoxy-phenyl) -2-oxo-ethoxy ] -phenyl } -ethanone (compound 165),

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (2, 4-dimethyl-phenyl) -2-oxo-ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone (compound 166),

1- [2- (4-chloro-benzyloxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 167),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-difluoromethoxy-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone (compound 168),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (4-isopropyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone (compound 169),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-fluoro-6-trifluoromethyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone (compound 170),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2, 3-difluoro-4-methyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone (compound 171),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methyl-benzyloxy) -phenyl ] -ethanone (compound 172),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methyl-benzyloxy) -phenyl ] -ethanone (compound 173),

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-pent-2-enyloxy-phenyl) -ethanone (compound 174),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methyl-quinolin-6-ylmethoxy) -phenyl ] -ethanone (compound 175),

1- [2- (2-chloro-benzyloxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 176),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methoxy-benzyloxy) -phenyl ] -ethanone (compound 177),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (4-methoxy-benzyloxy) -phenyl ] -ethanone (compound 178),

1- {2- [2- (3-chloro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 179),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (5-methyl-hexyloxy) -phenyl ] -ethanone (compound 180),

1- [2- (2-cyclohexyl-ethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 181),

5- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -pentanoic acid ethyl ester (compound 182),

1- [2- (3-benzyloxy-propoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 183),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (Compound 184),

2- (2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -ethyl) -isoindole-1, 3-dione (Compound 185),

2- (3- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -propyl) -isoindole-1, 3-dione (Compound 186),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-methyl-acetamide (compound 187),

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-2, 4-dimethoxy-phenyl) -ethanone (compound 188),

1- (3-Cyclopropylmethoxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 189),

1- (2-allyloxy-3-but-3-enyloxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 190),

1- (3-but-3-enyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 191),

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-propoxy-phenyl) -ethanone (compound 192),

1- (3-allyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 193),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2, 4-dimethoxy-3- (4-methyl-pent-3-enyloxy) -phenyl ] -ethanone (compound 194),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3- (2-hydroxy-ethoxy) -2, 4-dimethoxy-phenyl ] -ethanone (compound 195),

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-phenethyloxy-phenyl) -ethanone (compound 196),

1- (3-benzyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 197),

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-pent-2-enyloxy-phenyl) -ethanone (compound 198),

2- (3, 5-dichloro-pyridin-4-yl) -1- [2, 4-dimethoxy-3- (2-methoxy-ethoxy) -phenyl ] -ethanone (compound 199),

1- (3-but-2-ynyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 200),

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-prop-2-ynyloxy-phenyl) -ethanone (compound 201),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl ] -ethanone (compound 202),

n-benzyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 203),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-morpholin-4-yl-2-oxo-ethoxy) -phenyl ] -ethanone (compound 204),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-phenyl-acetamide (compound 205),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-methyl-N-phenyl-acetamide (compound 206),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-hydroxy-3-methyl-butyl) -acetamide (Compound 207),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide (compound 208),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-isopropyl-acetamide (Compound 209),

n-butyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 210),

n-cyclopentyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 211),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-methyl-butyl) -acetamide (Compound 212),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-methoxy-benzyl) -acetamide (Compound 213),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2, 2-dimethyl-propyl) -acetamide (compound 214),

n-cyclohexyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 215),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-methoxy-benzyl) -acetamide (compound 216),

n-cycloheptyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 217),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-methoxy-benzyl) -acetamide (compound 218),

n-cyclohexylmethyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 219),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-ethyl) -acetamide (compound 220),

(R) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (1-phenyl-ethyl) -acetamide (compound 221),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-hydroxy-propyl) -acetamide (compound 222),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-methoxy-ethyl) -acetamide (compound 223),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-dimethylamino-ethyl) -acetamide (compound 224),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-dimethylamino-propyl) -acetamide (compound 225),

(S) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (1-phenyl-ethyl) -acetamide (compound 226),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-isopropoxy-propyl) -acetamide (compound 227),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-furan-2-ylmethyl-acetamide (compound 228),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-pyridin-2-ylmethyl-acetamide (compound 229),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-pyridin-3-ylmethyl-acetamide (Compound 230),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-phenoxy-ethyl) -acetamide (compound 231),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-pyridin-4-ylmethyl-acetamide (compound 232),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-ethyl-benzyl) -acetamide (compound 233),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3, 5-difluoro-benzyl) -acetamide (Compound 234),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2, 3-difluoro-benzyl) -acetamide (compound 235),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyridin-2-yl-ethyl) -acetamide (Compound 236),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-methyl-benzyl) -acetamide (Compound 237),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-fluoro-benzyl) -acetamide (compound 238),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-methyl-benzyl) -acetamide (compound 239),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-methyl-benzyl) -acetamide (Compound 240),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-phenethyl-acetamide (compound 241),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyridin-4-yl-ethyl) -acetamide (compound 242),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-phenyl-propyl) -acetamide (compound 243),

n- (2-chloro-benzyl) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 244),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-piperidin-1-yl-ethyl) -acetamide (compound 245),

n- (3-chloro-benzyl) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 246),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-morpholin-4-yl-ethyl) -acetamide (compound 247),

n- (4-chloro-benzyl) -2- (6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 248),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyridin-3-yl-ethyl) -acetamide (compound 249),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyrrolidin-1-yl-ethyl) -acetamide (compound 250),

n- (2-acetylamino-ethyl) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 251),

(R) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-2-phenyl-ethyl) -acetamide (compound 252),

(S) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-2-phenyl-ethyl) -acetamide (compound 253),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-thiophen-2-ylmethyl-acetamide (compound 254),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -acetamide (compound 255),

(2R) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-indan-1-yl) -acetamide (compound 256),

n-cycloheptylmethyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 257),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- [2- (2-hydroxy-ethoxy) -ethyl ] -acetamide (compound 258),

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-dimethylamino-butyl) -acetamide (compound 259),

1- (3-cyclopentyloxy-2-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 260),

1- (3-cyclopropylmethoxy-2-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 261),

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-2-hydroxy-4-methoxy-phenyl) -ethanone (Compound 262),

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-4-methoxy-2-phenethyloxy-phenyl) -ethanone (compound 263),

1- [2- (5-cyclopropyl- [1, 3, 4] thiadiazol-2-ylmethoxy) -3-ethoxy-4-methoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 264),

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2-ethoxy-3-methoxy-phenoxy } -acetic acid benzyl ester (Compound 265),

1- (3-allyloxy-2-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 266),

2- { 2-allyloxy-6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -3-methoxy-phenoxymethyl } -benzonitrile (compound 267),

1- (3-allyloxy-4-methoxy-2-phenethyloxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 268),

1- { 3-allyloxy-2- [2- (4-fluoro-phenyl) -ethoxy ] -4-methoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (compound 269),

n-benzyl-2- {6- [2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide (compound 270),

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (3, 4-dimethoxy-2-phenethyloxy-phenyl) -ethanone (compound 271),

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone (compound 272),

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (1-oxo-pyridin-4-yl) -ethoxy ] -phenyl } -ethanone (compound 274),

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (2-hydroxy-3, 4-dimethoxy-phenyl) -ethanone (compound 275),

4- (2- {6- [2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -ethyl) -benzonitrile (compound 276),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-pyridin-4-yl-ethoxy) -phenyl ] -ethanone (compound 277),

4- (2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -ethyl) -benzonitrile (compound 278),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-pyridin-2-yl-ethoxy) -phenyl ] -ethanone (compound 279),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-pyridin-3-yl-ethoxy) -phenyl ] -ethanone (Compound 280),

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-methanesulfinyl-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone (compound 281),

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-methanesulfonyl-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone (compound 282),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (1-phenyl-propoxy) -phenyl ] -ethanone (compound 283),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-phenyl-propoxy) -phenyl ] -ethanone (compound 284),

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (1-methyl-2-phenyl-ethoxy) -phenyl ] -ethanone (compound 285),

2- {6- [2- (6-chloro-pyrazin-2-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide (compound 286),

2- {6- [2- (3-bromo-pyrazin-2-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide (compound 287),

2- {6- [2- (2, 6-dichloro-phenyl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide (compound 288),

2- [2, 3-dimethoxy-6- (2-pyridin-4-yl-acetyl) -phenoxy ] -N-propyl-acetamide (compound 289),

2- [2, 3-dimethoxy-6- (2-quinolin-4-yl-acetyl) -phenoxy ] -N-propyl-acetamide (compound 290),

2- [2, 3-dimethoxy-6- (2-pyrazin-2-yl-acetyl) -phenoxy ] -N-propyl-acetamide (compound 291),

2- {6- [2- (3-bromo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide (compound 292),

2- {6- [2- (3, 5-dibromo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide (compound 293),

2- {6- [2- (6-chloro-pyrimidin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide (compound 294),

2- {6- [2- (4-chloro-pyridin-2-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide (compound 295),

2- {6- [2- (2-chloro-pyridin-3-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide (Compound 296),

2- {2, 3-dimethoxy-6- [2- (2-methoxy-pyridin-4-yl) -acetyl ] -phenoxy } -N-propyl-acetamide (Compound 297),

2- {6- [2- (2-cyano-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide (compound 298),

2- [2, 3-dimethoxy-6- (2-pyridazin-3-yl-acetyl) -phenoxy ] -N-propyl-acetamide (compound 299),

2- (2-tert-butylamino-3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone (compound 300),

2- (2-amino-3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone (compound 301),

2- (3, 5-dichloro-pyridin-4-yl) -1- (4-ethoxy-3-methoxy-2-phenethyloxy-phenyl) -ethanone (compound 302),

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid (compound 504),

2-tert-Butoxycarbonylmethoxy-3, 4-dimethoxy-benzoic acid methyl ester (compound 506a),

2-carboxymethoxy-3, 4-dimethoxy-benzoic acid methyl ester (compound 506b),

3, 4-dimethoxy-2-propylcarbamoylmethoxy-benzoic acid methyl ester (compound 506c),

or 2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-ethyl-acetamide (compound 305),

and pharmaceutically acceptable and physiologically cleavable esters, pharmaceutically acceptable salts, hydrates, N-oxides, or solvates thereof.

In a preferred embodiment of the invention, X₃Represents N, and X₁、X₂、X₄And X₅represents-CH-. In another embodiment, X₁Represents N, and X₂、X₃、X₄And X₅represents-CH-. In another embodiment, X₂Represents N, and X₁、X₃、X₄And X₅represents-CH-. In another embodiment, X₄Represents N, and X₁、X₂、X₃And X₅represents-CH-, or X₅Represents N and X₁、X₂、X₃And X₄represents-CH-. In another preferred embodiment, X₁、X₂、X₃、X₄And X₅represents-CH-. In another embodiment, X₁And X₄Represents N and X₂、X₃And X₅represents-CH-, or X₂And X₅Represents N and X₁、X₃And X₄represents-CH-, or X₃And X₅Represents N and X₁、X₂And X₄represents-CH-. In another embodiment, X₁And X₂Represents N and X₃、X₄And X₅represents-CH-, or X₄And X₅Represents N and X₁、X₂And X₃represents-CH-.

Suitable substituents R of the ring B₁₁Including halogens such as chlorine, bromine or fluorine, cyano, methoxy, ethoxy, propoxy, or alkylamines such as t-butylamine.

Substituent R of ring B₁₁It may be preferably attached at ortho-positions (2-and 6-positions) and/or meta-positions (3-and 5-positions) relative to the position at which acetophenone is attached to ring B.

In another embodiment, when R₃When is hydrogen, X₁、X₂、X₃、X₄Or X₅Is nitrogen.

In one or more embodiments of the invention, the compounds of formula I as defined above are used in therapy, in particular for the treatment of skin diseases.

In one or more embodiments of the invention, the skin disease or disorder is selected from proliferative and inflammatory skin diseases, psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, steroid induced skin atrophy, skin aging, skin photoaging, acne, dermatitis, allergic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus and eczema.

The compounds of formula I may be obtained in crystalline form by concentration directly from an organic solvent or by crystallization or recrystallization from an organic solvent or a mixture of said solvent and a co-solvent, which may be organic or inorganic, for example water. The crystals may be isolated in a form substantially free of solvent or in the form of a solvate, such as a hydrate. The present invention encompasses all crystalline forms, such as polymorphs and pseudopolymorphs, and mixtures thereof.

The compounds of formula I may or may not contain asymmetrically substituted (chiral) carbon atoms, which lead to the presence of isomeric forms, such as enantiomers and possibly diastereomers. The invention relates to all these isomers in pure form or in the form of mixtures thereof (e.g. racemates). The compounds of the invention and intermediates in pure stereoisomeric form may be obtained by methods known in the art. The different isomeric forms may be separated by physical separation methods, such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using a chiral stationary phase. Enantiomers can be separated by selective crystallization of their diastereomeric salts with optically active amines such as L-ephedrine. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of suitable starting materials, provided that the reaction occurs stereoselectively or stereospecifically. Preferably, if a particular stereoisomer is desired, the compound can be synthesized by stereoselective or stereospecific methods of preparation. These processes advantageously use chirally pure starting materials.

The compounds of the invention, optionally in combination with other active compounds, are useful for the treatment of skin diseases or disorders, or acute or chronic skin wound disorders, in particular for the treatment of proliferative and inflammatory skin diseases, psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, steroid-induced skin atrophy, skin ageing, skin photoaging, acne, dermatitis, allergic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritis and eczema.

In addition to use in human therapy, the compounds of the present invention may also be used in veterinary therapy of animals, including mammals, such as horses, cattle, sheep, pigs, dogs and cats.

For therapeutic use, the compounds of the invention are generally in the form of pharmaceutical compositions. The present invention therefore relates to pharmaceutical compositions comprising a compound of formula I and optionally one or more other therapeutically active compounds, together with a pharmaceutically acceptable excipient, vehicle or carrier. Excipients must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Conveniently, the active ingredient is present in an amount of 0.05 to 99.9% by weight of the formulation.

The compounds may be administered in dosage unit form, once or more at appropriate intervals per day, but will generally depend on the condition of the patient and according to the prescription given by the physician. Conveniently, the dosage unit of the formulation comprises from 0.1mg to 1000mg, preferably from 1mg to 100mg, for example from 5 to 50mg, of a compound of formula I.

The appropriate dosage of the compounds of the invention will depend, inter alia, on the age and condition of the patient, the severity of the condition being treated and other factors well known to the attending physician. The compounds may be administered orally, parenterally or topically according to various dosing schedules, for example daily or at weekly intervals. In general, the single dose will be in the range of 0.01 to 400mg/kg body weight. The compounds may be administered as a bolus (i.e., one administration of the entire daily dose), or as divided doses administered twice or more daily.

In the case of topical treatment, it is more convenient to refer to a "use unit", which means a single dose that can be administered to a patient and which can be readily processed and packaged and maintained as a physically and chemically stable unit dose containing the active substance or mixture thereof with a solid or liquid pharmaceutically acceptable diluent or carrier.

The term "use unit" in connection with topical application refers to a unit (i.e. a single dose) which is capable of topical administration to a patient in an amount of 0.1mg to 10mg, and preferably 0.2mg to 1mg of the active ingredient per square centimeter of the affected area.

It can also be concluded that in certain treatment regimens, it may be beneficial to have the administration at longer intervals, for example, every other day, weekly, or even longer intervals.

If The treatment involves The administration of another therapeutically active compound, it is recommended for The effective dose of said compound to be consulted with Goodman & Gilman's The Pharmacological Basis of therapeutics, 9 th edition, J.G.Hardman and L.E.Limbird (eds.), McGraw-Hill 1995.

The administration of a compound of the invention and one or more other active compounds may be simultaneous or sequential.

Formulations include, for example, those suitable for oral (including sustained or extended release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarticular and intravenous), transdermal, ocular, topical, nasal or buccal administration.

The formulations may be conveniently presented in dosage unit form and may be prepared by any of The methods well known in The art of pharmacy, for example, as disclosed in Remington, The Science and Practice of pharmacy, 21 st edition, 2005. All methods include the step of bringing into association the active ingredient with the carrier, which carrier includes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; can be in the form of powder or granule; may be in the form of a solution or suspension in an aqueous liquid or a non-aqueous liquid such as ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oil may be an edible oil such as cottonseed oil, sesame oil, coconut oil or peanut oil. For aqueous suspensions, suitable dispersing or suspending agents include synthetic or natural gums, such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer, and polyvinylpyrrolidone. The active ingredient may also be administered in the form of a bolus, electuary or paste.

Tablets may be prepared by compressing or molding the active ingredient and, optionally, one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with: binders such as lactose, glucose, starch, gelatin, gum arabic, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, waxes, and the like; lubricants, such as sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like; disintegrants, such as starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycolate, crospovidone, and the like; or a dispersant such as polysorbate 80. The molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient and a suitable carrier, which has been moistened with an inert liquid diluent.

Formulations for rectal administration may be in the form of suppositories in which the compounds of the invention are mixed with low melting water soluble or insoluble solids such as cocoa butter, hydrogenated vegetable oils, polyethylene glycols or fatty acid esters of polyethylene glycols, while elixirs may be prepared using myristyl palmitate.

Formulations suitable for parenteral administration conveniently comprise sterile oily or aqueous preparations of the active ingredient which are preferably isotonic with the blood of the recipient, for example isotonic saline, isotonic glucose solution or buffer solutions. The preparation can be conveniently sterilized by, for example, filtration through a bacteria-retaining filter, addition of a sterilizing agent to the preparation, irradiation of the preparation or heating of the preparation. Liposome formulations as disclosed, for example, in Encyclopedia of pharmaceutical technology, Vol.9, 1994 are also suitable for parenteral administration.

Alternatively, the compounds of formula I may be presented in the form of a sterile solid formulation, for example a lyophilized powder, which is readily dissolved in a sterile solvent immediately prior to use.

Transdermal formulations may be in the form of plasters or patches.

Formulations suitable for ocular administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension.

Liposomal formulations or biodegradable polymer systems, such as those disclosed in Encyclopedia of pharmaceutical Technology, Vol.2, 1989, may also be used to present the active ingredient for ocular administration.

Formulations suitable for topical or ocular administration include liquid or semi-liquid formulations, for example, liniments, lotions, gels, dressings, oil-in-water or water-in-oil emulsions, such as creams, ointments or pastes; or solutions or suspensions, such as drops. The composition for ocular treatment may preferably further comprise a cyclodextrin.

For topical administration, the compounds of formula I may generally be present in an amount of from 0.01 to 20%, for example from 0.1% to about 10% by weight of the composition, but may also be present in an amount up to about 50% of the composition.

Formulations suitable for intranasal or buccal administration include powder, self-propelling and spray formulations, for example aerosols and sprays. These agents are disclosed in detail, for example, in Modern pharmaceuticals, second edition, g.s.banker and c.t.rhodes (main eds.), pages 427-432, Marcel Dekker, new york; modern pharmaceuticals, third edition, g.s.banker and c.t.rhodes (main edition), pages 619 and 718-; and Encyclopedia of pharmaceutical Technology, volume 10, J.Swarbrick and J.C Boylan (eds.), pp.191-221, Marcel Dekker, New York.

In addition to the above ingredients, the formulations of the compounds of formula I may also include one or more other ingredients such as diluents, buffers, flavoring agents, colorants, surfactants, thickeners, preservatives such as methyl hydroxybenzoate (including antioxidants), emulsifiers and the like.

When the active ingredient is administered in the form of a pharmaceutically acceptable non-toxic acid or base salt, preferred salts are, for example, those which are readily or sparingly soluble in water, in order to obtain a specific and suitable absorption rate.

The pharmaceutical composition may also comprise one or more other active ingredients commonly used in the treatment of skin diseases or disorders, such as those selected from the group consisting of proliferative and inflammatory skin diseases, psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, steroid-induced skin atrophy, skin ageing, skin photoaging, acne, dermatitis, allergic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus and eczema.

Examples of such other active ingredients may be selected from, for example, glucocorticoids, vitamin D and vitamin D analogues, antihistamines, Platelet Activating Factor (PAF) antagonists, anticholinergics, methylxanthines, beta-adrenergic agents, COX-2 inhibitors, salicylates, indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol lowering agents, retinoids, zinc salts and sulfasalazine.

Preparation method

The compounds of the present invention may be prepared by a variety of methods well known to those skilled in the art of synthesis. The compounds of formula I can be prepared, for example, using the reactions and techniques outlined below, as well as methods known in the art of synthetic organic chemistry or variations thereof as would be understood by one skilled in the art. Preferred methods include, but are not limited to, the methods described below. The reaction is carried out in a solvent which is suitable for the reagents and starting materials used and for the conversion carried out. Moreover, in the synthetic methods described below, it will be understood that all proposed experimental conditions (including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment, and method of work-up) are selected as standard conditions for the reaction, for which a person skilled in the art would readily understand. Not all compounds falling within the class described are compatible with certain experimental conditions required in certain of the described methods. These limitations on substituents compatible with the reaction conditions will be clear to those skilled in the art and alternative methods may be used. If desired, the compounds of the invention or any of the intermediates may be purified using standard procedures well known to synthetic organic chemists, for example as described in "Purification of Laboratory Chemicals", 5 th edition, 2003. The starting materials are known compounds, commercially available compounds or they can be prepared by conventional synthetic methods well known to those skilled in the art.

General methods, preparations and examples

¹H Nuclear Magnetic Resonance (NMR) spectra are typically recorded at 300 MHz. The exemplified chemical shift values (δ, in ppm) were obtained in the indicated solvent relative to an internal standard tetramethylsilane (δ ═ 0.00) or chloroform (δ ═ 7.25) standard. Unless ranges are recited, values for multiplets at about the midpoint are given, whether defined (doublet (d), triplet (t), quartet (q)) or undefined (m). (bs) represents a broad singlet. The organic solvent used is generally anhydrous. Chromatography was performed on Merck silica gel 60(0.040-0-063 mm). Unless otherwise indicated, the solvent ratio is referred to as v: v.

The following abbreviations are used throughout:

ADDP 1, 1' - (Azodicarbonyl) dipiperidine

AIBN azobisisobutyronitrile

Ar-Me aryl-methyl

DCE Dichloroethane

DCM dichloromethane

DMF N, N' -dimethylformamide

DMSO dimethyl sulfoxide

Et Ethyl group

h hours

HATU O- (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate

HetAr-Me heteroaryl-methyl

L liter

LDA lithium diisopropylamide

LiHMDS lithium hexamethyldisilazide

m mm

MCPBA m-chloroperoxybenzoic acid

Me methyl group

NBS N-bromosuccinimide

NMP 1-methyl-2-pyrrolidone

NMR nuclear magnetic resonance

rt Room temperature

Retention time of RT

TBAD azobiscarboxylic acid di-tert-butyl ester

TFA trifluoroacetic acid

THF tetrahydrofuran

TIS triethylsilane

Volume V

Preparative HPLC/MS

Preparative HPLC/MS was performed on a Dionex APS-system with two Shimadzu PP150 prep pumps and one ThermoMSQ Plus mass spectrometer. Column: waters XTerra C-18, 150mm × 19mm, 5 μm; solvent system: a ═ water (0.1% formic acid) and B ═ acetonitrile (0.1% formic acid); the flow rate is 18 mL/min; method (10 min): the linear gradient elution method ranged from 10% B to 100% B in 6 minutes and continued for an additional 2 minutes at 100% B. Fractions were collected based on the ion trace of the relevant ion and PDA signal (240-400 nm).

Analytical HPLC/MS

The method A comprises the following steps:

analytical HPLC/MS was carried out on a Dionex APS-system with a P680A analytical pump and a Thermo MSQ Plus mass spectrometer. Column: waters XTerra C-18, 150mm × 4.6mm, 5 μm; solvent system: a ═ water (0.1% formic acid) and B ═ acetonitrile (0.1% formic acid); the flow rate is 1.0 mL/min; method (10 min): the linear gradient elution method ranged from 10% B to 100% B in 6.6 minutes and continued for an additional 1.5 minutes at 100% B.

The method B comprises the following steps:

analytical HPLC/MS was performed on a system including a Waters 2795 HPLC, Micromass ZQ mass spectrometer, Waters 996 PDA. Column: waters XTerra C-18, 50mm x 3.0mm, 5 μm; solvent system: water acetonitrile 95: 5 (0.05% formic acid) and B acetonitrile (0.05% formic acid); the flow rate is 1.0 mL/min; method (8 min): the linear gradient elution method ranged from 10% B to 100% B in 6.0 minutes and continued for 1 minute at 100% B.

General methods and examples:

for example, the compounds of the present invention may be prepared according to the following non-limiting general procedures and examples:

method a)

Mono-or dialkylated compounds of formula Ia

Wherein R is₁As described herein, a compound of formula Ia is reacted with a suitable alkyl or alkenyl chloride, bromide, iodide, mesylate or tosylate under basic conditions (protective groups in Organic Chemistry, John Wiley&sons, master edition: t isGreene and p.g. wuts, third edition (1999), pages 249-72), or with a suitable alcohol, such as an alkyl alcohol, in a suitable solvent such as THF, benzene or DMF using Mitsunobu reaction conditions (see Synthesis (1981), 1; tet.lett. (1993), 34, 1639-42 and eur.j.org.chem. (2004), 2763-72). The reaction can be carried out in a one-pot process or in two successive steps.

Method b)

Alkylation of Compounds of formula Ic

Wherein R is₁And R₃(R₃Not H) compounds of formula Ic are reacted with alkyl, alkenyl or alkynyl chlorides, bromides, iodides, mesylates or tosylates as described herein under basic conditions or with alkyl alcohols in a suitable solvent such as THF, acetone, benzene, toluene or DMF using Mitsunobu reaction conditions.

Method c)

Alkylation of compounds of formula Id (formula I, wherein R3 ═ hydrogen)

Wherein R is₁And R₂(R₂Not H) compounds of formula Id are reacted with alkyl, alkenyl or alkynyl chlorides, bromides, iodides, mesylates or tosylates as described herein under basic conditions or with alkyl alcohols in a suitable solvent such as THF, acetone, benzene, toluene or DMF using Mitsunobu reaction conditions.

Method d)

Amide formation of Compounds of formula Ie

Wherein R is₁And R₂As described herein, the compound of formula Ie is reacted with a primary or secondary amine using a coupling reagent such as HATU (Carpino, l.a.j.am. chem.soc. (1993), 115, 4397), or any other standard peptide coupling reagent (Larry Yet, Albany Molecular Research, technical reports volume 4, No. 1, pages 1-7).

The starting materials of formulae Ia to Ie may be prepared according to standard procedures well known to those skilled in the art. For example, commercially available 2, 3, 4-methoxybenzoic acid (Aldrich) is reacted with MeI in a suitable base (e.g., K)₂CO₃Or Et₃N) in a suitable solvent (e.g. DMF, THF or DCM) at a temperature of from room temperature to 100 ℃. The resulting ester is then condensed with 3, 5-dichloro-4-methylpyridine (prepared, for example, according to the procedures of j.org.chem. (1961), 26, 789-92, Heterocycles (2001), 55, 2075-84 or PCT 9414742) in the presence of a suitable base (for example LDA or LiHMDS) in a suitable solvent (for example THF) at temperatures between-78 ℃ and room temperature. The resulting ketone was deprotected by the following reaction:

A) the reaction is carried out in the presence of a suitable acid (e.g., HI or HBr) in a suitable solvent (e.g., AcOH) at a temperature of 50 deg.C to 120 deg.C to provide the compound of formula Ia.

B) In the presence of a suitable Lewis acid (e.g. BCl)₃、BBr₃Or AlCl₃) In a suitable solvent, such as dichloromethane, at temperatures from 0 ℃ to room temperature to give compounds of formula Id.

A compound of formula Ia is reacted with an alkenyl chloride, bromide, iodide, mesylate or tosylate in a suitable base (e.g., K)₂CO₃Or Et₃N) in a suitable solvent (e.g. DMF, NMP, THF or DCM) at room temperatureA dialkylation reaction at a temperature of 100 ℃ to give the compound of formula Ib. The compound of formula Ib is then reacted with a suitable Lewis acid (e.g. BCl)₃、BBr₃Or AlCl₃) Deprotection in a suitable solvent (e.g. dichloromethane) at a temperature of from 0 ℃ to room temperature, followed by reaction with an alkenyl chloride, bromide, iodide, mesylate or tosylate in a suitable base (e.g. K)₂CO₃Or Et₃N) in a suitable solvent (e.g. DMF, NMP, THF or DCM) at a temperature of from room temperature to 100 ℃ to give the asymmetric compound of formula Ib.

A compound of formula Ia is reacted with an alkyl, alkenyl or alkynyl bromide or iodide in a suitable base (e.g., K)₂CO₃) Selective monoalkylation in the presence of a suitable solvent such as DMF or NMP at a temperature of from room temperature to 100 ℃ gives compounds of formula Ic or Id.

A compound of formula Id with an alkyl chloroacetate or bromoacetate in a suitable base (e.g. K)₂CO₃) The alkylation reaction is carried out in the presence of a suitable solvent (e.g. DMF or NMP) at a temperature of from room temperature to 100 ℃ and then under standard conditions (Protective Groups in Organic Chemistry, John Wiley&sons, master edition: hydrolysis of the carboxylic acid ester at T.Greene and P.G.Wuts, 3 rd edition (1999), p.384-86) affords compounds of formula Ie.

Preparation 1 (compound 501):

2, 3, 4-Trimethoxybenzoic acid methyl ester

2, 3, 4-Trimethoxybenzoic acid (Aldrich) (20g, 94mmol) was dissolved in anhydrous DMF (250 mL). Adding K₂CO₃(13g, 94mmol) and MeI (6.5mL, 103.4mmol), and the reaction mixture was heated to 50 ℃ for 5 hoursThen (c) is performed. The reaction mixture was cooled to room temperature and water (250mL) was added. EtOAc (1L) was added and the organic phase was washed with water (3X 500mL) and finally with NaCl (saturated) solution. The washed organic phase was MgSO₄Dried, filtered and concentrated in vacuo. Redissolved in toluene and evaporated. Methyl 2, 3, 4-trimethoxybenzoate was obtained as a pale yellow oil.¹H NMR(CDCl₃) δ is 7.60(1H, d), 6.70(1H, d), 3.99(3H, s), 3.91(3H, s), 3.89(3H, s), 3.88(3H, s). Yield 21g (99%).

Preparation 2 (compound 502):

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3, 4-trimethoxy-phenyl) -ethanone

Methyl 2, 3, 4-trimethoxybenzoate from preparation 1 (2.7g, 10mmol) and 3, 5-dichloro-4-methylpyridine (prepared according to literature procedures) were dissolved in anhydrous THF (40 mL). The reaction was cooled on ice and treated dropwise (over 5 min) by adding 1M lithium bis (trimethylsilyl) amide (12mL, 12 mmol). After 1.5 hours at 0 ℃ with NH₄Cl (saturated, 100mL) quenched the reaction. The organic product was extracted with EtOAc (2X 100mL) and the combined organic phases were washed with NaCl (saturated, 100 mL). Na for organic phase₂SO₄Dried, evaporated in vacuo and purified by flash chromatography using a gradient of EtOAc in heptane as eluent. To give 2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3, 4-trimethoxy-phenyl) -ethanone as a white solid.¹H NMR(CDCl₃) δ is 8.43(2H, s), 7.55(1H, d), 6.69(1H, d), 4.61(2H, s), 4.02(3H, s), 3.87(3H, s), 3.84(3H, s). Yield 2.3g (65%).

Example 1 (Compound 101)

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hydroxy-3, 4-dimethoxy-phenyl) -ethanone

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3, 4-trimethoxy-phenyl) -ethanone (20g, 56mmol) from preparation 2 was dissolved in DCM (75mL) under argon. BCl was added slowly at room temperature for 2 hours₃(95mL of a 1M solution in DCM). Water (50mL) was added slowly followed by EtOH (200 mL). The white precipitate was filtered and recrystallized from EtOH. To give 2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hydroxy-3, 4-dimethoxy-phenyl) -ethanone as a white solid.¹H NMR(CDCl₃) δ is 11.92(1H, s), 8.54(2H, s), 7.68(1H, d), 6.60(1H, d), 4.67(2H, s), 3.98(3H, s), 3.90(3H, s). Yield 14.2g (74%)

Preparation 3 (Compound 503)

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-dihydroxy-4-methoxy-phenyl) -ethanone

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3, 4-trimethoxy-phenyl) -ethanone (1.25g, 3.5mmol) from preparation 2 was dissolved in AcOH (100%, 9.25mL) under argon. HI (55-58%, 4.55mL) was added and the reaction mixture was heated at 80 ℃ for 18 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. Slow addition of NaHCO₃(sat, 150mL) followed by the addition of NaCl (sat, 50 mL). The organic product was extracted with EtOAc (4X 100 mL). The combined organic phases were washed with NaCl (saturated, 100mL), Na₂S₂O₃Washed twice (10%, 100 mL). With Na₂SO₄Dried and evaporated in vacuo. To obtain 2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-dihydroxy-4-methoxy-phenyl) -ethanone as a brown solidAnd (3) a body.¹H NMR(CDCl₃) δ is 11.88(1H, s), 8.54(2H, s), 7.51(1H, d), 6.60(1H, d), 5.62(1H, bs), 4.67(2H, s), 4.00(3H, s). Yield 0.935g (81%)

General procedure for the preparation of the compounds of formula If. Wherein R is₃As defined herein (R)₃Other than hydrogen):

the 2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-dihydroxy-4-methoxy-phenyl) -ethanone from preparation 3 (0.1mmol) was dissolved in anhydrous DMF (0.75 mL). Adding K₂CO₃(0.1mmol) and then 0.1mmol of alkyl bromide or iodide is added. The reaction mixture was heated to 70 ℃ for 18 hours. After cooling to room temperature, water (1mL) was added and the organic product was extracted with EtOAc (3X 1 mL). The combined organic phases were washed with NaCl (sat., 1mL) and then Na₂SO₄And (5) drying. The pure compound was obtained by re-dissolving the reaction mixture in DMSO, followed by standard preparative HPLC purification.

Using this method the following compounds were obtained:

example 2 (Compound 102)

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-hydroxy-2, 4-dimethoxy-phenyl) -ethanone LC/MS (method B): (m/z)342.1(MH +); RT ═ 3.34 minutes; purity (UV) 100%; alkyl halide: methyl iodide

Example 3 (Compound 103)

1- (2-allyloxy-3-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone LC/MS (method B): (m/z)368.2(MH +); RT ═ 3.81 minutes; purity (UV) ═ 100%

Alkyl halide: allyl bromide

Preparation of a Compound of formula IgGeneral procedure for the preparation of compounds wherein R₂＝R₃And is as defined herein (R)₃Other than hydrogen):

the 2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-dihydroxy-4-methoxy-phenyl) -ethanone from preparation 3 (0.1mmol) was dissolved in anhydrous DMF (0.75 mL). Adding K₂CO₃(0.2mmol) and then 0.2mmol of alkyl chloride, bromide or iodide is added. In the case of the alkyl chlorides, KI (0.05mmol) was additionally added. The reaction mixture was heated to 70 ℃ for 18 hours. After cooling to room temperature, water (1mL) was added and the organic product was extracted with EtOAc (3X 1 mL). The combined organic phases were washed with NaCl (sat., 1mL) and then Na₂SO₄And (5) drying. The reaction mixture was re-dissolved in DMSO and then purified by standard preparative HPLC to afford the pure compound.

Using this method the following compounds were obtained:

example 4 (Compound 104)

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-diethoxy-4-methoxy-phenyl) -ethanone LC/MS (method B): (m/z)384.1(MH +); RT ═ 4.69 minutes; purity (UV) 100%; alkyl halide: iodothane

Example 5 (Compound 105)

{ 2-tert-Butoxycarbonylmethoxy-6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -3-methoxy-phenoxy } -acetic acid tert-butyl ester

LC/MS (method B): (m/z)554.3 (MH-); RT ═ 5.39 minutes; purity (UV) 100%; alkyl halide: bromoacetic acid tert-butyl ester

Example 6 (Compound 106)

1- (2, 3-di-allyloxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone LC/MS (method B): (m/z)408.2(MH +); RT ═ 4.94 minutes; purity (UV) 100%; alkyl halide: allyl bromide

Example 107 (Compound 107)

1- (2, 3-bis-difluoromethoxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone LC/MS (method B): (m/z)428.1(MH +); RT ═ 4.23 min; purity (UV) ═ 100%

Alkyl halide: sodium chlorodifluoroacetate. Heating to 100 ℃ for 30 minutes.

General procedure for the preparation of Compounds of formula Ih, wherein R₃(R₃Not hydrogen) is as defined herein:

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hydroxy-3, 4-methoxy-phenyl) -ethanone (0.035mmol) obtained from example 1 was dissolved in anhydrous DMSO (0.25 mL). Adding K₂CO₃(0.025mL, 2M) in water, then 0.053mmol of alkyl chloride, bromide or iodide dissolved in 0.025mL of DMSO was added. The reaction mixture was left at room temperature for 48 hours. Purification by standard preparative HPLC gave the pure compound.

Using this method the following compounds were obtained:

example 108 (Compound 108)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (5-methyl-isoxazol-3-ylmethoxy) -phenyl ] -ethanone

LC/MS (method B): (m/z)437.1(MH +); RT ═ 4.01 min; purity (UV) 100%; alkyl halide: 3-chloromethyl-5-methylisoxazole

Example 109 (Compound 109)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methoxy-ethoxy) -phenyl ] -ethanone

LC/MS (method B): (m/z)400.1(MH +); RT ═ 3.90 minutes; purity (UV) 100%; alkyl halide: 1-bromo-2-methoxy-ethane

Example 110 (Compound 110)

1- (2-but-2-ynyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method B): (m/z)394.1(MH +); RT ═ 4.30 minutes; purity (UV) 100%; alkyl halide: 1-bromo-2-butyne

Example 111 (Compound 111)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methyl-but-2-enyloxy) -phenyl ] -ethanone

LC/MS (method B): (m/z)410.1(MH +); RT ═ 4.83 minutes; purity (UV) 100%; alkyl halide: 1-bromo-2-methyl-2-butene

Example 112 (Compound 112)

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-phenethyloxy-phenyl) -ethanone

¹H NMR(CDCl₃) δ is 8.48(2H, s), 7.61(1H, d), 7.31-7.08(5H, m), 6.75(1H, d), 4.50-4.46(4H, m), 3.92(3H, s), 3.77(3H, s), 3.18(2H, t). Alkyl halide: 1-bromo-2-phenyl-ethane

Example 113 (Compound 113)

1- (2-benzyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method B): (m/z)432.1(MH +); RT ═ 4.70 minutes; purity (UV) 100%; alkyl halide: benzyl bromide

Example 114 (Compound 114)

1- (2-allyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method B): (m/z)382(MH +); RT ═ 4.34 minutes; purity (UV) 100%; alkyl halide: allyl bromide

Example 115 (Compound 115)

1- [2- (benzoxazol-2-ylmethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method B): (m/z)473(MH +); RT ═ 4.36 minutes; purity (UV) 100%; alkyl halide: 2- (chloromethyl) -1, 3-benzoxazoles

Example 116 (Compound 116)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methyl-thiazol-4-ylmethoxy) -phenyl ] -ethanone

LC/MS (method B): (m/z)453(MH +); RT ═ 4.02 min; purity (UV) 100%; alkyl halide: 4- (chloromethyl) -2-methylthiazole

Example 117 (Compound 117)

1- [2- (5-cyclopropyl- [1, 3, 4] thiadiazol-2-ylmethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method B): (m/z)480.1(MH +); RT ═ 3.86 minutes; purity (UV) 100%; alkyl halide: 2- (chloromethyl) -5-cyclopropyl- [1, 3, 4] thiadiazole

Example 118 (Compound 118)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- ([1, 2, 4] oxadiazol-3-ylmethoxy) -phenyl ] -ethanone LC/MS (method B): (m/z)424(MH +); RT ═ 3.65 minutes; purity (UV) 100%; alkyl halide: 3- (chloromethyl) - [1, 2, 4] oxadiazole

Example 119 (Compound 119)

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid ethyl ester

¹H NMR(CDCl₃)δ＝8.48(2H，s)，7.61(1H，d)，6.76(1H，d)，4.92(1H，s)，4.79(2H，s)，4.25(2H，q)，3.93(3H，s)，3.88(3H，s)，1.27(3H，t)。

Alkyl halide: bromoacetic acid ethyl ester

Example 120 (Compound 120)

1- {2- [2- (4-chloro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

¹H NMR(CDCl₃)δ＝8.49(2H，s)，7.61(1H，d)，7.23-7.18(4H，m)，6.75(1H，d)，4.45(2H，t)，4.37(2H，s)，3.93(3H，s)，3.77(3H，s)，3.14(2H，t)。

Alkyl halide: 4-chlorobenzyl chloride

Example 121 (Compound 121)

1- [2- (5-chloro-thiophen-2-ylmethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone LC/MS (method B): (m/z)474(MH +); RT ═ 5.01 min; purity (UV) 100%; alkyl halide: 5-chloro-2- (chloromethyl) -thiophene

Example 122 (Compound 122)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-phenoxy-ethoxy) -phenyl]-ethanones¹H NMR(CDCl₃)δ＝8.48(2H，s)，7.65(1H，d)，7.23(2H，t)，6.92(1H，t)，6.85(2H，d)，6.76(1H，d)，4.78(2H，s)，4.69-4.63(2H，m)，4.39-4.33(2H，m)，3.94(3H，s)，3.92(3H，s)。

Alkyl halide: 1-bromo-2-phenoxy-ethane

Example 123 (Compound 123)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-p-tolyl-ethoxy) -phenyl ] -ethanone LC/MS (method B): (m/z)460(MH +); RT ═ 5.29 minutes; purity (UV) 100%; alkyl halide: 1-bromo-2- (4-methylphenyl) -ethane

Example 124 (Compound 124)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-phenyl-propoxy) -phenyl]-ethanones¹H NMR(CDCl₃) δ is 8.49(2H, s), 7.59(1H, d), 7.22(5H, m), 6.75(1H, d), 4.69(2H, s), 4.28(2H, t), 3.93(3H, s), 3.88(3H, s), 2.85(2H, t), 2.21(2H, m). Alkyl halide: 1-bromo-3-phenyl-propane

Example 125 (Compound 125)

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (3-methoxy-phenyl) -ethoxy ] -phenyl } -ethanone

LC/MS (method B): (m/z)476.2(MH +); RT ═ 4.86 minutes; purity (UV) 100%; alkyl halide: 1-bromo-2- (3-methoxyphenyl) -ethane

Example 126 (Compound 126)

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (4-methoxy-phenyl) -ethoxy ] -phenyl } -ethanone

LC/MS (method B): (m/z)476.2(MH +); RT ═ 4.84 minutes; purity (UV) 100%; alkyl halide: 1-bromo-2- (4-methoxyphenyl) -ethane

Example 127 (Compound 127)

1- {2- [2- (3-bromo-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

¹H NMR(DMSO-d₆)δ＝8.62(2H，s)，7.54(2H，m)，7.26(3H，m)，6.97(1H，d)，4.43(2H，t)，4.36(2H，s)，3.88(3H，s)，3.70(3H，s)，3.14(2H，t)。

Alkyl halide: 1-bromo-2- (3-bromophenyl) -ethane

Example 128 (Compound 128)

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (2-methoxy-phenyl) -ethoxy ] -phenyl } -ethanone

LC/MS (method B): (m/z)476.2(MH +); RT ═ 5.08 minutes; purity (UV) 100%; alkyl halide: 1-bromo-2- (2-methoxyphenyl) -ethane

Example 129 (Compound 129)

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone

LC/MS (method B): (m/z)464.3(MH +); RT ═ 4.83 minutes; purity (UV) 100%; alkyl halide: 1-bromo-2- (4-fluorophenyl) -ethane

Example 130 (Compound 130)

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (2-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone

LC/MS (method B): (m/z)464.2(MH +); RT ═ 4.99 min; purity (UV) 100%; alkyl halide: 1-bromo-2- (2-fluorophenyl) -ethane

Example 131 (Compound 131)

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (3, 4-dimethoxy-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone

¹H NMR(DMSO-d₆)δ＝8.60(2H，s)，7.52(1H，d)，6.95(1H，d)，6.89(1H，d)，6.81(1H，d)，6.73(1H，d)，4.43(2H，t)，4.26(2H，s)，3.88(3H，s)，3.76(3H，s)，3.68(3H，s)，3.55(3H，s)，3.06(2H，t)。

Alkyl halide: 1-bromo-2- (3, 4-dimethoxyphenyl) -ethane

Example 132 (Compound 132)

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid benzyl ester

LC/MS (method B): (m/z)490.2(MH +); RT ═ 4.66 minutes; purity (UV) 100%; alkyl halide: bromoacetic acid benzyl ester

Example 133 (Compound 133)

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid isopropyl ester LC/MS (method B): (m/z)442.2(MH +); RT ═ 4.44 minutes; purity (UV) 100%; alkyl halide: bromoacetic acid isopropyl ester

Example 134 (Compound 134)

3- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzoic acid methyl ester

LC/MS (method A): (m/z)489.9(MH +); RT ═ 8.14 minutes; purity (UV) 100%; alkyl halide: 3-chloromethyl benzoic acid methyl ester

Example 135 (Compound 135)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methyl-butoxy) -phenyl ] -ethanone LC/MS (method a): (m/z)412(MH +); RT ═ 8.99 min; purity (UV) ═ 100%

Alkyl halide: 1-bromo-3-methyl-butane

Example 136 (Compound 136)

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hexyloxy-3, 4-dimethoxy-phenyl) -ethanone

LC/MS (method A): (m/z)395.9(MH +); RT ═ 9.42 minutes; purity (UV) 100%; alkyl halide: 1-bromo-hexane

Example 137 (Compound 137)

1- (2-but-3-enyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone LC/MS (method a): (m/z)395.9(MH +); RT ═ 8.27 minutes; purity (UV) 100%; alkyl halide: 4-bromo-but-1-ene

Example 138 (Compound 138)

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-pent-4-enyloxy-phenyl) -ethanone LC/MS (method a): (m/z)410(MH +); RT ═ 8.62 minutes; purity (UV) ═ 100%

Alkyl halide: 5-bromo-pent-1-enes

Example 139 (Compound 139)

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-propoxy-phenyl) -ethanone

LC/MS (method A): (m/z)383.9(MH +); RT ═ 8.34 minutes; purity (UV) 100%; alkyl halide: 1-iodo-propane

Example 140 (Compound 140)

1- (2-butoxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)397.9(MH +); RT ═ 8.72 minutes; purity (UV) 100%; alkyl halide: 1-iodo-butane

Example 141 (Compound 141)

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-isobutoxy-3, 4-dimethoxy-phenyl) -ethanone

LC/MS (method A): (m/z)397.9(MH +); RT ═ 8.72 minutes; purity (UV) 100%; alkyl halide: 1-iodo-2-methyl-propane

Example 142 (Compound 142)

4- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -butyric acid ethyl ester

LC/MS (method A): (m/z)456(MH +); RT ═ 7.89 minutes; purity (UV) 100%; alkyl halide: 4-bromo-butyric acid ethyl ester

Example 143 (Compound 143)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (4-methyl-benzyloxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)445.9(MH +); RT ═ 8.69 minutes; purity (UV) ═ 97.1%; alkyl halide: 4-methyl-benzyl chloride

Example 144 (Compound 144)

1- [2- (3-chloro-benzyloxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)465.9(MH +); RT ═ 8.69 minutes; purity (UV) 100%; alkyl halide: 3-chloro-benzyl chloride

Example 145 (Compound 145)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-phenoxy-propoxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)476(MH +); RT ═ 8.59 minutes; purity (UV) 98.2%; alkyl halide: (3-bromo-propoxy) -benzene

Example 146 (Compound 146)

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (4-methoxy-phenyl) -2-oxo-ethoxy ] -phenyl } -ethanone

LC/MS (method A): (m/z)490(MH +); RT ═ 7.74 minutes; purity (UV) ═ 97.1%; alkyl halide: 2-bromo-1- (4-methoxy-phenyl) -ethanones

Example 147 (Compound 147)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzonitrile

LC/MS (method A): (m/z)456.9(MH +)(ii) a RT ═ 7.81 minutes; purity (UV) ═ 97.1%.¹H NMR(DMSO-d₆)δ＝8.60(2H，s)，7.91(1H，d)，7.81(1H，d)，7.78(1H，t)，7.59(1H，t)，7.55(1H，d)，7.02(1H，d)，5.43(2H，s)，4.50(2H，s)，3.92(3H，s)，3.81(3H，s)。

Alkyl halide: 2-chloromethyl-benzonitrile

Example 148 (Compound 148)

4- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzonitrile

LC/MS (method A): (m/z)456.9(MH +); RT ═ 7.82 minutes; purity (UV) 98.5%; alkyl halide: 4-chloromethyl-benzonitrile

Example 149 (Compound 149)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (naphthalen-2-ylmethoxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)481.9(MH +); RT ═ 8.86 minutes; purity (UV) ═ 77.3%; alkyl halide: 2-bromomethyl-naphthalene

Example 150 (Compound 150)

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-pentoxy-phenyl) -ethanone

LC/MS (method A): (m/z)411.9(MH +); RT ═ 9.06 minutes; purity (UV) 100%; alkyl halide: 1-iodo-pentane

Example 151 (Compound 151)

1- (2-cyclohexylmethoxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)438(MH +); RT ═ 9.59 minutes; purity (UV) 100%; alkyl halide: bromomethyl-cyclohexane

Example 152 (Compound 152)

3- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzonitrile

LC/MS (method A): (m/z)456.9(MH +); RT ═ 7.81 minutes; purity (UV) 96.5%; alkyl halide: 3-chloromethyl-benzonitrile

Example 153 (Compound 153)

1- {2- [2- (4-chloro-phenoxy) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)495.9(MH +); RT ═ 8.56 minutes; purity (UV) 100%; alkyl halide: 1- (2-bromo-ethoxy) -4-chloro-benzene

Example 154 (Compound 154)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-ethyl-butoxy) -3, 4-dimethoxy-phenyl ] -ethanone

LC/MS (method A): (m/z)426(MH +); RT ═ 9.39 minutes; purity (UV) ═ 92.5%

Alkyl halide: 1-iodo-2-ethyl-butane

Example 155 (Compound 155)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-hydroxy-ethoxy) -3, 4-dimethoxy-phenyl ] -ethanone LC/MS (method a): (m/z)385.9(MH +); RT ═ 6.22 minutes; purity (UV) ═ 88.0%

Alkyl halide: 1-iodo-2-hydroxy-ethane

Example 156 (Compound 156)

4- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzoic acid methyl ester

LC/MS (method A): (m/z)489.9(MH +); RT ═ 8.17 minutes; purity (UV) ═ 89.6%; alkyl halide: 4-chloromethyl benzoic acid methyl ester

Example 157 (Compound 157)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-naphthalen-2-yl-2-oxo-ethoxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)509.9(MH +); RT ═ 8.41 minutes; purity (UV) ═ 89.9%; alkyl halide: 2-bromo-1-naphthalen-2-yl-ethanones

Example 158 (Compound 158)

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (2, 5-dimethoxy-phenyl) -2-oxo-ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone

LC/MS (method A): (m/z)519.9(MH +); RT ═ 7.99 min; purity (UV) ═ 95.7%; alkyl halide: 2-bromo-2, 5-dimethoxy-phenyl-ethanone

Example 159 (Compound 159)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-oxo-2-p-tolyl-ethoxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)473.9(MH +); RT ═ 8.11 minutes; purity (UV) ═ 88.1%; alkyl halide: 2-bromo-1-p-tolyl-ethanone

Example 160 (Compound 160)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (4-fluoro-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone

LC/MS (method A): (m/z)449.9(MH +); RT ═ 8.32 minutes; purity (UV) 100%; alkyl halide: 4-fluoro-benzyl chloride

Example 161 (Compound 161)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-fluoro-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone

LC/MS (method A): (m/z)449.9(MH +); RT ═ 8.34 minutes; purity (UV) ═ 95.7%; alkyl halide: 2-fluoro-benzyl chloride

Example 162 (Compound 162)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-trifluoromethyl-benzyloxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)499.9(MH +); RT ═ 8.61 min; purity (UV) 98.9%; alkyl halide: 5-trifluoromethyl-benzyl chloride

Example 163 (Compound 163)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-trifluoromethoxy-benzyloxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)515.9(MH +); RT ═ 8.72 minutes; purity (UV) 98.9%; alkyl halide: 5-trifluoromethoxy-benzyl chloride

Example 164 (Compound 164)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (3-fluoro-5-trifluoromethyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone

LC/MS (method A): (m/z)558.9(MH +); RT ═ 8.71 minutes; purity (UV) 98.9%; alkyl halide: 3-fluoro-5-trifluoromethyl-benzyl chloride

Example 165 (Compound 165)

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (2-methoxy-phenyl) -2-oxo-ethoxy ] -phenyl } -ethanone

LC/MS (method A): (m/z)490(MH +); RT ═ 7.96 minutes; purity (UV) ═ 95.8%; alkyl halide: 2-bromo-1- (2-methoxy-phenyl) -ethanones

Example 166 (Compound 166)

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (2, 4-dimethyl-phenyl) -2-oxo-ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone

LC/MS (method A): (m/z)487.9(MH +); RT ═ 8.49 minutes; purity (UV) ═ 99.1%; alkyl halide: 2-bromo-1- (2, 4-dimethyl-phenyl) -ethanones

Example 167 (Compound 167)

1- [2- (4-chloro-benzyloxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)465.9(MH +); RT ═ 8.72 minutes; purity (UV) 98.5%; alkyl halide: 4-chloro-benzyl chloride

Example 168 (Compound 168)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-difluoromethoxy-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone

LC/MS (method A): (m/z)497.8(MH +); RT ═ 8.19 minutes; purity (UV) 98.5%; alkyl halide: 2-difluoromethoxy-benzyl chloride

Example 169 (Compound 169)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (4-isopropyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone

LC/MS (method A): (m/z)474(MH +); RT ═ 9.21 minutes; purity (UV) 100%; alkyl halide: 4-isopropyl-benzyl chloride

Example 170 (Compound 170)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-fluoro-6-trifluoromethyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone

LC/MS (method A): (m/z)517.9(MH +); RT ═ 8.52 minutes; purity (UV) 98.9%; alkyl halide: 2-fluoro-6-trifluoromethyl-benzyl chloride

Example 171 (Compound 171)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2, 3-difluoro-4-methyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone

LC/MS (method A): (m/z)481.9(MH +); RT ═ 8.71 minutes; purity (UV) 98.6%; alkyl halide: 2, 3-difluoro-4-methyl-benzyl chloride

Example 172 (Compound 172)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methyl-benzyloxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)445.9(MH +); RT ═ 8.67 min; purity (UV) 98.5%; alkyl halide: 2-methyl-benzyl chloride

Example 173 (Compound 173)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methyl-benzyloxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)446(MH +); RT ═ 8.69 minutes; purity (UV) 98.4%; alkyl halide: 3-methyl-benzyl chloride

Example 174 (Compound 174)

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-pent-2-enyloxy-phenyl) -ethanone

LC/MS (method A): (m/z)409.9(MH +); RT ═ 8.67 min; purity (UV) 98.3%; alkyl halide: 1-bromo-pent-2-enes

Example 175 (Compound 175)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methyl-quinolin-6-ylmethoxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)497(MH +); RT ═ 5.27 minutes; purity (UV) ═ 98.1%

Alkyl halide: 6-bromomethyl-2-methyl-quinolines

Example 176 (Compound 176)

1- [2- (2-chloro-benzyloxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)465.9(MH +); RT ═ 8.71 minutes; purity (UV) 96.3%; alkyl halide: 2-chloro-benzyl chloride

Example 177 (Compound 177)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methoxy-benzyloxy) -phenyl ] -ethanone LC/MS (method a): (m/z)461.9(MH +); RT ═ 8.26 min; purity (UV) 96.3%; alkyl halide: 3-methoxy-benzyl chloride

Example 178 (Compound 178)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (4-methoxy-benzyloxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)461.9(MH +); RT ═ 8.22 minutes; purity (UV) ═ 77.9%; alkyl halide: 4-methoxy-benzyl chloride

Example 179 (Compound 179)

1- {2- [2- (3-chloro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)479.9(MH +); RT ═ 8.81 minutes; purity (UV) 98.6%; alkyl halide: 1-bromo-2- (3-chloro-phenyl) -ethane

Example 180 (Compound 180)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (5-methyl-hexyloxy) -phenyl ] -ethanone

LC/MS (method A): (m/z)440(MH +); RT ═ 9.69 minutes; purity (UV) 100%; alkyl halide: 1-bromo-5-methyl-hexane

Example 181 (Compound 181)

1- [2- (2-cyclohexyl-ethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone LC/MS (method a): (m/z)452(MH +); RT 9.92 min; purity (UV) ═ 97.7%; alkyl halide: (2-bromo-ethyl) -cyclohexane

Example 182 (Compound 182)

5- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -pentanoic acid ethyl ester

LC/MS (method A): (m/z)470(MH +); RT ═ 8.11 minutes; purity (UV) 100%; alkyl halide: 4-bromo-pentanoic acid ethyl ester

Example 183 (Compound 183)

1- [2- (3-benzyloxy-propoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)490(MH +); RT ═ 8.64 min; purity (UV) ═ 97.5%; alkyl halide: (3-bromo-propoxymethyl) -benzene

Example 184 (Compound 184)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

¹H NMR(DMSO-d₆)δ＝8.64(2H，s)，7.67-7.58(2H，m)，7.37(1H，bs)，6.98(1H，d)，4.79(2H，s)，4.62(2H，s)，3.90(3H，s)，3.80(3H，s)。

Alkyl halide: 2-chloro-acetamide

Example 185 (Compound 185)

2- (2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -ethyl) -isoindole-1, 3-dione

¹H NMR(CDCl₃)δ＝8.36(2H，s)，7.74(2H，m)，7.60(3H，m)，6.75(1H，d)，4.52(2H，t)，4.48(2H，s)，4.21(2H，t)，3.91(3H，s)，3.83(3H，s)。

Alkyl halide: 2- (2-bromo-ethyl) -isoindole-1, 3-dione

Example 186 (Compound 186)

2- (3- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -propyl) -isoindole-1, 3-dione

¹H NMR(CDCl₃) δ is 8.48(2H, s), 7.81(2H, m), 7.70(2H, m), 7.59(1H, d), 6.75(1H, d), 4.67(2H, s), 4.31(2H, t), 3.96(2H, t), 3.93(3H, s), 3.89(3H, s), 2.30(2H, m). Alkyl halide: 2- (3-bromo-propyl) -isoindole-1, 3-dione

Example 187 (Compound 187)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-methyl-acetamide

¹H NMR(CDCl₃)δ＝8.52(2H，s)，7.75-7.64(2H，m)，6.79(1H，d)，4.67(2H，s)，4.60(2H，s)，3.96(3H，s)，3.87(3H，s)，2.86(3H，d)。

Alkyl halide: 2-chloro-N-methyl-acetamide

Example 305 (Compound 305)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-ethyl-acetamide

¹H NMR(DMSO-d₆) δ is 8.64(2H, s), 8.18(1H, bs), 7.61(1H, d), 6.99(1H, d), 4.77(2H7s), 4.62(2H, s), 3.91(3H, s), 3.79(3H, s), 3.15(2H, m), 1.01(3H, t). Alkyl halide: 2-chloro-N-ethyl-acetamide

General procedure for the preparation of Compounds of formula Ii or Ij, wherein R₂As defined above:

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-hydroxy-2, 4-methoxy-phenyl) -ethanone (0.035) from example 2(Ii)mmol) or 1- (2-allyloxy-3-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone from example 3(Ij) (0.035mmol) was dissolved in anhydrous 3-pentanone (0.4 mL). Adding solid K₂CO₃(0.052mmol) and then 0.052mmol of alkyl bromide or iodide dissolved in 3-pentanone (0.1mL) is added. In the case of alkyl bromides, KI (0.5 equivalent) is additionally added. The reaction mixture was heated to 70 ℃ for 18 hours. The sample was filtered and the solvent removed in vacuo. The reaction mixture was re-dissolved in DMSO and then purified by standard preparative HPLC to afford the pure compound.

Using this method the following compounds were obtained:

example 188 (Compound 188)

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-2, 4-dimethoxy-phenyl) -ethanone

LC/MS (method B): (m/z)370(MH +); RT ═ 4.45 minutes; purity (UV) 100%; alkyl halide: iodothane

Example 189 (Compound 189)

1- (3-cyclopropylmethoxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method B): (m/z)396.1(MH +); RT ═ 4.78 minutes; purity (UV) 100%; alkyl halide: bromomethyl-cyclopropane

Example 190 (Compound 190)

1- (2-allyloxy-3-but-3-enyloxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method B (m/z)422.1(MH +), RT 5.27 min; purity (UV) 100%

Alkyl halide: 4-bromo-but-1-ene

Example 191 (Compound 191)

1- (3-but-3-enyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)396.3(MH +); RT ═ 8.39 minutes; purity (UV) 94.0%; alkyl halide: 4-bromo-but-1-ene

Example 192 (Compound 192)

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-propoxy-phenyl) -ethanone

LC/MS (method A): (m/z)384.3(MH +); RT ═ 8.42 minutes; purity (UV) 100%; alkyl halide: 1-iodoethane

Example 193 (Compound 193)

1- (3-allyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)382.3(MH +); RT ═ 8.01 min; purity (UV) 100%; alkyl halide: allyl bromide

Example 194 (Compound 194)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2, 4-dimethoxy-3- (4-methyl-pent-3-enyloxy) -phenyl ] -ethanone LC/MS (method a): (m/z)424.3(MH +); RT ═ 8.99 min; purity (UV) 100%; alkyl halide: 5-bromo-2-methyl-pent-2-ene

Example 195 (Compound 195)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3- (2-hydroxy-ethoxy) -2, 4-dimethoxy-phenyl ] -ethanone

LC/MS (method A): (m/z)386.3(MH +); RT ═ 6.21 minutes; purity (UV) 70.5%; alkyl halide: 2-iodo-ethanol

Example 196 (Compound 196)

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-phenethyloxy-phenyl) -ethanone LC/MS (method a): (m/z)446.2(MH +); RT ═ 8.71 minutes; purity (UV) ═ 82.0%; alkyl halide: 2-phenyl-1-bromo-ethane

Example 197 (Compound 197)

1- (3-benzyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method A): (m/z)432.2(MH +); RT ═ 8.49 minutes; purity (UV) 96.3%; alkyl halide: benzyl bromide

Example 198 (Compound 198)

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-pent-2-enyloxy-phenyl) -ethanone LC/MS (method a): (m/z)410.3(MH +); RT ═ 8.67 min; purity (UV) 91.9%; alkyl halide: 1-bromo-pent-2-enes

Example 199 (Compound 199)

2- (3, 5-dichloro-pyridin-4-yl) -1- [2, 4-dimethoxy-3- (2-methoxy-ethoxy) -phenyl ] -ethanone LC/MS (method a): (m/z)400.3(MH +); RT ═ 7.34 minutes; purity (UV) ═ 91.6%; alkyl halide: 1-bromo-2-methoxy-ethane

Example 200 (Compound 200)

1- (3-but-2-ynyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone LC/MS (method a): (m/z)394.3(MH +); RT ═ 7.81 minutes; purity (UV) 100%; alkyl halide: 1-bromo-but-2-yne

Example 201 (Compound 201)

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-prop-2-ynyloxy-phenyl) -ethanone LC/MS (method a): (m/z)380.2(MH +); RT ═ 7.44 minutes; purity (UV) 100%; alkyl halide: 3-bromo-propyne

Preparation 4/example 273 (Compound 504)

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hydroxy-3, 4-methoxy-phenyl) -ethanone (1.37g, 4.1mmol) obtained from example 1 was dissolved in anhydrous NMP (50 mL). Ethyl bromoacetate (660. mu.L, 6.1mmol) was added followed by K₂CO₃(830mg, 6.1mmol) and the reaction mixture was stirred at room temperature overnight. Water (500mL) was added and the product was extracted with EtOAc (2X 250 mL). The combined organic phases were washed with water (250mL), brine (250mL) and MgSO₄And (5) drying. The solvent was removed in vacuo and the pure product, {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -was obtained by standard silica gel chromatography]-2, 3-dimethoxy-phenoxy } -acetic acid ethyl ester as white solid. Yield 990mg (78%). The compound was redissolved in MeOH-water (1: 1, 200mL) by heating. LiOH (490mg, 12mmol, 5 equiv.) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified to pH 1 by addition of 1N HCl (15mL) and extracted with EtOAc (2 × 250 mL). The combined organic phases were washed with brine (250mL) and MgSO₄And (5) drying. The solvent was removed in vacuo to give {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl [)]-2, 3-dimethoxy-phenoxy } -acetic acid as a white solid.¹H NMR(CDCl₃) δ is 8.52(2H, s), 7.76(1H, d), 6.81(1H, d), 4.85(2H, s), 4.66(2H, s), 3.99(3H, s), 3.88(3H, s). Yield 0.85g (92%).

General procedure for the preparation of Compounds of formula Ik, wherein R₉And R₁₂As defined herein:

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid (0.037mmol) obtained from preparation 4 was dissolved in anhydrous DMF (0.25 mL). Primary or secondary amines (0.045mmol) in DMF (0.05mL) were added followed by HATU (0.045mmol) in DMF (0.050 mL). The reaction mixture was left at room temperature for 48 hours. Purification by standard preparative HPLC gave pure compound.

Using this method the following compounds were obtained:

example 202 (Compound 202)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl ] -ethanone

¹H NMR(CDCl₃)δ＝8.47(2H，s)，7.64(1H，d)，6.76(1H，d)，4.92(2H，s)，4.88(2H，s)，3.94(3H，s)，3.89(3H，s)，3.53(2H，t)，3.39(2H，t)，1.98(2H，m)，1.86(2H，m)。

Amine: a pyrrolidine.

Example 203 (Compound 203)

N-benzyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

¹H NMR(CDCl₃)δ＝8.49(2H，s)，8.12(1H，bs)，7.66(1H，d)，7.29-7.20(5H，m)，6.77(1H，d)，4.72(2H，s)，4.55(2H，s)，4.50(2H，d)，3.95(3H，s)，3.81(3H，s)。

Amine: benzylamine

Example 204 (Compound 204)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-morpholin-4-yl-2-oxo-ethoxy) -phenyl ] -ethanone

¹H NMR(CDCl₃)δ＝8.48(2H，s)，7.63(1H，d)，6.78(1H，d)，4.96(2H，s)，4.80(2H，s)，3.94(3H，s)，3.89(3H，s)，3.72-3.61(6H，m)，3.54-3.45(2H，m)。

Amine: morpholine

Example 205 (Compound 205)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-phenyl-acetamide

¹H NMR(CDCl₃)δ＝9.97(1H，bs)，8.50(2H，s)，7.75(1H，d)，7.59(2H，d)，7.25(2H，t)，7.07(1H，t)，6.81(1H，d)，4.80(2H，s)，4.65(2H，s)，3.99(3H，s)，3.89(3H，s)。

Amine: aniline

Example 206 (Compound 206)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-methyl-N-phenyl-acetamide

¹H NMR(CDCl₃)δ＝8.48(2H，s)，7.59(1H，d)，7.45-7.32(3H，m)，7.25-7.19(2H，m)，6.70(1H，d)，4.83(2H，s)，4.68(2H，s)，3.90(3H，s)，3.77(3H，s)，3.32(3H，s)。

Amine: n-methylaniline

Example 207 (Compound 207)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-hydroxy-3-methyl-butyl) -acetamide

LC/MS (method A): (m/z)485(MH +); RT ═ 5.89 minutes; purity (UV) 100%; amine: 3-hydroxy-3-methyl-butylamine

Example 208 (Compound 208)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide

LC/MS (method A): (m/z)441(MH +); RT ═ 6.71 minutes; purity (UV) ═ 89.3%¹H NMR(CDCl₃)δ＝8.51(2H，s)，7.79(1H，bs)，7.67(1H，d)，6.78(1H，d)，4.67(2H，s)，4.60(2H，s)，3.97(3H，s)，3.87(3H，s)，3.27(2H，q)，1.50(2H，m)，0.87(3H，t)。

Amine: n-propylamine

Example 209 (Compound 209)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-isopropyl-acetamide

LC/MS (method A): (m/z)441(MH +); RT ═ 6.72 minutes; purity (UV) ═ 87.7%

¹H NMR(DMSO-d₆)δ＝8.64(2H，s)，8.01(1H，d)，7.65(1H，d)，6.99(1H，d)，4.77(2H，s)，4.61(2H，s)，3.91(4H，m)，3.80(3H，s)，1.04(6H，d)

Amine: isopropyl amine

Example 210 (Compound 210)

N-butyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

LC/MS (method A): (m/z)455(MH +); RT ═ 7.09 minutes; purity (UV) 100%; amine: butyl amine

Example 211 (Compound 211)

N-cyclopentyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

LC/MS (method A): (m/z)466.9(MH +); RT ═ 7.19 minutes; purity (UV) 100%; amine: cyclopentylamine

Example 212 (Compound 212)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-methyl-butyl) -acetamide

LC/MS (method A): (m/z)469(MH +); RT ═ 7.42 minutes; purity (UV) 100%; amine: 3-methyl-butylamine

Example 213 (Compound 213)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-methoxy-benzyl) -acetamide

¹H NMR(DMSO-d₆)δ＝8.67(1H，t)，8.64(2H，s)，7.61(1H，d)，7.15(2H，d)，6.99(1H，d)，6.75(2H，d)，4.75(2H，s)，4.70(2H，s)，4.26(2H，d)，3.90(3H，s)，3.76(3H，s)，3.70(3H，s)

Amine: 4-methoxy-benzylamines

Example 214 (Compound 214)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2, 2-dimethyl-propyl) -acetamide

LC/MS (method A): (m/z)469(MH +); RT ═ 7.44 minutes; purity (UV) 100%; amine: 2, 2-dimethyl-propylamine

Example 215 (Compound 215)

N-cyclohexyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

LC/MS (method A): (m/z)481(MH +); RT ═ 7.52 minutes; purity (UV) 100%; amine: cyclohexylamine

Example 216 (Compound 216)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-methoxy-benzyl) -acetamide

¹H NMR(DMSO-d₆)δ＝8.72(1H，t)，8.63(2H，s)，7.60(1H，d)，7.12(1H，t)，6.99(1H，d)，6.83-6.74(3H，m)，4.75(2H，s)，4.73(2H，s)，4.30(2H，d)，3.90(3H，s)，3.78(3H，s)，3.69(3H，s)。

Amine: 3-methoxy-benzylamines

Example 217 (Compound 217)

N-cycloheptyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

LC/MS (method A): (m/z)495(MH +); RT ═ 7.84 minutes; purity (UV) 92.2%; amine: cycloheptylamine

Example 218 (Compound 218)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-methoxy-benzyl) -acetamide

¹H NMR(DMSO-d₆)δ＝8.64(2H，s)，8.50(1H，t)，7.62(1H，d)，7.19(1H，t)，7.12(1H，d)，6.99(1H，d)，6.93(1H，d)，6.76(1H，t)，4.78(2H，s)，4.74(2H，s)，4.31(2H，d)，3.91(3H，s)，3.79(3H，s)，3.76(3H，s)。

Amine: 2-methoxy-benzylamines

Example 219 (Compound 219)

N-cyclohexylmethyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

LC/MS (method A): (m/z)495(MH +); RT ═ 7.86 minutes; purity (UV) ═ 100%

Amine: cyclohexylmethylamine

Example 220 (Compound 220)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-ethyl) -acetamide

LC/MS (method A): (m/z)442.9(MH +); RT ═ 5.41 minutes; purity (UV) 100%; amine: 2-hydroxy-ethylamine

Example 221 (Compound 221)

(R) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (1-phenyl-ethyl) -acetamide

LC/MS (method A): (m/z)502.9(MH +); RT ═ 7.37 minutes; purity (UV) 100%; amine: (R) -1-phenyl-ethylamine

Example 222 (Compound 222)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-hydroxy-propyl) -acetamide

LC/MS (method A): (m/z)457(MH +); RT ═ 5.51 minutes; purity (UV) 100%; amine: 3-hydroxy-propylamine

Example 223 (Compound 223)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-methoxy-ethyl) -acetamide

LC/MS (method A): (m/z)457(MH +); RT ═ 6.12 minutes; purity (UV) ═ 100%

Amine: 2-methoxy-ethylamine

Example 224 (Compound 224)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-dimethylamino-ethyl) -acetamide

LC/MS (method A): (m/z)470(MH +); RT ═ 4.26 min; purity (UV) 100%; amine: 2-dimethylamino-ethylamine

Example 225 (Compound 225)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-dimethylamino-propyl) -acetamide

LC/MS (method A): (m/z)484(MH +); RT ═ 4.29 minutes; purity (UV) 100%; amine: 3-dimethylamino-propylamine

Example 226 (Compound 226)

(S) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (1-phenyl-ethyl) -acetamide

LC/MS (method A): (m/z)503(MH +); RT ═ 7.39 minutes; purity (UV) 100%; amine: (S) -1-phenyl-ethylamine

Example 227 (Compound 227)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-isopropoxy-propyl) -acetamide

LC/MS (method A): (m/z)498.9(MH +); RT ═ 6.89 minutes; purity (UV) 100%; amine: 3-isopropoxy-propylamine

Example 228 (Compound 228)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-furan-2-ylmethyl-acetamide

LC/MS (method A): (m/z)478.9(MH +); RT ═ 6.74 minutes; purity (UV) 100%; amine: furan-2-yl-methylamines

Example 229 (Compound 229)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-pyridin-2-ylmethyl-acetamide

LC/MS (method A): (m/z)490(MH +); RT ═ 5.17 minutes; purity (UV) 100%; amine: pyridin-2-yl-methylamines

Example 230 (Compound 230)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-pyridin-3-ylmethyl-acetamide

LC/MS (method A): (m/z)490(MH +); RT ═ 4.62 minutes; purity (UV) 100%; amine: pyridin-3-yl-methylamines

Example 231 (Compound 231)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-phenoxy-ethyl) -acetamide

LC/MS (method A): (m/z)518.9(MH +); RT ═ 7.19 minutes; purity (UV) 98.3%; amine: 2-phenoxy-ethylamine

Example 232 (Compound 232)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-pyridin-4-ylmethyl-acetamide

LC/MS (method A): (m/z)490(MH +); RT ═ 4.46 minutes; purity (UV) ═ 100%

Amine: pyridin-4-yl-methylamines

Example 233 (Compound 233)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-ethyl-benzyl) -acetamide

LC/MS (method A): (m/z)517(MH +); RT ═ 7.71 minutes; purity (UV) 96.8%; amine: 4-Ethyl-benzylamine

Example 234 (Compound 234)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3, 5-difluoro-benzyl) -acetamide

LC/MS (method A): (m/z)524.9(MH +); RT ═ 7.27 minutes; purity (UV) 95.3%; amine: 3, 5-difluoro-benzylamines

Example 235 (Compound 235)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2, 3-difluoro-benzyl) -acetamide

LC/MS (method A): (m/z)524.9(MH +); RT ═ 7.22 minutes; purity (UV) 100%; amine: 2, 3-difluoro-benzylamines

Example 236 (Compound 236)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyridin-2-yl-ethyl) -acetamide

LC/MS (method A): (m/z)503.9(MH +); RT ═ 4.54 minutes; purity (UV) 100%; amine: 2-pyridin-2-yl-ethylamine

Example 237 (Compound 237)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-methyl-benzyl) -acetamide

LC/MS (method A): (m/z)503(MH +); RT ═ 7.37 minutes; purity (UV) 100%; amine: 2-methyl-benzylamine

Example 238 (Compound 238)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-fluoro-benzyl) -acetamide

LC/MS (method A): (m/z)506.9(MH +); RT ═ 7.14 minutes; purity (UV) 100%; amine: 3-fluoro-benzylamines

Example 239 (Compound 239)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-methyl-benzyl) -acetamide

LC/MS (method A): (m/z)503(MH +); RT ═ 7.39 minutes; purity (UV) 100%; amine: 3-methyl-benzylamine

Example 240 (Compound 240)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-methyl-benzyl) -acetamide

LC/MS (method A): (m/z)502.9(MH +); RT ═ 7.39 minutes; purity (UV) ═ 100%

Amine: 4-methyl-benzylamine

Example 241 (Compound 241)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-phenethyl-acetamide

LC/MS (method A): (m/z)503(MH +); RT ═ 7.29 minutes; purity (UV) 100%; amine: 2-phenyl-ethylamine

Example 242 (Compound 242)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyridin-4-yl-ethyl) -acetamide

¹H NMR(DMSO-d₆) δ is 8.65(2H, s), 8.44(2H, d), 8.33(1H, t), 7.60(1H, d), 7.30(2H, d), 6.99(1H, d), 4.74(2H, s), 4.62(2H, s), 3.90(3H, s), 3.75(3H, s), 3.44(2H, q), 2.81(2H, t). Amine: 2-pyridin-4-yl-ethylamine

Example 243 (Compound 243)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-phenyl-propyl) -acetamide

LC/MS (method A): (m/z)517(MH +); RT ═ 7.56 minutes; purity (UV) ═ 100%

Amine: 3-phenyl-propylamines

Example 244 (Compound 244)

N- (2-chloro-benzyl) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

LC/MS (method A): (m/z)522.9(MH +); RT ═ 7.46 minutes; purity (UV) 100%; amine: 2-chloro-benzylamine

Example 245 (Compound 245)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-piperidin-1-yl-ethyl) -acetamide

LC/MS (method A): (m/z)510(MH +); RT ═ 4.46 minutes; purity (UV) 92.5%; amine: 2-piperidin-1-yl-ethylamines

Example 246 (Compound 246)

N- (3-chloro-benzyl) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

LC/MS (method A): (m/z)522.8(MH +); RT ═ 7.46 minutes; purity (UV) 100%; amine: 3-chloro-benzylamine

Example 247 (Compound 247)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-morpholin-4-yl-ethyl) -acetamide

LC/MS (method A): (m/z)512(MH +); RT ═ 4.31 minutes; purity (UV) ═ 98.1%

Amine: 2-morpholin-4-yl-ethylamine

Example 248 (Compound 248)

N- (4-chloro-benzyl) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

LC/MS (method A): (m/z)522.9(MH +); RT ═ 7.49 minutes; purity (UV) 98.7%; amine: 4-chloro-benzylamine

Example 249 (Compound 249)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyridin-3-yl-ethyl) -acetamide

LC/MS (method A): (m/z)504(MH +); RT ═ 4.47 minutes; purity (UV) 100%; amine: 2-pyridin-3-yl-ethylamine

Example 250 (Compound 250)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyrrolidin-1-yl-ethyl) -acetamide

LC/MS (method A): (m/z)496(MH +); RT ═ 4.37 minutes; purity (UV) 100%; amine: 2-pyrrolidin-1-yl-ethylamine

Example 251 (Compound 251)

N- (2-acetylamino-ethyl) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

LC/MS (method A): (m/z)484(MH +); RT ═ 5.31 minutes; purity (UV) ═ 100%

Amine: 2-acetylamino-ethylamine

Example 252 (Compound 252)

(R) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-2-phenyl-ethyl) -acetamide

LC/MS (method A): (m/z)518.9(MH +); RT ═ 6.47 minutes; purity (UV) ═ 73.4%; amine: (R) -2-hydroxy-2-phenyl-ethylamine

Example 253 (Compound 253)

(S) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-2-phenyl-ethyl) -acetamide

LC/MS (method A): (m/z)519(MH +); RT ═ 6.47 minutes; purity (UV) ═ 73.8%; amine: (S) -2-hydroxy-2-phenyl-ethylamine

Example 254 (Compound 254)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-thiophen-2-ylmethyl-acetamide

LC/MS (method A): (m/z)494.9(MH +); RT ═ 6.97 minutes; purity (UV) 100%; amine: thien-2-yl-methylamines

Example 255 (Compound 255)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -acetamide

LC/MS (method A): (m/z)524(MH +); RT ═ 5.66 minutes; purity (UV) ═ 95.7%; amine: 3- (2-oxo-pyrrolidin-1-yl) -propylamine

Example 256 (Compound 256)

(2R) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-indan-1-yl) -acetamide

LC/MS (method A): (m/z)530.8(MH +); RT ═ 6.62 minutes; purity (UV) 90.4%; amine: (2R) -2-hydroxy-indan-1-yl-amines

Example 257 (Compound 257)

N-cycloheptylmethyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

LC/MS (method A): (m/z)509(MH +); RT ═ 8.19 minutes; purity (UV) 100%; amine: cycloheptylmethyl amine

Example 258 (Compound 258)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- [2- (2-hydroxy-ethoxy) -ethyl ] -acetamide

LC/MS (method A): (m/z)487(MH +); RT ═ 5.41 minutes; purity (UV) 100%; amine: 2- (2-hydroxy-ethoxy) -ethylamine

Example 259 (Compound 259)

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-dimethylamino-butyl) -acetamide

LC/MS (method A): (m/z)497.9(MH +); RT ═ 4.36 minutes; purity (UV) 100%; amine: 4-dimethylamino-butylamine

Preparation 5 (Compound 505)

Resin-bound 2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-dihydroxy-4-methoxy-phenyl) -ethanones

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-dihydroxy-4-methoxy-phenyl) -ethanone (530mg, 1.6mmol) from preparation 3 was dissolved in anhydrous NMP (5mL) and K was added₂CO₃(210mg, 1.5mmol) followed by bromomethyl-Wang's resin (560mg, L-1.45 mmol/g, 0.81 mmol). The reaction mixture was vortexed overnight at room temperature. The resin was filtered and washed with MeOH: water (4: 1, 3X 10mL), NMP (3X 25mL), MeOH (3X 25mL), dry THF (5X 25mL), and dried in vacuo to give 760mg of resin-bound 2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-dihydroxy-4-methoxy-phenyl) -ethanone.

General procedure for the preparation of Compounds of formula Im, wherein R₂As defined above:

resin-bound 2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-dihydroxy-4-methoxy-phenyl) -ethanone obtained from preparation 5 (90mg, L ═ 1.07mmol/g, 0.1mmol) was treated with 1mL of a stock of R2-OH (0.5mmol) and PBu3(0.5mmol) cooled to 0 ℃, followed by 0.5mL of TBAD (0.5 mmol). After 3 hours at room temperature, the reaction mixture was filtered and 1mL of R2-OH (0.5mmol) and PBu were added₃(0.5mmol) of the stock solution. After cooling to 0 ℃ 0.5mL of TBAD (0.5mmol) stock was added. The reaction mixture was vortexed overnight at room temperature. The resin was washed with THF (5X 3mL) and DCE (5X 3 mL). The product was cleaved by addition of DCE-TFA-TIS (90: 10: 1, 1mL) stock. After 30 minutes, the original lysis solution was replaced by 1mL of fresh lysis solution. After a further 30 minutes, the combined lysis solutions were evaporated in vacuo. The reaction mixture was re-dissolved in DMSO and then purified by standard preparative HPLC to afford the pure compound.

Using this method the following compounds were obtained:

example 260 (Compound 260)

1- (3-cyclopentyloxy-2-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone LC/MS (method B): (m/z)396(MH +); RT ═ 4.84 minutes; purity (UV) ═ 100% alcohol: cyclopentanol

Example 261 (Compound 261)

1- (3-cyclopropylmethoxy-2-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method B): (m/z)382.1(MH +); RT ═ 4.36 minutes; purity (UV) ═ 100%

Alcohol: cyclopropyl carbinols

Example 262 (Compound 262)

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-2-hydroxy-4-methoxy-phenyl) -ethanone

The 2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-dihydroxy-4-methoxy-phenyl) -ethanone (450mg, 1.4mmol) from preparation 3 was dissolved in anhydrous DMF (10 mL). Adding K₂CO₃(566mg, 4.1mmol) followed by iodoethane (442. mu.L, 5.5mmol) was added. The reaction mixture was stirred at room temperature overnight. Water (10mL) was added and the organic product was extracted with EtOAc (2X 25 mL). The combined organic phases were washed with water (10mL) and brine (10mL), then MgSO₄And (5) drying. The solvent was removed in vacuo and purified by standard silica gel chromatography to give the pure product, 2- (3, 5-dichloro-pyridin-4-yl) -1- (2,3-diethoxy-4-methoxy-phenyl) -ethanone as a white solid. Yield 220mg (42%). The compound was dissolved in DCM (1mL) under argon. Slowly add BCl at room temperature₃(0.97mL, 1M solution in DCM). After 2 hours EtOH (2mL) was added slowly. The solvent was removed in vacuo and purified by standard silica gel chromatography to give the pure product, 2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-2-hydroxy-4-methoxyphenyl) -ethanone, as a white solid.¹H NMR(DMSO-d₆) δ is 11.36(1H, s), 8.67(2H, s), 7.88(1H, d), 6.77(1H, d), 4.80(2H, s), 3.96(2H, q), 3.91(3H, s), 1.26(3H, t). Yield 100mg (49%)

General procedure for the preparation of Compounds of formula In, wherein R₃(R₃Not hydrogen) is as defined above:

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-2-hydroxy-4-methoxy-phenyl) -ethanone (12mg, 0.034mmol) obtained in example 263 was dissolved in anhydrous DMSO (0.25 mL). Adding K₂CO₃(0.025mL, 2M concentration) of an aqueous solution, then 1.5 equivalents of alkyl bromide or alkyl iodide dissolved in 0.025mL of LDMSO were added. The reaction mixture was left at room temperature for 48 hours. Purification by standard preparative HPLC gave pure compound.

Using this method the following compounds were obtained:

example 263 (Compound 263)

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-4-methoxy-2-phenethyloxy-phenyl) -ethanone

¹H NMR(CDCl₃)δ＝8.47(2H，s)，7.61(1H，d)，7.26(4H，m)，7.10(1H，t)，6.75(1H，d)，4.49(2H，t)，4.43(2H，s)，4.01(2H，q)，3.91(3H，s)，3.17(2H，t)，1.35(3H，t)。

Alkyl halide: 2-bromo-1-phenyl-ethane

Example 264 (Compound 264)

1- [2- (5-cyclopropyl- [1, 3, 4] thiadiazol-2-ylmethoxy) -3-ethoxy-4-methoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

¹H NMR(CDCl₃)δ＝8.47(2H，s)，7.61(1H，d)，6.81(1H，d)，5.64(2H，s)，4.56(2H，s)，4.15(2H，q)，3.95(3H，s)，2.39(1H，m)，1.41(3H，t)，1.56-1.11(4H，m)。

Alkyl halide: 2-chloromethyl-5-cyclopropyl- [1, 3, 4] thiadiazole

Example 265 (Compound 265)

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2-ethoxy-3-methoxy-phenoxy } -acetic acid benzyl ester

¹H NMR(DMSO-d₆)δ＝8.62(2H，s)，7.51(1H，d)，7.32(5H，m)，6.96(1H，d)，5.19(2H，s)，4.74(2H，s)，3.98(2H，q)，3.88(3H，s)，1.27(3H，t)。

Alkyl halide: 2-bromo-acetic acid benzyl ester

Example 266 (Compound 266)

1- (3-allyloxy-2-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

1- (2, 3-di-allyloxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (3.9g, 9.55mmol) from example 6 was dissolved in MeOH (96mL) under argon and cooled to 0 ℃. Adding Pd (PPh)₃)₄(110mg，0.0955mmol) and then K was added₂CO₃(1.3g, 9.55 mmol). The cooling bath was removed and the reaction mixture was stirred for 3 hours and then evaporated in vacuo. The crude product was dissolved in EtOAc (100mL) and washed with NH₄Cl (saturated, 50mL) was washed twice. Na for organic phase₂SO₄Dried and evaporated in vacuo and purified by flash chromatography using a gradient of toluene and 2% EtOAc as eluent. 1- (3-allyloxy-2-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone was obtained as a white solid.¹H NMR(CDCl₃) δ is 11.90(1H, s), 8.53(2H, s), 7.68(1H, d), 6.58(1H, d), 6.10(1H, m), 5.26(2H, m), 4.66(2H, s), 4.59(2H, d), 3.96(3H, s). Yield 2.2g (64%).

General procedure for the preparation of Compounds of formula Io, wherein R₃(R₃Not hydrogen) is as defined above:

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-2-hydroxy-4-methoxy-phenyl) -ethanone (12mg, 0.034mmol) obtained in example 263 was dissolved in anhydrous DMSO (0.25 mL). Adding K₂CO₃(0.025mL, 2M concentration) of an aqueous solution, then 1.5 equivalents of alkyl bromide or alkyl iodide dissolved in 0.025mL of LDMSO were added. The reaction mixture was left at room temperature for 48 hours. Purification by standard preparative HPLC gave pure compound.

Using this method the following compounds were obtained:

example 267 (Compound 267)

2- { 2-allyloxy-6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -3-methoxy-phenoxymethyl } -benzonitrile

LC/MS (method B): (m/z)383.2(MH +); RT ═ 4.72 minutes; purity (UV) 100%; alkyl halide: 2-chloromethyl-benzonitrile

Example 268 (Compound 268)

1- (3-allyloxy-4-methoxy-2-phenethyloxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method B): (m/z)472.3(MH +); RT ═ 5.32 minutes; purity (UV) 100%; alkyl halide: 1-bromo-2-phenyl-ethane

Example 269 (Compound 269)

1- { 3-allyloxy-2- [2- (4-fluoro-phenyl) -ethoxy ] -4-methoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone

LC/MS (method B): (m/z)490.2(MH +); RT ═ 5.26 minutes; purity (UV) 100%; alkyl halide: 1-bromo-2- (4-fluoro-phenyl) -ethane

General procedure for the preparation of Compounds of formula Ip, wherein R₃As defined above:

1- (2-alkoxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone (0.021mmol) from the above example was dissolved in anhydrous DCM (0.25 mL). Methylrhenium trioxide (0.105mmol) was added followed by hydrogen peroxide (0.042mmol) and the reaction mixture was stirred at room temperature overnight. Adding MnO₂(0.063 mmol). After 2 minutes, the reaction mixture was filtered and evaporated in vacuo. The crude product was redissolved in DMSO (0.4 mL). Purification by standard preparative HPLC gave pure compound.

Using this method the following compounds were obtained:

example 270 (Compound 270)

N-benzyl-2- {6- [2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide

¹H NMR(CDCl₃) δ is 8.15(2H, s), 8.10(1H, bs), 7.62(1H, d), 7.30(5H, m), 6.76(1H, d), 4.72(2H, s), 4.50(2H, d), 4.46(2H, s), 3.95(3H, s), 3.80(3H, s). N-benzyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] acetyl obtained in example 203 was used]-2, 3-dimethoxy-phenoxy } -acetamide as starting material.

Example 271 (Compound 271)

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (3, 4-dimethoxy-2-phenethyloxy-phenyl) -ethanone

¹H NMR(CDCl₃)δ＝8.13(2H，s)，7.61(1H，d)，7.26(5H，m)，6.75(1H，d)，4.40(2H，t)，4.30(2H，s)，3.93(3H，s)，3.79(3H，s)，3.17(2H，t)。

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-phenethyloxy-phenyl) -ethanone obtained from example 112 was used as starting material.

Example 272 (Compound 272)

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone

¹H NMR(CDCl₃)δ＝8.19(2H，s)，7.61(1H，d)，7.26(2H，t)，6.95(2H，t)，6.75(1H，d)，4.44(2H，t)，4.34(2H，s)，3.93(3H，s)，3.77(3H，s)，3.14(2H，t)。

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone obtained in example 129 was used as starting material.

Example 274 (Compound 274)

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (1-oxo-pyridin-4-yl) -ethoxy ] -phenyl } -ethanone

¹H NMR(DMSO-d₆)δ＝8.62(2H，s)，8.11(2H，d)，7.54(1H，d)，7.39(2H，d)，6.97(1H，d)，4.41(4H，m)，3.88(3H，s)，3.67(3H，s)，3.11(2H，t)。

Example 100 was used as the starting material.

Example 275 (Compound 275)

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (2-hydroxy-3, 4-dimethoxy-phenyl) -ethanone

¹H NMR(DMSO-d₆)δ＝11.20(IH7bs)，8.64(2H，s)，7.84(1H，d)，6.77(1H，d)，4.70(2H，bs)，3.91(3H，s)，3.72(3H，s)。

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hydroxy-3, 4-dimethoxy-phenyl) -ethanone obtained from example 1 was used as starting material.

Example 276 (Compound 276)

4- (2- {6- [2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -ethyl) -benzonitrile

¹H NMR(DMSO-d₆)δ＝8.61(2H，s)，7.73(2H，d)，7.55(3H，m)，6.96(1H，d)，4.45(2H，t)，4.20(2H，s)，3.88(3H，s)，3.66(3H，s)，3.22(2H，t)。

Example 100 was used as the starting material.

General procedure for the preparation of Compounds of formula Iq, wherein R₃(R₃Not hydrogen) is as defined above:

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hydroxy-3, 4-dimethoxyl) -1-ol obtained in example 1 was added under argonPhenyl-ethanone (1.5mmol) or 2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (2-hydroxy-3, 4-dimethoxy-phenyl) -ethanone from example 274 (1.5mmol), PBu₃(1.5mmol) and R3-OH (1.0mmol) were dissolved in anhydrous benzene (10 mL). The reaction mixture was cooled to 0 ℃ and then treated with ADDP (1.5 mmol). After 0.5 h, the reaction mixture was warmed to room temperature and stirred overnight. Decalite was added and the reaction mixture was evaporated in vacuo and purified by flash chromatography using a gradient of petroleum ether and EtOAc as eluent.

Using this method the following compounds were obtained:

example 277 (Compound 277)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-pyridin-4-yl-ethoxy) -phenyl ] -ethanone

¹H NMR(DMSO-d₆)δ＝8.63(2H，s)，8.44(2H，d)，7.53(1H，d)，7.37(2H，d)，6.97(1H，d)，4.46(4H，m)，3.88(3H，s)，3.66(3H，s)，3.15(2H，t)。

R3-OH: 2-pyridin-4-yl-ethanol

Example 278 (Compound 278)

4- (2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -ethyl) -benzonitrile

¹H NMR(DMSO-d₆)δ＝8.63(2H，s)，7.70(2H，d)，7.55(3H，m)，6.97(1H，d)，4.47(2H，t)，4.30(2H，s)，3.89(3H，s)，3.68(3H，s)，3.23(2H，t)。

R3-OH: preparation of 4- (2-hydroxy-ethyl) -benzonitrile from 2- (4-bromo-phenyl) -ethanol

Example 279 (compound 279)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-pyridin-2-yl-ethoxy) -phenyl ] -ethanone

¹H NMR(DMSO-d₆) δ is 8.62(2H, s), 8.41(1H, t), 7.65(1H, t), 7.50(1H, d), 7.38(1H, d), 7.10(1H, m), 6.95(1H, d), 4.61(2H, t), 4.38(2H, s), 3.88(3H, s), 3.72(3H, s), 3.28(2H, t). R3-OH: 2-pyridin-2-yl-ethanol

Example 280 (Compound 280)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-pyridin-3-yl-ethoxy) -phenyl ] -ethanone

¹H NMR(DMSO-d₆) δ is 8.64(2H, s), 8.55(1H, s), 8.34(1H, d), 7.77(1H, d), 7.53(1H, d), 7.28(1H, m), 6.97(1H, d), 4.47(2H, s), 4.43(2H, t), 3.88(3H, s), 3.64(3H, s), 3.15(2H, t). R3-OH: 2-pyridin-3-yl-ethanol

Example 281 (Compound 281)

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-methanesulfinyl-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone

(CDCl₃)δ＝8.50(2H，s)，7.59(3H，m)，7.49(2H，d)，6.78(1H，d)，4.48(4H，m)，3.93(3H，s)，3.74(3H，s)，3.24(2H，t)，2.63(3H，s)。

R3-OH: 2- (4-Methanesulfinyl-phenyl) -ethanol, prepared by oxidizing 2- (4-methylthio-phenyl) -ethanol with 1.5 equivalents of MCPBA in DCM at room temperature overnight.¹H NMR(CDCl₃) δ is 7.88(2H, d), 7.45(2H, d), 3.92(2H, t), 3.04(3H, s), 2.97(2H7t), 1.70(1H, bs). LC/MS (method B): (m/z)185(MH +); RT 1.27 min

Example 282 (Compound 282)

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-methanesulfonyl-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone

¹H NMR(CDCl₃)δ＝8.50(2H，s)，7.88(2H，d)，7.59(1H，d)，7.53(2H，d)，6.77(1H，d)，4.51(2H，s)，4.49(2H，t)，3.93(3H，s)，3.72(3H，s)，3.27(2H，t)，2.98(3H，s)。

R3-OH: 2- (4-methanesulfonyl-phenyl) -ethanol, prepared by oxidation of 2- (4-methylsulfanyl-phenyl) -ethanol with 1.5 equivalents of MCPBA in DCM at room temperature.¹H NMR(CDCl₃) δ is 7.59(2H, d), 7.40(2H, d), 3.90(2H, t), 2.94(2H, t), 2.72(3H, s), 1.85(1H, bs). LC/MS (method B): (m/z)201(MH +); RT 1.48 min

Example 283 (Compound 283)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (1-phenyl-propoxy) -phenyl ] -ethanone

¹H NMR(DMSO-d₆)δ＝8.65(2H，s)，7.34(6H，m)，6.85(1H，d)，5.48(1H，t)，4.63(2H，s)，3.85(3H，s)，3.72(3H，s)，2.14(1H，m)，1.95(1H，m)，0.88(3H，t)。

R3-OH: 1-phenyl-propan-1-ol

Example 284 (Compound 284)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-phenyl-propoxy) -phenyl ] -ethanone

¹H NMR(DMSO-d₆)δ＝8.62(2H，s)，7.51(1H，d)，7.35(2H，d)，7.23(2H，t)，7.06(IH7t)，6.95(1H，d)，4.33(4H，m)，3.88(3H，s)，3.69(3H，s)，3.33(1H，m)，1.37(3H，d)。

R3-OH: 2-phenyl-propan-1-ol

Example 285 (Compound 285)

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (1-methyl-2-phenyl-ethoxy) -phenyl ] -ethanone

¹H NMR(DMSO-d₆)δ＝8.66(2H，s)，7.46(1H，d)，7.28(4H，d)，7.17(1H，m)，6.93(1H，d)，4.94(1H，m)，4.60(2H，m)，3.88(3H，s)，3.58(3H，s)，3.02(2H，m)，1.18(3H，d)。

R3-OH: 1-phenyl-propan-2-ols

Preparation 6 (compound 506):

methyl 2, 3, 4-trimethoxybenzoate (25.7g, 114mmol) was dissolved in DCM (25mL) under argon. Dropwise addition of BCl₃(133mL, 1M in DCM, 133mmol) and the reaction mixture was left at room temperature for 2 h. EtOH (200mL) was added and the reaction mixture was stirred for 2 hours. The precipitate was filtered and recrystallized from EtOAc-petroleum ether to give 6g (25%) of methyl 2-hydroxy-3, 4-dimethoxy-benzoate as a white solid.¹H NMR(CDCl₃) δ is 10.90(1H, s), 7.59(1H, d), 6.48(1H, d), 3.93(3H, s), 3.92(3H, s), 3.89(3H, s). Methyl 2-hydroxy-3, 4-dimethoxy-benzoate (6g, 28.2mmol) was redissolved in NMP (35mL) and treated with tert-butyl bromoacetate (42.4mmol) and K₂CO₃(42.4 mmol). The reaction mixture was heated to 50 ℃ overnight. The reaction mixture was poured into water (300 mL). The organic product was extracted with EtOAc (2X 100mL) and the combined organic phases were washed with NaCl (saturated, 100 mL). With Na₂SO₄The organic phase was dried, evaporated in vacuo and purified by flash chromatography using a gradient of EtOAc in heptane as eluent to give methyl 2-tert-butoxycarbonylmethoxy-3, 4-dimethoxy-benzoate (compound 506a) as a colorless oil.¹H NMR(CDCl₃) δ is 7.58(1H, d), 6.71(1H, d), 4.56(2H, s), 3.90(3H, s), 3.87(3H, s), 3.86(3H, s), 1.50(9H, s). Yield 8.19g (89%). Methyl 2-tert-butoxycarbonylmethoxy-3, 4-dimethoxy-benzoate (8.19g, 25.1mmol) was dissolved in DCM (50mL) and treated with triethylsilane (4mL, 25.1mmol) and TFA (9.66mL, 125.5mmol)And (6) processing. The reaction mixture was left overnight. The reaction mixture was evaporated in vacuo, redissolved in toluene (200mL) and evaporated to dryness. This procedure was repeated three times to give methyl 2-carboxymethoxy-3, 4-dimethoxy-benzoate (compound 506b) as a white solid.¹H NMR(CDCl₃) δ is 12.6(1H, bs), 7.75(1H, d), 6.73(1H, d), 4.84(2H, s), 3.95(3H, s), 3.92(3H, s), 3.85(3H, s). Yield 6.71g (99%). 2-Carboxymethoxy-3, 4-dimethoxy-benzoic acid methyl ester (6.71g, 24.8mmol) was dissolved in dry DMF (130mL) under argon. Propylamine (4.1mL, 49.8mmol) was added followed by HATU (11.32g, 29.8mmol) and the reaction mixture was left overnight. The solvent was evaporated in vacuo and the crude mixture was redissolved in EtOAc (150 mL). With CaCl₂The organic phase was washed with aqueous solution (2X 50mL), water (2X 50mL) and brine (50 mL). Na for organic phase₂SO₄Dried, evaporated in vacuo and purified by flash chromatography using a gradient of EtOAc in heptane as eluent. 3, 4-dimethoxy-2-propylcarbamoylmethoxy-benzoic acid methyl ester (compound 506c) was obtained as a white solid.¹H NMR(CDCl₃) δ is 8.47(1H, bs), 7.71(1H, d), 6.70(1H, d), 4.69(2H, s), 3.93(3H, s), 3.87(3H, s), 3.83(3H, s), 3.33(2H, q), 1.64(2H, m), 0.99(3H, t). Yield 6.67g (86%).

General process for the preparation of compounds of formula Ir, wherein Ar and HetAr are as defined above:

3, 4-dimethoxy-2-propylcarbamoylmethoxy-benzoic acid methyl ester from preparation 6 (28mg, 0.09mmol) and Ar-Me or HetAr-Me compound (1.2 equiv., see below) were dissolved in dry THF (1mL) under argon. The mixture was cooled to 0 ℃ and treated dropwise by addition of LiHMDS (0.273mL of a 1M solution). The reaction mixture was allowed to warm to room temperature and left overnight. By reaction of NH₄Cl (sat, 2mL) quench with EtOAc (2X 2mL)) The organic product is extracted. The combined organic phases were washed with NaCl (saturated, 2 mL). Na for organic phase₂SO₄Dried, evaporated in vacuo, and redissolved in MeOH (0.350mL) followed by standard HPLC purification.

Using this method the following compounds were obtained:

example 286 (Compound 286)

2- {6- [2- (6-chloro-pyrazin-2-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide

LC/MS (method B): (m/z)408.4(MH +); RT ═ 3.33 minutes; purity (UV) 91%

HetAr-Me: 2-chloro-6-methyl-pyrazines

Example 287 (Compound 287)

2- {6- [2- (3-bromo-pyrazin-2-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide

LC/MS (method B): (m/z)454.3(MH +); RT ═ 3.26 minutes; purity (UV) ═ 86% HetAr-Me: 2-bromo-3-methyl-pyrazines

Example 288 (Compound 288)

2- {6- [2- (2, 6-dichloro-phenyl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide

¹H NMR(CDCl₃) δ is 7.84(1H, bs), 7.68(1H, d), 7.34(2H, d), 7.19(1H, t), 6.77(1H, d), 4.66(2H, s), 4.60(2H, s), 3.95(3H, s), 3.86(3H, s), 3.25(2H, q), 1.48(2H, m), 0.86(3H, t). Ar-Me: 1, 3-dichloro-2-methyl-benzene

Example 289 (Compound 289)

2- [2, 3-dimethoxy-6- (2-pyridin-4-yl-acetyl) -phenoxy ] -N-propyl-acetamide

¹H NMR(DMSO-d₆)δ＝8.49(2H，bs)，8.15(1H，t)，7.55(1H, d), 7.24(2H, d), 6.95(1H, d), 4.56(2H, s), 4.44(2H, s), 3.88(3H, s), 3.77(3H, s), 3.09(2H, q), 1.42(2H, m), 0.81(3H, t). HetAr-Me: 4-methyl-pyridines

Example 290 (Compound 290)

2- [2, 3-dimethoxy-6- (2-quinolin-4-yl-acetyl) -phenoxy ] -N-propyl-acetamide

LC/MS (method B): (m/z)423.4(MH +); RT 2.45 min; purity (UV) 100%; HetAr-Me: 4-methyl-quinolines

Example 291 (Compound 291)

2- [2, 3-dimethoxy-6- (2-pyrazin-2-yl-acetyl) -phenoxy ] -N-propyl-acetamide

LC/MS (method B): (m/z)374.1(MH +); RT 2.58 min; purity (UV) ═ 81% HetAr-Me: 2-methyl-pyrazines

Example 292 (Compound 292)

2- {6- [2- (3-bromo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide

LC/MS (method B): (m/z)453.07(MH +); RT ═ 3.13 minutes; purity (UV) 100%; HetAr-Me: 3-bromo-4-methyl-pyridine

Example 293 (Compound 293)

2- {6- [2- (3, 5-dibromo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide

LC/MS (method B): (m/z)531.0(MH +); RT ═ 3.68 minutes; purity (UV) 100%; HetAr-Me: 3, 5-dibromo-4-methyl-pyridine

Example 294 (Compound 294)

2- {6- [2- (6-chloro-pyrimidin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide

LC/MS (method B): (m/z)408.3(MH +); RT ═ 3.19 and 3.79 minutes (possible keto and enol isomers); purity (UV) 100%; HetAr-Me: 4-chloro-6-methyl-pyrimidine

Example 295 (Compound 295)

2- {6- [2- (4-chloro-pyridin-2-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide

LC/MS (method B): (m/z)407.4(MH +); RT ═ 3.50 minutes; purity (UV) 100%; HetAr-Me: 4-chloro-2-methyl-pyridine

Example 296 (Compound 296)

2- {6- [2- (2-chloro-pyridin-3-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide

LC/MS (method B): (m/z)407.4(MH +); RT ═ 3.26 minutes; purity (UV) 100%; HetAr-Me: 2-chloro-3-methyl-pyridine

Example 297 (Compound 297)

2- {2, 3-dimethoxy-6- [2- (2-methoxy-pyridin-4-yl) -acetyl ] -phenoxy } -N-propyl-acetamide

LC/MS (method B): (m/z)403.3(MH +); RT ═ 3.24 minutes; purity (UV) 100%; HetAr-Me: 2-methoxy-4-methyl-pyridine

Example 298 (Compound 298)

2- {6- [2- (2-cyano-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide

LC/MS (method B): (m/z)398.4(MH +); RT ═ 3.23 min; purity (UV) 94%

HetAr-Me: 4-methyl-pyridine-2-carbonitrile

Example 299 (Compound 299)

2- [2, 3-dimethoxy-6- (2-pyridazin-3-yl-acetyl) -phenoxy ] -N-propyl-acetamide

LC/MS (method B): (m/z)374.2(MH +); RT 2.39 min; purity (UV) 90%

HetAr-Me: 3-methyl-pyridazines

Example 300 (Compound 300)

2- (2-tert-butylamino-3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone from example 272 was converted to 2- (2-tert-butylamino-3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone according to the method described in j.org.chem. (2007), 72, 4554-57. Pure 2- (2-tert-butylamino-3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone was obtained by standard HPLC purification methods.

LC/MS (method B): (m/z)535.2(MH +); RT ═ 6.21 minutes; purity (UV) ═ 100%

Example 301 (Compound 301)

2- (2-amino-3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone

2- (2-tert-butylamino-3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] obtained in example 300]-3, 4-dimethoxy-phenyl } -ethanone (16.5mg, 0.0308mmol), triethylsilane (2 equiv.) and TFA (0.1mL) were heated to 50 ℃ in dichloroethane (0.2mL) for 24 hours. CoarseThe mixture was evaporated in vacuo, redissolved in dichloroethane (1mL) and incubated with NaHCO₃(saturated, 2X 0.5mL) washing. Na for organic phase₂SO₄Drying and evaporating the solvent in vacuo. Flash chromatography with a gradient of MeOH in dichloromethane as eluent gave pure 2- (2-amino-3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -ethyl]-3, 4-dimethoxy-phenyl } -ethanone.

LC/MS (method B): (m/z)479.3(MH +); RT ═ 4.53 minutes; purity (UV) ═ 100%

Example 302 (Compound 302)

2- (3, 5-dichloro-pyridin-4-yl) -1- (4-ethoxy-3-methoxy-2-phenethyloxy-phenyl) -ethanone

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-phenethyloxy-phenyl) -ethanone from example 112 (89.3mg, 0.1mmol) was treated with piperidine (0.8mL) and water (0.32 mL). The yellow suspension was heated to 90 ℃ for 54 hours. The solvent was evaporated in vacuo. NH for crude mixture₄Cl (sat, 1mL) and the organic product extracted with EtOAc (3X 2 mL). The combined organic phases are washed with Na₂SO₄Drying and evaporating the solvent in vacuo. Purification by flash chromatography using a gradient of EtOAc in toluene as eluent gave 2- (3, 5-dichloro-pyridin-4-yl) -1- (4-hydroxy-3-methoxy-2-phenethyloxy-phenyl) -ethanone as a white solid. Yield 8.6mg (20%). 2- (3, 5-dichloro-pyridin-4-yl) -1- (4-hydroxy-3-methoxy-2-phenethyloxy-phenyl) -ethanone (5.5mg, 0.013mmol) was dissolved in DMSO (0.45mL) followed by K₂CO₃(0.019mL of a 1M aqueous solution) and iodoethane (0.019mL of a 1M solution in DMSO). The reaction mixture was left at room temperature for 48 hours and purified by standard HPLC purification methods. To obtain 2- (3, 5-dichloro-pyridin-4-yl) -1- (4-ethoxy-3-methoxy-2-phenethyloxy-phenyl) -Ethanone, as a colorless solid. Yield 3.2mg (36%).

¹H NMR(CDCl₃)δ＝8.48(2H7s)，7.59(1H，d)，7.27(4H，m)，7.11(1H，t)，6.73(1H，d)，4.48(4H，m)，4.14(2H，q)，3.78(3H，s)，3.18(2H，t)，1.49(3H，t)。

Example 303

PDE4 test

Human recombinant PDE4(Gene bank accession No. NM 006203) was mixed with the test compound, cAMP (1X 10) at a concentration of up to 10uM^-5M) and low levels (0.021 MBq) of radiolabeled cAMP were incubated for 1 hour, respectively. At the end of the incubation, cleavage of the substrate was assessed by binding of AMP product to SPA beads, which when bound to the radiotracer, produced chemiluminescence. AMP products inhibit the binding of the radiotracer to the beads and compete for the luminescent signal.

Results were calculated as the molar concentration that resulted in 50% inhibition of substrate cleavage compared to control samples and are given as-log IC₅₀And (M) represents.

Compounds 101, 103, 104, 106, 148, 150, 155, 157, 206, 208, 234, 236, 241, 243, 244, 246, 248, 249, 251, 258, 260, 272, 274-5, 277, 285, 287, 290, 292, 293, 296, 301, and 302 were shown to be effective inhibitors, which are log IC₅₀(M) is higher than 6.

Example 304

TNF alpha release

Human Peripheral Blood Mononuclear Cells (PBMCs) were isolated from buffy coats. Blood was mixed with saline at a ratio of 1: 1 and PBMC were isolated using Lymphoprep tubes (Nycomed, Norway). PBMC were suspended at a concentration of 5X 105c/ml in RPMI 1640 containing 2% Fetal Calf Serum (FCS), penicillin/streptomycin and 2mM L-glutamine. Cells were preincubated with test compound for 30 min in 96-well tissue culture plates and stimulated with lipopolysaccharide 1mg/ml (Sigma) for 18 h. The TNF-alpha levels in the culture supernatants were determined by enzyme immunoassay using biotinylated primary and secondary antibodies from R & D systems. The results are expressed as pIC50 values calculated from an inhibition curve using the secretion of LPS-stimulated wells as a positive control and the secretion of non-stimulated cells as a negative control.

Compounds 101, 104, 106-₅₀(M) is higher than 6.

Claims (16)

1. A compound of formula I, and pharmaceutically acceptable salts or N-oxides thereof

Wherein X₁、X₂、X₃、X₄And X₅Each independently represents-CH-or N;

or X₃、X₄And X₅Each independently represents-CH-or N, and X₁And X₂Each independently represents C and forms part of another 6-membered aromatic ring; wherein

Ring B represents pyridyl, pyrazinyl, quinolyl, pyrimidinyl or pyridazinyl, which is optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, cyano, methoxy and-NR'₂Wherein R' each independently represents hydrogen or C_1-4An alkyl group;

wherein R is₁Represents methyl, ethyl or hydrogen;

R₂and/or R₃represents-CH₂COOH, methyl, hydrogen, allyl, ethyl, tert-butoxycarbonylmethyl, difluoromethyl, benzyl, 1-hexyl, 1-propyl, 1-butyl, 1-pentyl, 4-fluoro-benzyl, 2-fluoro-benzyl, 3-trifluoromethyl-benzyl, 3-trifluoromethoxy-benzyl, 3-fluoro-5-trifluoromethyl-benzyl, 4-chloro-benzyl, 2-difluoromethoxy-benzyl, 4-isopropyl-benzyl, 2-fluoro-6-trifluoromethyl-benzyl, 2, 3-difluoro-4-methyl-benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 2-chloro-benzyl, 3-methoxy-benzyl, tert-butoxycarbonylmethyl, difluoromethyl, benzyl, 4-methoxy-benzyl, cyclopropylmethyl;

R₁₁represents one or more, identical or different substituents selected from: hydrogen, halogen, cyano, amino, C₁-C₆Alkyl or C₁-C₆An alkoxy group;

provided that R is₁、R₂And R₃Not all are methyl;

with the proviso that when R₂And R₃When both are hydrogen, R₁And not methyl or hydrogen.

2. A compound of formula I, and pharmaceutically acceptable salts or N-oxides thereof

Wherein X₁、X₂、X₃、X₄And X₅Each independently represents-CH-or N;

or X₃、X₄And X₅Each independently represents-CH-or N, and X₁And X₂Each independently represents C and forms part of another 6-membered aromatic ring; wherein

Ring B represents pyridyl, pyrazinyl, quinolyl, pyrimidinyl or pyridazinyl, which is optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, cyano, methoxy and-NR'₂Wherein R' each independently represents hydrogen or C_1-4An alkyl group;

wherein R is₁Represents methyl, ethyl or hydrogen;

R₂and/or R₃Has the following definitions:

(1)R₂and/or R₃Represents C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, each of which is optionally substituted by one or more C_1-6Alkyl radical, C_1-6Alkoxy, hydroxy, C_3-8Cycloalkyl or phenoxy, wherein said phenoxy is optionally substituted with one or more halogens, and said C_1-6Alkoxy is optionally substituted with one phenyl; or

(2)R₂And/or R₃Represents aryl C_1-6Alkyl, wherein the aryl is phenyl or naphthyl, and the phenyl is optionally substituted with one or more C_1-6Alkoxycarbonyl, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy or cyano substitution; or

(3)R₂And/or R₃Represents C_1-6Alkyl substituted with one heterocycle, wherein the heterocycle is selected from isoAzolyl, benzoOxazolyl, thiazolyl, thiadiazolyl,Oxadiazolyl, pyridinyl, quinolinyl, thienyl, isoindolyl, pyrrolidinyl, or morpholinyl, and the heterocycle is optionally substituted with one or more C_1-6Alkyl, halogen, oxo or C_3-8Cycloalkyl substitution; or

(4)R₂And/or R₃Represents C_1-6Alkyl radical, which is substituted by a C_1-6Alkoxycarbonyl or arylcarbonyl, wherein said C is_1-6Alkoxycarbonyl is optionally substituted by one phenyl group and the aryl group of the arylcarbonyl group is selected from phenyl or naphthyl and is optionally substituted by one or more C_1-6Alkyl or C_1-6Alkoxy substitution; or

(5)R₂And/or R₃represents-CH₂-C(O)NR₉-R₁₂Wherein

R₉Represents hydrogen or C_1-6An alkyl group, a carboxyl group,

R₁₂represents hydrogen, C_1-6Alkyl, phenyl C_1-6Alkyl, or C_3-8Cycloalkyl, each of which is optionally substituted by one or more C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl, hydroxy, dimethylamino, phenoxy, halogen, C substituted by hydroxy_1-6Alkoxy, heteroaryl or heterocycloalkyl substituted,

wherein said heteroaryl or heterocycloalkyl is selected from: furyl, pyridyl, morpholinyl, pyrrolidinyl, thienyl, or indanyl, wherein said indanyl is optionally substituted with one or more hydroxy groups and said pyrrolidinyl is optionally substituted with one or more oxo groups; or

(6)R₂And/or R₃Represents C_3-8Cycloalkyl, or phenyl C_1-6Alkyl, wherein the phenyl is optionally substituted by one or more C_1-6Alkylsulfonyl or C_1-6Alkylsulfinyl substitution;

R₁₁represents one or more, identical or different substituents selected from: hydrogen, halogen, cyano, amino, C₁-C₆Alkyl or C₁-C₆An alkoxy group;

provided that R is₁、R₂And R₃Not all are methyl;

with the proviso that when R₂And R₃When both are hydrogen, R₁And not methyl or hydrogen.

3. The compound according to claim 1 or 2, wherein optionally substituted with R₁₁Substituted ring B represents 2- (6-chloro-pyrazinyl), 2-pyrazinyl, 4- (3-bromo-pyridyl), 4- (3, 5-dibromo-pyridyl), 4- (6-chloro-pyrimidinyl), 2- (4-chloro-pyridyl), 3- (2-chloro-pyridyl), 4- (2-methoxy-pyridyl), 4- (2-cyano-pyridyl), 3-pyridazinyl, 4- (2-tert-butylamino-3, 5-dichloro-pyridyl), 4- (2-amino-3, 5-dichloro-pyridyl), 4- (3, 5-dichloro-pyridyl); optionally substituted phenyl, phenyl, 2- (3-bromo-pyrazinyl), 4-pyridyl, 4-quinolyl or 4- (3, 5-dichloro-1-oxy-pyridyl).

4. A compound according to claim 1 or 2, wherein formula I represents general formula Iz,

wherein X₃represents-CH-or N.

5. The compound of claim 2, wherein R₃represents-CH₂-C (O) NH-n-propyl.

6. The compound of claim 2, wherein R₂Represents a methyl group.

7. A compound selected from:

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hydroxy-3, 4-dimethoxy-phenyl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-hydroxy-2, 4-dimethoxy-phenyl) -ethanone,

1- (2-allyloxy-3-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 3-diethoxy-4-methoxy-phenyl) -ethanone,

{ 2-tert-Butoxycarbonylmethoxy-6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -3-methoxy-phenoxy } -acetic acid tert-butyl ester,

1- (2, 3-di-allyloxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

1- (2, 3-bis-difluoromethoxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (5-methyl-iso-propyl-)Azol-3-ylmethoxy) -phenyl]-an ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methoxy-ethoxy) -phenyl ] -ethanone,

1- (2-but-2-ynyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methyl-but-2-enyloxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-phenethyloxy-phenyl) -ethanone,

1- (2-benzyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

1- (2-allyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

1- [2- (benzo)Azol-2-ylmethoxy) -3, 4-dimethoxy-phenyl]-2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methyl-thiazol-4-ylmethoxy) -phenyl ] -ethanone,

1- [2- (5-cyclopropyl- [1, 3, 4] thiadiazol-2-ylmethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- ([1, 2, 4] methyl ethyl ether [)]Oxadiazol-3-ylmethoxy) -phenyl]-an ethanone,

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid ethyl ester,

1- {2- [2- (4-chloro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

1- [2- (5-chloro-thiophen-2-ylmethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-phenoxy-ethoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-p-tolyl-ethoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-phenyl-propoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (3-methoxy-phenyl) -ethoxy ] -phenyl } -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (4-methoxy-phenyl) -ethoxy ] -phenyl } -ethanone,

1- {2- [2- (3-bromo-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (2-methoxy-phenyl) -ethoxy ] -phenyl } -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (2-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (3, 4-dimethoxy-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone,

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid benzyl ester,

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid isopropyl ester,

3- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzoic acid methyl ester,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methyl-butoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-hexyloxy-3, 4-dimethoxy-phenyl) -ethanone,

1- (2-but-3-enyloxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-pent-4-enyloxy-phenyl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-propoxy-phenyl) -ethanone,

1- (2-butoxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (2-isobutoxy-3, 4-dimethoxy-phenyl) -ethanone,

4- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -butyric acid ethyl ester,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (4-methyl-benzyloxy) -phenyl ] -ethanone,

1- [2- (3-chloro-benzyloxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-phenoxy-propoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (4-methoxy-phenyl) -2-oxo-ethoxy ] -phenyl } -ethanone,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzonitrile,

4- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzonitrile,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (naphthalen-2-ylmethoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-pentoxy-phenyl) -ethanone,

1- (2-cyclohexylmethoxy-3, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

3- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzonitrile,

1- {2- [2- (4-chloro-phenoxy) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-ethyl-butoxy) -3, 4-dimethoxy-phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-hydroxy-ethoxy) -3, 4-dimethoxy-phenyl ] -ethanone,

4- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxymethyl } -benzoic acid methyl ester,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-naphthalen-2-yl-2-oxo-ethoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (2, 5-dimethoxy-phenyl) -2-oxo-ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-oxo-2-p-tolyl-ethoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (4-fluoro-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-fluoro-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-trifluoromethyl-benzyloxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-trifluoromethoxy-benzyloxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (3-fluoro-5-trifluoromethyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (2-methoxy-phenyl) -2-oxo-ethoxy ] -phenyl } -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (2, 4-dimethyl-phenyl) -2-oxo-ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone,

1- [2- (4-chloro-benzyloxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-difluoromethoxy-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (4-isopropyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2-fluoro-6-trifluoromethyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2- (2, 3-difluoro-4-methyl-benzyloxy) -3, 4-dimethoxy-phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methyl-benzyloxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methyl-benzyloxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (3, 4-dimethoxy-2-pent-2-enyloxy-phenyl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-methyl-quinolin-6-ylmethoxy) -phenyl ] -ethanone,

1- [2- (2-chloro-benzyloxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (3-methoxy-benzyloxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (4-methoxy-benzyloxy) -phenyl ] -ethanone,

1- {2- [2- (3-chloro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (5-methyl-hexyloxy) -phenyl ] -ethanone,

1- [2- (2-cyclohexyl-ethoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

5- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -pentanoic acid ethyl ester,

1- [2- (3-benzyloxy-propoxy) -3, 4-dimethoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- (2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -ethyl) -isoindole-1, 3-dione,

2- (3- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -propyl) -isoindole-1, 3-dione,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-methyl-acetamide,

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-2, 4-dimethoxy-phenyl) -ethanone,

1- (3-cyclopropylmethoxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

1- (2-allyloxy-3-but-3-enyloxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

1- (3-but-3-enyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-propoxy-phenyl) -ethanone,

1- (3-allyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2, 4-dimethoxy-3- (4-methyl-pent-3-enyloxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3- (2-hydroxy-ethoxy) -2, 4-dimethoxy-phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-phenethyloxy-phenyl) -ethanone,

1- (3-benzyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-pent-2-enyloxy-phenyl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [2, 4-dimethoxy-3- (2-methoxy-ethoxy) -phenyl ] -ethanone,

1- (3-but-2-ynyloxy-2, 4-dimethoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (2, 4-dimethoxy-3-prop-2-ynyloxy-phenyl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl ] -ethanone,

n-benzyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-morpholin-4-yl-2-oxo-ethoxy) -phenyl ] -ethanone,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-phenyl-acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-methyl-N-phenyl-acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-hydroxy-3-methyl-butyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-isopropyl-acetamide,

n-butyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

n-cyclopentyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-methyl-butyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-methoxy-benzyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2, 2-dimethyl-propyl) -acetamide,

n-cyclohexyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-methoxy-benzyl) -acetamide,

n-cycloheptyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-methoxy-benzyl) -acetamide,

n-cyclohexylmethyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-ethyl) -acetamide,

(R) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (1-phenyl-ethyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-hydroxy-propyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-methoxy-ethyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-dimethylamino-ethyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-dimethylamino-propyl) -acetamide,

(S) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (1-phenyl-ethyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-isopropoxy-propyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-furan-2-ylmethyl-acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-pyridin-2-ylmethyl-acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-pyridin-3-ylmethyl-acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-phenoxy-ethyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-pyridin-4-ylmethyl-acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-ethyl-benzyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3, 5-difluoro-benzyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2, 3-difluoro-benzyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyridin-2-yl-ethyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-methyl-benzyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-fluoro-benzyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-methyl-benzyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-methyl-benzyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-phenethyl-acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyridin-4-yl-ethyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (3-phenyl-propyl) -acetamide,

n- (2-chloro-benzyl) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-piperidin-1-yl-ethyl) -acetamide,

n- (3-chloro-benzyl) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-morpholin-4-yl-ethyl) -acetamide,

n- (4-chloro-benzyl) -2- (6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyridin-3-yl-ethyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-pyrrolidin-1-yl-ethyl) -acetamide,

n- (2-acetylamino-ethyl) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

(R) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-2-phenyl-ethyl) -acetamide,

(S) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-2-phenyl-ethyl) -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-thiophen-2-ylmethyl-acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -acetamide,

(2R) -2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (2-hydroxy-indan-1-yl) -acetamide,

n-cycloheptylmethyl-2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- [2- (2-hydroxy-ethoxy) -ethyl ] -acetamide,

2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N- (4-dimethylamino-butyl) -acetamide,

1- (3-cyclopentyloxy-2-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

1- (3-cyclopropylmethoxy-2-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-2-hydroxy-4-methoxy-phenyl) -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (3-ethoxy-4-methoxy-2-phenethyloxy-phenyl) -ethanone,

1- [2- (5-cyclopropyl- [1, 3, 4] thiadiazol-2-ylmethoxy) -3-ethoxy-4-methoxy-phenyl ] -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2-ethoxy-3-methoxy-phenoxy } -acetic acid benzyl ester,

1- (3-allyloxy-2-hydroxy-4-methoxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

2- { 2-allyloxy-6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -3-methoxy-phenoxymethyl } -benzonitrile,

1- (3-allyloxy-4-methoxy-2-phenethyloxy-phenyl) -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

1- { 3-allyloxy-2- [2- (4-fluoro-phenyl) -ethoxy ] -4-methoxy-phenyl } -2- (3, 5-dichloro-pyridin-4-yl) -ethanone,

n-benzyl-2- {6- [2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetamide,

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (3, 4-dimethoxy-2-phenethyloxy-phenyl) -ethanone,

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone,

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- {3, 4-dimethoxy-2- [2- (1-oxo-pyridin-4-yl) -ethoxy ] -phenyl } -ethanone,

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (2-hydroxy-3, 4-dimethoxy-phenyl) -ethanone,

4- (2- {6- [2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -ethyl) -benzonitrile,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-pyridin-4-yl-ethoxy) -phenyl ] -ethanone,

4- (2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -ethyl) -benzonitrile,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-pyridin-2-yl-ethoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-pyridin-3-yl-ethoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-methanesulfinyl-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-methanesulfonyl-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (1-phenyl-propoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (2-phenyl-propoxy) -phenyl ] -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- [3, 4-dimethoxy-2- (1-methyl-2-phenyl-ethoxy) -phenyl ] -ethanone,

2- {6- [2- (6-chloro-pyrazin-2-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide,

2- {6- [2- (3-bromo-pyrazin-2-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide,

2- {6- [2- (2, 6-dichloro-phenyl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide,

2- [2, 3-dimethoxy-6- (2-pyridin-4-yl-acetyl) -phenoxy ] -N-propyl-acetamide,

2- [2, 3-dimethoxy-6- (2-quinolin-4-yl-acetyl) -phenoxy ] -N-propyl-acetamide,

2- [2, 3-dimethoxy-6- (2-pyrazin-2-yl-acetyl) -phenoxy ] -N-propyl-acetamide,

2- {6- [2- (3-bromo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide,

2- {6- [2- (3, 5-dibromo-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide,

2- {6- [2- (6-chloro-pyrimidin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide,

2- {6- [2- (4-chloro-pyridin-2-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide,

2- {6- [2- (2-chloro-pyridin-3-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide,

2- {2, 3-dimethoxy-6- [2- (2-methoxy-pyridin-4-yl) -acetyl ] -phenoxy } -N-propyl-acetamide,

2- {6- [2- (2-cyano-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide,

2- [2, 3-dimethoxy-6- (2-pyridazin-3-yl-acetyl) -phenoxy ] -N-propyl-acetamide,

2- (2-tert-butylamino-3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone,

2- (2-amino-3, 5-dichloro-pyridin-4-yl) -1- {2- [2- (4-fluoro-phenyl) -ethoxy ] -3, 4-dimethoxy-phenyl } -ethanone,

2- (3, 5-dichloro-pyridin-4-yl) -1- (4-ethoxy-3-methoxy-2-phenethyloxy-phenyl) -ethanone,

{6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -acetic acid,

and pharmaceutically acceptable salts thereof.

8. A compound which is 2- {6- [2- (3, 5-dichloro-pyridin-4-yl) -acetyl ] -2, 3-dimethoxy-phenoxy } -N-propyl-acetamide or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1-8 and a pharmaceutically acceptable vehicle or excipient or a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, further comprising one or more additional therapeutically active compounds.

11. Use of a compound according to any one of claims 1 to 8, and pharmaceutically acceptable salts or N-oxides thereof, for the manufacture of a medicament for the prevention, treatment or alleviation of a skin disease or condition, or an acute or chronic skin wound condition.

12. The use according to claim 11, wherein the skin disease or disorder is selected from proliferative and inflammatory skin diseases.

13. The use of claim 11, wherein the skin disease or disorder is selected from psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, skin aging, acne, dermatitis, urticaria, pruritus and eczema.

14. The use of claim 13, wherein the skin atrophy is steroid induced skin atrophy.

15. The use of claim 13, wherein the skin aging is skin photoaging.

16. The use of claim 13, wherein the dermatitis is allergic dermatitis, seborrheic dermatitis, or contact dermatitis.