The present invention provides compounds of Formula I: ##STR00001##
and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated by FXR. Specifically, the present invention relates to isoxazole derivatives useful as agonists for FXR and methods for their preparation and use.

The invention relates to a method of manufacturing triazine, pyrimidine and pyridine derivatives of formula (I), wherein U, V, W and Z are nitrogen or carbon atoms, whereby at least one of U, V and W is nitrogen, and the other substituents are defined as in the specification, by condensing a corresponding halo-triazine, pyrimidine or pyridine in a type of Suzuki coupling with a pyridyl- or pyrimidinyl-borane, wherein the amino function is protected as a formamidine. The invention further relates to suitable intermediates and methods of manufacturing of such intermediates. Furthermore the invention relates to pure 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine in solid form. ##STR00001##

The invention relates to a method of manufacturing triazine, pyrimidine and pyridine derivatives of formula (I), wherein U, V, W and Z are nitrogen or carbon atoms, whereby at least one of U, V and W is nitrogen, and the other substituents are defined as in the specification, by condensing a corresponding halo-triazine, pyrimidine or pyridine in a type of Suzuki coupling with a pyridyl- or pyrimidinyl-borane, wherein the amino function is protected as a formamidine. The invention further relates to suitable intermediates and methods of manufacturing of such intermediates. Furthermore the invention relates to pure 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine in solid form. ##STR00001##

A target bipyridine compound is synthesized with high purity and a high yield in a simple and safe manner in a short period of time. A method for synthesizing a di-tert-butyl-2,2-bipyridine compound is provided, and the method includes a step of reacting, in a reaction solvent, a tert-butylpyridine compound with a dispersion product obtained by dispersing an alkali metal in a dispersion solvent. A method for synthesizing a bipyridine compound having no substituents is also provided, and the method includes a step of reacting, in a reaction solvent, pyridine with a dispersion product obtained by dispersing an alkali metal in a dispersion solvent.

A target bipyridine compound is synthesized with high purity and a high yield in a simple and safe manner in a short period of time. A method for synthesizing a di-tert-butyl-2,2-bipyridine compound is provided, and the method includes a step of reacting, in a reaction solvent, a tert-butylpyridine compound with a dispersion product obtained by dispersing an alkali metal in a dispersion solvent. A method for synthesizing a bipyridine compound having no substituents is also provided, and the method includes a step of reacting, in a reaction solvent, pyridine with a dispersion product obtained by dispersing an alkali metal in a dispersion solvent.

The present invention relates to a preparation method of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide capable of enabling 4-chlorine-N-methylpyridine-2-formamide to react with 4-amino-3-fluorophenol in the presence of an inorganic base. The present invention employs the inorganic base to replace potassium t-butoxide in the prior art, thus effectively solving the problem of a potential safety hazard of the potassium t-butoxide in industrial production. In addition, after the reaction is completed, the present invention employs a crystallization method for separation to obtain a reaction product; thus compared with the methods of extraction, concentration and column isolation and purification employed in the prior art, the present invention has a simpler operation and a lower cost, results in less environment pollution and a higher yield, and is very suitable for industrial production.

The present invention relates to a preparation method of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide capable of enabling 4-chlorine-N-methylpyridine-2-formamide to react with 4-amino-3-fluorophenol in the presence of an inorganic base. The present invention employs the inorganic base to replace potassium t-butoxide in the prior art, thus effectively solving the problem of a potential safety hazard of the potassium t-butoxide in industrial production. In addition, after the reaction is completed, the present invention employs a crystallization method for separation to obtain a reaction product; thus compared with the methods of extraction, concentration and column isolation and purification employed in the prior art, the present invention has a simpler operation and a lower cost, results in less environment pollution and a higher yield, and is very suitable for industrial production.

The invention relates to a drier composition for an autoxidizable alkyd based coating composition, comprising: a) at least one Fe complex comprising Fe and at least one nitrogen donor ligand, wherein the nitrogen donor ligand is selected from tridentate, tetradentate, pentadentate and hexadentate nitrogen donor ligands; b) at least one metal salt of a carboxylic acid, wherein the metal is selected from Mn, Ce, V, and Cu; and c) at least one ligand comprising at least one moiety selected from 1,4,7-tri-azacyclononanyl, 2,2-bipyridyl, 1,10-phenantrolinyl, imidazolyl, pyrazolyl, porphyrinyl, aliphatic, cycloaliphatic, and aromatic amines. The present invention also relates to coating composition comprising the drier composition, and a method of reducing skinning tendency of an autoxidizable alkyd based coating composition while accelerating drying time thereof upon application of the autoxidizable alkyd based coating composition to a substrate as a coating, comprising adding the above drier composition to the autoxidizable alkyd based coating composition.

The invention relates to a drier composition for an autoxidizable alkyd based coating composition, comprising: a) at least one Fe complex comprising Fe and at least one nitrogen donor ligand, wherein the nitrogen donor ligand is selected from tridentate, tetradentate, pentadentate and hexadentate nitrogen donor ligands; b) at least one metal salt of a carboxylic acid, wherein the metal is selected from Mn, Ce, V, and Cu; and c) at least one ligand comprising at least one moiety selected from 1,4,7-tri-azacyclononanyl, 2,2-bipyridyl, 1,10-phenantrolinyl, imidazolyl, pyrazolyl, porphyrinyl, aliphatic, cycloaliphatic, and aromatic amines. The present invention also relates to coating composition comprising the drier composition, and a method of reducing skinning tendency of an autoxidizable alkyd based coating composition while accelerating drying time thereof upon application of the autoxidizable alkyd based coating composition to a substrate as a coating, comprising adding the above drier composition to the autoxidizable alkyd based coating composition.

A method of preparing benzyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (I) from benzyl 4,5-difluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (II) is described. The method includes the use of amination and chlorination process steps to provide the compound of Formula I.