This present disclosure relates to protein kinase C (PKC) modulating compounds, methods of treating a subject with cancer using the compounds, and combination treatments with a second therapeutic agent.

This present disclosure relates to protein kinase C (PKC) modulating compounds, methods of treating a subject with cancer using the compounds, and combination treatments with a second therapeutic agent.

The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, wherein: the group X—Y is —NHSO.sub.2— or —SO.sub.2NH—; Z is a monocyclic aryl or heteroaryl group, each of which is optionally substituted by one or more substituents selected from alkyl, cycloalkyl, halo, alkoxy, CN, haloalkyl and OH; R.sub.1 is H or alkyl; R.sub.2 is selected from COOH and a tetrazolyl group; R.sub.3 is selected from H, C land alkyl; R.sub.4 is selected from H and halo; R.sub.5 is selected from H, alkyl, haloalkyl, SO.sub.2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R.sub.6 is H; R.sub.7 is selected from H, CN, haloalkyl, halo, SO.sub.2-alkyl, SO.sub.2NR.sub.12R.sub.13, heteroaryl, CONR.sub.10R.sub.11 and alkyl, wherein said heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; R.sub.8 is selected from H, alkyl, haloalkyl and halo; and R.sub.9 is H, alkyl or halo; R.sub.10 and R.sub.11 are each independently H or alkyl; and R.sub.12 and R.sub.13 are each independently H or alkyl. Further aspects of the invention relate to such compounds for use in the field of immuno-oncology and related applications. Another aspect of the invention relates to compounds of formulae (la) and (lb).

##STR00001##

The present invention provides a method for preparing an intermediate of florfenicol, comprising: reacting p-methylthiobenzaldehyde with isocyanoacetate under catalysis of a chiral catalyst. In the reaction, the chiral product is oxidized to form a methylsulfone-substituted product which is subsequently deformylized to obtain the intermediate. In the method of the present invention, the chiral center of the intermediate is directly generated in the first step of reaction, and the yield of the first step reaches 75%-80%, which is significantly higher than the conventional chiral resolution methods (about 40% yield), and the product has high chiral purity. The method of the present invention does not use anhydrous copper sulfate that pollutes the environment, which reduces the environmental pressure. The compound of p-methylthiobenzaldehyde and the compound of isocyanoacetate are used to react to form a chiral intermediate, which has higher material availability and efficiency than linear synthesis methods.

The present invention provides a method for preparing an intermediate of florfenicol, comprising: reacting p-methylthiobenzaldehyde with isocyanoacetate under catalysis of a chiral catalyst. In the reaction, the chiral product is oxidized to form a methylsulfone-substituted product which is subsequently deformylized to obtain the intermediate. In the method of the present invention, the chiral center of the intermediate is directly generated in the first step of reaction, and the yield of the first step reaches 75%-80%, which is significantly higher than the conventional chiral resolution methods (about 40% yield), and the product has high chiral purity. The method of the present invention does not use anhydrous copper sulfate that pollutes the environment, which reduces the environmental pressure. The compound of p-methylthiobenzaldehyde and the compound of isocyanoacetate are used to react to form a chiral intermediate, which has higher material availability and efficiency than linear synthesis methods.

Provided is a compound of Formula (I):

##STR00001## wherein the variable groups are defined herein.

There are provided compounds of formula IIb, ##STR00001##
wherein LG.sup.1 represents imidazolyl, chloro or aryloxy, which compounds are useful in the preparation of compounds that have antiinflammatory activity (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

There are provided compounds of formula IIb, ##STR00001##
wherein LG.sup.1 represents imidazolyl, chloro or aryloxy, which compounds are useful in the preparation of compounds that have antiinflammatory activity (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

The present disclosure relates to HIF-2α inhibitors and methods of making and using them for treating cancer. Certain compounds were potent in HIF-2α scintillation proximity assay, luciferase assay, and VEGF ELISA assay, and led to tumor size reduction and regression in 786-O xenograft bearing mice in vivo.

Derivatives of an organic substance containing one or more groups selected from the group consisting of sulfanyl, selanyl and sulfino may be produced by reacting an organic substance containing one or more groups selected from the group consisting of sulfanyl, selanyl and sulfino with an olefin compound containing an ethylene structure having at least two electron-withdrawing groups except halogen atoms under an acidic condition to form a derivative of the organic substance