The present disclosure provides compounds that are cGAS antagonists, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy.

The present invention provides IP4-4,6 substituted derivatives, their methods of synthesis and their uses. In some aspects, the IP4-4,6 derivative is a compound of formula I wherein R.sub.1, R.sub.3, R.sub.7, and R.sub.11 are OPO.sub.3.sup.2?, and R.sub.5 and R.sub.9 are selected from the group consisting of O(Alkyl).sub.nX, O(Alkyl).sub.yCy(Alkyl.sub.2).sub.y-Z, O(Alkyl).sub.yA(Alkyl).sub.y-Z, and their thiophosphate analogs. Also provided are methods, pharmaceutical compositions and formulations, methods of use, articles of manufacture, and kits for the treatment of diseases and conditions such as pathological crystallization-related diseases and conditions.

Compounds having activity as PKM2 activators are disclosed. The compounds have the following structure (I): ##STR00001##
including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

There are provided compounds of formula I,

##STR00001##

wherein R.sup.1A to R.sup.1E, R.sup.2 to R.sup.4, R.sup.5a, L and X.sup.1 to X.sup.3 have meanings given in the description, which compounds have anti-inflammatory 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; and Z.sup.1 represents a structural fragment of formula V: ##STR00002##
wherein R.sup.2 to R.sup.4, R.sup.5a, L and X.sup.1 to X.sup.3 have meanings given in the description, or a salt or protected derivative thereof, wherein said protected derivative is a compound in which the carboxyl moiety of R.sup.4 is protected as a C.sub.1-8 alkyl ester. The compounds have antiinflammatory activity, for example 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.

Provided are phosphonopyrazole-based phosphohistidine analogs that are useful as haptens for the preparation of immunogens, immunogens that include these haptens linked to carrier molecules, antibodies thereto and uses of these antibodies, haptens, immunogens and phosphohistidine analogs. The invention is based in part on new pHis analogs that are chemically stable and which have been used as haptens and immunogens to generate specific anti-pHis antibodies that bind with high affinity and specificity.

In one aspect, the invention relates to compounds having the formula XII: ##STR00001##
where R.sup.a, R.sup.b, R.sup.2, R.sup.7, and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds described herein are prodrugs of compounds having neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising these compounds; methods of using these compounds; and processes and intermediates for preparing these compounds.

Disclosed herein are novel quinone methide analog precursors and embodiments of a method and a kit of using the same for detecting one or more targets in a biological sample. The method of detection comprises contacting the sample with a detection probe, then contacting the sample with a labeling conjugate that comprises an enzyme. The enzyme interacts with a quinone methide analog precursor comprising a detectable label, forming a reactive quinone methide analog, which binds to the biological sample proximally to or directly on the target. The detectable label is then detected. In some embodiments, multiple targets can be detected by multiple quinone methide analog precursors interacting with different enzymes without the need for an enzyme deactivation step.

Disclosed herein are novel quinone methide analog precursors and embodiments of a method and a kit of using the same for detecting one or more targets in a biological sample. The method of detection comprises contacting the sample with a detection probe, then contacting the sample with a labeling conjugate that comprises an enzyme. The enzyme interacts with a quinone methide analog precursor comprising a detectable label, forming a reactive quinone methide analog, which binds to the biological sample proximally to or directly on the target. The detectable label is then detected. In some embodiments, multiple targets can be detected by multiple quinone methide analog precursors interacting with different enzymes without the need for an enzyme deactivation step.

Compounds having activity as PKM2 activators are disclosed. The compounds have the following structure (I):

##STR00001##

including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.