Reactions that directly install nitrogen into CH bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Selective intramolecular CH amination reactions that achieve high levels of reactivity, while maintaining excellent site-selectivity and functional-group tolerance is a challenging problem. Herein is reported a manganese perchlorophthalocyanine catalyst [Mn.sup.III(ClPc)] for intermolecular benzylic CH amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site-selectivity. In the presence of Brnsted or Lewis acid, the [Mn.sup.III(ClPc)]-catalyzed CH amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies indicate that CH amination proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where CH cleavage is the rate-determining step of the reaction. Collectively these mechanistic features contrast previous base-metal catalyzed CH aminations.

Reactions that directly install nitrogen into CH bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Selective intramolecular CH amination reactions that achieve high levels of reactivity, while maintaining excellent site-selectivity and functional-group tolerance is a challenging problem. Herein is reported a manganese perchlorophthalocyanine catalyst [Mn.sup.III(ClPc)] for intermolecular benzylic CH amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site-selectivity. In the presence of Brnsted or Lewis acid, the [Mn.sup.III(ClPc)]-catalyzed CH amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies indicate that CH amination proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where CH cleavage is the rate-determining step of the reaction. Collectively these mechanistic features contrast previous base-metal catalyzed CH aminations.

The invention relates to new benzonitrile derivatives of the formula (I) wherein R.sup.1 to R.sup.3 and A are as defined in the description and Claims, to their medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.

##STR00001##

Described herein are compounds, pharmaceutical compositions and medicaments that include such compounds, and methods of using such compounds to modulate transient receptor potential vanilloid 1 receptor (TRPV1) activity.

Novel thioalkylcarboxylate-modified CDs and pharmaceutical compositions comprising these thioalkylcarboxylate-modified CDs are disclosed, as well as methods of using the disclosed thioalkylcarboxylate-modified CDs and pharmaceutical compositions thereof to neutralize or reduce undesired effects or symptoms associated with one or more fentanyl related compounds in a subject in need thereof. The use of the disclosed thioalkylcarboxylate-modified CDs to detect the presence of one or more fentanyl related compounds in a sample is also disclosed, which comprises contacting the sample with said thioalkylcarboxylate-modified CDs or a composition comprising these CDs.

Novel thioalkylcarboxylate-modified CDs and pharmaceutical compositions comprising these thioalkylcarboxylate-modified CDs are disclosed, as well as methods of using the disclosed thioalkylcarboxylate-modified CDs and pharmaceutical compositions thereof to neutralize or reduce undesired effects or symptoms associated with one or more fentanyl related compounds in a subject in need thereof. The use of the disclosed thioalkylcarboxylate-modified CDs to detect the presence of one or more fentanyl related compounds in a sample is also disclosed, which comprises contacting the sample with said thioalkylcarboxylate-modified CDs or a composition comprising these CDs.

Provided herein, inter alia, are methods and compounds for inhibiting K-Ras and for treating cancer.

The disclosure features amino lipids and compositions involving the same. Nanoparticle compositions include an amino lipid as well as additional lipids such as phospholipids, structural lipids, PEG lipids, or a combination thereof. Nanoparticle compositions further including therapeutic and/or prophylactic agents such as RNA are useful in the delivery of therapeutic and/or prophylactic agents to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.

The disclosure features amino lipids and compositions involving the same. Nanoparticle compositions include an amino lipid as well as additional lipids such as phospholipids, structural lipids, PEG lipids, or a combination thereof. Nanoparticle compositions further including therapeutic and/or prophylactic agents such as RNA are useful in the delivery of therapeutic and/or prophylactic agents to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.

The invention provides amides that inhibit cellular necrosis and/or human receptor interacting protein 1 kinase (RIP1), including corresponding sulfonamides, and pharmaceutically acceptable salts, hydrates and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition.