Applicants have developed an amplification system and methodology for IHC and ISH staining that utilizes click chemistry to covalently bind reporter molecules to tissue.

The present disclosure relates to novel synthetic method of making 1, 4-diazo N-heterocycles via intermolecular amphoteric diamination of allenes, and to the compounds made by the novel synthetic method.

Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NK.sub.1) receptor. The compounds have the general formula (I):

##STR00001##

This disclosure provides compounds with Bcl inhibitory activity based on a new chemical scaffold. Phosphonamidate compounds typically include a P-phenyl phosphonamidate moiety which is substituted with an N-aryl or N-heteroaryl group. The P-phenyl phosphonamidate moiety may be optionally substituted at phosphorus with thio (S) instead of oxo (O), and/or with a thioxy group or a second amino group instead of an oxy group. One of the heteroatoms attached to phosphorus may be cyclically linked to the N-substituted nitrogen atom that is attached to the phosphorus to provide a heterocyclic ring. By incorporating such a cyclic constraint between two phosphorus substituents of the core linking moiety, a favorable binding conformation may be promoted in the compounds. Selected compounds promote apoptosis in senescent cells, and can be developed for treating senescent-related conditions, such as osteoarthritis, ophthalmic disease, pulmonary disease, and atherosclerosis. Selected compounds promote apoptosis in cancer cells, and can be developed as chemotherapeutic agents.

An optically active 2,3-bisphosphinopyrazine derivative represented by the following general formula (1):

##STR00001##

wherein R.sup.1 represents a group selected from a branched alkyl group having 3 or more carbon atoms, an adamantyl group, an optionally substituted cycloalkyl group, and an optionally substituted aryl group; R.sup.2 represents a group selected from a branched alkyl group having 3 or more carbon atoms, an adamantyl group, and an optionally substituted cycloalkyl group, provided that when R.sup.1 is a tert-butyl group, R.sup.1 and R.sup.2 are not the same; R.sup.3 represents a monovalent substituent; n represents an integer of 0 to 4; and * represents an asymmetric center on a phosphorus atom.

The present disclosure relates to novel synthetic method of making 1, 4-diazo N-heterocycles via intermolecular amphoteric diamination of allenes, and to the compounds made by the novel synthetic method.

The invention features compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use.

##STR00001##

Compounds represented by Formula (I) and (II) and salts thereof are described herein. The compounds or salts of Formula (I) and (II) may be used to treat senescence-associated diseases and disorders.

##STR00001##

Disclosed are compounds of Formulas (I), (II), (III), (IV), and (V):

##STR00001##

and/or a salt thereof, wherein R.sub.1 is OH or OP(O)(OH).sub.2, and X.sub.1, X.sub.2, X.sub.3, R.sub.2, R.sub.2a, R.sub.a, R.sub.b, and R.sub.c are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P.sub.1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

The present disclosure provides reagents that can be used to label synthetic oligonucleotides with rhodamine dyes or dye networks that contain rhodamine dyes.