The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, and methods of making and using thereof.

The present invention relates to inhibitors of histone deacetylases, in particular HDAC8, that are useful for the treatment of cancer and other diseases and disorders, as well as the synthesis and applications of said inhibitors.

The present invention relates to inhibitors of histone deacetylases, in particular HDAC8, that are useful for the treatment of cancer and other diseases and disorders, as well as the synthesis and applications of said inhibitors.

The present invention relates to a process to prepare ethyleneamines of the formula NH.sub.2—(C.sub.2H.sub.4—NH—).sub.pH wherein p is at least 2 wherein one or more units —NH—C.sub.2H.sub.4—NH— are present as a piperazine unit or precursors thereof wherein optionally one or more units —NH—C.sub.2H.sub.4—NH— are present as a cyclic ethylene urea unit or between two units —NH—C.sub.2H.sub.4—NH— a carbonyl moiety is present, by reacting an ethanolamine-functional compound, an amine-functional compound in the presence of a carbon oxide delivering agent, wherein at least one of the amine-functional compound or the ethanolamine-functional compound contains a piperazine unit, and the reaction is performed in a liquid that comprises water. ##STR00001##

The present invention relates to a process to prepare ethyleneamines of the formula NH.sub.2—(C.sub.2H.sub.4—NH—).sub.pH wherein p is at least 2 wherein one or more units —NH—C.sub.2H.sub.4—NH— are present as a piperazine unit or precursors thereof wherein optionally one or more units —NH—C.sub.2H.sub.4—NH— are present as a cyclic ethylene urea unit or between two units —NH—C.sub.2H.sub.4—NH— a carbonyl moiety is present, by reacting an ethanolamine-functional compound, an amine-functional compound in the presence of a carbon oxide delivering agent, wherein at least one of the amine-functional compound or the ethanolamine-functional compound contains a piperazine unit, and the reaction is performed in a liquid that comprises water. ##STR00001##

A process for preparing polyethyleneamines of formula NH2-(CH2-CH2-NH-)pH wherein p is at least 3 and wherein one or more —NH-CH2-CH2-NH— units may be piperazine units and/or ethylene urea derivatives of these compounds, includes reacting monoethylene glycol with an amine-functional compound having at least two —NH— units, of which at least one is selected from primary amine groups and cyclic secondary amine groups, in the presence of a carbon oxide-delivering agent. The amine-functional compound includes at least one —NH-CH2-CH2-NH— unit, and one or more —NH-CH2-CH2-NH— units may be in the form of cyclic ethylene urea moieties, piperazine moieties, or linear ethylene urea moieties. The molar ratio of amine-functional compound to monoethylene glycol is above 1.2:1 and the molar ratio of carbon oxide delivering agent to —NH-CH2-CH2-NH— units is at least 0.5:1. The process makes it possible to obtain ethylene amines and derivatives thereof without using ammonia or metal-containing catalysts.

A process for preparing polyethyleneamines of formula NH2-(CH2-CH2-NH-)pH wherein p is at least 3 and wherein one or more —NH-CH2-CH2-NH— units may be piperazine units and/or ethylene urea derivatives of these compounds, includes reacting monoethylene glycol with an amine-functional compound having at least two —NH— units, of which at least one is selected from primary amine groups and cyclic secondary amine groups, in the presence of a carbon oxide-delivering agent. The amine-functional compound includes at least one —NH-CH2-CH2-NH— unit, and one or more —NH-CH2-CH2-NH— units may be in the form of cyclic ethylene urea moieties, piperazine moieties, or linear ethylene urea moieties. The molar ratio of amine-functional compound to monoethylene glycol is above 1.2:1 and the molar ratio of carbon oxide delivering agent to —NH-CH2-CH2-NH— units is at least 0.5:1. The process makes it possible to obtain ethylene amines and derivatives thereof without using ammonia or metal-containing catalysts.

The invention is directed to substituted bridged cycloalkane derivatives. Specifically, the invention is directed to compounds according to Formula IIIQ:

##STR00001##

wherein X.sup.6′, a, b, C.sup.8′, D.sup.8′, L.sup.82′, L.sup.83′, R.sup.81′, R.sup.82′, R.sup.83′, R.sup.84′, R.sup.85′, R.sup.86′, z.sup.82′, z.sup.84′, z.sup.85′, and z.sup.86′ are as defined herein; or salts thereof.

The compounds of the invention are inhibitors of the ATF4 pathway. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting the ATF4 pathway and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

The invention is directed to substituted bridged cycloalkane derivatives. Specifically, the invention is directed to compounds according to Formula IIIQ:

##STR00001##

wherein X.sup.6′, a, b, C.sup.8′, D.sup.8′, L.sup.82′, L.sup.83′, R.sup.81′, R.sup.82′, R.sup.83′, R.sup.84′, R.sup.85′, R.sup.86′, z.sup.82′, z.sup.84′, z.sup.85′, and z.sup.86′ are as defined herein; or salts thereof.

The compounds of the invention are inhibitors of the ATF4 pathway. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting the ATF4 pathway and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, and methods of making and using thereof.