Abstract: This disclosure relates to substituted urea eIF2? kinase activators including methods of making and using the same. For example, such activators can include cycloalkyl aryl ureas, which activate at least one eIF2? kinase. These compounds may be useful for treatment of diseases such as, for example, cancer, hemolytic anemia not caused by infectious agents, Wolcott-Rallison syndrome, neurodegenerative disease, tuberous sclerosis complex, fragile-X syndrome, autism spectrum disorder, and ribosomal defect disease.