In anaplastic large cell lymphomas, chromosomal translocations involving the kinase domain of anaplastic lymphoma kinase (ALK), generally fused to the 5' part of the nucleophosmin gene, produce highly oncogenic ALK fusion proteins that deregulate cell cycle, apoptosis, and differentiation in these cells. Other fusion oncoproteins involving ALK kinase, such as echinoderm microtubule-associated protein-like 4-ALK, have recently been found in patients with non-small cell lung cancer, breast, and colorectal patients. Research has recently focused on developing inhibitors for targeted therapy of these ALK-positive tumours. Because kinase inhibitors that target the inactive conformation are thought to be more specific than ATP-targeted inhibitors, we therefore investigated the possibility of using two known inhibitors targeting inactive kinases, doramapimod and sorafenib, to design new urea derivatives as ALK inhibitors. We generated a homology model of ALK in its inactive conformation complexed to doramapimod or sorafenib in its active site. The results elucidated why doramapimod is a weak inhibitor and why sorafenib is an inactive inhibitor of ALK. Virtual screening of commercially available compounds using the homology model of ALK yielded candidate inhibitors, and these were tested using biochemical assays. Herein, we present the design, synthesis and biological activity as well as structure-activity relationships of a novel series of urea compounds as potent ALK inhibitors. Some compounds showed inhibition of purified ALK in the high nanomolar range and selective antiproliferative activity on ALK-positive cells.