Indeno[1,2‐d]pyrido[1,2‐a]pyrimidines: A New Class of Receptor Tyrosine Kinase Inhibitors

Receptor tyrosine kinases (RTKs) are important mediators of signal transduction and play critical roles in cell growth, differentiation, metabolism, and apoptosis, and are deeply involved in oncogenesis. Binding of growth factors to the extracellular domains of RTKs leads to their dimerization, resulting in activation of the intracellular kinase domain, which eventually enables autophosphorylation at specific tyrosine residues. This family is also represented in oncogenic fusion proteins such as the Bcr-Abl protein of the Philadelphia chromosome. RTKs are organized into different families based on sequence homology and structural characteristics. There are more than 90 known protein kinase genes; 58 encode transmembrane receptor TKs distributed in 20 subfamilies, and 32 encode cytoplasmic non-receptor TKs distributed in 10 subfamilies. 2] Tyrosine kinases have been validated as suitable pharmacological targets for anticancer drugs, and several TK inhibitors have shown promising results in preclinical in vitro and in vivo models; others have been approved for the treatment in patients with cancer. This is best exemplified by the tyrosine kinase inhibitor imatinib (Gleevec), which has shown impressive activity against chronic myelogenous leukemia (CML) and has also been successful in the treatment of gastrointestinal stromal tumors, other leukemias, and solid tumors. The majority of the recently developed RTK inhibitors, including imatinib, target multiple mechanisms and are known as multiplex or multi-target tyrosine kinase inhibitors (MTKIs). A common characteristic of most of these drugs is that they are inhibitors of angiogenesis and also target additional receptors located on the surface of the cancer cell. Representative examples include the already approved and registered sunitinib and sorafenib, as well as AMG 706. Considering the observed development of tumor resistance to tyrosine kinase inhibitors and in order to circumvent drug-associated side effects, the discovery of new templates and their subsequent elaboration to clinically useful RTK inhibitors continues to be an important issue. Herein we report the discovery of a new class of cell-permeable RTK inhibitors belonging to the indeno ACHTUNGTRENNUNG[1,2-d]pyrido ACHTUNGTRENNUNG[1,2-a]pyrimidine-11,12dione class of compounds. Chemistry