Pyrazolo[3,4-d]pyrimidines as potent inhibitors of the insulin-like growth factor receptor (IGF-IR) Robert D. Hubbard, * Nwe Y. Bamaung, Fabio Palazzo, Qian Zhang, Peter Kovar, Donald J. Osterling, Xiaoming Hu, Julie L. Wilsbacher, Eric F. Johnson, Jennifer Bouska, Jieyi Wang, Randy L. Bell, Steven K. Davidsen and George S. Sheppard Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA Received 2 July 2007; revised 11 July 2007; accepted 12 July 2007 Available online 25 July 2007 Abstract—A high throughput screen of Abbott’s compound repository revealed that the pyrazolo[3,4-d]pyrimidine class of kinase inhibitors possessed moderate potency for IGF-IR, a promising target for cancer chemotherapy. The synthesis and subsequent opti- mization of this class of compounds led to the discovery of 14, a compound that possesses in vivo IGF-IR inhibitory activity. Ó 2007 Elsevier Ltd. All rights reserved. Receptor tyrosine kinases (RTKs) have recently become validated targets for cancer chemotherapy. The clinical successes of agents that inhibit RTKs, such as Bcr-Abl (Gleevec Ò ), EGFR (Tarceva Ò ), and EGFR/ErbB-2 (Tykerb Ò ), have revealed that a variety of RTKs can be successfully exploited for cancer treatment. 1 There- fore, the search for additional RTKs has led to the pro- posal that small-molecule inhibitors of the insulin-like growth factor receptor (IGF-IR) might yield effective anti-cancer agents. 2 IGF-IR is a member of a complex system of growth factors and receptors that includes the following: insulin receptor (IR), insulin-like growth factor I/II (IGF-I/IGF-II), and six insulin-like growth factor binding proteins. 3 The complexity of the signaling family is further increased due to the presence of hybrid receptors, which are composed of both IGF-IR and IR. 4 In normal tissue, IGF-IR is essential for growth, devel- opment, and the suppression of apoptosis. This is a con- sequence of the ability of IGF-IR to simultaneously activate the anti-apoptotic phosphoinositide-3-kinase/ Akt pathway, and the mitogenic extracellular signal reg- ulated kinase (ERK)/mitogen-activated protein kinase pathway. 5 In malignant cells, the ability of IGF-IR to simultaneously control both the pro-survival and the proliferative aspects of the cellular machinery allows these cells to avoid apoptosis, induce the production of key angiogenic factors, and promote tumor cell invasion. 6 A variety of approaches have been or are currently being employed to target IGF-IR, which include antibodies to the extracellular domain of the receptor, dominant-neg- ative receptor proteins, antisense RNA, siRNA, and small-molecule inhibitors. 7 The latter agents can be di- vided into roughly two categories, substrate inhibitors of IGF-IR 8 and ATP-competitive inhibitors of IGF- IR. 9 One of the first examples of an ATP-competitive inhibitor of IGF-IR in both enzymatic and cellular as- says was recently disclosed (1, NVP-ADW742, Fig. 1). 10 Prior to the completion of our SAR efforts, compound 2 was reported to also possess IGF-IR enzy- matic and cellular activity. 11 During a high throughput screen of our compound repository, we noted that the pyrazolopyrimidine class of kinase inhibitors, such as 3 possessed moderate potency for IGF-IR. 12 The remainder of this communication will focus on the syn- thesis and IGF-IR inhibitory properties of this promis- ing class of compounds. The synthesis of the pyrazolopyrimidines begins with boronation of the appropriate bromide 5 with diborane reagent 4 to afford 6 in 85–99% yield (Scheme 1). The known ketone 7 was treated with morpholine and for- mic acid, which after recrystallization from DMF/IPA afforded the desired trans-diastereomer, 13 which was re- acted with the aforementioned boronates 6 under Suzuki 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.07.037 Keywords: Insulin-like growth factor receptor (IGF-IR); Kinase; Inhi- bitor; Pyrazolo[3,4-d]pyrimidine. * Corresponding author. Tel.: +1 847 936 9242; fax: +1 847 935 5165; e-mail: robert.d.hubbard@abbott.com Bioorganic & Medicinal Chemistry Letters 17 (2007) 5406–5409