Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo- [2,1-f][1,2,4]triazine based VEGFR-2 kinase inhibitors Robert M. Borzilleri, a Zhen-wei Cai, a Christopher Ellis, a Joseph Fargnoli, b Aberra Fura, c Tracy Gerhardt, b Bindu Goyal, a John T. Hunt, a Steven Mortillo, b Ligang Qian, a John Tokarski, d Viral Vyas, c Barri Wautlet, b Xioping Zheng a and Rajeev S. Bhide a, * a Departments of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, b Departments of Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4 c Departments of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeto NJ 08543-4000, USA d Departments of Structural Biology and Modeling, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA Received 2 December 2004; revised 23 December 2004; accepted 30 December 2004 Available online 22 January 2005 Abstract—A versatile synthesis of the suitably functionalized pyrrolo[2,1-f][1,2,4]triazine nucleus is described. SAR at the C C-6 positions of the 4-(3-hydroxy-4-methylphenylamino)pyrrolo[2,1-f][1,2,4]triazine template led to compounds with good potency against VEGFR-2 kinase. Glucuronidation of the phenol group is mitigated by incorporation of a basic amino group C-6 side chain of the pyrrolotriazine nucleus. Ó 2005 Elsevier Ltd. All rights reserved. Angiogenesis, the growth and expansion of blood vessels from preexisting vasculature, is involved in a variety of disease states that include diabetic retinopathy, rheuma- toid arthritis, and tumor growth. 1 Vascular endothelial growth factors(VEGF) and their cognatereceptors (VEGFR), are critically involved in multiple processes of angiogenesis that include increased vascular perme- ability, endothelial cell (EC) migration,proliferation, and survival. 2 Of these receptors, VEGFR-2 is predomi- nantly expressed on ECs and is involved in various as- pects of tumor angiogenesis.Consequently,this receptor tyrosine kinase has become an attractive target for the treatment of multiple tumor types. 3 Positive re- sults from the clinical trials of Bevacizumab (Avastin TM ), a monoclonalantibody against VEGF, demonstrated increased benefit in survival when used in combination with cytotoxic agents. 4 Accordingly, reduction in tumor growth via disruption of the VEGF pathway is a viable strategy for cancer therapy. We recently reported the discovery of the pyrrolotri- azine nucleus as a template for potent inhibitors of epi- dermalgrowth factor receptor (EGFR) and VEGFR-2 ( Fig. 1). 5 In that preliminary report, the structure–activ- ity relationships (SAR) focused on the effects of methyl substitution at the 5-, 6-, and 7-positions of pyrrolotri- azines containingdifferentC-4 aniline substituents. Herein we describe the expanded SAR studies of the 4-(3-hydroxyphenylamino)pyrrolotriazines on the inhi- bition of VEGFR-2 kinase activity.This paperalso highlightsa generalsynthesisof substituted C-5 and C-6 pyrrolotriazines, which provided an opportunity to improve the in vitro potency and metabolic stability of these compounds. 0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.12.079 Keywords: VEGFR-2; Angiogenesis; SAR; Kinase receptor. * Corresponding author. Tel.: +1 609 252 4395; fax: +1 609 252 6601; e-mail: rajeev.bhide@bms.com N N N HN R 5 R 6 OH Me 2 4 R 7 5 6 Figure 1.Generalstructure ofthe pyrrolo[2,1-f][1,2,4]triazine based VEGFR-2 inhibitors reported previously. 5 Bioorganic & Medicinal Chemistry Letters 15 (2005) 1429–1433