Discovery and SAR of a series of 3-[(6-piperidine-4-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-ones as IGF-1 receptor kinase inhibitors

MEDI 363

Peiying Liu, peiying.liu@bms.com1, Upender Velaparthi1, Mark D. Wittman, mark.wittman@bms.com2, Mark G. Saulnier1, K. Zimmermann3, Xiaopeng Sang, xiaopeng.sang@bms.com1, David B. Frennesson4, Francis Y. Lee5, Joan Carboni6, Ann Greer6, Aixin Li6, Ricardo Attar, Ricardo.Attar@bms.com6, Marco Gottardis7, Zheng Yang6, and Dolatrai M. Vyas8. (1) Discovery Chemistry, Bristol Myers Squibb Co, Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, (2) Bristol-Myers Squibb Co, Pharmaceutical Research Institute, Wallingford, CT, 5 Research Parkway, Wallingford, CT 06492-7660, (3) Pharmaceutical Research Institute, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, (4) Infectious Disease Chemistry, Bristol Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, (5) Oncology Drug Discovery, Bristol Myers Squibb Co, Pharmaceutical Research Institute, Route 206 and Province Line Rd, Princeton, NJ 08543, (6) Bristol-Myers Squibb Co, Pharmaceutical Research Institute, Princeton, NJ, Rt 206 and Province Line Rd, Princeton, NJ 08543, (7) Oncology Drug Discovery, Bristol-Myers Squibb Co, Pharmaceutical Research Institute, Princeton, NJ, Route 206 and Province Line Rd, Princeton, NJ 08543, (8) Discovery Chemistry, Bristol Myers Squibb Co, Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492
Signaling through the insulin-like growth factor I (IGF-1R) pathway mediates events which promote the malignant phenotype such as mitogenisis (via stimulation of signaling cascades through Ras/Raf/MARK kinase) and cell survival (via activation of the PI3K/Akt/mTor kinase pathway). Epidemiological studies have shown that elevated IGF-1 levels correlate with increased risk of developing colon, breast, prostate, and lung tumors. Previously we reported BMS-536924 as a new small molecule kinase inhibitor of IGF-1R with robust efficacy in IGF-Sal tumor model. As part of our continuous efforts toward the identification of IGF-1 receptor kinase inhibitors with improved enzyme and cell potency, we have recently identified a novel series of 3-[(6-piperidine-4-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one derivatives. The synthesis and detailed SAR of this series as IGF-1 receptor kinase inhibitors are presented.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007