1912445-55-6Relevant articles and documents
Leveraging High-Throughput Experimentation to Drive Pharmaceutical Route Invention: A Four-Step Commercial Synthesis of Branebrutinib (BMS-986195)
Borovika, Alina,Fan, Junying,Forest, Robert V.,Geng, Peng,Guerrero, Carlos A.,Lou, Sha,Simmons, Eric M.,Skliar, Dimitri,Steinhardt, Sarah E.,Stevens, Jason M.,Strotman, Neil A.,Tan, Yichen
, (2022/03/01)
The invention of a commercial route to the Bruton's tyrosine kinase inhibitor branebrutinib (BMS-986195) in four total chemical steps is described. The execution of high-throughput experimentation (HTE) coupled with a first-principles approach across the proposed synthetic route enabled the identification of a novel indolization reaction that rapidly generated high synthetic complexity, as the centerpiece of the synthesis. A parallel HTE strategy during route design enabled the efficient and rapid evaluation of multiple options within a short timeframe to complete rigorous process development while mitigating the risks associated with implementing new chemistry featuring an aggressive disconnection strategy.
Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK)
Watterson, Scott H.,Liu, Qingjie,Beaudoin Bertrand, Myra,Batt, Douglas G.,Li, Ling,Pattoli, Mark A.,Skala, Stacey,Cheng, Lihong,Obermeier, Mary T.,Moore, Robin,Yang, Zheng,Vickery, Rodney,Elzinga, Paul A.,Discenza, Lorell,D'Arienzo, Celia,Gillooly, Kathleen M.,Taylor, Tracy L.,Pulicicchio, Claudine,Zhang, Yifan,Heimrich, Elizabeth,McIntyre, Kim W.,Ruan, Qian,Westhouse, Richard A.,Catlett, Ian M.,Zheng, Naiyu,Chaudhry, Charu,Dai, Jun,Galella, Michael A.,Tebben, Andrew J.,Pokross, Matt,Li, Jianqing,Zhao, Rulin,Smith, Daniel,Rampulla, Richard,Allentoff, Alban,Wallace, Michael A.,Mathur, Arvind,Salter-Cid, Luisa,Macor, John E.,Carter, Percy H.,Fura, Aberra,Burke, James R.,Tino, Joseph A.
, (2019/04/17)
Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fc receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.
Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK)
Watterson, Scott H.,Liu, Qingjie,Beaudoin Bertrand, Myra,Batt, Douglas G.,Li, Ling,Pattoli, Mark A.,Skala, Stacey,Cheng, Lihong,Obermeier, Mary T.,Moore, Robin,Yang, Zheng,Vickery, Rodney,Elzinga, Paul A.,Discenza, Lorell,D'Arienzo, Celia,Gillooly, Kathleen M.,Taylor, Tracy L.,Pulicicchio, Claudine,Zhang, Yifan,Heimrich, Elizabeth,McIntyre, Kim W.,Ruan, Qian,Westhouse, Richard A.,Catlett, Ian M.,Zheng, Naiyu,Chaudhry, Charu,Dai, Jun,Galella, Michael A.,Tebben, Andrew J.,Pokross, Matt,Li, Jianqing,Zhao, Rulin,Smith, Daniel,Rampulla, Richard,Allentoff, Alban,Wallace, Michael A.,Mathur, Arvind,Salter-Cid, Luisa,Macor, John E.,Carter, Percy H.,Fura, Aberra,Burke, James R.,Tino, Joseph A.
, p. 3228 - 3250 (2019/04/17)
Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fc receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.
PROCESS FOR PREPARING INDOLE CARBOXAMIDE COMPOUNDS
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, (2018/03/25)
Disclosed is a process for preparing (S)-4-(3-(but-2-ynamido)piperidin fluoro-2,3-dimethyl-lH-indole-7-carboxamide, comprising the steps of: preparing a compound of Formula (III); converting the compound of Formula (III) to a compound of Formula (V); and reacting the compound of Formula (V) with a compound of Formula (VI) to provide (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7- carboxamide.
INDOLE CARBOXAMIDE COMPOUNDS
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Paragraph 0787; 0854, (2016/05/19)
Disclosed are compounds of Formula (I): or a salt thereof, wherein: X is CR4 or N; R1, R2, R3, R4, and A are defined herein. Also disclosed are methods of using such compounds as inhibitors of Bruton's tyrosine kinase (Btk), and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
