- PROCESS FOR PREPARING TETRAHYDROCARBAZOLE CARBOXAMIDE COMPOUND
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Disclosed is a process for preparing Compound 8: (8) comprising the step of reacting Compound of 7: (7) wherein R is C1-8 alkyl or benzyl in the presence of a base. Also disclosed are intermediates and processes for preparing the intermediates.
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Page/Page column 58
(2018/07/29)
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- Adventures in Atropisomerism: Total Synthesis of a Complex Active Pharmaceutical Ingredient with Two Chirality Axes
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A strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.
- Beutner, Gregory,Carrasquillo, Ronald,Geng, Peng,Hsiao, Yi,Huang, Eric C.,Janey, Jacob,Katipally, Kishta,Kolotuchin, Sergei,La Porte, Thomas,Lee, Andrew,Lobben, Paul,Lora-Gonzalez, Federico,Mack, Brendan,Mudryk, Boguslaw,Qiu, Yuping,Qian, Xinhua,Ramirez, Antonio,Razler, Thomas M.,Rosner, Thorsten,Shi, Zhongping,Simmons, Eric,Stevens, Jason,Wang, Jianji,Wei, Carolyn,Wisniewski, Steven R.,Zhu, Ye
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p. 3736 - 3740
(2018/07/25)
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- Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers
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Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fc? receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.
- Watterson, Scott H.,De Lucca, George V.,Shi, Qing,Langevine, Charles M.,Liu, Qingjie,Batt, Douglas G.,Beaudoin Bertrand, Myra,Gong, Hua,Dai, Jun,Yip, Shiuhang,Li, Peng,Sun, Dawn,Wu, Dauh-Rurng,Wang, Chunlei,Zhang, Yingru,Traeger, Sarah C.,Pattoli, Mark A.,Skala, Stacey,Cheng, Lihong,Obermeier, Mary T.,Vickery, Rodney,Discenza, Lorell N.,D'Arienzo, Celia J.,Zhang, Yifan,Heimrich, Elizabeth,Gillooly, Kathleen M.,Taylor, Tracy L.,Pulicicchio, Claudine,McIntyre, Kim W.,Galella, Michael A.,Tebben, Andy J.,Muckelbauer, Jodi K.,Chang, Chiehying,Rampulla, Richard,Mathur, Arvind,Salter-Cid, Luisa,Barrish, Joel C.,Carter, Percy H.,Fura, Aberra,Burke, James R.,Tino, Joseph A.
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p. 9173 - 9200
(2016/10/22)
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- SUBSTITUTED TETRAHYDROCARBAZOLE AND CARBAZOLE CARBOXAMIDE COMPOUNDS
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Disclosed are compounds of Formula (I) wherein: the two dotted lines represent either two single or two double bonds; Q is: R1 is F, Cl, —CN, or —CH3; R2 is Cl or —CH3; R3 is —C(CH3)2OH or —CH2CH2OH; Ra is H or —CH3; each Rb is independently F, Cl, —CH3, and/or —OCH3; and n is zero, 1, or 2. 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.
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Paragraph 0631 - 0633
(2015/01/07)
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