1188302-00-2Relevant articles and documents
Development of a Practical and Greener Process for the Dual Leucine Zipper Kinase Inhibitor GDC-0134 Comprising Two SNAr Reactions, Oxidation and Suzuki Coupling
Hoffmann-Emery, Fabienne,Niedermann, Katrin,Rege, Pankaj D.,Konrath, Manuel,Lautz, Christian,Kraft, Anne Katrin,Steiner, Carine,Bliss, Fritz,Hell, André,Fischer, Rolf,Carrera, Diane E.,Beaudry, Danial,Angelaud, Remy,Malhotra, Sushant,Gosselin, Francis
, p. 313 - 322 (2022/02/01)
A sustainable second-generation process for GDC-0134 was developed with a particular focus on safety and greenness, while complying with strong specifications to supply pivotal clinical studies. Through these efforts, we discovered solvents to replace the solvents classified as substances of very high concern by the REACH regulation in two SNAr steps. We further established a safer and faster way to oxidize the sulfanyl to the sulfonyl intermediate by dosing H2O2 at higher temperatures, reducing accumulation while minimizing uncontrolled H2O2 decomposition. The reaction conditions for the Suzuki coupling and the second SNAr were modified to increase the selectivity in these two steps. A change in the solvent for the final crystallization allowed operation at higher concentrations and delivery of a highly pure active pharmaceutical ingredient (API). The new improved process reduced the process mass intensity by approximately 40% and was successfully used to produce 150 kg of GDC-0134.
PYRAZOLE DERIVATIVES AND USES THEREOF AS INHIBITORS OF DLK
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, (2015/07/07)
The present invention provides for compounds of formula 0 and various embodiments thereof, and compositions comprising compounds of formula 0 and various embodiments thereof. In compounds of formula 0, the groups R1A, R1B, R1C, R1D, R2, R3, R4, R5 and R6 have the meaning as described herein. The present invention also provides for methods of using compounds of formula 0 and compositions comprising compounds of formula 0 as DLK inhibitors and for treating neurodegeneration diseases and disorders.
3-SUBSTITUTED PYRAZOLES AND USE AS DLK INHIBITORS
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, (2014/08/06)
The present invention provides for compounds of Formula (I) and various embodiments thereof, and compositions comprising compounds of Formula (I) and various embodiments thereof. (I) In compounds of Formula I, the groups R1, R2, R3, R4, R5, R6 and R7 have the meaning as described herein. The present invention also provides for methods of using compounds of Formula I and compositions comprising compounds of Formula (I) as DLK inhibitors and for treating neurodegeneration diseases and disorders.
