On May 31, 2018, Gray, Nathanael S.; Dobrovolsky, Dennis; Huang, Hai-Tsang published a patent.Application In Synthesis of 3,5-Dibromo-1-methylpyrazin-2(1H)-one The title of the patent was Degradation of Bruton’s tyrosine kinase (BTK) by conjugation of BTK inhibitors with E3 ligase ligand and methods of use. And the patent contained the following:
The present invention provides bifunctional compounds Targeting Ligand-Linker-Degron [I; the Targeting Ligand (TL) is capable of binding to one or more protein kinases (TL = II [B = (un)substituted Ph or 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, S; when Y1 is absent, B is bonded to a carbon atom or Y4 in III; Y1 = absent or C(O), wherein Y1 is bonded to a carbon atom or Y4 in III; Y2 = O or NR10a; Y3 = C(O)NR10b or NR10bC(O); Y4 = NR51 or, when Y1 is bonded to Y4 or when Y1 is absent and B is bonded to Y4, Y4 = N (wherein R51 = H, alkyl, haloalkyl, etc.); each R5 = alkyl, haloalkyl, alkoxy, etc.; R6 = H, alkyl, haloalkyl; each R7 = alkyl, haloalkyl, alkoxy, etc.; each R8 = alkyl, haloalkyl, alkoxy, etc.; R9 = alkyl, haloalkyl, alkoxy, etc.; R10a and R10b = H, alkyl or haloalkyl; o1, o2 or o3 = 0-3], etc.); the Linker is a group that covalently binds to the Targeting Ligand and the Degron; and the Degron is capable of binding to a ubiquitin ligase] or enantiomers, diastereomers, or stereoisomers thereof, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, which act as protein degradation inducing moieties for Bruton’s tyrosine kinase (BTK). Compound IV was prepared in a multi-step synthesis, starting from tert-Bu piperazine-1-carboxylate and 4-nitrobenzoic acid. The present application also relates to methods for the targeted degradation of BTK through the use of the bifunctional compounds I that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to BTK which can be utilized in the treatment of disorders modulated by BTK. Exemplified compound IV was tested and showed BTK degradation in the cell assay. Pharmaceutical composition comprising compound I was disclosed. The experimental process involved the reaction of 3,5-Dibromo-1-methylpyrazin-2(1H)-one(cas: 87486-34-8).Application In Synthesis of 3,5-Dibromo-1-methylpyrazin-2(1H)-one
The Article related to bifunctional compound preparation protein btk degradation inducer ubiquitin ligase, antitumor bifunctional compound preparation bruton’s tyrosine kinase btk inhibitor, Heterocyclic Compounds (One Hetero Atom): Pyridines and other aspects.Application In Synthesis of 3,5-Dibromo-1-methylpyrazin-2(1H)-one