On February 9, 2017, Bradner, James; Buckley, Dennis; Winter, Georg published a patent.Formula: C14H10N2O6 The title of the patent was Methods to induce targeted protein degradation through bifunctional molecules. And the patent contained the following:
The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to nucleic acids, polypeptides, cells, and methods for highly regulated, targeted degradation of proteins through the use of the bifunctional compounds A polynucleotide comprising a first nucleotide sequence encoding a first polypeptide to which a Targeting Ligand of formula I (wherein ring containing T1-T5 is (a) T1, T2, T4 = N; T3, T5 = C, or (b) T1 = N, T2 = O; T3-T5 = C; A1 is S and C=C; A2 is NH and derivatives and O; each R1 is independently C1-3 alkyl, (CH2)0-3CN, (CH2)0-3OH, etc.; R2 is H, C1-6 alkyl, (CH2)0-3heterocyclyl, etc.; R3 is independently C1-3 alkyl, (CH2)0-3CN, (CH2)0-3OH, etc.; R4 is C1-3 alkyl) is capable of binding, and a second nucleotide sequence encoding a second polypeptide, wherein the first polypeptide and the second polypeptide are linked together with a peptide bond to form a fused polypeptide, is claimed. Example compound II was prepared by acylation of N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide trifluoroacetate with (S)-2-(4-(4-cyanophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid. Exemplified compounds I demonstrated to have potent biol. activities, e.g., binding to the protein target, mediating protein degradation, etc. (data given). The title bifunctional compounds Degron-Linker-Targeting Ligand [Degron = I (ring A = II, III; Y = a bond, O, NH, etc.; X = C(O), C(R3); X1-X2 = C(R3):N or C(R3)2C(R3)2; R1 = halo, NO2, NH2, etc.; R3 = H, alkyl optionally substituted with aryl or 5-10 membered heteroaryl; each R31 = (independently) alkyl; R4 = (independently) H or alkyl; or two R4, together with the carbon atom to which they are attached, form C(O), carbocycle, or 4-6 membered heterocycle comprising 1-2 heteroatoms selected from N and O; R5 = H, alkyl, F or Cl; n = 0-2; m = 0-3; t = 0-1); Linker = IV (p1 = 0-12; p2 = 0-12; p3 = 0-6; each W = (independently) absent, CH2, O, S, NH or NR5; Z = absent, CH2, O, NH or NR5; each R5 = (independently) alkyl; Q = absent, C(O)NH, C(O)O, etc.); Targeting Ligand = V (ring containing T1-T5 = (a) T1, T2, T4 = N; T3, T5 = C, or (b) T1 = N, T2 = O; T3-T5 = C; A1 = S or C:C; A2 = NR15 or O; nn1 = 0-2; each R11 = (independently) alkyl, (CH2)0-3CN, (CH2)0-3halogen, etc.; R12 = H, alkyl, (CH2)0-3heterocyclyl, etc.; nn2 = 0-3; each R13 = alkyl, (CH2)0-3CN, (CH2)0-3halogen, etc.; R14 = alkyl; R15 = H or alkyl); with the proviso] which act as protein degradation inducing moieties, were prepared E.g., a multi-step synthesis of VI, starting from JQ1 (VII), was described. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the title bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. Exemplified compounds I demonstrated to have potent biol. activities, e.g., binding to the protein target (e.g. BRD4), mediating protein degradation, etc. (data given). The present application also provides methods for making compounds of the application and intermediates thereof. The experimental process involved the reaction of 2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxylic acid(cas: 1216805-11-6).Formula: C14H10N2O6
The Article related to bifunctional compound preparation targeted protein degradation inducer, Heterocyclic Compounds (More Than One Hetero Atom): Diazepines and other aspects.Formula: C14H10N2O6
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem