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[0012]
A general limitation associated with conventional occupancy-driven target inhibition approaches is that they often require systemic target engagement, which requires sustained high concentrations of potent small molecule inhibitors over prolonged periods of time
This enhances off-target effects and can lead to unwanted side effects or toxicity in the therapeutic setting
Method used
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preparation example Construction
[0236] Preparation process of 3-fluorohydroxyproline (F-HYP)
[0237] As indicated above, applicants have developed a novel process for the preparation of 3-fluoro-hydroxyproline intermediate compounds for the preparation of compounds of formula A. Compounds of formula A comprising, for example, a 3-fluoro-hydroxyproline central scaffold are useful for providing novel VHL binding ligand compounds of structures A-L comprising a 3-fluoro-hydroxyproline central scaffold. The general procedure for providing two such 3-fluoro-hydroxyprolines, novel VHL conjugates with a central scaffold of 3-fluoro-hydroxyproline, and PROTACs of structure A-L-B, wherein formula A The compounds are based on the 3-fluoro-hydroxyproline central scaffold.
[0238] Fluoroprolines are fluorinated amino acids that are readily obtained from the interconversion of the hydroxyproline functional group. (2S,4R)-4-hydroxyproline, or L-hydroxyproline (C 5 h 9 o 3 N), with the chemical name 4-hydroxypyrrolid...
Embodiment
[0304] Example compound 18e: (2R, 3S, 4S)-1-((S)-1-(4-((2S, 4R)-1-acetyl-4-(4-chlorobenzyl)-2-methyl Base-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-12-(tert-butyl)-1,10-dioxo-5,8-dioxa-2,11- Diazatridecane-13-yl)-3-fluoro-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;
[0305] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, hydrate, solvate, or polycrystal thereof.
[0306] As discussed above, there is provided a PROTAC compound having the structure A-L-B, wherein A is an E3 ubiquitin ligase protein-binding ligand compound of formula I, preferably of formula IA, wherein L and B are any of the above detailed descriptions. In one aspect, wherein the L group is in the R 1 , R 3 , R 4 , R 5 or R 8 The position is directly bound to the compound of formula I or IA. L group in R 1 , R 3 , R 4 , R 5 or R 8 Exemplary compounds at positions that bind directly to compounds of Formula I or IA are provided in Groups I to V below.
[0307]...
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Abstract
There is provided novel small molecule E3 ubiquitin ligase protein binding ligand compounds, and to their utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for their preparationthereof, and use in medicine. There is particularly provided novel small molecule E3 ubiquitin ligase protein binding inhibitorcompounds based on a fluorohydroxyproline scaffold, to their utility asligands in synthesizing novel PROTACs, and to synthetic methods therefor.
Description
technical field [0001] The present invention relates to a novel small molecule E3 ubiquitin ligase protein-binding ligand compound and inhibitor, and relates to its application in protein degradation targeting chimeras (PROTACs), its preparation process, and its application in medicine . The invention particularly relates to a novel small molecule E3 ubiquitin ligase protein-binding ligand compound based on a fluorinated hydroxyprolinescaffold, and relates to its application in synthesizing novel PROTACs and its synthesis method. Background technique [0002] Hydroxyproline (Hyp) is a naturally occurring proline derivative that exists mainly in two isomeric forms in collagen: 4-hydroxyproline and 3-hydroxyproline (ratio 70:1) . Hydroxyproline synthesis in vivo is a post-translational modification of peptide-bound proline catalyzed by prolyl hydroxylase. Hyp is an interesting fragment for drug discovery due to its special conformational stiffness, which is found in many n...
Claims
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