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Embodiment approach
[0466] The present invention also provides the following enumerated embodiment (E):
[0467] E1: In one embodiment, the present invention provides a compound of formula XIV or a pharmaceutically acceptable salt thereof according to A1, wherein Z is selected from the group consisting of:
[0468] i) covalent bonds,
[0469] ii) carbonyl,
[0470] iii)-NR 1 -,
[0471] iv) -O-CH 2 -C(=O)-NR 1 -,
[0472] v)-C(=O)-NR 1 -,and
[0473] vi)-NR 1 -C(=O)-.
[0474] E2: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 or E1, or a pharmaceutically acceptable salt thereof, wherein R 1 for hydrogen.
[0475] E3: In one embodiment, the present invention provides a compound of formula XIV or a pharmaceutically acceptable salt thereof according to any one of A1 and E1 to E2, wherein each R 2 for-C 1-6 Alkyl or -N(R 5 , R 6 ).
[0476] E4: In one aspect, the present invention provides a compound of formula XIV or a pharmace...
Embodiment A
[0969] Tablets of the following composition are prepared in the usual way:
[0970]
[0971]
[0972] Table 1: Possible tablet compositions
[0973] preparation steps
[0974] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.
[0975] 2. Dry the granules at 50°C.
[0976] 3. Pass the granules through suitable milling equipment.
[0977] 4. Add ingredient 5 and stir for three minutes; compress on a suitable tablet machine.
Embodiment B-1
[0979] Prepare capsules of the following composition:
[0983] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.
[0984] 2. Add ingredients 4 and 5 and mix for 3 minutes.
[0985] 3. Fill into suitable capsules.
[0986] The compound of formula XIV, lactose and cornstarch are mixed first in a mixer and then in a pulverizer. The mixture is returned to the mixer; add the talc and mix thoroughly. The mixture is machine filled into suitable capsules, such as hard gelatin capsules.
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Abstract
The present invention provides heterocyclic compounds that bind to the ubiquitously expressed E3 ligase proteincereblon (CRBN) and their use for the treatment of abnormal cellular proliferation in a human or other host. The present invention also provides compounds that can be used as synthetic intermediates in the synthesis of bifunctional compounds used for targeted protein degradation.
Description
[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 814,706, filed March 6, 2019. The entire content of this application is incorporated herein by reference. technical field [0003] The present invention provides compounds that bind to the ubiquitously expressed E3 ligase proteincereblon (CRBN), which can alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in the breakdown of intrinsic downstream proteins that mediate disease. The present invention also provides compounds useful as synthetic intermediates for the preparation of bifunctional compounds for targeted protein degradation. Accordingly, the compounds of the invention are useful in the treatment or prevention of abnormal cell proliferation, including tumors and cancers. Background technique [0004] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. S...
Claims
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