Claims for Patent: 8,546,608

Summary for Patent: 8,546,608

Title:	Proteasome inhibitors and methods of using the same
Abstract:	The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.
Inventor(s):	Raffaella Bernardini, Alberto Bernareggi, Paolo G. Cassara, Sankar Chatterjee, Germano D'Arasmo, Sergio De Munari, Edmondo Ferretti, Mohamed Iqbal, Ernesto Menta, Patricia A. Messina McLaughlin, Ambrogio Oliva
Assignee:	Takeda Pharmaceutical Co Ltd, Cephalon LLC
Application Number:	US13/249,738
Patent Claims:	1. A compound having Formula (I): or a pharmaceutically acceptable salt, stereoisomeric or tautomeric form thereof, wherein: R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C7 cycloalkyl; R2 is H; Q is —B(OH)2, —B(OR14)2, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; R14 is H, C1-C4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; X is RAC(═O)—; RANHC(═O)—, RAS(O)2—, RASC(═O)—, or RA; RA is C1-C20 alkyl optionally substituted with R20; C2-C20 alkenyl optionally substituted with R20; C2-C20 alkynyl optionally substituted with R20; carbocyclyl optionally substituted with 1-5 R22; or heterocarbocyclyl optionally substituted with 1-5 R22; R20 is selected from the group consisting of: —OR20a, —SR20a, —S(═O)R20a, —S(═O)2R20a, —S(═O)2—NHR20a, —SC(═O)R20a, —C(═O)R20a, —C(═O)NHR20a, —C(═O)O—R20a, phthalimido, —(O-alkyl)r, —O-alkyl-OH, —(O-alkyl)r—OH, —OR20c, —SR20c, —O-alkyl-R20c, —S- alkyl-R20c, —S(═O)—R20c, —S(═O)2—R20c, —S(═O)2—NHR20c, —SC(═O)R20c, —C(═O)R20c, —C(═O)OR20c, —C(═O)NHR20c, carbocyclyl optionally substituted with 1-5 R22; and heterocarbocyclyl optionally substituted with 1-5 R22; R20a is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl; wherein said alkyl, alkenyl, or alkynyl is optionally substituted by one or more halo, C1-C4 alkyl, aryl, heteroaryl or —NHR20b; R20c is carbocyclyl optionally substituted with 1-5 R22; or heterocarbocyclyl optionally substituted with 1-5 R22; R22 is selected from the group consisting of: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—, alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, (alkyl-O)r-alkyl, HO-(alkyl-O)r-alkyl-, —OH, —SH, —CN, —N3, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)2—, H2NS(═O)—, and H2NS(═O)2—; and r is 2, 3, 4, 5, 6, 7, 8, 9, or 10. 2. The compound of claim 1 wherein X is RAC(═O)—. 3. The compound of claim 1 wherein X is RAC(═O)—and RA is aryl optionally substituted with 1-3 substituents selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, alkyl-OC(═O)—, alkyl-C(═O)—, alkyl-OC(═O)NH—, alkyl-C(═O)NH—, —OH, —CN, alkyl-S(═O)—, and alkyl-S(═O)2.