US 2009/0291918 A1 · 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.

A compound of Formula (I)

or 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 —(CH2)aCH2NHC(═NR4)NH—Y, —(CH2)bCH2CONR5R6, —(CH2)nCH2N(R4)CONH2, —(CH2)dCH(R7)NR9R10, or —(CH2)eCH(R7)ZR8;
a, b, and c are each, independently, 0, 1, 2, 3, 4, 5, or 6;
d and e are each, independently, 0, 1, 2, 3, or 4;
R4 is H or C1-C10 alkyl;
R5 and R6 are each, independently, H, C1-C10 alkyl, carbocyclyl, heterocarbocyclyl, or an amino protecting group;
alternatively, R5 and R6 together with the N atom to which they are attached form a heterocarbocyclyl group;
R7 is H or C1-C10 alkyl;
R3 is H, C1-C10 alkyl, alkyl-S(═O)2—, aryl-S(═O)2—, H2NS(═O)2—, —SO3H, or a protecting group;
R9 is H, C1-C10 alkyl, carbocyclyl, or heterocarbocyclyl;
R10 is H, C1-C10 alkyl, carbocyclyl, heterocarbocyclyl, C1-C10 alkyl-C(═O)—, C2-C10 alkenyl-C(═O)—, C2-C10 alkynyl-C(═O)—, carbocyclyl-C(═O)—, heterocarbocyclyl-C(═O)—, carbocyclylalkyl-C(═O)—, heterocarbocyclylalkyl-C(═O)—, C1-C10 alkyl-S(═O)2—, carbocyclyl-S(═O)2—, heterocarbocyclyl-S(═O)2—, carbocyclylalkyl-S(═O)2—, heterocarbocyclylalkyl-S(═O)2—, C1-C10 alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocarbocyclyl-NHC(═O)—, carbocyclylalkyl-NHC(═O)—, heterocarbocyclylalkyl-NHC(═O)—, C1-C10 alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocarbocyclyl-OC(═O)—, carbocyclylalkyl-OC(═O)—, heterocarbocyclylalkyl-OC(═O)—, C1-C10 alkyl-NH—C(═O)—NHS(═O)2—, carbocyclyl-NH—C(═O)—NHS(═O)2—, heterocarbocyclyl-NH—C(═O)—NHS(═O)2—, C1-C10 alkyl-S(═O)2—NH—C(═O)—, carbocyclyl-S(═O)2—NH—C(═O)—, heterocarbocyclyl-S(═O)2—NH—C(═O)—, or an amino protecting group;
wherein R10 is optionally substituted with 1, 2 or 3, R23;
alternatively, R9 and R10 together with the N atom to which they are attached form a heterocarbocyclyl group optionally substituted with 1, 2 or 3 R23;
Y is H, —CN, —NO2, —S(═O)2R11 or a guanidino protecting group;
R11 is C1-C6 alkyl, aryl, or NR12R13;
R12 and R13 are, independently, H, C1-C10 alkyl, carbocyclyl, heterocarbocyclyl, or an amino protecting group;
alternatively, R12 and R13 together with the N atom to which they are attached form a heterocarbocyclyl group;
Z is O, S, Se, or Te;
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—, RAOC(═O)—, 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 R21;
or
heterocarbocyclyl optionally substituted with 1-5 R21;
R20 is selected from the group consisting of:
—CN, halo, haloalkyl-, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —CO2H, —C(═O)CO2H, —C(═O)NH2, —C(═O)H, —S(═O)NH2, —S(═O)2NH2, —OH, —SH, —NH2, —NH(alkyl), —N(alkyl)2, —NHC(═O)NH2, —NHC(═O)R20a, —NHC(═O)OR20a, —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, NHS(═O)2R20a, —NHR20b, phthalimido, —(O-alkyl)r-OH, —(O-alkyl)r-(O-alkyl), —OR20c, —SR20c, —O-alkyl-R20c, —S-alkyl-R20c, —S(═O)—R20c, —S(=)2—R20c, —S(═O)2—NHR20c, —SC(═O)R20c, —C(═O)R20c, —C(═O)OR20c, —C(═O)NHR20c, carbocyclyl optionally substituted with 1-5 R21;
and
heterocarbocyclyl optionally substituted with 1-5 R21;
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, OH, CN, C1-C4 alkyl, C1-C4 alkoxy, C2-C8 alkoxyalkoxy, aryl, heteroaryl or —NHR20b;
R20b is an amino protecting group;
R20c is carbocyclyl optionally substituted with 1-5 R22;
or heterocarbocyclyl optionally substituted with 1-5 R22
R21 is selected from the group consisting of:
C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, —OR21a, —SR21a, —CN, halo, haloalkyl, —NH2, —NH(alkyl), —N(alkyl)2, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH, —C(═O)O-alkyl, —C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)2-alkyl, —S(═O)-aryl, —S(═O)2-aryl, carbocyclyl optionally substituted with 1-5 R22, and heterocarbocyclyl optionally substituted with 1-5 R22;
R21a is H, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, carbocyclyl or heterocarbocyclyl;
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—;
R23 is selected from the group consisting of:
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, F, Cl, Br, I, haloalkyl, —NH2, —NHR23a, —N(R23a)2, —N3, —NO2, —CN, —CNO, —CNS, —C(═O)OR23a, —C(═O)R23a, —OC(═O)R23a, —N(R23a)C(═O)R23a, —N(R23a)C(═O)OR23a, —C(═O)N(R23a)2, ureido, —OR23a, —SR23a, —S(═O)—(C1-C6 alkyl), —S(═O)2—(C1-C6 alkyl), —S(═O)-aryl, —S(═O)2-aryl, —S(═O)2—N(R23a)2;
carbocyclyl optionally substituted with 1-5 R24;
and
heterocarbocyclyl optionally substituted with 1-5 R24;
R23a is H or C1-C6 alkyl;
alternatively, two R23a may be combined, together with the N atom to which they are attached, to form a 5 to 7 membered heterocyclic group;
and
R24 is selected from the group consisting of:
C1-C4 alkyl, C2-C4 alkenyl, C2-C4 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 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
with the proviso that when Q is a 1,1,2,2-tetramethylethanediol boronic ester, then X is not aralkyloxycarbonyl;
with the proviso that when Q is a 1,1,2,2-tetramethylethanediol boronic ester, and R1 is cycloalkyl, then R2 is not —CH2CONH2;
and
with the proviso that when X is RAC(═O)—, RA is a C4-C15 straight-chained alkyl substituted with R20, and R20 is —CN, —CO2H, —C(═O)O—R20a, —NHS(═O)2R20a, —NHC(═O)R20a, —NHR20b, carbocyclyl, or phthalimido;
then R2 is not —(CH2)aCH2NHC(═NR4)NH—Y, wherein Y is H, —CN, —NO2, or a guanidino protecting group.

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Proteasome inhibitors and methods of using the same

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Proteasome inhibitors and methods of using the same

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Abstract

Claims91