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PROTEASOME INHIBITORS AND METHODS OF USING THE SAME

  • US 20090291918A1
  • Filed: 07/01/2009
  • Published: 11/26/2009
  • Est. Priority Date: 08/14/2003
  • Status: Active Grant
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Forward Citations
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Assignments
First Claim
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1. 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;

    orheterocarbocyclyl 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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