Methods for inhibiting proteasome

A method for treating cancer comprising administering to a mammal in need thereof, either alone or in combination with at least one other anticancer agent, compound having Formula (III):

• 40
• or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
• X is a boronic acid or a boron ester of formula BY1Y2;
• Y1 and Y2 are independently selected from:
• a) C1-C6 alkoxy, or
• when taken together, Y1 and Y2 form:
• b) a cyclic boron ester comprising from 2 to 16 carbon atoms;
• R1 is selected from the group:
• ethyl, n-propyl, i-propyl, n-butyl, allyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and 3-butenyl;
• Ra is selected at each occurrence from the group:
• C1-3 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CF3, OH, ═O, C1-6 alkoxy, SH, —S—C1-6 alkyl;
• phenyl substituted with 0-3 Rb;
• naphthyl substituted with 0-3 Rb;
• —O—(CH2)q-phenyl substituted with 0-3 Rb;
• —O—(CH2)q-naphthyl substituted with 0-3 Rb;
• and
• 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0-3 Rb;
• Rb is selected at each occurrence from the group:
• C1-6 alkyl, Cl, F, Br, I, OH, C1-6 alkoxy, —CN, —NO2, C(O)OR7, NRdRd, CF3, OCF3, and C3-6 cycloalkyl;
• R2 is H;
• R3 is selected from the group:
• C1-6 alkyl substituted with 0-2 Ra;
• C2-6 alkenyl substituted with 0-2 Ra;
• C2-6 alkynyl substituted with 0-2 Ra;
• —(CH2)q—C3-6 cycloalkyl substituted with 0-2 Ra;
• —(CH2)q-phenyl substituted with 0-2 Ra;
• —(CH2)q-naphthyl substituted with 0-2 Ra;
• —(CH2)q-5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0-2 Ra;
• R4 is selected from the group:
• H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl;
• phenyl substituted with 0-3 Rb;
• benzyl substituted with 0-3 Rb;
• and
• phenethyl substituted with 0-3 Rb;
• R5 is H or Q-R5a;
• Q is 0, 1, or 2 amino acids;
• R5a is selected from the group:
• —S(O)R6, —S(O)2R6, —C(O)R6, —C(O)OR8, —C(O)NHR6, C1-3 alkyl-R6a, C2-6 alkenyl-R6a, and C2-6 alkynyl-R6a;
• R6 is selected from the group:
• C1-6 alkyl substituted with 0-3 Rc;
• phenyl substituted with 0-3 Rc;
• naphthyl substituted with 0-3 Rc;
• benzyl substituted with 0-3 Rc;
• and
• 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group:
• O, S, and N, substituted with 0-3 Rc;
• R6a is selected from the group:
• phenyl substituted with 0-3 Rc;
• naphthyl substituted with 0-3 Rc;
• benzyl substituted with 0-3 Rc;
• and
• 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group:
• O, S, and N, substituted with 0-3 Rc;
• Rc is selected at each occurrence from the group:
• C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, Cl, F, Br, I, ═O, OH, phenyl, C(O)OR7, NRdRd, —CN, and NO2;
• Rd is selected at each occurrence from the group:
• H and CH3;
• R7 is selected at each occurrence from the group:
• H and C1-6 alkyl;
• R8 is selected from the group:
• C1-6 alkyl, benzyl, and C3-6 cycloalkyl-methyl;
• n is 1 or 2;
• and
• q is selected from the group:
• 0, 1, and 2.

A method for inhibiting proteasome which comprises contacting a mammal in need thereof with a therapeutically effective amount of a compound of Formula I:

• 41
• or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
• the lactam ring of Formula (I) is substituted with 0-2 Rb;
• X is selected from the group:
• B(OH)2, BY1Y2, and C(═O)C(═O)NHR1a;
• Y1 and Y2 are independently selected from:
• a) —OH,
• b) —F,
• c) —NR18R19,
• d) C1-C8 alkoxy, or
• when taken together, Y1 and Y2 form:
• e) a cyclic boron ester comprising from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
• f) a cyclic boron amide comprising from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
• or
• g) a cyclic boron amide-ester comprising from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
• R1 is selected from the group:
• C1-10 alkyl substituted with 0-3 Ra;
• C2-10 alkenyl substituted with 0-3 Ra;
• C2-10 alkynyl substituted with 0-3 Ra;
• and
• C3-6 cycloalkyl substituted with 0-3 Ra;
• R1a is selected from the group:
• C1-10 alkyl substituted with 0-3 Ra;
• C2-10 alkenyl substituted with 0-3 Ra;
• C2-10 alkynyl substituted with 0-3 Ra;
• and
• C3-6 cycloalkyl substituted with 0-3 Ra;
• Ra is selected at each occurrence from the group:
• C1-3 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CF3, OH, ═O, C1-6 alkoxy, SH, —S—C1-6 alkyl;
• phenyl substituted with 0-3 Rb;
• naphthyl substituted with 0-3 Rb;
• —O—(CH2)q-phenyl substituted with 0-3 Rb;
• —O—(CH2)q-naphthyl substituted with 0-3 Rb;
• and
• 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0-3 Rb;
• Rb is selected at each occurrence from the group:
• C1-6 alkyl, Cl, F, Br, I, OH, C1-6 alkoxy, —CN, —NO2, C(O)OR7, NRdRd, CF3, OCF3, and C3-6 cycloalkyl;
• R2 is H;
• alternatively, R1 and R2 combine to form a C3-5 cycloalkyl group;
• R3 is selected from the group:
• C1-6 alkyl substituted with 0-2 Ra;
• C2-6 alkenyl substituted with 0-2 Ra;
• C2-6 alkynyl substituted with 0-2 Ra;
• —(CH2)q-C3-6 cycloalkyl substituted with 0-2 Ra;
• —(CH2)q-phenyl substituted with 0-2 Ra;
• —(CH2)q-naphthyl substituted with 0-2 Ra;
• and
• —(CH2)q-5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0-2 Ra;
• R4 is selected from the group:
• H;
• C1-6 alkyl substituted with 0-3 Rb;
• phenyl substituted with 0-3 Rb;
• benzyl substituted with 0-3 Rb;
• and
• phenethyl substituted with 0-3 Rb;
• R5 is H or Q-R5a;
• Q is 0, 1, 2, or 3 amino acids;
• R5a is selected from the group:
• —S(O)R6, —S(O)2R6, —C(O)R6, —C(O)OR8, —C(O)NHR6, C1-3 alkyl-R6a, C2-6 alkenyl-R6a, and C2-6 alkynyl-R6a;
• R6 is selected from the group:
• C1-6 alkyl substituted with 0-3 Rc;
• phenyl substituted with 0-3 Rc;
• naphthyl substituted with 0-3 Rc;
• benzyl substituted with 0-3 Rc;
• and
• 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group:
• O, S, and N, substituted with 0-3 Rc;
• R6a is selected from the group:
• phenyl substituted with 0-3 Rc;
• naphthyl substituted with 0-3 Rc;
• benzyl substituted with 0-3 Rc;
• and
• 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group:
• O, S, and N, substituted with 0-3 Rc;
• Rc is selected at each occurrence from the group:
• C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, Cl, F, Br, I, ═O, OH, phenyl, C(O)OR7, NRdRd, —CN, and NO2;
• Rd is selected at each occurrence from the group:
• H and CH3;
• R7 is selected at each occurrence from the group:
• H and C1-6 alkyl;
• R8 is selected from the group:
• C1-6 alkyl, benzyl, and C3-6 cycloalkyl-methyl;
• R18 and R19 at each occurrence are independently selected from H, C1-C4 alkyl, aryl(C1-C4 alkyl)-, and C3-C7 cycloalkyl;
• n is selected from the group:
• 1, 2, and 3;
• and
• q is 0, 1, or 2.