Lactacystin analogs

A pharmaceutical composition comprising a compound having the following formula

• wherein Z1 is O, S, SO2, NH, or NRa, Ra, being C1-6 alkyl;
• X1 is O, S, CH2, two singly bonded H, CH(Rb) in the E or Z configuration, or C(Rb) (Rc) in the E or Z configuration, each of Rb and Rc, independently, being C1-6 alkyl, C6-12 aryl, C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or halogen, X1 being two singly bonded H when Z1 is SO2;
• Z2 is O, S, NH, NRd, CHR1, or CHOR1 in the (R) or (S) configuration, wherein Rd is C1-6 alkyl and R1 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, NRdRe (except where Z2 is CHOR1), or the side chain of a naturally occurring α-amino acid, or R1 and R2 taken together are a bivalent moiety, provided that when R1 and R2 are taken together, Z1 is NH or NRa and Z2 is CHR1;
• Re being H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, and the bivalent moiety forming a C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or C6-12 aryl, where the H in CHR1 is deleted when R1 and R2 taken together form a C3-8 heteroaryl or C6-12 aryl;
• R2 is C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, azido, C2-6 alkynyl, halogen, ORf SRf, NRfRg, —ONRfRg, —NRg(ORf), or —NRg(SRf) (each of Rf and Rg, independently, being H, C1-6, alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl), or R1 and R2 taken together are a bivalent moiety, the bivalent moiety forming a C3-8cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or C6-12 aryl, where the H in CHR1 is deleted when R1 and R2 taken together form a C3-8 heteroaryl or C6-12 aryl;
• A1 is H, the side chain of any naturally occurring α-amino acid, or is of the following formula,
• —(CH2)m—Y—(CH2)n—R3X3
• wherein Y is O, S, C═O, C═S, —(CH═CH)—, vinylidene, —C═NORh, —C═NNRiRi,, sulfonyl, methylene, CHX4 in the (R) or (S) configuration, or deleted, X4 being halogen, methyl, halomethyl, ORh, SRh, NRiRi′, —NRi(ORh), or —NRi(NRiRi′), wherein Rh is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, C1-10 acyl, C1-6 alkylsulfonyl, and C6-10 arylsulfonyl, and each of Ri and Ri′, independently is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-10 acyl;
• m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3;
• and R3 is straight chain or branched C1-8 alkylidene, straight chain or branched C1-8 alkylene, C3-10 cycloalkylidene, C3-10 cycloalkylene, phenylene, C6-14 arylalkylidene, C6-14 arylalkylene, or deleted, and X3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C1-6 alkyl)oxycarbonyl, (C7-14 arylalkyl)oxycarbonyl, or C6-14 aryl;
• or R3 and X3 taken together are the side chain of any naturally occurring α-amino acid where the carbon to which A1 and L0 are attached is a quaternary carbon;
• and
• L0 is —(C═X2)—L1, —(C═X2)—L2, or —C(L2)—CH2—O, wherein X2 is O or S;
• L2 is H, C1-6 haloalkyl, C1-6 alkyl, or C6-14 aryl, and L1 is a moiety having 0 to 25 carbon atoms, 1 to 10 heteroatoms, and 0 to 6 halogen atoms, L1 being linked by an oxygen or sulfur atom to the carbon atom bonded to X2;
• where A1 is C5-20 alkyl when L0 is carboxyl or (C1-4 alkyl)oxycarbonyl and A1 is alkyl;
• where only one of A1 and L0 is selected from carboxyl and (C1-4 alkyl)oxycarbonyl;
• and where L1 has between 0 and 3 non-aromatic acyclic carbon atoms when it has 5 heteroatoms;
• and
• a pharmaceutically acceptable carrier.