Biocompatible biodegradable fumagillin analog conjugates

A compound of the Formula V:

• wherein,
• X is O, S(═O), optionally substituted CH2, or optionally substituted NH;
• q is 0, 1, or 2;
• R is (2S,3R)-2-methyl-3-(3-methylbut-2-enyl)oxirane, 2-methylhepta-2,5-diene, (2R,3S)-2-isopentyl-3-methyloxirane, 6-methylhept-2-ene, (Z)-acetaldehyde O-benzyl oxime, C2-heterocyclic-C1-C6 alkyl, C2-heterocyclic-C2-C6 alkenyl, C1-C6 alkyl, C2-C6 alkenyl, C2-heterocyclic-C1-C6-alkenyl-COO—C1-C6 alkyl, C2-heterocyclic-C1-C6 alkyl-COO—C1-C6-alkyl, C1-C6 alkyl=N—O—C1-C6 alkyl-aryl, C(O)C1-C6 alkyl, CN, or halogen;
• R8 is selected from the group consisting of VI, VII, VIII, IX, X, XI, XII, and XIIA whose formulas are represented below:
• R′—CO2H, optionally substituted —NH2—, or —N cyclic imide, NHC(O) (C1-C6 alkyl)-C(O)R″, R′ is meta or para in relation to the —S— atom;
• and
• R″ is —OH, —O—C1-C6 alkyl, or —NH2 optionally acylated through the carboxyl group of an amino acid;
• wherein R9 is H or C(O)R11;
• R10 is —NH2, —NHCH(C1-C6 alkyl)-, —NHC(O) (C1-C6 alkyl), N-cyclized imide;
• —NH acylated through the carboxyl group of an amino acid,
• wherein the nitrogen of the amino group of the amino acid is optionally protected, and
• R11 is OH, OC1-C6 alkyl, or optionally substituted —NH2;
• wherein N12 is H, C1-C6 alkyl, —(C1-C6)—COOH, —(C1-C6)—C(O)O—(C1-C6), —CH2CH2O—R13, —C(O)(C1-C6 alkyl), an amino acid attached through the carboxyl group of the amino acid;
• R13 is —H or an amino acid attached through the carboxyl group of the amino acid, wherein the nitrogen of the amino acid is optionally protected, C(O) (C1-C6 alkyl)-COR″;
• R″ is —OH, —OC1-C6 alkyl, or —NH2 optionally acylated through the carboxyl group of an amino acid;
• [-------] represents an optional methylene bridge (—CH2—) between carbons 2 and 5 of the piperazine moiety;
• and
• Z′ is a bond, —C1-C6 alkyl, —NHC(O)—, or —NHSO2—;
• wherein R14 is —H, CO2H, —CO2(C1-C6 alkyl), —C(O)NH—C1-C6 alkyl-OH, wherein the 0 of —C(O)NH—C1-C6 alkyl-OH is optionally acylated with the carboxyl group of an amino acid;
• optionally substituted —NH, C1-C6-alkyl-NH2, wherein the NH2 is optionally substituted;
• and
• [-------] represents an optional ethylene bridge (—CH2CH2—) between carbons 1 and 4 of the cyclohexane moiety;
• Z′ is a bond, —CH2—, —CH2—S—, CH2CH2—, —C(H) (Me)-, NHCH2——NHCH(CH3)—, —NHCH2CH2—;
• R15 is H, optionally substituted —NH, —NHC(O) (C1-C6-alkyl), —N cyclized imide optionally containing a heteroatom within the cyclic structure, —NHC(O)CH2OCH2C(O)OH, NHC(O)CH(C1-C6 alkyl)-N cyclized imide, —NHC(O)CH(R″)NHC(O)—(C1-C6 alkyl)-C(O)OH, —NHC(O)—(C1-C6 alkyl)-C(O)OH, —C(O)O(C1-C6 alkyl), —C(O)N(H)(C1-C6 alkyl)-OH, or NO2;
• and
• R″ or —C1-C6 alkyl;
• wherein Y′ is C1-C3 alkyl, or NH—C1-C3 alkyl and is attached to positions 1, 2, or 3 of the indole;
• and
• R16 is H, C1-C6 alkyl, —CH2COOH, or —CH2CH2OH, wherein the O of —CH2CH2OH can be optionally acylated with an amino acid;
• wherein R″ is —OH, —OC1-C6 alkyl, —NH optionally acylated through the carboxyl group of an amino acid;
• and
• wherein Y″ is C(O)N(CH3)(OCH3), C(O)OCH3, CH2Cl, or NHC(O)CH2Cl.