Human Adam-10 Inhibitors

摘要

The present invention provides compounds useful for inhibiting the ADAM-10 protein, with selectivity versus MMP-1. Such compounds are useful in the in vitro study of the role of ADAM-10 (and its inhibition) in biological processes. The present invention also comprises pharmaceutical compositions comprising one or more ADAM-10 inhibitors according to the invention in combination with a pharmaceutically acceptable carrier. Such compositions are useful for the treatment of cancer, arthritis, and diseases related to angiogenesis. Correspondingly, the invention also comprises methods of treating forms of cancer, arthritis, and diseases related to angiogenesis in which ADAM-10 plays a critical role.

主权项

1. A compound of structural formula I: and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof wherein L1 is —C(O)—, —S(O)2—, or —(CH2)n—; R1 is —H, —OR11, —(CH2)nR11, —C(O)R11, or —NR12R13;
R11, R12, and R13 independently are
a) R50;b) saturated or mono- or poly-unsaturated C5-C14-mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one or two R50 substituents;c) C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, or —C(O)H, each of which is optionally substituted with one, two or three substituents independently selected from R50 and saturated or mono- or poly-unsaturated C5-C14-mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two or three R50 substituents;or R12 and R13 together with the N to which they are covalently bound, a C5-C6 heterocycle optionally containing a second annular heteroatom and optionally substituted with one or two R50 substituents; R2 is —R21-L2-R22;
R21 is saturated or mono- or poly-unsaturated C5-C14-mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three R50 substituents;L2 is —O—, —C(O)—, —CH2—, —NH—, —S(O2)— or a direct bond;R22 is saturated or mono- or poly-unsaturated C5-C14-mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three R50 substituents; and R50 is R51-L3-(CH2)n—;
L3 is —O—, —NH—, —S(O)0-2—, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NHC(O)—, —C6H4—, or a direct bond;R51 is —H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halo, —CF3, —OCF3, —OH, —NH2, mono-C1-C6alkyl amino, di-C1-C6alkyl amino, —SH, —CO2H, —CN, —NO2, —SO3H, or a saturated or mono- or poly-unsaturated C5-C14-mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three substituents; wherein n is 0, 1, 2, or 3; provided that an O or S is not singly bonded to another O or S in a chain of atoms.