INHIBITORS OF LEUKOTRIENE A4 HYDROLASE

摘要

The present invention is directed to compounds encompassed by the Formula (I), pharmaceutical compositions thereof, methods for inhibiting LTA-4 hydrolase, and methods for the treatment of a disease and disorder which is ameliorated by the inhibition of LTA4-h activity. Non-limiting examples of such diseases and conditions include inflammatory and autoimmune diseases and disorders.

主权项

1. A compound having the Formula (I): wherein: R is i) the group;or
ii) the group;or
iii) an optionally substituted heteroaryl;n1, n2, and n3 are each independently 0 to 2;r is 0 to 4;R1a, R1b, R1c, R1d and R1e are each independently hydrogen, OR10, C(O)OR10, C(O)R10, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C3-C15cycloalkyl, optionally substituted C3-C15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro;R3 is a direct bond, —O—, —R12—O—, —O—R12—, —O—R12—O—, an optionally substituted straight or branched C1 to C12 alkylene chain, an optionally substituted straight or branched C2 to C12 alkenylene chain, or an optionally substituted straight or branched C2 to C12 alkynylene chain;R4 is a direct bond, —O—R12a, an optionally substituted straight or branched C1 to C12 alkylene chain, an optionally substituted straight or branched C2 to C12 alkenylene chain, or an optionally substituted straight or branched C2 to C12 alkynylene chain;each R5a and R6a are each independently hydrogen and optionally substituted alkyl;or R5a and R6a together can be an oxo group;R7 is hydrogen, C(O)R10, C(O)OR10, C(O)—R13—N(R10)R11, N(R10)C(O)N(R10)R11, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C3-C15 cycloalkyl, optionally substituted C3-C15 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;each R9 is independently —OR10, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, halo, optionally substituted aryl, or optionally substituted heteroaryl;each R10 and R11 is independently hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C3-C15 cycloalkyl, optionally substituted C3-C15 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;or R10 and R11, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;R12 is an optionally substituted straight or branched C1 to C12 alkylene chain, an optionally substituted straight or branched C2 to C12 alkenylene chain, or an optionally substituted straight or branched C2 to C12 alkynylene chain;R12a is an optionally substituted straight or branched C1 to C12 alkylene chain, an optionally substituted straight or branched C2 to C12 alkenylene chain, or an optionally substituted straight or branched C2 to C12 alkynylene chain;each R13 is independently a direct bond, an optionally substituted straight or branched C1 to C12 alkylene chain, an optionally substituted straight or branched C2 to C12 alkenylene chain, or an optionally substituted straight or branched C3 to C12 alkynylene chain; andR15 is an optionally substituted phenyl or an optionally substituted pyridyl;as a single stereoisomer or as a mixture of stereoisomers; or a pharmaceutically acceptable salt, solvate, polymorph, clathrate, ammonium ion, N-oxide or prodrug thereof.