| abstract |
Compounds of formula (la) and pharmaceutically acceptable salts, solvates, and hydrates thereof and related methods of modulatin perforin activity on a cell: wherein Ring A is selected from a 6-10 membered aryl, 5-6 membered cycloalkyi, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl rings comprise at least one heteroatom selected from N, O or S; and wherein the aryl, cycloalkyi, heteroaryl or heterocyclyl rings are optionally substituted with 1 to 3 substituents selected from halo, nitro, -C1-Cealkyl, -C1-Ceaminoalkyl, -C1-C6hydroxyalkyl, -haloC1-C6alkyl, -C1- C6alkoxyl, -haloC1-C<aIkoxyl, heteroaryl, aryl, hydroxyl, -C(0)Ci-C6alkyl, -OC(0)Ci- C6alkyl, -CH2OC(O)CrC6alkyl, -C(O)OC1,-C6alkyI, -NHC(O)C1,-C6alkyl, -NHS(O)2C1- C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NH2, and -C(O)NJJ; Ring B is a 6-10 membered arylene or a 5-6 membered heteroarylene comprising at least one heteroatom selected from N, 0 or S; and wherein the aryl or heteroaryl is optionally, substituted with one or more substituents selected from -NJJ, -OJ, halo,C1 -C6alkyl, -haloC1- C6alkyl, -C1-C6alkoxy, -haloC1-C6alkoxyl, and -C(0)NJJ; Ring C is is selected from a 5-10 membered heteroarylene or a 5-10 membered heterocyclene, each comprising at least one heteroatom selected from N, S and O; Ring D is an optionally substituted benzofused 9-11 membered heterocyclyl or optionally substituted ben2ofused 9-11 membered heteroaryl comprising at least one heteroatom selected from N or O; L is a linker selected from branched and unbranched C1-C4 alkylene, -S(0)2-NH-, -C(0)-NH-, -NH-C(0)-NH-, -S(0)2-NH-C(0)-NH-, -S(0)2-NH-C(0) - and -CH=CH-; wherein Rings B and C, and Rings C and D, are connected to each other via a C-C bond at any of the available C atoms on each respective ring; and J in each occurrence is independently selected from H, optionally substituted C1-C6alkyl or optionally substituted haloC1-C6alkyl. |