Preparation and use of ortho-sulfonamide bicyclic heteroaryl hydroxamic acids as matrix metalloproteinases and tace inhibitors

摘要

This invention provides, low molecular weight, non-peptide inhibitors of matrix metalloproteinases and TNF- alpha converting enzyme (TACE, tumor necrosis factor- alpha converting enzyme) of formula (B) wherein (B) is (1), (2), or (3); P and Q are (4) or (5), provided that when P is (4), Q is (5), and vice versa; T, U, W, and X are each, independently, carbon or nitrogen, provided that when T or U is carbon, either may be optionally substituted with R1; Y is carbon, nitrogen, oxygen or sulfur, provided that at least one of T, U, W, X, and Y is not carbon, and further provided that no more than 2 of T, U, W, and X are nitrogen; (6) is a phenyl ring or is a heteroaryl ring of ring 5-6 atoms which may contain 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur, in addition to any heteroatoms defined by W or X; wherein the phenyl or heteroaryl ring may be optionally mono-, di-, or tri- substituted with R1; Z is a phenyl, naphthyl, heteroaryl, or heteroaryl fused to phenyl, wherein the heteroaryl moiety contains of 5-6 ring atoms and 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein the phenyl, naphthyl, heteroaryl, or phenyl fused heteroaryl moieties may be optionally mono-, di-, or tri-substituted with R1; R1 is hydrogen, halogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cyclocalkyl of 3-6 carbon atoms, -(CH2)nZ, -OR2, -CN, -COR2, perfluoroalkyl of 1-4 carbon atoms, -CONR2R3, -S(O)xR2-OPO(OR2)OR3, -PO(OR2)R3, -OC(O)NR2R3, -COOR2, -CONR2R3, -SO3H, -NR2R3, -NR2COR3, -NR2COOR3, -SO2NR2R3, -NR2CONR2R3, -NR2C(=NR3)NR2R3, -SO2NHCOR4, -CONHSO2R4, -tetrazol-5-yl, -SO2NHCN, -SO2NHCONR2R3, or Z; V is a saturated or partially unsaturated heterocycloalkyl ring of 5-7 ring atoms having 1-3 heteroatoms selected from N, O, or S, which may be optionally mono-, or di-substituted with R2; R2 and R3 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V; R4 is alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V; R5 is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, Z, or V; n = 1-6; x = 0-2 or a pharmaceutically acceptable salt thereof.