Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors

A method of inhibiting pathological changes mediated by matrix metalloproteinases in a mammal in need thereof which comprises providing to said mammal a therapeutically effective amount of a compound having the formula:

• B
• wherein B is
• 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;
• provided that no more than 2 of T, U, W, and X are nitrogen;
• is a heteroaryl ring of ring 5-6 which may contain 0-2 heteratoms selected from nitrogen, oxygen, and sulfur, in addition to any heteroatoms defined by W or X;
• wherein the 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, —NO2, -N(R2)SO2R3, —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.

A method of inhibiting pathological changes mediated by TNF-α converting enzyme (TACE) in a mammal in need thereof, which comprises providing to said mammal a therapeutically effective amount of a compound having the formula:

• B
• wherein B is
• 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;
• provided that no more than 2 of T, U, W, and X are nitrogen;
• is a heteroaryl ring of ring 5-6 which may contain 0-2 heteratoms selected from nitrogen, oxygen, and sulfur, in addition to any heteroatoms defined by W or X;
• wherein the 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, —NO2, —N(R2)SO2R3, —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.

A pharmaceutical composition comprising a compound having the formula:

• B
• wherein B is
• 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;
• provided that no more than 2 of T, U, W, and X are nitrogen;
• is a heteroaryl ring of ring 5-6 which may contain 0-2 heteratoms selected from nitrogen, oxygen, and sulfur, in addition to any heteroatoms defined by W or X;
• wherein the 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, —NO2, —N(R2) SO2R3, —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, and a pharmaceutical carrier.