Multicyclic sulfonamide compounds as inhibitors of histone deacetylase for the treatment of disease

A compound having structural formula I,

• or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein:
• a) R8 is selected from the group consisting of
• i) hydrogen;
• and
• vi) optionally substituted acyl of the formula —C(O)RE, wherein RE is defined such that the compound having structural formula I may be hydrolyzed to yield a pharmaceutically acceptable acid HOC(O)RE;
• b)T is sulfur;
• c) R6 and R7 are each independently selected from the group consisting of hydrogen and lower alkyl;
• or R6 and R7 taken together form an optionally substituted cycloalkyl;
• d) Q is selected from the group consisting of a bond, —(CH2)m—, —(CH2)nNH—, —(CH2)m(CO)—, —(CH2)mNH(CO)—, and —(CH2)mC(O)NH—, wherein m is 0-2 and n is 1-2, wherein if Q is not symmetric, Q may be attached in either order;
• e) R1, R2, R4, and R5 are each independently selected from the group consisting of
• i) hydrogen;
• ii) optionally substituted lower alkyl;
• iii) optionally substituted aryl, alkaryl, or cycloalkyl;
• iv) halogen or perhaloalkyl;
• v) an alkoxy of formula —(X1)n1—O—X2, where
• X1 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, and aryl;
• X2 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, lower perfluoroalkyl, optionally substituted aryl, and optionally substituted cycloalkyl;
• and
• n1 is 0, 1, 2 or 3;
• vi) an acyl of formula —(X3)n1—C(O)—X4, where
• X3 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, and aryl;
• X4 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, perfluoroalkyl, hydroxy, optionally substituted alkoxy, amino, and —NH—X5,
• where X5 is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl;
• and
• n1 is 0, 1, 2, or 3;
• vii) cyano;
• viii) an amino of formula —(X15)n15—NX16X17, where
• X15 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, and aryl;
• X16 and X17 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted aryl, and —C(O)X6,
• where X6 is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl;
• and
• n15 is 0 or 1;
• x) a thioether or thiol of formula —(X22)n22—S—X23, where
• X22 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, and aryl;
• X23 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, perflouralkyl, and optionally substituted aryl;
• and
• n22 is 0, 1 , 2, or 3;
• xi)
• (f) R3 is selected from the group consisting of
• (i) an N-sulfonamido of structure
• ii) an S-sulfonamide of formula
• g) R18 is G1-G2-,
• G2 is selected from the group consisting of a bond and optionally substituted lower alkylene;
• and
• G1 comprises at least two rings and is selected from the group consisting of optionally substituted fused polycyclic aryl, optionally substituted fused polycyclic aryl and cycloalkyl, optionally substituted fused polycyclic aryl and heterocycloalkyl, optionally substituted linked bi-aryl, optionally substituted linked aryl-heteroaryl, and optionally substituted linked aryl-heterocycloalkyl;
• h) R19 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, and optionally substituted aralkyl;
• and
• (i) R20 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, and optionally substituted lower aralkyl.