Compounds, conjugates and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines

A compound having the structure of formula II:

• MLD)s]t II
• or a pharmaceutically acceptable salt thereof, wherein:
• M is a cell-specific ligand unit;
• each L is independently a linker unit;
• each D independently has the structure of formula I-c or I-d,
• or a pharmaceutically acceptable salt thereof, wherein:
• each is independently a single bond or a double bond, as valency permits;
• each R1 is independently R, —C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, —S(O)2OR, —C(R)2OR, or —S(O)2N(R)2;
• each R is independently hydrogen or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• or:
• two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each R2 is independently R, —[C(R)2]q—OR, —[C(R)2]q—N(R)2, —[C(R)2]q—SR, —[C(R)2]q—OSi(R)3, —[C(R)2]q—OC(O)R, —[C(R)2]q—OC(O)OR, —[C(R)2]q—OC(O)N(R)2, —[C(R)2]q—OC(O)N(R)—SO2R or —[C(R)2]q—OP(OR)2;
• or
• R1 and R2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen or sulfur;
• each q is independently 0, 1, 2, 3, or 4;
• each R3′ is independently R or an electron-withdrawing group;
• each R4 is independently absent when is a double bond or is independently R or halogen;
• each R5 is independently absent when is a double bond or is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• each of R6 and R6′ is independently R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, or —OSi(R)3;
• or
• R6 and R6′ are taken together to form ═O, ═C(R)2 or ═NR;
• each n is independently 0, 1, 2, 3, or 4;
• each R7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R)3, —SR, —N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —P(R)2, —P(OR)2, —P(O)(R)2, —P(O)(OR)2, —P(O)[N(R)2]2, —B(R)2, —B(OR)2, or —Si(R)3;
• or
• two R7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each R8 is independently —(S)m—Rx wherein m is 1, 2, or 3, and Rx is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(S)R, —S(O)R, —S(O)2R, or —S(O)2N(R)2;
• and
• each R9 is independently —(S)p—Ry wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and Ry is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(S)R, —S(O)R, —S(O)2R, or —S(O)2N(R)2;
• or
• R8 and R9 are taken together to form —S—, —(S)m—[C(R)2]q—(S)p—, —(S)m—(S)p—, —(S)m—C(O)—(S)p—, —(S)m—C(S)—(S)p—,
• —(S)m—S(O)—(S)p—, or —(S)m—S(O)2—(S)p—;
• s is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• and
• t is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

A compound having the structure of formula III:

• M-LD)s III
• or a pharmaceutically acceptable salt thereof, wherein:
• M is a cell-specific ligand unit;
• L is a linker unit;
• each D independently has the structure of formula I-c or I-d,
• or a pharmaceutically acceptable salt thereof, wherein:
• each is independently a single bond or a double bond, as valency permits;
• each R1 is independently R, —C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, —S(O)2OR, —C(R)2OR, or —S(O)2N(R)2;
• each R is independently hydrogen or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• or:
• two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each R2 is independently R, —[C(R)2]q—OR, —[C(R)2]q—N(R)2, —[C(R)2]q—SR, —[C(R)2]q—OSi(R)3, —[C(R)2]q—OC(O)R, —[C(R)2]q—OC(O)OR, —[C(R)2]q—OC(O)N(R)2, —[C(R)2]q—OC(O)N(R)—SO2R or —[C(R)2]q—OP(OR)2;
• or
• R1 and R2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen or sulfur;
• each q is independently 0, 1, 2, 3, or 4;
• each R3′ is independently R or an electron-withdrawing group;
• each R4 is independently absent when is a double bond or is independently R or halogen;
• each R5 is independently absent when is a double bond or is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• each of R6 and R6′ is independently R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, or —OSi(R)3;
• or
• R6 and R6′ are taken together to form ═O, ═C(R)2 or ═NR;
• each n is independently 0, 1, 2, 3, or 4;
• each R7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R)3, —SR, —N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —P(R)2, —P(OR)2, —P(O)(R)2, —P(O)(OR)2, —P(O)[N(R)2]2, —B(R)2, —B(OR)2, or —Si(R)3;
• or
• two R7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each R8 is independently —(S)m—Rx wherein m is 1, 2, or 3, and Rx is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(S)R, —S(O)R, —S(O)2R, or —S(O)2N(R)2;
• and
• each R9 is independently —(S)p—Ry wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and Ry is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(S)R, —S(O)R, —S(O)2R, or —S(O)2N(R)2;
• or
• R8 and R9 are taken together to form —S—, —(S)m—[C(R)2]q—(S)p—, —(S)m—(S)p—, —(S)m—C(O)—(S)p—, —(S)m—C(S)—(S)p—, —(S)m—S(O)—(S)p—, or —(S)m—S(O)2—(S)p—;
• and
• s is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.