Peptidyl prodrugs and linkers and stabilizers useful therefor

A compound having the structure:

• or a pharmaceutically acceptable salt thereof;
• wherein
• X and Z are members independently selected from O, S and NR23
• wherein
• R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
• R1 is H, substituted or unsubstituted lower alkyl, or C(O)R8, wherein R8 is a member selected from NR9R10 and OR9,
• in which
• R9, and R10 are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
• R2 is CH3;
• R11 is C(O)NR12R13
• in which
• R12, and R13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, and at least one of R12 and R13 comprises a cleaveable group;
• R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, OR15
• wherein
• R15 and R16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R15 and R16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms;
• and
• X1 is a leaving group.

A compound having the structure:

• or a pharmaceutically acceptable salt thereof;
• wherein
• X and Z are members independently selected from O, S and NR23
• wherein
• R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
• R1 is H, substituted or unsubstituted lower alkyl, or C(O)R8, wherein R8 is a member selected from NR9R10 and OR9,
• in which
• R9, and R10 are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
• R2 is H, or substituted or unsubstituted lower alkyl;
• R11 is C(O)NR12R13
• in which
• R12, and R13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, and at least one of R12 and R13 comprises a cleaveable group;
• R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, OR15
• wherein
• R15 and R16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R15 and R16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, wherein at least one of R4, R5, R15 and R16 comprises:
• wherein
• R30 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
• R31 and R32 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, or R31 and R32 together are:
• wherein
• R33 and R34 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
• R35 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and NR36
• wherein
• R36 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
• and
• X5 is a single bond, O or NR37
• wherein R37 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
• and
• X1 is a leaving group.

A compound having the structure:

• or a pharmaceutically acceptable salt thereof;
• wherein
• X and Z are members independently selected from O, S and NR23
• wherein
• R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
• R1 is H, substituted or unsubstituted lower alkyl, or C(O)R8, wherein R8 is a member selected from NR9R10 and OR9,
• in which
• R9, and R10 are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
• R2 is H, or substituted or unsubstituted lower alkyl;
• R11 is a peptidyl moiety having the structure:
• wherein
• X3 is a member selected from protected or unprotected reactive functional groups, detectable labels and targeting agents;
• L1 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
• AA1, AAb and AAb+1 are members independently selected from natural and unnatural α-amino acids;
• L2 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
• q and v are integers independently selected from 0 and 1;
• and b is an integer from 0 to 20;
• R4 and R3 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, OR15
• wherein
• R15 and R16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R15 and R16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms;
• and
• X1 is a leaving group.

A compound having the structure:

• or a pharmaceutically acceptable salt thereof;
• wherein
• X and Z are members independently selected from O, S and NR23
• wherein
• R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
• R1 is H, substituted or unsubstituted lower alkyl, or C(O)R8, wherein R8 is a member selected from NR9R10 and OR9,
• in which
• R9, and R10 are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
• R2 is H, or substituted or unsubstituted lower alkyl;
• R11 is C(O)NR12R13
• in which
• R12, and R13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, and at least one of R12 and R13 comprises a cleaveable group:
• R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, OR15
• wherein
• R15 and R16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R15 and R16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms,
• wherein a member selected from R4 and R5 is:
• wherein
• X2 and Z1 are members independently selected from O, S and NR3;
• R17 and R18 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR19R20, NC(O)R19, OC(O)NR19, OC(O)OR19, C(O)R19, OR19,
• wherein
• R19 and R20 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted peptidyl, wherein R19 and R20 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms;
• and
• X1 is a leaving group.

A compound having the structure:

• or a pharmaceutically acceptable salt thereof;
• wherein
• X and Z are members independently selected from O, S and NR23
• wherein
• R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
• R1 is H, substituted or unsubstituted lower alkyl, or C(O)R8, wherein R8 is a member selected from NR9R10 and OR9,
• in which
• R9, and R10 are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
• R2 is H, or substituted or unsubstituted lower alkyl;
• R11 is C(O)NR12R13
• in which
• R12, and R13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, and at least one of R12 and R13 comprises a cleaveable group;
• R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, OR15
• wherein
• R15 and R16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R15 and R16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, wherein at least one member selected from R15 and R16 has the structure:
• wherein
• X4 is member selected from protected or unprotected reactive functional groups, detectable labels and targeting agents;
• L3 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
• AA1, and AAc are members independently selected from natural and unnatural α-amino acids;
• L4 is a linker selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl;
• R24 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
• p and t are integers independently selected from 0 and 1;
• and c is an integer from 0 to 20;
• X1 is a leaving group;
• and
• wherein represents a point at which R15 or R16 is attached to a remainder of the compound.