Prodrugs comprising an aminoalkyl glycine linker

A prodrug or a pharmaceutically acceptable salt thereof comprising:

• a conjugate D-L;
• wherein:
• D is a primary or secondary amine- or hydroxyl-comprising biologically active moiety;
• and
• L comprises a linker moiety -L1 represented by formula (I):
• wherein:
• the dashed line indicates attachment to the primary or secondary amine or hydroxyl of the biologically active moiety by forming an amide or ester linkage, respectively;
• R1, R1a, R2, R2a, R3, and R3a are independently of each other selected from the group consisting of —H, —C(R8R8aR8b), —C(═O)R8, —C≡N, —C(═NR8)R8a, —CR8(═CR8aR8b), —C≡CR8, and -T;
• R4, R5, and R5a are independently of each other selected from the group consisting of —H, —C(R9R9aR9b), and -T;
• a1 and a2 are independently of each other 0 or 1;
• each occurrence of R6, R6a, R7, R7a, R8, R8a, R8b, R9, R9a, and R9b is independently selected from the group consisting of —H, halogen, —CN, —COOR10, —OR10, —C(O)R10, —C(O)N(R10R10a), —S(O)2N(R10R10a), —S(O)N(R10R10a), —S(O)2R10, —S(O)R10, —N(R10)S(O)2N(R10aR10b), —SR10, —N(R10R10a), —NO2, —OC(O)R10, —N(R10)C(O)R10a, —N(R10)S(O)2R10a, —N(R10)S(O)R10a, —N(R10)C(O)OR10a, —N(R10)C(O)N(R10aR10b), —OC(O)N(R10R10a), -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl,
• wherein:
• -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more R11, which are the same or different;
• and
• C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are further optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R12), —S(O)2N(R12)—, —S(O)N(R12)—, —S(O)2—, —S(O)—, —N(R12)S(O)2N(R12a)—, —S—, —N(R12)—, —OC(OR12)(R12a)—, —N(R12)C(O)N(R12a)—, and —OC(O)N(R12)—;
• each occurrence of R10, R10a, and R10b is independently selected from the group consisting of —H, -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl, wherein:
• -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more R11, which are the same or different;
• and
• C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are further optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R12)—, —S(O)2N(R12)—, —S(O)N(R12)——S(O)2—, —S(O)—, —N(R12)S(O)2N(R12a)—, —S—, —N(R12)—, —OC(OR12)(R12a)—, —N(R12)C(O)N(R12a)—, and —OC(O)N(R12)—;
• each occurrence of T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl, each occurrence of T being further independently optionally substituted with one or more R11, which are the same or different;
• each occurrence of R11 is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR13, —OR13, —C(O)R13, —C(O)N(R13R13a), —S(O)2N(R13R13a), —S(O)N(R13R13a), —S(O)2R13, —S(O)R13, —N(R13)S(O)2N(R13aR13b), —SR13, —N(R13R13a), —NO2, —OC(O)R13, —N(R13)C(O)R13a, —N(R13)S(O)2R13a, —N(R13)S(O)R13a, —N(R13)C(O)OR13a, —N(R13)C(O)N(R13aR13b), —OC(O)N(R13R13a), and C1-6 alkyl, which C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
• each occurrence of R12, R12a, R13, R13a, R13b, and R9b is independently selected from the group consisting of —H and C1-6 alkyl, which C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
• optionally, one or more of the pairs R1/R1a, R2/R2a, R3/R3a, R6/R6a and R7/R7a are joined together with the atom to which they are attached to form a C3-10 cycloalkyl or a 3- to 10-membered heterocyclyl;
• and
• optionally, one or more of the pairs R1/R2, R1/R3, R1/R4, R1/R5, R1/R6, R1/R7, R2/R3, R2/R4, R2/R5, R2/R6, R2/R7, R3/R4, R3/R5, R3/R6, R3/R7, R4/R5, R4/R6, R4/R7, R5/R6, R5/R7, and R6/R7 are joined together with the atoms to which they are attached to form a ring A, where:
• each ring A is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl;
• and
• wherein -L1 is substituted with one to five -L2-Z moieties,
• where:
• each -L2- is independently a single chemical bond or a spacer moiety;
• and
• each —Z is independently a carrier moiety which comprises a polymer with a molecular weight of at least 5 kDa.