Claims for Patent: 8,906,847

Summary for Patent: 8,906,847

Title:	Prodrug comprising a drug linker conjugate
Abstract:	The present invention relates to a prodrug or a pharmaceutically acceptable salt thereof comprising a drug linker conjugate D-L, wherein -D is an amine containing biologically active moiety; and -L is a non-biologically active linker moiety -L1 represented by formula (I), wherein the dashed line indicates the attachment to the amine of the biologically active moiety and wherein R1, R1a, R2, R2a, R3, R3a, X, X1, X2, X3 have the meaning as indicated in the description and the claims and wherein L1 is substituted with one to four groups L2-Z and optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by a substituent; wherein L2 is a single chemical bond or a spacer; and Z is a carrier group. The invention also relates to A-L, wherein A is a leaving group, pharmaceutical composition comprising said prodrugs and their use as medicaments.
Inventor(s):	Felix Cleemann, Ulrich Hersel, Silvia Kaden, Harald Rau, Thomas Wegge
Assignee:	Ascendis Pharma GmbH, Ascendis Pharma AS
Application Number:	US12/865,693
Patent Claims:	1. A prodrug or a pharmaceutically acceptable salt thereof comprising: a cleavable drug-linker conjugate D-L, which is configured so that the bond between the moiety D and the moiety L is cleaved after the drug-linker conjugate D-L is administered so as to release a drug D-H; wherein: -D is a nitrogen containing biologically active moiety; -L is a non-biologically active linker moiety -L1; and -L1 comprises an amine-containing nucleophile, and is represented by formula (I): wherein: the dashed line indicates the attachment to the nitrogen of the biologically active moiety by forming an amide bond; X is C(R4R4a), N(R4), O, C(R4R4a), —C(R5R5a)C(R5R5a)—C(R4R4a) , C(R4R4a)—N(R6), N(R6)—C(R4R4a), C(R4R4a)—O, or O—C(R4R4a); X1 is C, or S(O); X2 is C(R7R7a), or C(R7R7a)—C(R8R8a); X3 is O, S, or N—CN; R1, R1a, R2, R2a, R3, R3a, R4, R4a, R5, R5a, R6, R7, R7a, R8, and R8 are independently selected from the group consisting of H, and C1-4 alkyl; optionally, one or more of the pairs R1a/R4a, R1a/R5a, R4a/R5a, and R7a/R8a form a chemical bond; optionally, one or more of the pairs R1/R1a, R2/R2a, R4/R4a, R5/R5a, R7/R7a, and R8/R8a joined together with the atom to which they are attached to form a C3-7 cycloalkyl, or 4 to 7 membered heterocyclyl; optionally, one or more of the pairs R1/R4, R1/R5, R1/R5, R4/R6, R7/R8, and R2/R3 are joined together with the atoms to which they are attached to form a ring A; optionally, R3/R3a are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle; A is selected from the group consisting of: phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 4 to 7 membered heterocyclyl, and 9 to 11 membered heterobicyclyl; and —N(R3R3a) is the amine-containing nucleophile; wherein L1 is substituted with one to four groups L2-Z and optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by a substituent, and wherein one or more further optional substituents are independently selected from the group consisting of: halogen, CN, COOR9, OR9, C(O)R9, C(O)N(R9R9a), S(O)2N(R9R9a), S(O)N(R9R9a), S(O)2R9, S(O)R9, N(R9)S(O)2N(R9aR9b), SR9, N(R9R9a), NO2, OC(O)R9, N(R9)C(O)R9a, N(R9)S(O)2R9a, N(R9)S(O)R9a, N(R9)C(O)OR9a, N(R9)C(O)N(R9aR9b), OC(O)N(R9R9a), T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more R10, which are the same or different; wherein C1-50 allkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of: T, —C(O)O—, —O—, —C(O)—, —C(O)N(R11)—, —S(O)2N(R11)—, —S(O)N (R11)—, —S(O)2—, —S(O)—, —N(R11)S(O)2N(R11a)—, —S—, —N(R11)—, —OC(O)R11, —N(R11)C(O)—, —N(R11)S(O)2—, —N(R11)S(O)—, —N(R11)C(O)O—, —N(R11)C(O)N(R1la)—, and —OC(O)N(R11R11a); wherein R9, R9a, R9b are independently selected from the group consisting of: H, T, C1-50 allkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more R10, which are the same or different; and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of: T, —C(O)O—, —O—, —C(O)—, —C(O)N(R11)—, —S(O)2N(R11)—, —S(O)N(R11)—, —S(O)2—, —S(O)—, —N(R11)S(O)2N(R11a)—, —S—, —N(R11)—, —OC(O)R11, —N(R11)C(O)—, —N(R11)S(O)2—, —N(R11)S(O)—, —N(R11)C(O)O—, —N(R11)C(O)N(R11a)—, and —OC(O)N(Rl1R11a); wherein T is selected from the group consisting of: phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 4 to 7 membered heterocyclyl, and 9 to 11 membered heterobicyclyl; wherein T is optionally substituted with one or more R10, which are the same or different; wherein R10 is: halogen, CN, oxo (═O), COOR12, OR12, C(O)R12, C(O)N(R 12R12a), S(O)2N(R12R12a), S(O)N(R12R12a)S(O)2R12, S(O)R12, N(R12)S(O)2N(R12aR12b), SR12, N(R12R12a), NO2, OC(O)R12, N(R12)C(O)R12a, N(R12)S(O)2R12a, N(R12)S(O)R12a, N(R12)C(O)OR12a, N(R12)C(O)N(R12aR12b), OC(O)N(R12R12a), or C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and wherein R11, R11a, R12, R12a, and R12b are independently selected from the group consisting of: H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; wherein L2 is a single chemical bond or a spacer; and wherein Z is a carrier group. 2. The prodrug of claim 1; wherein X3 is O. 3. The prodrug of claim 1; wherein: X is N(R4); X1 is C; and X3 is O. 4. The prodrug of claim 1; wherein X2 is C(R7R7a). 5. The prodrug of claim 1; wherein L1 is selected from the group consisting of: wherein: R is H, or C1-4 alkyl; and Y is NH, O, or S. 6. The prodrug of claim 1; wherein L1 is selected from the group consisting of: wherein R is H, or C1-4 alkyl. 7. The prodrug of claim 1; wherein: L2 is a single chemical bond; or L2-Z is selected from the group consisting of: COOR9, OR9, C(O)R9, C(O)N(R9R9a), S(O)2N(R9R9a), S(O)N(R9R9a), S(O)2R9, S(O)R9, N(R9)S(O)2N(R9aR9b), SR9, N(R9R9a), OC(O)R9, N(R9)C(O)R9a, N(R9)S(O)2R9a, N(R9)S(O)R9a, N(R9)C(O)OR9a, N(R9)C(O)N(R9aR9b), OC(O)N(R9R9a), T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more R10, which are the same or different; and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of —T—, —C(O)O—, —O—, —C(O)—, —C(O)N(R11)—, —S(O)2N(R11)—, —S(O)N(R11)—, —S(O)2—, —S(O)——N(R11)S(O)2N(R11a)—, —S—, —N(R11)—, —OC(O)R11, —N(R11)C(O)—, —N (R11)S(O)2—, —N(R11)S(O)—, —N(R11)C(O)O—, —N(R11)C(O)N(R11a)—, and —OC(O)N(R 11R11a); and wherein: R9, R9a, and R9b are independently selected from the group consisting of: H, Z, T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more R10, which are the same or different; and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of: T, —C(O)O—, —O—, —C(O)—, —C(O)N(R11)—, —S(O)2N(R11)—, —S(O)N(R11)—, —S(O)2—, —S(O)—, —N(R11)S(O)2N(R11a)—, —S—, —N(R11)—, —OC(O)R11, —N(R11)C(O)—, —N(R11)S(O)2—, —N(R11)C(O)O—, —N(R11)C(O)N(R11a)—, and —OC(O)N(R11R11a); T is selected from the group consisting of: phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 4 to 7 membered heterocyclyl, and 9 to 11 membered heterobicyclyl; wherein T is optionally substituted with one or more R10, which are the same or different; R10 is selected from the group consisting of: Z, halogen, CN, oxo (═O), COOR12, OR12, C(O)R12, C(O)N(R12R12a), S(O)2N(R12R12a), S(O)N(R12R12a), S(O)2R12, S (O)R12, N(R12)S(O)2N(R12aRl2b), SR12, N(R12R12a), NO2; OC(O)R12, N(R12)C(O)R12a, N(R12)S(O)2R12a, N(R12)S(O)R12a, N(R12)C(O)OR12a, N(R12)C(O)N(R12aR12b)OC(O)N(R12R12a), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and R11, R11a, R12, R12a, and R12b are independently selected from the group consisting of: H, Z, or C1-6 alkyl; wherein C1-6 , alkyl is optionally substituted with one or more halogen, which are the same or different; provided that one of R9, R9a, R9b, R10, R11, R11a, R12, R12a, and R12b is Z. 8. The prodrug of claim 1; wherein L2 is a C1-20 alkyl chain, which is: optionally interrupted by one or more groups independently selected from —O— and C(O)N(R3aa); and optionally substituted with one or more groups independently selected from OH and C(O)N(R3aaR3aaa); and wherein R3aa and R3aaa are independently selected from the group consisting of H, and C1-4 alkyl. 9. The prodrug of claim 1; wherein L2 has a molecular weight in the range of from 14 g/mol to 750 g/mol. 10. The prodrug of claim 1; wherein L2 is attached to Z via a terminal group selected from the group consisting of: 11. The prodrug of claim 1; wherein L is represented by formula (Ia): wherein R3aa and R3aaa: are independently selected from the group consisting of H and C1-4 alkyl; or are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle. 12. The prodrug of claim 1; wherein L is represented by formula (Ib): wherein R3aa is H or C1-4 alkyl. 13. The prodrug of claim 1; wherein R1 in formula (I) is L2-Z. 14. The prodrug of claim 1; wherein R3 in formula (I) is L2-Z. 15. The prodrug of claim 1; wherein R3 and R3a in formula (I) are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle which is substituted with L2-Z. 16. The prodrug of claim 1; wherein D-H is a small molecule bioactive agent or a biopolymer. 17. The prodrug of claim 1; wherein D-H is a biopolymer selected from the group of biopolymers consisting of proteins, polypeptides, oligonucleotides, and peptide nucleic acids. 18. The prodrug of claim 1; wherein D-H is a polypeptide selected from the group of polypeptides consisting of: ACTH, adenosine deaminase, agalsidase, alfa-1 antitrypsin (AAT), alfa-1 proteinase inhibitor (API), alteplase, amylins (amylin, symlin), anistreplase, ancrod serine protease, antibodies (monoclonal or polyclonal, and fragments or fusions), antithrombin III, antitrypsins, aprotinin, asparaginases, atosiban, biphalin, bivalirudin, bone-morphogenic proteins, bovine pancreatic trypsin inhibitor (BPTI), cadherin fragments, calcitonin (salmon), collagenase, complement C1 esterase inhibitor, conotoxins, cytokine receptor fragments, DNase, dynorphin A, endorphins, enfuvirtide, enkephalins, erythropoietins, exendins, factor VII, factor VIIa, factor VIII, factor VIIIa, factor IX, fibrinolysin, fibroblast growth factor (FGF), growth hormone releasing peptide 2 (GHRP2), fusion proteins, follicle-stimulating hormones, gramicidin, ghrelin, desacyl-ghrelin, granulocyte colony stimulating factor (G-CSF), galactosidase, glucagon, glucagon-like peptides, glucocerebrosidase, granulocyte macrophage colony stimulating factor (GM-CSF), human heat shock proteins (HSP), phospholipase-activating protein (PLAP), gonadotropin chorionic (hCG), hemoglobins, hepatitis B vaccines, hirudin, human serine protease inhibitor, hyaluronidases, idurnonidase, immune globulins, influenza vaccines, interleukins (1 alfa, 1 beta, 2, 3, 4, 6, 10, 11, 12, 13, 21), IL-1 receptor antagonist (thIL-1ra), insulins, insulin like growth factors, insulin-like growth factor binding protein (rhIGFBP), interferons (alfa 2a, alfa 2b, alfa 2c, beta 1a, beta 1b, gamma 1a, gamma 1b), intracellular adhesion molecule, keratinocyte growth factor (KGF), P-selectin glycoprotein ligand (PSGL), transforming growth factors, lactase, leptin, leuprolide, levothyroxine, luteinizing hormone, lyme vaccine, natriuretic peptides (ANP, BNP, CNP and fragments), neuropeptide Y, pancrelipase, pancreatic polypeptide, papain, parathyroid hormone, PDGF, pepsin, peptide YY, platelet activating factor acetylhydrolase (PAF-AH), prolactin, protein C, thymalfasin, octreotide, secretin, sermorelin, soluble tumor necorsis factor receptor (TNFR), superoxide dismutase (SOD), somatropins (growth hormone), somatoprim, somatostatin, streptokinase, sucrase, terlipressin, tetanus toxin fragment, tilactase, thrombins, thymosin, thyroid stimulating hormone, thyrotropin, tumor necrosis factor (TNF), TNF receptor-IgG Fc, tissue plasminogen activator (tPA), TSH, urodilatin, urate oxidase, urokinase, vaccines, vascular endothelial growth factor (VEGF), vasoactive intestinal peptide, vasopressin, ziconotide, lectin, and ricin. 19. The prodrug of claim 1; wherein D-H is a protein prepared by recombinant DNA technologies. 20. The prodrug of claim 1; wherein D-H is a protein selected from the group of proteins consisting of: antibody fragments, single chain antigen binding proteins, catalytic antibodies, and fusion proteins. 21. The prodrug of claim 1; wherein D-H is a small molecule bioactive agent selected from the group of agents consisting of: central nervous system-active agents, anti-infective, anti-allergic, immunomodulating, anti-obesity, anticoagulants, antidiabetic, anti-neoplastic, antibacterial, anti-fungal, analgesic, contraceptive, anti-inflammatory, steroidal, vasodilating, vasoconstricting, and cardiovascular agents with at least one primary or secondary amino group. 22. The prodrug of claim 1; wherein D-H is a small molecule bioactive agent selected from the group of agents consisting of: acarbose, alaproclate, alendronate, amantadine, amikacin, amineptine, aminoglutethimide, amisulpride, amlodipine, amotosalen, amoxapine, amoxicillin, amphetamine, amphotericin B, ampicillin, amprenavir, amrinone, anileridine, apraclonidine, apramycin, articaine, atenolol, atomoxetine, avizafone, baclofen, benazepril, benserazide, benzocaine, betaxolol, bleomycin, bromfenac, brofaromine, carvedilol, cathine, cathinone, carbutamid, cefalexine, clinafloxacin, ciprofloxacin, deferoxamine, delavirdine, desipramine, daunorubicin, dexmethylphenidate, dexmethylphenidate, diaphenylsulfon, dizocilpine, dopamin, dobutamin, dorzolamide, doxorubicin, duloxetine, eflornithine, enalapril, epinephrine, epirubicin, ergoline, ertapenem, esmolol, enoxacin, ethambutol, fenfluramine, fenoldopam, fenoterol, fingolimod, flecainide, fluvoxamine, fosamprenavir, frovatriptan, furosemide, fluoexetine, gabapentin, gatifloxacin, gemiflocacin, gentamicin, grepafloxacin, hexylcaine, hydralazine, hydrochlorothiazide, icofungipen, idarubicin, imiquimod, inversine, isoproterenol, isradipine, kanamycin A, ketamin, labetalol, lamivudine, levobunolol, levodopa, levothyroxine, lisinopril, lomefloxacin, loracarbef, maprotiline, mefloquine, melphalan, memantine, meropenem, mesalazine, mescaline, methyldopa, methylenedioxymethamphetamine, metoprolol, milnacipran, mitoxantron, moxifloxacin, norepinephrine, norfloxacin, nortriptyline, neomycin B, nystatin, oseltamivir, pamidronic acid, paroxetine, pazufloxacin, pemetrexed, perindopril, phenmetrazine, phenelzine, pregabalin, procaine, pseudoephedrine, protriptyline, reboxetine, ritodrine, sabarubicin, salbutamol, serotonin, sertraline, sitagliptin, sotalol, spectinomycin, sulfadiazin, sulfamerazin, sertraline, sprectinomycin, sulfalen, sulfamethoxazol, tacrine, tamsulosin, terbutaline, timolol, tirofiban, tobramycin, tocainide, tosufloxacin, trandolapril, tranexamic acid, tranylcypromine, trimerexate, trovafloxacin, valaciclovir, valganciclovir, vancomycin, viomycin, viloxazine, and zalcitabine. 23. The prodrug of claim 1; wherein Z is a polymer of at least 500 Da or a C8-18 alkyl group. 24. The prodrug of claim 1; wherein Z is selected from the group of optionally crosslinked polymers consisting of: poly(propylene glycol), poly(ethylene glycol), dextran, chitosan, hyaluronic acid, alginate, xylan, mannan, carrageenan, agarose, cellulose, starch, hydroxyalkyl starch (HAS), poly(vinyl alcohols), poly(oxazolines), poly(anhydrides), poly(ortho esters), poly(carbonates), poly(urethanes), poly(acrylic acids), poly(acrylamides), poly(acrylates), poly(methacrylates), poly(organophosphazenes), polyoxazoline, poly(siloxanes), poly(amides), poly(vinylpyrrolidone), poly(cyanoacrylates), poly(esters), poly(iminocarbonates), poly(amino acids), collagen, gelatin, hydrogel, a blood plasma protein, and copolymers thereof. 25. The prodrug of claim 1; wherein Z is a protein. 26. The prodrug of claim 1; wherein Z is a protein selected from the group consisting of albumin, transferrin, and immunoglobulin. 27. The prodrug of claim 1; wherein Z is a linear or branched poly(ethylene glycol) with a molecular weight from 2,000 Da to 150,000 Da. 28. The prodrug of claim 1; wherein: D-H is a GLP-1 receptor agonist; and Z is a hydrogel. 29. The prodrug of claim 28; wherein the GLP-1 receptor agonist is Exendin-4. 30. The prodrug of claim 28; wherein in formula (I): X is N(R4); X1 is C; and X3 is O. 31. The prodrug of claim 1; wherein D-H is a GLP-1 receptor agonist; wherein L is represented by formula (Ia): wherein R3aa and R3aaa: are independently selected from the group consisting of H and C1-4 alkyl; or are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle; and wherein Z is a hydrogel. 32. A prodrug precursor comprising: a compound of formula Act-L; wherein: Act is a leaving group; and L is a non-biologically active linker moiety L1 which comprises an amine-containing nucleophile, and which is represented by formula (I): wherein: the dashed line indicates the attachment to the nitrogen of the biologically active moiety by forming an amide bond; X is C(R4R4a), N(R4), O, C(R4R4a)—C(R5R5a)—, C(R5R5a)—C(R4R4a), C(R4R4a)—N(R6), N(R6)—C(R4R4a), (R4R4a)—O, or O—C(R4R4a); X1 is C, or S(O); X2 is C(R7R7a), or C(R7R7a)—C(R8R8a); X3 is O, S, or N—CN; R1; R1a, R2, R2a, R3, R3a, R4, R4a, R5, R5a, R6, R7, R7a, R8, and R8a are independently selected from the group consisting of H, and C1-4 alkyl; optionally, one or more of the pairs R1a/R4a,R1a/R5a, R4a/R5a, and R7a/R8a form a chemical bond; optionally, one or more of the pairs R1/R1a, R2/R2a, R4/R4a, R5/R5a, R7/R7a, and R8/R8a are joined together with the atom to which they are attached to form a C3-7 cycloalkyl, or 4 to 7 membered heterocyclyl; optionally, one or more of the pairs R1/R4, R1/R5, R1/R6, R4/R5, R4/R6, R7/R8, and R2/R3 are joined together with the atoms to which they are attached to form a ring A; optionally, R3/R3a are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle; A is selected from the group consisting of: phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 4 to 7 membered heterocyclyl, and 9 to 11 membered heterobicyclyl; and —N(R3R3a) is the amine-containing nucleophile; wherein L1 is substituted with one to four groups L2-Z and optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by a substituent, and wherein one or more further optional substituents are independently selected from the group consisting of: halogen, CN, COOR9, OR9, C(O)R9, C(O)N(R9R9a), S(O)2N(R9R9a), S(O)N(R9R9a), S(O)2R9S(O)R9, N(R9)S(O)2N(R9aR9b), SR9, N(R9R9a), NO2, OC(O)R9, N(R9)C(O)R9a, N(R9)S(O)2, R9a, N(R9)S(O)R9a, N(R9)C(O)OR9a, N(R9)C(O)N(R9aR9b), OC(O)N(R9R9a), T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein T C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more R10, which are the same or different; wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of: T, —C(O)O—, —O—, —C(O)—, —C(O)N(R11)—, —S(O)2N(R11)—, —S(O)N(R11)—, —S(O)2—, —S(O)—, —N(R11)S(O)2N(R11a)—, —S—, —N(R11)—, —OC(O)R11),—N(R11)C(O)—, —N(R11)S(O)2—, —N(R11)S(O)—,—N(R11)C(O)O—, —N(R11)C(O)N(R11a)—, and —OC(O)N(R11R11a); wherein R9, R9a, R9b are independently selected from the group consisting of: H, T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more R10, which are the same or different; and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of: T, —C(O)O—, —O—, —C(O)—, —C(O)N(R11)—, —S(O)2N(R11)—, —S(O)N(R11)—, —S(O)2—, —S(O)—, —N(R11)S(O)2N(R11a)—, —S—, —N(R11)—OC(O)R11, —N(R11)C(O)—, —N(R11)S(O)2, —N(R11)S(O)—, —N(R11)C(O)—, —N(R11)C(O)N(R11a)—, and —OC(O)N(R 11R11a); wherein T is selected from the group consisting of: phenyl, naphthyl, indeny, indanyl, tetralinyl, C3-10 cycloalkyl, 4 to 7 membered heterocyclyl, and 9 to 11 membered heterobicyclyl; wherein T is optionally substituted with one or more R10, which are the same or different; wherein R10 is: halogen, CN, oxo (═O), COOR12, OR12, C(O)R12, C(O)N(R12R12a), S(O)2N (R12R12a)S(O)N(R12R12a)S(O) R12, S(O)R12, N(R12)S(O)2N(R12aR12b) , SR12, N(R12R12a) , NO2, OC(O)R12,N(R12)C(O)R12a, N(R12)S(O)2R12a, N(R12)S(O)R12a, N(R12)C(O)OR12a, N(R12)C(O)N(R12aR12b), OC(O)N(R12R12a), or C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and wherein R11, R11a, R12, R12a, and R12b are independently selected from the group consisting of; H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; wherein L2 is a single chemical bond or a spacer; and wherein Z is a carrier group. 33. The prodrug precursor of claim 32; wherein Act is chloride, bromide, fluoride, nitrophenoxy, imidazolyl, N-hydroxysuccinimidyl, N-hydroxybenzotriazolyl, N-hydroxyazobenzotriazolyl, pentafluorophenoxy, 2-thiooxo-thiazolidinyl, or N-hydroxysillfosuccinimidyl. 34. A pharmaceutical composition comprising: a prodrug of claim 1 or a pharmaceutical salt thereof; and a pharmaceutically acceptable excipient. 35. A method comprising: administering the prodrug of claim 1. 36. A method comprising: administering the pharmaceutical composition of claim 34. 37. The prodrug of claim 1; wherein D-H is a GLP-1 receptor agonist; and wherein L is represented by formula (Ib): wherein: R3aa is H or C1-4 alkyl; and Z is a hydrogel.