Prodrug moieties and compounds comprising the same

Abstract

Disclosed herein are compounds that can be used to prepare prodrugs, methods of producing prodrugs using the compounds, and prodrugs produced by such methods. The prodrugs produced using the compounds disclosed herein are highly soluble, allowing for good oral bioavailability.

Description

[0001] PRODRUG MOIETIES AND COMPOUNDS COMPRISING THE SAME

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 600,382, filed on November 17, 2023, which is incorporated herein by reference in its entirety.

[0004] FIELD

[0005] Provided herein are compounds that can be used to prepare prodrugs, methods of producing prodrugs using the compounds, and prodrugs produced by such methods. The prodrugs produced using the compounds disclosed herein are highly soluble, allowing for good oral bioavailability.

[0006] BACKGROUND

[0007] A significant number of currently marketed small molecule pharmaceutical compounds are nearly insoluble. However, improvements in solubility tend to increase hydrophilicity, which can reduce target engagement. Prodrug moieties, such as succinic acid esters and formyl phosphates, can be used to increase solubility of the compounds without ultimately affecting target engagement, as the solubilizing prodrug moiety is eventually cleaved to release the active compound. However, such methodology is largely limited to drugs with alcohols or NH-containing heterocycles. Certain prodrug moieties can also cleave too quickly; in the case of orally-administered drugs, early cleavage can result in precipitation of the pharmaceutical compound in the stomach or intestine.

[0008] SUMMARY

[0009] Disclosed herein are compounds that can be used as building blocks to prepare prodrugs with significantly increased solubility. Also disclosed herein are prodrug compounds prepared from the building block compounds, and methods of preparing prodrug compounds. The resulting prodrugs can be cleaved in vivo, e.g., by phosphatases. In some embodiments, the prodrugs can undergo controlled cleavage, so as to maximize oral bioavailability.

[0010] In one aspect, disclosed herein is a compound of formula (I):

[0011] or a salt thereof, wherein:

[0012] Z is -CR3aR3b-O-CR4aR4b-LG, -(CR5aR5b)P-CO-E, -(CR6aR6b)-LG, or -CR7aR7b-O- CR8aR8b-O-CR9aR9b-LG; one of Rlaand Rlbis -0P0(0Ra)2, and the other is selected from hydrogen, alkyl, halo, haloalkyl, and -(CRbRc)m-X;

[0013] R2a, R2b, and R2care each independently selected from hydrogen, alkyl, halo, haloalkyl, and -(CRdRe)n-Y; wherein, when Rlais -0P0(0Ra)2, Rlband R2a, together with the carbon atoms to which they are attached, are optionally taken together to form an optionally substituted ring;

[0014] X and Y are each independently selected from cyano, nitro, -ORf, -NR8Rh, -COOR1, - CONR'Rk, -S(O)2NR1Rm, -PO(ORn)2, and -PO(ORO)CH2PO(ORP)2; m, n, and p are each independently 0, 1, or 2;

[0015] R3a, R3b, R6a, R6b, R7a, and R7bare each independently selected from hydrogen and alkyl;

[0016] R4aand R4bare each hydrogen, or are taken together to form an oxo group;

[0017] R5aand R5bare each independently selected from hydrogen, alkyl, halo, and alkoxy;

[0018] R8aand R8bare each hydrogen, or are taken together to form an oxo group;

[0019] R9aand R9bare each selected from hydrogen and alkyl, or are taken together to form an oxo group;

[0020] Ra, Rf, Rg, Rh, R1, RJ, Rk, R1, Rm, Rn, R°, and Rpare each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, and arylalkyl; wherein Rgand Rh, R' and Rk, and R1and Rm, together with the nitrogen atoms to which they are attached, are optionally taken together to form an optionally substituted ring;

[0021] Rb, Rc, Rd, and Reare each independently selected from hydrogen and alkyl;

[0022] E is halo or -OH; and

[0023] LG is selected from -O-Q, halo, and hydroxy, wherein Q is optionally substituted aryl, optionally substituted heterocyclyl, or -SO2R8, wherein R8is selected from alkyl and optionally substituted aryl. In some embodiments, when Rlais -OPO(ORa)2, then either: Rlbis -(CRbRc)m-X, wherein X is -COOR1or -PO(ORn)2; or at least one of R2a, R2b, and R2cis -(CRdRe)n-Y, wherein Y is -COOR1or -PO(ORn)2. In some embodiments, when Rlbis -OPO(ORa)2, then either: Rlais -(CRbRc)m-X, wherein X is -COOR1or -PO(ORn)2; or at least one of R2a, R2b, and R2Cis -(CRdRe)n-Y, wherein Y is -COOR1or -PO(ORn)2.

[0024] In some embodiments, Z is -CR3aR3b-O-CR4aR4b-LG, -(CR5aR5b)P-CO-E, or - (CR6aR6b)-LG.

[0025] In some embodiments, Z is -CR3aR3b-O-CR4aR4b-LG.

[0026] In some embodiments, R3aand R3bare each independently selected from hydrogen and methyl.

[0027] In some embodiments, R4aand R4bare taken together to form an oxo group. In some embodiments, R4aand R4bare each hydrogen.

[0028] In some embodiments, Z is -(CR5aR5b)p-CO-E. In some embodiments, p is 2, each R5aand R5bis independently selected from hydrogen and methyl, and E is selected from chloro and hydroxy.

[0029] In some embodiments, Z is -(CR6aR6b)-LG. In some embodiments, R6aand R6bare each independently selected from hydrogen and methyl, and LG is halo or hydroxy. In some embodiments, LG is bromo or hydroxy.

[0030] In some embodiments, Z is -CR7aR7b-O- CR8aR8b-O-CR9aR9b-LG. In some embodiments, R7aand R7bare each hydrogen. In some embodiments, R8aand R8bare each hydrogen, and R9aand R9bare taken together to form an oxo group. In some embodiments, R8aand R8btaken together to form an oxo group, and R9aand R9bare each hydrogen.

[0031] In some embodiments, Ra, Rf, Rg, Rh, R1, Rj, Rk, R1, Rm, Rn, R°, and Rpare each independently selected from hydrogen, C1-C4 alkyl, phenyl, and phenyl-Ci-C2-alkyl.

[0032] In some embodiments, Rb, Rc, Rd, and Reare each independently selected from hydrogen and methyl.

[0033] In some embodiments, R2a, R2b, and R2care each independently selected from hydrogen, C1-C4 alkyl, halo, and -(CRdRe)n-Y, wherein n is 0 or 1, Rdand Reare each hydrogen, and Y is selected from cyano, -ORf, -COOR1, and -PO(ORn)2, wherein each Rf, R1, and Rnis independently selected from hydrogen and C1-C4 alkyl.

[0034] In some embodiments, LG is -O-Q, wherein Q is optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, LG is -O-Q, wherein Q is phenyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from nitro and halo. In some embodiments, LG is -O-(4-nitrophenyl) or -O-pentafluorophenyl. In some embodiments, LG is -O-Q, wherein Q is an optionally substituted pyrrolidine-2, 5-dione. In some embodiments, LG is -O-Q, wherein Q is -SO2R8, wherein R8is methyl.

[0035] In some embodiments, LG is halo or hydroxy.

[0036] In some embodiments, the compound has formula (la) or (lb):

[0037] In some embodiments, the compound has formula (la).

[0038] In some embodiments, the compound is selected from the group consisting of:

[0039] and salts thereof.

[0040] In some embodiments, disclosed herein is a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein:

[0041] Z’ is -CR3aR3b-O-CR4aR4b-, -(CR5aR5b)P-CO-, -(CR6aR6b)- , or -CR7aR7b-O- CR8aR8b-

[0042] O-CR9aR9b-; one of Rlaand Rlbis -OPO(ORa)2, and the other is selected from hydrogen, alkyl, halo, haloalkyl, and -(CRbRc)m-X;

[0043] R2a, R2b, and R2care each independently selected from hydrogen, alkyl, halo, haloalkyl, and -(CRdRe)n-Y; wherein, when Rlais -OPO(ORa)z, Rlband R2a, together with the carbon atoms to which they are attached, are optionally taken together to form an optionally substituted ring;

[0044] X and Y are each independently selected from cyano, nitro, -ORf, -NR8Rh, -COOR1, -

[0045] CONRJRk, -S(0)2NR‘Rm, -PO(ORn)2, and -PO(OR°)CH2PO(ORP)2; m, n, and p are each independently 0, 1, or 2;R3aR3bR6a,R6b,R7aand R7b are each independently selected from hydrogen and alkyl;

[0046] R4aand R4bare each hydrogen, or are taken together to form an oxo group;

[0047] R5aand R5bare each independently selected from hydrogen, alkyl, halo, and alkoxy;

[0048] R8aand R8bare each hydrogen, or are taken together to form an oxo group;

[0049] R9aand R9bare each selected from hydrogen and alkyl, or are taken together to form an oxo group;

[0050] Ra, Rf, Rs, Rh, R1, R1, Rk, R1, Rm, Rn, R°, and Rpare each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, and arylalkyl; wherein Rgand Rh, R' and Rk, and R1and Rm, together with the nitrogen atoms to which they are attached, are optionally taken together to form an optionally substituted ring;

[0051] Rb, Rc, Rd, and Reare each independently selected from hydrogen and alkyl; and

[0052] D is a pharmaceutically active compound.

[0053] In some embodiments, when Rlais -OPO(ORa)2, then either: Rlbis -(CRbRc)m-X, wherein X is -C00R1or -PO(ORn)2; or at least one of R2a, R2b, and R2cis -(CRdRe)n-Y, wherein Y is -C00R1or -PO(ORn)2. In some embodiments, when Rlbis -OPO(ORa)2, then either: Rlais -(CRbRc)m-X, wherein X is -C00R1or -PO(ORn)2; or at least one of R2a, R2b, and R2Cis -(CRdRe)n-Y, wherein Y is -COOR1or -PO(OR")2.

[0054] In some embodiments, Z’ is -CR3aR3b-O-CR4aR4b-, -(CR5aR5b)P-CO-, or -(CR6aR6b)-.

[0055] In some embodiments, Z’ is -CR3aR3b-O-CR4aR4b-.

[0056] In some embodiments, R3aand R3bare each independently selected from hydrogen and methyl.

[0057] In some embodiments, R4aand R4bare each hydrogen. In some embodiments, R4aand R4bare taken together to form an oxo group.

[0058] In some embodiments, Z’ is -CH2-.

[0059] In some embodiments, Z’ is -(CR5aR5b)P-CO-. In some embodiments, p is 2, and R5aand R5bare each independently selected from hydrogen and methyl.

[0060] In some embodiments, Z’ is -(CR6aR6b)-. In some embodiments, R6aand R6bare each independently selected from hydrogen and methyl.

[0061] In some embodiments, Z’ is -CR7aR7b-O- CR8aR8b-O-CR9aR9b-LG. In some embodiments, R7aand R7bare each hydrogen. In some embodiments, R8aand R8bare each hydrogen, and R9aand R9bare taken together to form an oxo group. In some embodiments, R8aand R8btaken together to form an oxo group, and R9aand R9bare each hydrogen. In some embodiments, Ra, Rf, Rg, Rh, R1, Rj, Rk, R1, Rm, Rn, R°, and Rpare each independently selected from hydrogen, C1-C4 alkyl, phenyl, and phenyl-Ci -Ch-alky 1. In some embodiments, Rb, Rc, Rd, and Reare each independently selected from hydrogen and methyl.

[0062] In some embodiments, R2a, R2b, and R2care each independently selected from hydrogen, C1-C4 alkyl, halo, and -(CRdRe)n-Y, wherein n is 0 or 1, Rdand Reare each hydrogen, and Y is selected from cyano, -ORf, -COOR1, and -PO(ORn)2, wherein each Rf, R1, and Rnis independently selected from hydrogen and C1-C4 alkyl.

[0063] In some embodiments, the compound has formula (Ila) or (lib):

[0064] In some embodiments, group D is attached to the compound via a nitrogen atom or an oxygen atom. In some embodiments, the pharmaceutically active compound is selected from the group consisting of: analgesics; anesthetics; antibacterials; anticonvulsants; antidementia agents; antidepressants; antiemetics; antifungals; antigout agents; anti-inflammatories; antimigraine agents; antimyasthenic agents; antimycobacterials; antineoplastics; antiparasitics; antiparkinson agents; antipsychotics; antispasticity agents; antivirals; anxiolytics; bipolar agents; blood glucose regulators; blood products I modifiers I volume expanders; cardiovascular agents; central nervous system agents; dental and oral agents; dermatological agents; enzyme replacements / modifiers; gastrointestinal agents; genitourinary agents; hormonal agents; immunological agents; inflammatory bowel disease agents; metabolic bone disease agents; ophthalmic agents; otic agents; respiratory tract agents; sedatives / hypnotics; and skeletal muscle relaxants. In some embodiments, the pharmaceutically active compound is an antineoplastic agent.

[0065] In some embodiments, the pharmaceutically active compound is selected from the group consisting of abrocitinib, acalbrutinib, amisulpride, apalutamide, apixaban, aprepitant, ARV-766, asciminib, atorvastatin, avacopan, avapritinib, bavdegalutamide, bicalutamide, cabazitaxel, carvedilol, cefdinir, cefprozil, celecoxib, clarithromycin, dabrafenib, desloratadine, docetaxel, doravirine, doxorubicin, DT2216, efavirenz, enzalutamide, eragidomide, etravirine, ezetimibe, FHD-609, glimepiride, glipizide, glyburide, golcadomide, hydrochlorothiazide, hydroxyzine pamoate, ibrutinib, idelalisib, imatinib, ivacaftor, lamotrigine, lenalidomide, linezolid, lopinavir, meloxicam, metaxalone, methylphenidate, mezigdomide, modafinil, N-desalkylquetiapine, niclosamide, nilotinib, NX-2127, olanzapine, olaparib, oliceridine, osimertinib, oteseconazole, oxcarbazepine, paclitaxel, pacritinib, palbociclib, pioglitazone, pomalidomide, pralsetinib, quetiapine, raloxifene, rilpivirine, rilzabrutinib, rimegepant, ripretinib, ritonavir, rivaroxaban, selpercatinib, selumetinib, simvastatin, SN-38, sorafenib, sotorasib, tacrolimus, tazemetostat, tucatinib, valdecoxib, vemurafenib, vepdegestrant, vociprotafib, and zanubrutinib. In some embodiments, the pharmaceutically active compound is selected from the group consisting of apixaban, carvedilol, dabrafenib, desloratadine, enzalutamide, lenalidomide, paclitaxel, and vemurafenib. In some embodiments, the pharmaceutically active compound is paclitaxel.

[0066] In some embodiments, the compound of formula (II) is a compound shown in FIGS. 1-51 and Table 2.

[0067] Also disclosed herein is a method of preparing a prodrug of a pharmaceutically active compound, comprising: reacting a compound of formula (I) with a pharmaceutically active compound in the presence of a base to form a protected prodrug compound; and removing protecting groups from the protected prodrug compound, to thereby provide the prodrug of the pharmaceutically active compound.

[0068] In some embodiments, the reacting step comprises: (a) combining the compound of formula (I) and the pharmaceutically active compound to form a mixture; and (b) adding the base to the mixture. In some embodiments, the reacting step comprises: (a) reacting the pharmaceutically active compound with a base to form a mixture; and (b) adding the compound of formula (I) to the mixture.

[0069] In another aspect, disclosed herein is a method of treating a disorder in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof.

[0070] In another aspect, disclosed herein is a system or kit comprising a compound of formula (I), or a salt thereof, and a pharmaceutically active compound.

[0071] In another aspect, disclosed herein is a compound of formula (I), or a salt thereof, for use in preparing a prodrug compound.

[0072] In another aspect, disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0073] Other aspects and embodiments of the disclosure will become apparent in light of the following description and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] FIG. 1 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is apalutamide.

[0075] FIG. 2 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is apixaban.

[0076] FIG. 3 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is aprepitant.

[0077] FIGS. 4A-4C show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is atorvastatin.

[0078] FIG. 5 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is bicalutamide.

[0079] FIGS. 6A-6B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is carvedilol.

[0080] FIG. 7 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is cefdinir.

[0081] FIG. 8 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is cefprozil.

[0082] FIG. 9 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is celecoxib.

[0083] FIGS. 10A-10B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is clarithromycin.

[0084] FIG. 11 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is dabrafenib.

[0085] FIG. 12 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is doravirine.

[0086] FIG. 13 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is efavirenz.

[0087] FIG. 14 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is enzalutamide.

[0088] FIG. 15 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is etravirine.

[0089] FIG. 16 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is ezetimibe. FIG. 17 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is glimepiride.

[0090] FIG. 18 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is glipizide.

[0091] FIG. 19 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is glyburide.

[0092] FIG. 20 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is hydrochlorothiazide.

[0093] FIG. 21 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is hydroxyzine pamoate.

[0094] FIG. 22 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is ibrutinib.

[0095] FIG. 23 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is imatinib.

[0096] FIG. 24 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is ivacaftor.

[0097] FIG. 25 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is lamotrigine.

[0098] FIG. 26 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is lenalidomide.

[0099] FIG. 27 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is lopinavir.

[0100] FIG. 28 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is desloratadine.

[0101] FIG. 29 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is meloxicam.

[0102] FIG. 30 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is metaxalone.

[0103] FIG. 31 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is methylphenidate.

[0104] FIG. 32 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is modafinil.

[0105] FIGS. 33A-33B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is niclosamide. FIGS. 34A-34B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is nilotinib.

[0106] FIG. 35 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is olanzapine.

[0107] FIG. 36 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is oxcarbazepine.

[0108] FIG. 37 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is osimertinib.

[0109] FIGS. 38A-38B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is paclitaxel.

[0110] FIG. 39 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is palbociclib.

[0111] FIG. 40 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is pomalidomide.

[0112] FIG. 41 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is pioglitazone.

[0113] FIGS. 42A-42B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is quetiapine or its active metabolite, N- desalkylquetiapine.

[0114] FIG. 43 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is raloxifene.

[0115] FIG. 44 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is rilpivirine.

[0116] FIG. 45 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is ritonavir.

[0117] FIG. 46 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is rivaroxaban.

[0118] FIG. 47 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is simvastatin.

[0119] FIGS. 48A-48B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is SN-38.

[0120] FIGS. 49A-49B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is tacrolimus. FIG. 50 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is valdecoxib.

[0121] FIGS. 51A-51B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is vemurafenib.

[0122] FIG. 52 shows a comparison of caco-2 experiments to measure i) Permeability of Sol- moiety-drug conjugate; ii) Permeability of the released drug from Sol-moiety; and iii) the permeability of the parent drug (Papp A to B) measured in a separate experiment. The permeability of the Sol-moiety by products X and Y were also measured as well as the hydrolysis rate using human placental alkaline phosphatase.

[0123] FIG. 53 shows comparison of mouse PK AUC’s of the Sol-moiety drug conjugates 7, 49, 62, 41, 148, 78, 155, 131 and Sol-moiety by-products X and Y, with a bar chart to highlight the AUC values for the Sol-moiety drug conjugates 7, 49, 62, 41, 148, 78, 155, and 131.

[0124] FIGS. 54A-B show a comparison of mouse pharmacokinetic data of enzalutamide. FIG. 54A: Plasma concentrations of enzalutamide were measured over a 72-hour time course. Enzalutamide was dosed intravenously using a standard DMSO-based formulation and orally using a carboxymethylcellulose / Tween 80 suspension, and PO dosing of Sol-enzalutamide 7 and 10 was performed using deionized water as a vehicle. FIG. 54B: Bar chart to show the difference in oral bioavailability observed for enzalutamide comparing a standard formulation and delivery due to Sol-enzalutamide 7 and 10.

[0125] FIG. 55 shows a comparison of alkaline phosphatase, Caco-2 and mouse pharmacokinetic data using the Sol-moiety-drug conjugates 7, 10, 11 and 13. Compounds were dosed at an equivalent of 5 mg / kg of enzalutamide in saline solution and plasma concentrations measured over 24 hours.

[0126] FIGS. 56A-B show a comparison of pharmacokinetic profiles of vemurafenib and Sol-vemurafenib 49 and 51. FIG. 56A: Plasma concentrations of vemurafenib were measured over 24 h following IV and PO dose of vemurafenib (Vem) in a lipid-based vehicle. Sol- vemurafenib analogs 49 and 51were dosed via oral gavage in saline solution. FIG. 56B: Bar chart displaying oral bioavailability of vemurafenib using a 20% PEG 400 based formulation compared to delivery with Sol-vemurafenib 49 and 51dosed via oral gavage in saline solution.

[0127] FIGS. 57A-B show a comparison of mouse pharmacokinetic data for paclitaxel. FIG. 57A: Plasma concentrations of paclitaxel were measured over 24 hours. Paclitaxel was administered intravenously in a DMSO-based formulation whereas the Sol-paclitaxel analog 133 and the paclitaxel formyl phosphate prodrug Compound Z were all dosed via oral gavage in saline solution. FIG. 57B Comparison of oral bioavailability between Sol-paclitaxel 133 and paclitaxel possessing a formyl phosphate prodrug Compound Z.

[0128] FIGS. 58A-C show results of an efficacy study using pancreatic BxPC-3 xenograft mouse model. FIG. 58A: Comparison of paclitaxel administered intravenously once a week (QWK) as a dose of 12.5 mg / kg formulated in Cremophor® EL, ethanol and saline solution and Sol-paclitaxel 133 dosed orally once every other day (QOD) at 25 mg / kg and 75 mg / kg (18 mg / kg and 55 mg / kg equivalent of paclitaxel dose respectively) formulated in saline solution. Drug was administered over 21 -day period and then monitored for an additional 25 days with tumor volume measured twice a week. FIG. 58B: Mouse weight plotted for the duration of the efficacy study (46 days). FIG. 58A: Plasma and tumor concentrations of paclitaxel 6 and 24 h post dose for each dose group. ND = not detectable.

[0129] DETAILED DESCRIPTION

[0130] Provided herein are building block compounds that can be used to prepare soluble prodrug compounds. The building block compounds are capable of installing a prodrug moiety that can be cleaved in vivo (e.g., by phosphatases) to release the active form of the pharmaceutical compound. Also disclosed herein are prodrug compounds comprising the prodrug moieties provided by the building blocks, and methods of synthesizing prodrug compounds from the building blocks. These highly soluble prodrug moieties provide a platform technology for preparing soluble prodrugs of pharmaceutical compounds, which may be particularly useful for insoluble pharmaceutical compounds, such as BCS Class II and BCS Class IV drugs. Increasing the solubility of such compounds could allow more widespread use of highly effective drugs that are currently challenging to formulate, and could allow for more straightforward routes of administration.

[0131] Definitions

[0132] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0133] As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise.

[0134] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6- 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0135] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2ndedition, University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0136] As used herein, the term “alkyl” refers to a radical of a straight or branched saturated hydrocarbon chain. The alkyl chain can include, e.g., from 1 to 24 carbon atoms (C1-C24 alkyl), 1 to 16 carbon atoms (C1-C16 alkyl), 1 to 14 carbon atoms (C1-C14 alkyl), 1 to 12 carbon atoms (C1-C12 alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (Ci-Cs alkyl), 1 to 6 carbon atoms (Ci-Ce alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 1 to 2 carbon atoms (C1-C2 alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.

[0137] As used herein, the term “aryl” refers to a radical of a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 71 electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms (“C6-C14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl,” i.e., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl,” e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl,” e.g., anthracenyl and phenanthrenyl).

[0138] As used herein, the term “arylalkyl” refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced with an aryl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl.

[0139] As used herein, the term “cycloalkyl” refers to a radical of a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl.

[0140] As used herein, the term “cyano” refers to a -CN group.

[0141] As used herein, the term “halogen” or “halo” refers to F, Cl, Br, or I.

[0142] As used herein, the term “haloalkyl” refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”). Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.

[0143] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 7t electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzo triazolyl, benzothiophenyl, isobenzo thiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0144] As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin-2-onyl), and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1- methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5-bicyclic heterocyclyl ring) include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6- membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6- membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7- diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (1,5)-8- azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0145] As used herein, the term “nitro” refers to an -NO2 group.

[0146] When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof.

[0147] As used herein, in chemical structures the indication: represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the rest of the compound).

[0148] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0149] When substituent groups are specified by their conventional chemical formulae, written from left to right, such indication also encompass substituent groups resulting from writing the structure from right to left. For example, if a bivalent group is shown as -CH2O-, such indication also encompasses -OCH2-; similarly, -OC(O)NH- also encompasses - NHC(O)O-.

[0150] The terms “administer,” “administering,” or “administration,” as used herein refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition.

[0151] As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.

[0152] An “effective amount” of a compound or composition refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition). As will be appreciated by those skilled in the art, the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of a compound or composition may reduce tumor burden or stop the growth or spread of a tumor.

[0153] A “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0154] A “subject” to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys).

[0155] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. Compounds

[0156] Disclosed herein are compounds of formula (I): or a salt thereof, wherein:

[0157] Z is -CR3aR3b-O-CR4aR4b-LG, -(CR5aRSb)P-CO-E, -(CR6aR6b)-LG, or -CR7aR7b-O- CR8aR8b-O-CR9aR9b-LG; one of Rlaand Rlbis -OPO(ORa)2, and the other is selected from hydrogen, alkyl, halo, haloalkyl, and -(CRbRc)m-X;

[0158] R2a, R2b, and R2care each independently selected from hydrogen, alkyl, halo, haloalkyl, and -(CRdRe)n-Y; wherein, when Rlais -OPO(ORa)2, Rlband R2a, together with the carbon atoms to which they are attached, are optionally taken together to form an optionally substituted ring;

[0159] X and Y are each independently selected from cyano, nitro, -ORf, -NRgRh, -COOR1, - CONRjRk, -S(O)2NR'Rm, -PO(ORn)2, and -PO(OR°)CH2PO(ORP)2; m, n, and p are each independently 0, 1, or 2;

[0160] R3a, R3b, R6a, R6b, R7a, and R7bare each independently selected from hydrogen and alkyl;

[0161] R4aand R4bare each hydrogen, or are taken together to form an oxo group;

[0162] R5aand RSbare each independently selected from hydrogen, alkyl, halo, and alkoxy;

[0163] RSaand R8bare each hydrogen, or are taken together to form an oxo group;

[0164] R9aand R9bare each selected from hydrogen and alkyl, or are taken together to form an oxo group;

[0165] Ra, Rf, Rg, Rh, R1, Rj, Rk, R1, Rm, Rn, R°, and Rpare each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, and arylalkyl; wherein R8and Rb, R1and Rk, and R1and Rm, together with the nitrogen atoms to which they are attached, are optionally taken together to form an optionally substituted ring;

[0166] Rb, Rc, Rd, and Reare each independently selected from hydrogen and alkyl;

[0167] E is halo or -OH; and LG is selected from -O-Q, halo, and hydroxy, wherein Q is optionally substituted aryl, optionally substituted heterocyclyl, or -SO2R8, wherein R8is selected from alkyl and optionally substituted aryl.

[0168] In some embodiments, one of Rlaand Rlbis -OPO(ORa)2, wherein each Rais independently selected from hydrogen, Ci-Ce alkyl (e.g., C1-C4 alkyl, such as ethyl or tertbutyl), and benzyl; and the other one of Rlaand Rlbis selected from hydrogen and - (CRbRc)m-X, wherein m is 0 or 1, Rcand Rdare each hydrogen, and X is selected from -ORf, -COOR1, and -PO(ORn)2, wherein each Rf, R1, and Rnis independently selected from hydrogen and C1-C4 alkyl.

[0169] In some embodiments, Rlais -OPO(ORa)2, and Rlband R2a, together with the carbon atoms to which they are attached, form an optionally substituted ring. In some embodiments, the optionally substituted ring is a phenyl ring that is optionally substituted with at least one substituent selected from alkyl, -ORf, -COOR1, and -PO(ORn)2, wherein each Rf, R1, and R11is independently selected from hydrogen and C1-C4 alkyl.

[0170] In some embodiments, Z’ is -CR3aR3b-O-CR4aR4b-, -(CR5aR5b)P-CO-, or -(CR6aR6b)-.

[0171] In some embodiments, Z is -CR3aR3b-O-CR4aR4b-LG.

[0172] In some embodiments, R3aand R3bare each independently selected from hydrogen and C1-C4 alkyl. In some embodiments, R3aand R3bare each independently selected from hydrogen and methyl. In some embodiments, R3aand R3bare each hydrogen. In some embodiments, R3ais hydrogen and R3bis methyl. In some embodiments, R3aand R3bare each methyl.

[0173] In some embodiments, R4aand R4bare taken together to form an oxo group. In some embodiments, R4aand R4bare each hydrogen.

[0174] In some embodiments, Z is -(CR5aRSb)p-CO-E, wherein E is halo or -OH. In some embodiments, p is 2, each R,aand R5bis independently selected from hydrogen and methyl, and E is chloro or -OH. In some embodiments, Z is -CiCHshClLCOOH or - C(CH3)2CH2COC1.

[0175] In some embodiments, Z is -(CR6aR6b)-LG. In some embodiments, R6aand R6bare each independently selected from hydrogen and hydrogen and C1-C4 alkyl. In some embodiments, R6aand R6bare each independently selected from hydrogen and methyl. In some embodiments, R6aand R6bare each hydrogen. In some embodiments, R6ais hydrogen and R6bis methyl. In some embodiments, R6aand R6bare each methyl.

[0176] In some embodiments, Z’ is -CR7aR7b-O- CR8aR8b-O-CR9aR9b-LG. In some embodiments, R7aand R7bare each hydrogen. In some embodiments, RSaand R8bare each hydrogen, and R9aand R9bare taken together to form an oxo group. In some embodiments, R8aand R8btaken together to form an oxo group, and R9aand R9bare each hydrogen.

[0177] In some embodiments, Ra, Rf, Rg, Rh, R1, R', Rk, R1, Rm, Rn, R°, and Rpare each independently selected from hydrogen, C1-C4 alkyl, phenyl, and phenyl-Ci-C2-alkyl. In some embodiments, Ra, Rf, Rg, Rh, R1, R1, Rk, R1, Rm, Rn, R°, and Rpare each independently selected from hydrogen, methyl, ethyl, iso-propyl, tert-butyl, phenyl, and benzyl.

[0178] In some embodiments, Rb, Rc, Rd, and Reare each independently selected from hydrogen and methyl.

[0179] In some embodiments, R2a, R2b, and R2care each independently selected from hydrogen, C1-C4 alkyl, halo, and -(CRdRe)n-Y, wherein n is 0 or 1, Rdand Reare each hydrogen, and Y is selected from cyano, -ORf, -COOR1, and -PO(ORn)2, wherein each Rf, R1, and Rnis independently selected from hydrogen and C1-C4 alkyl. In some embodiments, R2a, R2b, and R2care each independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, -COOH, -COO(tBu), -CH2COOH, -CH2COOCH3, -P(O)(Oh)2, and -P(O)(OEt)2.

[0180] In some embodiments, LG is -O-Q. In some embodiments, LG is -O-Q, wherein Q is optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, LG is -O-Q, wherein Q is phenyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from nitro and halo. In some embodiments, LG is -O-(4-nitrophenyl), -O-(2,4- dinitrophenyl), or -O- (pentafluorophenyl). In some embodiments, LG is -O-(4-nitrophenyl) or -O-(pentafluorophenyl). In some embodiments, LG is -O-(4-nitrophenyl). In some embodiments, LG is O-(pentafluorophenyl). In some embodiments, LG is -O-Q, wherein Q is an optionally substituted pyrrolidine-2, 5-dione. In some embodiments, LG is -O-Q, wherein Q is pyrrolidine-2, 5-dione.

[0181] In some embodiments, LG is halo. In some embodiments, LG is bromo.

[0182] In some embodiments, the compound has formula (la) or (lb):

[0183] In some embodiments, the compound has a structure selected from:

[0184] pharmaceutically acceptable salts thereof, wherein each Ra, R1, and Rnis independently selected from hydrogen, alkyl (e.g., C1-C4 alkyl), and benzyl. One skilled in the art will recognize that in the above compounds, in some embodiments, Ra, R1, and R11are independently alkyl or benzyl, such that these building block compounds are in protected form. Such forms are particularly suitable for reaction with a pharmaceutically active compound, to form a protected prodrug compound. In other embodiments, the disclosure also provides the building blocks in their unprotected forms (i.e., wherein Ra, R1, and R'1are hydrogen). In some embodiments, such compounds could be reacted directly with a pharmaceutically active compound to form a prodrug compound, or the compounds could be protected before such reactions.

[0185] In some embodiments, the compound is selected from the group consisting of:

[0186] and salts thereof.

[0187] Additional compounds of formula (I) include:

[0188] Compounds of formula (I) (including compounds of formula (la) and (lb)) are building blocks that can be used to prepare prodrug compounds. The compounds of formula (I) provide a moiety that aids in solubilization of a pharmaceutically active compound, and allows for cleavage of the prodrug moiety in vivo (e.g., by a phosphatase) to release the pharmaceutically active compound. The compounds of formula (I) can react with suitable groups on pharmaceutically active compounds, such as amines, to provide prodrug compounds.

[0189] Accordingly, also disclosed herein are compounds of formula (II): or a pharmaceutically acceptable salt thereof, wherein:

[0190] Z’ is -CR3aR3b-O-CR4aR4b-, -(CR5aR5b)P-CO-, -(CR6aR6b)- , or -CR7aR7b-O- CRSaR8b- O-CR9aR9b-; one of Rlaand Rlbis -OPO(ORa)2, and the other is selected from hydrogen, alkyl, halo, haloalkyl, and -(CRbRc)m-X;

[0191] R2a, R2b, and R2care each independently selected from hydrogen, alkyl, halo, haloalkyl, and -(CRdRe)n-Y; wherein, when Rlais -OPO(ORa)2, Rlband R2a, together with the carbon atoms to which they are attached, are optionally taken together to form an optionally substituted ring

[0192] X and Y are each independently selected from cyano, nitro, -ORf, -NRsRh, -COOR1, - CONRJRk, -S(O)2NR'Rm, -PO(ORn)2, and -P0(0Ro)CH2P0(0Rp)2; m, n, and p are each independently 0, 1, or 2;

[0193] R3a, R3b, R6a, R6b, R7a, and R7bare each independently selected from hydrogen and alkyl;

[0194] R4aand R4bare each hydrogen, or are taken together to form an oxo group;

[0195] R5aand R5bare each independently selected from hydrogen, alkyl, halo, and alkoxy; R8aand R8bare each hydrogen, or are taken together to form an oxo group;

[0196] R9aand R9bare each selected from hydrogen and alkyl, or are taken together to form an oxo group;

[0197] Ra, Rf, Rs, Rh, R1, R1, Rk, R1, Rm, Rn, R°, and Rpare each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, and arylalkyl; wherein Rgand Rh, R' and Rk, and R1and Rm, together with the nitrogen atoms to which they are attached, are optionally taken together to form an optionally substituted ring;

[0198] Rb, Rc, Rd, and Reare each independently selected from hydrogen and alkyl; and

[0199] D is a pharmaceutically active compound.

[0200] In some embodiments, one of Rlaand Rlbis -0P0(0Ra)2, wherein each Rais independently selected from hydrogen, Ci-Ce alkyl (e.g., C1-C4 alkyl, such as ethyl or tert- butyl), and benzyl; and the other one of Rlaand Rlbis selected from hydrogen and - (CRbRc)m-X, wherein m is 0 or 1, Rcand Rdare each hydrogen, and X is selected from -0Rf, -C00R1, and -P0(0Rn)2, wherein each Rf, R1, and Rnis independently selected from hydrogen and C1-C4 alkyl.

[0201] In some embodiments, Z’ is -CR3aR3b-O-CR4aR4b-, -(CR5aR5b)p-CO-, or -(CR6aR6b)-.

[0202] In some embodiments, Z’ is -CR3aR3b-O-CR4aR4b-.

[0203] In some embodiments, R3aand R3bare each independently selected from hydrogen and C1-C4 alkyl. In some embodiments, R3aand R3bare each independently selected from hydrogen and methyl. In some embodiments, R3aand R3bare each hydrogen. In some embodiments, R3ais hydrogen and R3bis methyl. In some embodiments, R3aand R3bare each methyl.

[0204] In some embodiments, R4aand R4bare taken together to form an oxo group. In some embodiments, R4aand R4bare each hydrogen.

[0205] In some embodiments, Z’ is -CH2-.

[0206] In some embodiments, Z’ is -(CR5aR5b)P-CO-. In some embodiments, p is 2, and R5aand R5bare each independently selected from hydrogen and methyl. In some embodiments, Z’ is -C(CH3)2CH2CO-.

[0207] In some embodiments, Z’ is -(CR6aR6b)-. In some embodiments, R6aand R6bare each independently selected from hydrogen and hydrogen and C1-C4 alkyl. In some embodiments, R6aand R6bare each independently selected from hydrogen and methyl. In some embodiments, R6aand R6bare each hydrogen. In some embodiments, R6ais hydrogen and R6bis methyl. In some embodiments, R6aand R6bare each methyl. In some embodiments, Z’ is -CR7aR7b-O- CR8aR8b-O-CR9aR9b-LG. In some embodiments, R7aand R7bare each hydrogen. In some embodiments, R8aand R8bare each hydrogen, and R9aand R9bare taken together to form an oxo group. In some embodiments, R8aand R8btaken together to form an oxo group, and R9aand R9bare each hydrogen.

[0208] In some embodiments, Ra, Rf, Rg, Rh, R1, R', Rk, R1, Rm, Rn, R°, and Rpare each independently selected from hydrogen, C1-C4 alkyl, phenyl, and phenyl-Ci-C2-alkyl. In some embodiments, Ra, Rf, R8, Rh, R1, RJ, Rk, R1, Rm, Rn, R°, and Rpare each independently selected from hydrogen, methyl, ethyl, iso-propyl, tert-butyl, phenyl, and benzyl.

[0209] In some embodiments, Rb, Rc, Rd, and Reare each independently selected from hydrogen and methyl.

[0210] In some embodiments, R2a, R2b, and R2care each independently selected from hydrogen, C1-C4 alkyl, halo, and -(CRdRe)n-Y, wherein n is 0 or 1, Rdand Reare each hydrogen, and Y is selected from cyano, -ORf, -COOR1, and -PO(ORn)2, wherein each Rf, R1, and Rnis independently selected from hydrogen and C1-C4 alkyl. In some embodiments, R2a, R2b, and R2care each independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, -COOH, -COO(tBu), -CH2COOH, -CH2COOCH3, -P(O)(Oh)2, and -P(O)(OEt)2.

[0211] In some embodiments, the compound has formula (Ila) or (lib):

[0212] D is a pharmaceutically active compound. In some embodiments, the pharmaceutically active compound is attached to the remainder of the compound via a nitrogen atom, e.g., from an amine, an amide, an aniline, a sulfonamide, a heterocyclic moiety, or a heteroaryl moiety. In some embodiments, the pharmaceutically active compound is attached to the remainder of the compound via an oxygen atom, e.g., from an alcohol.

[0213] The group D can be any pharmaceutically active compound. In particular embodiments, the group D is a small molecule therapeutic. In some embodiments, the pharmaceutically active compound is selected from the group consisting of: analgesics (e.g., opioid analgesics and non-opioid analgesic); anesthetics (e.g., local anesthetics); antibacterials (e.g., aminoglycosides, beta-lactams such as cephalosporins and penicillins, macrolides, quinolones, sulfonamides, tetracyclines, antifolates, glycopeptides, lincomycins, nitrofurans, oxazolidinones, and the like); anticonvulsants (e.g., calcium channel modifying agents, gamma-aminobutyric acid augmenting agents, glutamate reducing agents, sodium channel inhibitors, and the like); antidementia agents (e.g., cholinesterase inhibitors, glutamate pathway modifiers); antidepressants (e.g., monoamine oxidase inhibitors, serotonin / norepinephrine reuptake inhibitors, tricyclics, and the like); antiemetics; antifungals; antigout agents; anti-inflammatories (e.g., nonsteroidal anti-inflammatories, glucocorticoids, and the like); antimigraine agents; antimyasthenic agents; antimycobacterials (e.g., antituberculars); antineoplastics (e.g., alkylating agents, antiangiogenic agents, antiestrogens / modifiers, antimetabolites, aromatase inhibitors, molecular target inhibitors, retinoids, topoisomerase I inhibitors, and the like); antiparasitics (e.g., anthelmintics, antiprotozoals, pediculicides / scabicides); antiparkinson agents; antipsychotics (e.g., atypical antipsychotics, conventional antipsychotics); antispasticity agents; antivirals (e.g., anticytomegalovirus agents, antihepatitis agents, antiherpetic agents, anti-human immunodeficiency virus agents (e.g., fusion inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, protease inhibitors), anti-influenza agents, and the like); anxiolytics (e.g., antidepressants); bipolar agents; blood glucose regulators (e.g., antidiabetic agents, glycemic agents); blood products / modifiers / volume expanders (e.g., anticoagulants, blood formation products, coagulants, platelet aggregation inhibitors); cardiovascular agents (e.g., alpha- adrenergic agonists, alpha- adrenergic blocking agents, antiarrhythmics, beta-adrenergic blocking agents, calcium channel blocking agents, diuretics, dyslipidemics, renin-angiotensin-aldosterone system inhibitors, vasodilators, and the like); central nervous system agents (e.g., amphetamines, non- amphetamines); dental and oral agents; dermatological agents; enzyme replacements / modifiers; gastrointestinal agents (e.g., antispasmodics, H2 blocking agents, irritable bowel syndrome agents, protectants, proton pump inhibitors, and the like); genitourinary agents (e.g., antispasmodics, benign prostatic hypertrophy agents, phosphate binders); hormonal agents (e.g., glucocorticoids / mineralcorticoids, androgens, estrogens, progestins, selective estrogen receptor modifying agents, antiandrogens, antithyroid agents); immunological agents (e.g., immune stimulants, immune suppressants, immunomodulators); inflammatory bowel disease agents (e.g., glucocorticoids, salicylates, sulfonamides); metabolic bone disease agents; ophthalmic agents (e.g., ophthalmic anti-allergy agents, antiglaucoma agents, ophthalmic anti-inflammatories, ophthalmic prostaglandin and prostamide compounds); otic agents; respiratory tract agents (e.g., antihistamines, antiinflammatories, antileukotrienes, bronchodilators, mast cell stabilizers, pulmonary hypertensives); sedatives / hypnotics; and skeletal muscle relaxants. The above groups include therapeutic categories and pharmacologic classes listed in the United States Pharmacopeia (USP), which model-guidelines.

[0214] The prodrug moieties disclosed herein may be particularly useful for Class II and Class IV compounds according to the Biopharmaceutical Classification System (BCS), which classifies pharmaceutical compounds based on their solubility and permeability (see, e.g., Tsume et al. Eur. J. Pharm. Sci. 2014, 57: 152-163). Class II compounds have high permeability but low solubility, and BCS Class IV compounds have low permeability and low solubility. The prodrug moieties disclosed herein may aid in solubilization of these low solubility compounds, allowing for more straightforward modes of formulation and administration. Accordingly, in some embodiments, the pharmaceutically active compound is a BCS Class II compound or a BCS Class IV compound.

[0215] In some embodiments, the pharmaceutically active compound is an anticoagulant (e.g., a factor Xa inhibitor such as apixaban or rivaroxaban). In some embodiments, the pharmaceutically active compound is an antineoplastic agent, such as an anti- angiogenic agent (e.g., pomalidomide, lenalidomide), a kinase inhibitor (e.g., abrocitinib, acalbrutinib, asciminib, avapritinib, dabrafenib, osimertinib, ibrutinib, idelalisib, imatinib, nilotinib, palbociclib, pacritinib, pralsetinib, rilzabrutinib ripretinib, selpercatinib, selumetinib, sorafenib, tucatinib, vemurafenib, zanubrutinib), an antimicrotubule agent (e.g., cabazitaxel, docetaxel, paclitaxel), a topoisomerase I inhibitor (e.g., SN-38), a protein degrader (e.g., bavdegalutamide, eragidomide, golcadomide, mezigdomide, vepdegestrant, NX-2127, DT2216, ARV-766, FHD-609), an intercalating agent (e.g., doxorubicin), a PARP inhibitor (e.g., olaparib), a KRAS inhibitor (e.g., sotorasib), an EZH2 inhibitor (e.g., tazemetostat). In some embodiments, the pharmaceutically active compound is an antiandrogen (e.g., enzalutamide, apalutamide, bicalutamide). In some embodiments, the pharmaceutically active compound is an antiemetic (e.g., aprepitant, amisulpride). In some embodiments, the pharmaceutically active compound is an antiparasitic, such as an anthelmintic (e.g., niclosamide). In some embodiments, the pharmaceutically active compound is a cardiovascular agent, such as a beta-adrenergic blocking agent (e.g., carvedilol), a dyslipidemic agent such as a statin (e.g., atorvastatin, simvastatin), a cholesterol absorption inhibitor (e.g., ezetimibe), an antiplatelet agent (e.g., clopidogrel), or a diuretic (e.g., hydrochlorothiazide). In some embodiments, the pharmaceutically active compound is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, such as ivacaftor. In some embodiments, the pharmaceutically active compound is an antibacterial agent, such as a cephalosporin (e.g., cefdinir, cefprozil), a macrolide (e.g., clarithromycin), or an oxazolidinone (e.g., linezolid). In some embodiments, the pharmaceutically active compound is an anti-inflammatory, such as a nonsteroidal anti-inflammatory (e.g., celecoxib, meloxicam, valdecoxib). In some embodiments, the pharmaceutically active compound is an antiviral agent, such as a non- nucleoside reverse transcriptase inhibitor (e.g., doravirine, efavirenz, etravirine, rilpivirine), or a protease inhibitor (e.g., lopinavir, nelfinavir, ritonavir). In some embodiments, the pharmaceutically active compound is a blood glucose regulator, such as an antidiabetic agent (e.g., ezetimibe, glimepiride, glipizide, glyburide, pioglitazone). In some embodiments, the pharmaceutically active compound is an anticonvulsant, such as lamotrigine or oxcarbazepine. In some embodiments, the pharmaceutically active compound is an antihistamine, such as desloratadine or hydroxyzine pamoate. In some embodiments, the pharmaceutically active compound is a skeletal muscle relaxant, such as metaxalone. In some embodiments, the pharmaceutically active compound is a central nervous system agent, such a CNS stimulant (e.g., methylphenidate, modafinil). In some embodiments, the pharmaceutically active compound is an antipsychotic, such as an atypical antipsychotic (e.g., olanzapine, quetiapine, / / -desalkylquetiapine, amisulpride). In some embodiments, the pharmaceutically active compound is a hormonal agent, such as a selective estrogen receptor modifying agent (e.g., raloxifene). In some embodiments, the pharmaceutically active compound is an immunological agent, such as an immune suppressant (e.g., tacrolimus). In some embodiments, the pharmaceutically active compound is a cytochrome P450 3A4 inhibitor (e.g., avacopan). In some embodiments, the pharmaceutically active compound is an opioid agonist (e.g., oliceridine). In some embodiments, the pharmaceutically active compound is an antifungal agent (e.g., oteseconazole). In some embodiments, the pharmaceutically active compound is a calcitonin gene-related peptide receptor antagonist (e.g., rimegepant). In some embodiments, the pharmaceutically active compound is an active metabolite of a drug compound.

[0216] In some embodiments, the pharmaceutically active compound is selected from the group consisting of apixaban, carvedilol, dabrafenib, desloratadine, enzalutamide, lenalidomide, paclitaxel, and vemurafenib. In some embodiments, the pharmaceutically active compound is paclitaxel.

[0217] As with compounds of formula (I), compounds of formula (II) (including compounds of formula (Ila) and (lib)) include groups such as Ra, R1, and Rn(among others) which in some embodiments are independently selected from hydrogen, alkyl (e.g., C1-C4 alkyl), and benzyl. One skilled in the art will recognize that, in some embodiments, Ra, R1, and Rnare independently alkyl or benzyl, such that the prodrug compounds are in protected form. Such forms may be produced, for example, from a reaction of a compound of formula (I) with a pharmaceutically active compound to form the compounds of formula (II), and produce protected prodrug compound. These groups may be subsequently deprotected to provide compounds in which Ra, R1, and Rnare hydrogen. All protected and deprotected forms of compounds of formula (II) are contemplated herein.

[0218] In some embodiments, the compound of formula (II) is a compound shown in the Drawings (e.g., a compound shown in any one of FIGS. 1-51), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) is a compound shown in Table 2 herein, or a pharmaceutically acceptable salt thereof.

[0219] The compounds of the present disclosure may have at least one asymmetric center. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this disclosure.

[0220] The independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. The absolute stereochemistry of a compound may be determined by using X-ray crystallography to determine the crystal structure of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

[0221] If desired, racemic mixtures of compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to pure enantiomers by cleavage of the added chiral residue. Racemic mixtures of compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. The compound (e.g., a compound of formula (I) or formula (II)) may possess tautomeric forms, and tautomers also constitute embodiments of the disclosure.

[0222] The present disclosure also includes isotopically-labeled compounds (e.g., an isotopically-labeled compound of formula (I) or formula (II)), which are identical to those recited in formula (I) or formula (II), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,18O,31P,35S,18F, and36C1, respectively. Substitution with heavier isotopes such as deuterium, i.e.2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in compounds of formula (I) or (II) arenC,13N,15O, and18F. Isotopically-labeled compounds of formula (1) or (II) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent.

[0223] Compounds of formula (I) or (II) can be synthesized by a variety of methods, including those illustrated in the Examples. Compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel’s Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0224] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Reactions can be worked up in a conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.

[0225] Standard experimentation, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006).

[0226] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[0227] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described herein using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0228] The synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure or the claims. Alternatives, modifications, and equivalents of the synthetic methods and specific examples are contemplated.

[0229] The disclosed compounds may exist as salts, including pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use.

[0230] Salts may be prepared during the final isolation and purification of the compounds, or separately. For example, salts may be prepared by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water, and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para- toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quatemized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like. In one embodiment, the compound is in the form of a trifluoroacetate salt.

[0231] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a phosphate, phosphonate or carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine , pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1 -ephenamine and N,N’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0232] Compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the disclosure may also exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0233] Compounds of formula (II) disclosed herein are prodrug compounds, which can be cleaved in vivo (e.g., by phosphatases) to provide the pharmaceutically active agents. Exemplary mechanisms by which the compounds can be cleaved is shown in Scheme 1. Scheme 1

[0234] Pharmaceutical Compositions

[0235] The disclosed prodrug compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the disclosure are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease or condition, the prophylactically effective amount will be less than the therapeutically effective amount. The pharmaceutical compositions may include pharmaceutically acceptable carriers.

[0236] The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0237] Thus, the compounds and their pharmaceutically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington’s Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0238] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis). In some embodiments, the composition is in a form suitable for parenteral administration, e.g., intravenous, intramuscular, or subcutaneous administration. In some embodiments, the composition is in a form suitable for an implant, e.g., an ocular implant.

[0239] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.

[0240] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90% by weight of the composition.

[0241] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, com oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10% by weight of the composition.

[0242] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as com starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50% by weight of the composition.

[0243] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10% by weight of the composition.

[0244] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1% by weight of the composition.

[0245] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.

[0246] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s), when used, in a systemic or topical composition is typically about 0.001 to about 1% by weight of the composition.

[0247] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5% by weight of the composition. Suitable preservatives include benzalkonium chloride, methyl paraben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5% by weight of the composition.

[0248] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5% by weight of the composition.

[0249] Suitable solvents include water, saline (e.g., isotonic saline), ethyl oleate, glycerin, hydroxylated castor oils, alcohols such as ethanol, and aqueous buffer solutions, such as phosphate buffer solutions. In some embodiments, the solvent is water. In some embodiments, the solvent is saline. In some embodiments, the solvent is an aqueous buffer solution, such as phosphate-buffered saline. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100% by weight of the composition.

[0250] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8% by weight of the composition.

[0251] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington’s Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon’s Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5% by weight of the composition.

[0252] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% by weight of an active compound and 50% to 99.99% by weight of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% by weight of actives and 90% to 99.9% by weight of a carrier including a diluent and a solvent.

[0253] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5% by weight, and more particularly from about 25% to about 50% by weight of actives. The oral dosage compositions include about 50% to about 95% by weight of carriers, and more particularly, from about 50% to about 75% by weight. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0254] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a prodrug compound disclosed herein), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non- biodegradable type.

[0255] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this disclosure.

[0256] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0257] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners. Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0258] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a prodrug compound disclosed herein), or a pharmaceutically acceptable salt thereof), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0259] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this disclosure are described in the following references: Modem Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0260] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0261] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0262] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1 ,2-diol, butane- 1 ,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95% by weight of the composition.

[0263] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95% by weight of the composition.

[0264] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95% by weight of the composition.

[0265] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5 -carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95% by weight of the composition.

[0266] The amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition.

[0267] Suitable powders include beta-cyclodex trins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95% by weight of the composition.

[0268] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1% by weight of the composition. Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

[0269] Methods of Use

[0270] Compounds of formula (I) can be used as building blocks to synthesis prodrug compounds, such as compounds of formula (II). Accordingly, disclosed herein are methods of synthesizing compounds of formula (II) from compounds of formula (I). The prodrug compounds of formula (II) can be used as pharmaceutical compounds. Accordingly, disclosed herein are methods of treating a subject by administering a therapeutically effective amount of a compound of formula (II).

[0271] For example, in some embodiments, disclosed herein is a method of preparing a prodrug of a pharmaceutically active compound (e.g., a compound of formula (I)), comprising reacting a compound of formula (I) with the pharmaceutically active compound in the presence of a suitable base. In some embodiments, the method comprises first combining the compound of formula (I) and the pharmaceutically active compound to form a mixture, and subsequently adding the base to the mixture. In other embodiments, the method comprises first reacting the pharmaceutically active compound with a base to form a mixture, and subsequently adding the compound of formula (I) to the mixture.

[0272] Any suitable base can be used in the disclosed methods. For example, in some embodiments the base is selected from a hydride-containing base (e.g., sodium hydride), an organic base such as 4-dimethylaminopyridine, triethylamine, 2,6-lutidine, pyridine, or N,N- diisopropylethylamine, or a lithium-containing base such as lithium bis(trimethylsilyl)amide or lithium diisopropylamide, or an inorganic carbonate such as potassium carbonate or cesium carbonate.

[0273] The reactions can be carried out in any suitable solvent or solvent system. For example, in some embodiments, the reaction is carried out in an organic solvent selected from N, A-di methyl formamide, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, 1 ,4-dioxane, dichloromethane, 1 ,2-dichloroethane, acetonitrile, or the like.

[0274] In some embodiments, the reaction is carried out at a temperature above room temperature (i.e., in the presence of heat). In some embodiments, the reaction is carried out at a temperature below room temperature (i.e., with cooling). One skilled in the art will understand how to manipulate the reaction conditions based on the selection of the particular starting materials. After the initial reaction steps, the prodrug compound (e.g., compound of formula (II) can be isolated and purified from the reaction mixture via any suitable means, such as those discussed generally above.

[0275] The prodrug compounds of formula (II) can be used in methods of treating a disorder in a subject. The disorder to be treated will vary depending on the identity of the pharmaceutically active compound. For example, in some embodiments, disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an antineoplastic agent (e.g., an anti-angiogenic agent (e.g., pomalidomide, lenalidomide), a kinase inhibitor (e.g., abrocitinib, acalbrutinib, asciminib, avapritinib, dabrafenib, osimertinib, ibrutinib, idelalisib, imatinib, nilotinib, palbociclib, pacritinib, pralsetinib, rilzabrutinib ripretinib, selpercatinib, selumetinib, sorafenib, tucatinib, vemurafenib, zanubrutinib), an antimicrotubule agent (e.g., cabazitaxel, docetaxel, paclitaxel), a topoisomerase I inhibitor (e.g., SN-38)), a protein degrader (e.g., bavdegalutamide, eragidomide, golcadomide, mezigdomide, vepdegestrant, NX-2127, DT2216, ARV-766, FHD-609), an intercalating agent (e.g., doxorubicin), a PARP inhibitor (e.g., olaparib), a KRAS inhibitor (e.g., sotorasib), an EZH2 inhibitor (e.g., tazemetostat), or an antiandrogen (e.g., enzalutamide, apalutamide, bicalutamide). In some embodiments, the cancer is selected from breast cancer, colorectal cancer, ovarian cancer, prostate cancer, lung cancer (e.g., nonsmall cell lung cancer), a blood cancer (e.g., multiple myeloma), a lymphoma (e.g., mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma), a melanoma (e.g., unresectable or metastatic melanoma), or a leukemia (e.g., chronic lymphocytic leukemia).

[0276] In some embodiments, disclosed herein is a method of treating or reducing risk of stroke, embolism, or deep vein thrombosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an anticoagulant (e.g., a factor Xa inhibitor such as apixaban or rivaroxaban).

[0277] In some embodiments, disclosed herein is a method of treating or preventing nausea and / or vomiting in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an antiemetic (e.g., aprepitant, amisulpride). In some embodiments, the subject has cancer and the nausea and / or vomiting is chemotherapy induced. In some embodiments, disclosed herein is a method of treating a tapeworm infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an antiparasitic, such as an anthelmintic (e.g., niclosamide).

[0278] In some embodiments, disclosed herein is a method of treating or preventing a cardiovascular disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is a cardiovascular agent, such as a beta-adrenergic blocking agent (e.g., carvedilol), a dyslipidemic agent such as a statin (e.g., atorvastatin, simvastatin), a cholesterol absorption inhibitor (e.g., ezetimibe), an antiplatelet agent (e.g., clopidogrel), or a diuretic (e.g., hydrochlorothiazide). In some embodiments, the cardiovascular disorder is selected from high blood pressure, high cholesterol, stroke, or the like.

[0279] In some embodiments, disclosed herein is a method of treating cystic fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, such as ivacaftor.

[0280] In some embodiments, disclosed herein is a method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an antibacterial agent, such as a cephalosporin (e.g., cefdinir, cefprozil), a macrolide (e.g., clarithromycin), or an oxazolidinone (e.g., linezolid).

[0281] In some embodiments, disclosed herein is a method of treating inflammation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an anti-inflammatory, such as a nonsteroidal anti-inflammatory (e.g., celecoxib, meloxicam, valdecoxib).

[0282] In some embodiments, disclosed herein is a method of treating a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an antiviral agent, such as a non-nucleoside reverse transcriptase inhibitor (e.g., doravirine, efavirenz, etravirine, rilpivirine), or a protease inhibitor (e.g., lopinavir, nelfinavir, ritonavir). In some embodiments,

[0283] In some embodiments, disclosed herein is a method of treating diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is a blood glucose regulator, such as an antidiabetic agent (e.g., ezetimibe, glimepiride, glipizide, glyburide, pioglitazone).

[0284] In some embodiments, disclosed herein is a method of treating seizures in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an anticonvulsant, such as lamotrigine or oxcarbazepine.

[0285] In some embodiments, disclosed herein is a method of treating allergies in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an antihistamine, such as desloratadine or hydroxyzine pamoate.

[0286] In some embodiments, disclosed herein is a method of treating muscle spasms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is a skeletal muscle relaxant, such as metaxalone.

[0287] In some embodiments, disclosed herein is a method of treating a sleep disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is a central nervous system agent, such a CNS stimulant (e.g., methylphenidate, modafinil).

[0288] In some embodiments, disclosed herein is a method of treating attention deficit hyperactivity disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is a central nervous system agent, such a CNS stimulant (e.g., methylphenidate).

[0289] In some embodiments, disclosed herein is a method of treating a mental disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an antipsychotic, such as an atypical antipsychotic (e.g., olanzapine, quetiapine, AMesalkylquetiapine, amisulpride). In some embodiments, the mental disorder is selected from bipolar disorder, schizophrenia, and major depressive disorder.

[0290] In some embodiments, disclosed herein is a method of treating osteoporosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is a hormonal agent, such as a selective estrogen receptor modifying agent (e.g., raloxifene).

[0291] In some embodiments, disclosed herein is a method of treating an immune disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an immunological agent, such as an immune suppressant (e.g., tacrolimus). In some embodiments, the immune disorder comprises a transplant rejection. In some embodiments, disclosed herein is a method of treating an immune disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is a cytochrome P450 3A4 inhibitor (e.g., avacopan). In some embodiments, the immune disorder is anti-neutrophil cytoplasmic autoantibody-associated vasculitis.

[0292] In some embodiments, disclosed herein is a method of treating pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an opioid receptor agonist (e.g., oliceridine).

[0293] In some embodiments, disclosed herein is a method of treating a fungal infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is an antifungal agent (e.g., oteseconazole).

[0294] In some embodiments, disclosed herein is a method of treating migraine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), wherein the pharmaceutically active compound (i.e., group D in the compound of formula (II)) is a calcitonin gene-related peptide receptor antagonist (e.g., rimegepant).

[0295] Systems and Kits For use in methods described herein, systems, kits, and articles of manufacture are also provided, which include a compound or pharmaceutical composition described herein (e.g., a compound of formula (I) or a salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof). In some embodiments, such systems and kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

[0296] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, in some embodiments the container(s) includes a compound of formula (I) or a salt thereof, or a compound formula (II) or a pharmaceutically acceptable salt thereof, optionally in a composition or in combination with another agent as disclosed herein. In particular embodiments (e.g., for prodrug compounds of formula (II)), the container(s) have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0297] Also disclosed herein are systems and kits for preparing prodrug compounds, comprising a compound of formula (I) or a salt thereof, and optionally a pharmaceutically active compound. Such systems and kits can be used for the preparation of prodrug compounds of formula (II) described herein. For example, in some embodiments, disclosed herein is a kit comprising a compound of formula (I) or a salt thereof, and instructions for using the compound of formula (I) to prepare a prodrug of a pharmaceutically active compound. In some embodiments, disclosed herein is a system comprising a compound of formula (I) or a salt thereof, and a pharmaceutically active compound. Such a system can be used in a method described herein, such as a method of preparing a prodrug compound of formula (II). Examples

[0298] Abbreviations used in the Examples include the following: Bn is benzyl; t-Bu is tert- butyl; DCC is dicyclohexyl carbodiimide; DCM is dichloromethane; DIPEA is N,N- diisopropylethylamine; DMAP is 4-dimethylaminopyridine; DMF is N,N- dimethylformamide; DMSO is dimethylsulfoxide; EtOAc is ethyl acetate; EtOH is ethanol; h is hours; LCMS is liquid chromatography mass spectrometry; MeCN is acetonitrile; MeOH is methanol; and THF is tetrahydrofuran.

[0299] General Methods. Reactions were performed under ambient atmosphere unless otherwise noted. Qualitative TLC analysis was performed on 250 mm thick, 60 G, glass- backed, F254 silica (EMD Millipore). All solvents used were ACS grade Sure-Seal, and all other reagents were used as received unless otherwise noted. Chromatography was performed on a Biotage Selekt instrument using either Biotage Star silica HC columns or Biotage Star C-18 HP Sphere 25 / rm pre-packed cartridges. Compounds were stored in a freezer (—20 °C) following synthesis. Structure determination was performed using]H,13C,19F, and31P spectra that were recorded on a Bruker Neo-500 spectrometer, and low-resolution mass spectra (ESI-MS) that were collected on an Agilent LCMS iQ instrument. Unless stated, all chemical building blocks were purchased from commercial sources or were synthesized according to the protocols included in the Supplementary Information. Final compounds were submitted at a purity of >95% by NMR and LCMS.

[0300] The following reagents were purchased from commercial sources: Dibenzyl phosphite (CAS: 17176-77-1 ); di-tert-butyl phosphite (CAS: 13086-84-5); 2-hydroxybenzyl alcohol is (CAS: 99-90-01); 4-hydroxybenzyl alcohol (CAS: 623-05-2); 4-nitrophenyl chloroformate (CAS: 7693-46-1); 6-bromo-2,2-diemthyl-4H-benzodioxin (CAS: 52113-69-6).

[0301] Example 1: Synthesis of Precursor Compounds

[0302] Synthesis of tert-butyl 3-formyl-4-hydroxy-benzoate

[0303] A mixture of 3 -formyl-4-hydroxy -benzoic acid (3.0 g, 18.06 mmol), I,l-di-terL buloxy-M A-dmielhyl-melhanamine (8.34 mL, 36.1 2 mmol) in THF (1.2 mL) was heated at 100 °C for 1 h. Additional di-n?rt-butoxy-M,JV-DMF (3 mL) was added. Heated for 2 h at 100 ºC. Cooled, evaporated to dryness under reduced pressure. White solid forms upon standing. Chromatography (2–20% EtOAc in hexanes) provided the desired product as a white solid (1.74 g; 43%).1H NMR (500 MHz, CDCl3) δ 11.35 (s, 1H), 9.95 (s, 1H), 8.25 (d, J = 2 Hz, 1H), 8.14 (dd, J = 8.6 and 2 Hz, 1H), 7.01 (d, J = 8.6 Hz) and 1.60 (s, 9H). Synthesis of tert-butyl 4-hydroxy-3-(hydroxymethyl)benzoate Sodium borohydride (430 m solution of tert-butyl 3-formyl-4- hydroxy-benzoate (1.25 g; 5.6 mmol) in 10 ml THF. The reaction was stirred at 70 ºC 1h, cooled to room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in water, acidified to pH 1 with 2N HCl solution and extracted into EtOAc, washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (5–60% EtOAc in hexanes) provided the title product (1.09 g; 87%) as a crystalline white solid.1H NMR (500 MHz, CDCl3) δ 7.89–7.83 (m, 2H), 7.69 (d, J = 2.1 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.93 (s, 2H), 1.57 (s, 9H). Synthesis of tert-butyl 4-ditert-butoxyphosphoryloxy-3-(hydroxymethyl)benzoate Di-tert-butoxyphosphine (9 was added to a cooled (5 ºC) solution of tert-butyl 4-hydroxy-3-(hydroxymethyl)benzoate (1.09 g; 4.86 mmol), N,N- diisopropylethylamine (2.53 mL; 14.58 mmol) and carbon tetrabromide (8.05 g; 24.30 mmol) in CH3CN (20 mL) Added additional DMAP (100 mg; 0.81 mmol) with every addition. After 3 h, the reaction mixture was quenched with water and extracted into EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (10–80% EtOAc in hexanes) provide the desired product (0.79 g; 39%) as a colorless solid.1H NMR (500 MHz, CDCl3) δ 8.32–8.25 (m, 2H), 8.09 (t, J = 1.8 Hz, 1H), 7.99 (dd, J = 8.6, 2.2 Hz, 1H), 7.53 (dd, J = 8.7, 0.8 Hz, 1H), 7.44–7.37 (m, 2H), 5.42 (s, 2H), 1.59 (d, J = 1.6 Hz, 9H), 1.52 (d, J = 0.7 Hz, 18H) Synthesis of tert-butyl 4-diethoxyphosphoryloxy-3-(hydroxymethyl)benzoate Diethyl chlorophosphate (0. l) was added to a cooled (5 ºC) solution of tert-butyl 4-hydroxy-3-(hydroxymethyl)benzoate (0.71 g; 5.48 mmol), N,N- diethylisopropylamine (0.95 mL; 5.48 mmol)) in CH3CN (20 mL). After 3 h, the reaction mixture was quenched with water and extracted into EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (10–80% EtOAc in hexanes) provide the desired product (0.79 g; 39%) as a colorless solid.1H NMR (500 MHz, CDCl3) δ 8.14–8.08 (m, 1H), 7.95 (dd, J = 8.5, 2.3 Hz, 1H), 7.28–7.23 (m, 2H), 4.69 (s, 2H), 4.32–4.14 (m, 4H), 1.59 (s, 9H), 1.37 (td, J = 7.1, 1.1 Hz, 6H). Synthesis of benzyl 3-formyl-4-hydroxybenzoate Paraformaldehyde (0.79 g, 26.2 as added to a flask containing benzyl 4- hydroxybenzoate (2.0 g, 8.76 mmol), triethylamine (2.44 mL, 17.52 mmol) and MgCl2 (1.66 g, 17.5 mmol) in acetonitrile (30 mL). The mixture was stirred at reflux for 12 h, cooled to room temperature and diluted with EtOAc (~150 mL). The resulting solution was washed with 1M HCl (3 ×100 mL) solution, water (2 × 100 mL), brine solution and dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (0–10% EtOAc in hexanes) provided the desired product as a white solid (1.24 g, 55%).1H NMR (500 MHz, CDCl3) δ 11.43 (s, 1H), 9.97 (s, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.25 (dd, J = 8.8, 2.2 Hz, 1H), 7.49–7.45 (m, 2H), 7.45–7.32 (m, 3H), 7.06 (d, J = 8.7 Hz, 1H), 5.40 (s, 2H). Synthesis of benzyl 4-hydroxy-3-(hydroxymethyl)benzoate Sodium Borohydride (366 mg, 9 was added to a solution of benzyl 3- formyl-4-hydroxy-benzoate (1.24 g, 4.84 mmol) in tetrahydrofuran (20 mL) and then heated at 70 ºC 1 hour and then cooled to room temperature and then acidified by the addition aqueous 1N HCl solution. The product was extracted with EtOAc, washed with brine solution, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (20–80% EtOAc in hexanes) provided the desired product (1.09 g, 87%) as a white solid.1H NMR (500 MHz, CDCl3) δ 7.97 (dd, J = 8.5, 2.2 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.49–7.32 (m, 5H), 6.93 (d, J = 8.5 Hz, 1H), 5.34 (s, 2H), 4.94 (s, 2H). Synthesis of benzyl 4-dibenzyloxyphosphoryloxy-3-(hydroxymethyl)benzoate A solution of benzyl 4-hydrox ethyl)benzoate (1.09 g, 4.22 mmol) in MeCN (14 mL) was slowly added to a cooled (5 ºC) solution of diisopropylethylamine (2.21 mL, 12.66 mmol), dibenzyl phosphonate (0.94 mL, 4.22 mmol), 4-dimethylaminopyridine (103 mg, 0.84 mmol), carbon tetrachloride (1.63 mL, 16.88 mmol) in acetonitrile (10 mL). The reaction mixture was left to stir at room temperature for 16 h and then diluted with EtOAc, washed with aqueous 1M HCl solution, brine solution, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (20–80% EtOAc in hexanes) provided the desired product (0.78 g, 35%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 8.17 (dd, J = 2.4, 1.0 Hz, 1H), 7.94 (dd, J = 8.5, 2.2 Hz, 1H), 7.49–7.25 (m, 16H), 7.25–7.06 (m, 2H), 5.38 (s, 2H), 5.15 (d, J = 9.0 Hz, 4H), 4.62 (s, 2H). Synthesis of tert-butyl 4-hydroxy-3-methyl-benzoate A solution of DCC (712 mg, 3.4 n THF (35 mL) was slowly added to a mixture of 4-hydroxy-3-methyl-benzoic acid (500 mg, 3.29), 4-dimethylaminopyridine (150 mg, 1.23 mmol) in tert-butanol (45 mL). After stirring for 4 h, the reaction mixture was filtered, and then evaporated to dryness under reduced pressure. Chromatography (0–40% EtOAc in hexanes) provided the desired product (324 mg, 47%) as a colorless waxy solid.1H NMR (500 MHz, CDCl3) δ 7.98–7.78 (m, 1H), 7.73–7.64 (m, 2H), 6.70 (d, J = 8.3 Hz, 1H), 2.29–2.17 (m, 3H) and 1.51 (s, 9H). Synthesis of tert-butyl-4-hydroxy-3-methyl-5-(hydroxymethyl)-benzoate To a vial containing tert-buty ethyl-benzoate (2.677 g, 12.86 mmol) precooled at 0 ºC was added dropwise 1M aq. NaOH solution (32.14 mL, 32.14 mmol). The mixture was then stirred at 0 ºC for 5 min to assure full dissolution. Formalin solution (37% in water, 8.12 mL, 299.9 mmol) was added dropwise and the vial was warmed up to 55 ºC overnight. The reaction was then diluted with sat. aq. NH4Cl and EtOAc, and the phases were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine solution, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (0–50% EtOAc in hexanes) provided the desired product (1.50 g, 49% yield) as a white solid.1H NMR (500 MHz, CDCl3) δ 7.74–7.72 (m, 1H), 7.53 (dt, J = 2.1, 0.7 Hz, 1H), 4.91 (d, J = 5.6 Hz, 2H), 2.27 (s, 3H), 1.57 (s, 9H). Synthesis of tert-butyl 4-((di-tert-butoxyphosphoryl)oxy)-3-(hydroxymethyl)-5- methylbenzoate CCl4(0.47 mL, 3.36 mmol, 4.0 equiv) was added dropwise to a cooled (–10 ºC ) flask containing 2-tert-butoxyphosphonoyloxy-2-methyl-propane (0.17 mL, 0.86 mmol), DIPEA (0.44 mL, 2.52 mmol), and DMAP (0.021 g, 0.17 mmol). The resulting mixture was stirred at this temperature for 30 min before the dropwise addition of a solution of tert-butyl 4- hydroxy-3-(hydroxymethyl)-5-methyl-benzoate (0.20 g, 0.84 mmol) in MeCN (2.5 mL). The mixture was allowed to warm to room temperature over 12 h and then quenched with sat. aq. NH4Cl. The aqueous phase was extracted with CH2Cl2, washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure to give the crude product as a yellow syrup.1H NMR (500 MHz, CDCl3) δ 7.71 – 7.70 (m, 1H), 7.52 (d, J = 2.1 Hz, 1H), 4.9 (s, 2H), 2.5 (s, 3H), 1.58 (s, 9H), 1.57 (s, 18H). Synthesis of tert-butyl 4-((diethoxyphosphoryl)oxy)- 3-(hydroxymethyl)-5- methylbenzoate 1-[Chloro(ethoxy)phosphor mL, 0.5 mmol) was added dropwise to a solution of tert-butyl 4-hydroxy-3-(hydroxymethyl)-5-methyl-benzoate (100 mg, 0.42 mmol) in DCM (2 mL). The mixture cooled to 0 °C and DIPEA (0.11 mL) was added slowly. The resulting mixture was allowed to stir at room temperature for 12 h and then diluted with EtOAc, washed with water, sat. aq. NH4Cl solution, brine solution, dried (MgSO4), and evaporated to dryness under reduced pressure. Chromatography (10–100% EtOAc in hexanes) provided the desired product (16 mg, 10% yield) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), 4.63 (s, 2H), 4.33–4.15 (m, 4H), 2.37 (s, 3H), 1.58 (s, 9H), 1.34 (td, J = 7.1, 1.2 Hz, 6H). Synthesis of tert-butyl 3-fluoro-4-hydroxy-5-(hydroxymethyl)benzoate Formaldehyde 30% (2.39 mL , . as added dropwise to a solution of tert- butyl 3-fluoro-4-hydroxy-benzoate (250 mg, 1.18 mmol) in sodium hydroxide (0.98 mL, 2.95 mmol). In water (1 mL). The resulting solution was heated at 60 ºC for 12 h, cooled to room temperature and then acidified by the addition of aq.1M HCl solution. Extraction with EtOAc, washed with brine solution, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (10–50% EtOAc in hexanes) provided the desired product (46 mg, 16%) as colorless oil.1H NMR (500 MHz, CDCl3) δ 7.76–7.63 (m, 1H), 7.61 (dd, J = 2.1, 1.1 Hz, 1H), 4.91 (s, 2H), 1.59 (s, 9H).Synthesis of tert-butyl 4-((diethoxyphosphoryl)oxy)-3-fluoro-5-(hydroxymethyl)benzoateN,N-Diisopropylethylamine l) was added to a solution of tert-butyl 3-fluoro-4-hydroxy-5-(hydroxymethyl)benzoate (1.36 g, 5.61 mmol), and diethyl chlorophosphate (1.22 mL, 8.42 mmol) in DCM (18 mL). After stirring at room temperature for 12 h, the solution was extracted into EtOAc, washed with aq.1N HCl solution, brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (10–60% EtOAc in hexanes) provided the desired product (1.05 g, 49%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.90 (t, J = 1.9 Hz, 1H), 7.73 (dd, J = 10.3, 2.1 Hz, 1H), 4.67 (s, 2H), 4.36–4.16 (m, 4H), 1.58 (s, 9H), 1.38 (td, J = 7.0, 1.2 Hz, 6H). Synthesis of tert-butyl 4-hydroxy-3-(hydroxymethyl)-5-methoxybenzoate NaBH4 (66.24 mg, 1.75 mm ion wise to a solution of tert-butyl 4- diethoxyphosphoryloxy-3-formyl-5-methoxy-benzoate (680 mg, 1.75 mmol) in THF (8 mL) and cooled to 0 ºC. The resulting solution was stirred for 2 h and then treated with a sat’d aq. soln. NH4Cl solution and extracted with EtOAc. The organic phase was separated, washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure to provide the desired product (445 mg, 100% yield) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 1.9 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 4.77 (s, 2H), 3.94 (s, 3H), 1.59 (s, 9H). MS (ESI) m / z = 253.1 [M−H]+. Synthesis of tert-butyl 4-((diethoxyphosphoryl)oxy)- 3-(hydroxymethyl)-5- methoxybenzoate Tert-butyl 4-hydroxy-3-(hyd hoxy-benzoate (500 mg, 1.97 mmol) and 4-DMAP (0.03 mL, 0.2 mmol) were dissolved in acetonitrile (14 mL). The flask was then cooled to 0 °C in an ice water bath before diethyl chlorophosphate (0.37 mL, 2.56 mmol) was added dropwise, followed by N,N-diisopropylethylamine (0.69 mL, 3.93 mmol). The flask was then removed from the ice water bath and heated to 50 °C. The reaction mixture was then allowed to stir for 2 hours before diluting the mixture with EtOAc (50 mL) and washing with saturated aq. ammonium chloride solution followed by brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (20-60% EtOAc and hexanes) to give the desired product (594 mg, 69%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 7.55 (s, 1H), 4.64 (d, J = 5.3 Hz, 2H), 4.30–4.18 (m, 4H), 3.89 (s, 3H), 1.57 (s, 9H), 1.39–1.30 (m, 6H). MS (ESI) m / z = 391.1 [M+H]+. Synthesis of tert-butyl 3-chloro-4-hydroxy-5-(hydroxymethyl)benzoate NaBH4(2.06 g, 54.54 mmol) was added portion-wise to a stirred solution of tert-butyl 3-chloro-5-formyl-4-hydroxy-benzoate (14.0 g, 54.54 mmol) in THF (250 mL) cooled to 0°C. The reaction mixture was stirred at 0 ºC for about 30 min and the excess borohydride quenched by the addition of sat’d aq. NH4Cl solution. The organic phase was extracted with EtOAc, dried over sodium sulfate, and then evaporated to dryness under reduced pressure. Chromatography (SiO2; 20–80 EtOAc in hexanes) provided the title product (8.71 g, 61%) as an off-white solid.1H NMR 400MHz (DMSO-d6): δ 10.13 (s,1H), 7.84 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 5.41(s, 1H), 4.54 (s, 2H),1.52 (s, 9H). MS (ESI) m / z = 258 [M+H]+. Synthesis of tert-butyl 4-((diethoxyphosphoryl)oxy)-3-chloro-5- (hydroxymethyl)benzoate 1-[Chloro(ethoxy)phosphor g, 23.0 mmol) was then added dropwise to a flask containing a mixture of tert-butyl 3-chloro-4-hydroxy-5- (hydroxymethyl)benzoate (3.5 g, 13.52 mmol) and (N,N-diisopropylethylamine (0.2 mL, 1.16 mmol) in DCM (67 mL). The reaction mixture was allowed to stir under an atmosphere of argon at room temperature overnight. Excess chlorophosphate was quenched by the addition of water. The organic phase was extracted with DCM, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (SiO2; 40–80% EtOAc in hexanes) gave the desired product (as a colorless oil.1H NMR (500 MHz, CDCl3) δ 8.01 (s, 2H), 4.66 (s, 2H), 4.36–4.19 (m, 4H), 1.59 (s, 9H), 1.36 (td, J = 7.0, 1.2 Hz, 6H). Synthesis of 6-diethoxyphosphoryl-2,2-dimethyl-4H-1,3-benzodioxine 6-Bromo-2,2-dimethyl-4H-1,3 (100 mg, 0.41 mmol) was added to a heat gun-dried flask and purged with nitrogen, followed by THF (2 mL). The resulting solution was cooled to −78 °C and then, 2.5 M n-BuLi solution in hexanes (0.18 mL, 0.45 mmol) was added dropwise. Once complete, the reaction was permitted to stir at this temperature for 1 hour. Finally, a solution of diethyl chlorophosphate (0.09 mL, 0.62 mmol) in anhydrous THF (2 mL) was added dropwise. The reaction was warmed to room temperature, quenched by addition of sat’d aq. NH4Cl solution and extracted with CH2Cl2, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (40% EtOAc in hexanes) gave the desired product (0.06 g; 46%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.57 (ddd, 12.8, 8.4, 1.8 Hz, 1H), 7.48 (dd, J = 12.8, 1.8, 1H), 6.88 (dd, J = 8.4, 3.6 Hz, 1H) 4.86 (s, 2H), 4.02–4.18 (m, 4H), 1.55 (s, 6H), 1.32 (t, J = 7.1 Hz, 6H) Synthesis of 4-diethoxyphosphoryl-2-(hydroxymethyl)phenol 6-Diethoxyphosphoryl-2,2-dim benzodioxine (1.g, 3.33 mmol) was dissolved in 16 mL of THF and 16 mL of 1 M HCl. The reaction was washed with sat’d aq. NaHCO3 solution and extracted with EtOAc, dried (MgSO4) and evaporated to dryness under reduced pressure to give the desired product (0.94 g; 95%) as a colorless oil which was used in the following step without further purification.1H NMR (500 MHz, CDCl3) δ 7.71–7.65 (m, 2H), 7.09 (dd, J = 8.2, 3.7), 5.43 (s, 2H), 4.15–4.04 (m, 8H), 1.36–1.31 (m, 2H). LC-MS: m / z = 262.1 [M+H]+and 260.9 [M−H]+. Synthesis of [4-diethoxyphosphoryl-2-(hydroxymethyl)phenyl] diethyl phosphate DIPEA (0.09 mL, 0.51 mmo ooled (0 ºC) solution of 4- diethoxyphosphoryl-2-(hydroxymethyl)phenol (121 mg, 0.46 mmol) in CH2Cl2 (2.3 mL). The reaction mixture was left to stir for 10 min. under a nitrogen atmosphere and then diethoxy chlorophosphate (0.07 mL, 0.51 mmol) was added. The reaction was warmed to room temperature over 3 h and then quenched by addition of saturated aq. NaHCO3solution, extracted with CH2Cl2, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (0–10% MeOH in CH2Cl2) provided the desired product (109 mg; 56%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.98 (td, J = 13.1, 1.2 Hz, 1H), 7.73 (ddd, J = 13.1, 8.3, 2.7 Hz, 1H), 7.35 (ddd, J = 8.4, 32.7, 1.8 Hz, 1H), 4.73 (s, 2H), 4.28–4.21 (m, 4H), 4.16–4.04 (m, 4H), 1.37 (td, J = 7.1, 1.14, 6H), 1.31 (t, J = 7.1 Hz, 6H).

[0304] Synthesis of 6-dibenzyloxyphosphoryl-2,2-dimethyl-4H-1,3-benzodioxine A mixture of 6-bromo-2,2-dim benzodioxine (100 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium (47 mg, 0.04 mmol) and benzyloxyphosphonoyloxymethylbenzene (0.1 mL, 0.41 mmol) and triethylamine (0.07 mL, 0.49 mmol) in anhydrous THF (2 mL) was heated in a microwave reactor for 10 min at 120 ºC. The reaction was filtered, washing with DCM and evaporated to dryness under reduced pressure. Chromatography (10–50% EtOAc in hexanes) provided 6-dibenzyloxyphosphoryl- 2,2-dimethyl-4H-1,3-benzodioxine (84 mg, 48 % yield) as a yellow oil.1H NMR (500 MHz, CDCl3) δ 7.60 (ddd, J = 12.9, 8.4, 1.9 Hz, 1H), 7.43 (dd, J = 13.6, 1.8 Hz, 1H), 7.34 (d, J = 3.6 Hz, 10H), 6.87 (dd, J = 8.4, 3.8 Hz, 1H), 5.14–5.02 (m, 4H), 4.82 (s, 2H), 1.56 (s, 6H).LRMS (ESI+) m / z calcd for C24H25O5P [M + H]+424.23, found 425.1 [M + H]+. Synthesis of dibenzyl (4-hydroxy-3-(hydroxymethyl)phenyl)phosphonate 6-Dibenzyloxyphosphoryl-2 -benzodioxine (408 mg, 0.96 mmol) was dissolved in acetone (1 mL) and 1M aq. HCl solution (1 mL). The mixture was left to stir at room temperature for 24 h and then diluted with EtOAc, dried (MgSO4), and evaporated to dryness under reduced pressure to give the desired product (330 mg, 80%) as a white solid.1H NMR 400MHz (DMSO-d6): δ 10.28 (s,1H), 7.77 (d, J = 13.2Hz, 1H), 7.49–7.45 (m,1H), 7.35–7.32 (m, 10H), 6.90–6.88 (m, 1H), 5.16 (t, J = 5.2Hz, 1H), 5.01–4.94 (m, 4H) and 4.48 (d, J = 5.2Hz, 2H). Synthesis of dibenzyl (4-(bis(benzyloxy)phosphoryl)-2-(hydroxymethyl)phenyl) phosphate 4-Dibenzyloxyphosphoryl-2 henol (0.33 g, 0.86 mmol) was dissolved in 1.7 mL of MeCN (2 mL) and carbon tetrachloride (0.33 mL, 3.43 mmol) before the addition of benzyloxyphosphonoyloxymethylbenzene (0.23 mL, 1.03 mmol), N,N- diisopropylethylamine (0.45 mL, 2.58 mmol), and DMAP (20 mg, 0.17 mmol) at 0 ºC. After 2 hours, the reaction was diluted with DCM, washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (0–10% MeOH in DCM) provided the desired product (0.310 g, 53%) as a colorless oil.1H NMR (500 MHz, MeOD) δ 7.90 (dt, J = 13.6, 1.6 Hz, 1H), 7.60 (ddd, J = 13.2, 8.3, 2.0 Hz, 1H), 7.35–7.30 (m, 21 H), 5.48 (s, 4H), 5.16 (d, J = 9.5 Hz, 2H), 5.09–5.03 (m, 4H). Synthesis of 6-substituted [4-diethoxyphosphoryl-2-(hydroxymethyl)phenyl] diethyl phosphates Prepared according to the synthetic procedure for the synthesis of [4- diethoxyphosphoryl-2-(hydroxymethyl)phenyl] diethyl phosphate. Synthesis of 6-dibenzyloxyphosphoryl-2,2,8-trimethyl-4H-1,3-benzodioxine 6-Bromo-2,2,8-trimethyl-4H- ne (0.259 g, 1.01 mmol, 1.0 equiv.) was azeotroped with toluene until a viscous oil was obtained. The residue was dissolved in anhydrous THF (4 mL), and then cooled to –78 ºC under an atmosphere of nitrogen. A solution of 2.8 M n-butyl lithium (0.41 mL, 1.1 mmol) was added dropwise over 1 min and then left to stir at –78 ºC for 1 h. Then a solution of anhydrous [benzyloxy(chloro)phosphoryl]oxymethylbenzene (0.366 g, 1.23 mmol) in THF (1 mL) was added dropwise over 4 min. After stirring for an additional 2 h, the excess base was quenched with an ice-cold saturated aqueous NaHCO3solution (5 mL). The biphasic mixture was extracted into EtOAc, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (25 g SiO2, 30–100% EtOAc in hexanes) to obtain the desired product (82 mg, 18%) as a yellow oil.1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 13.3 Hz, 1H), 7.35–7.29 (m, 10H), 7.25 (d, J = 13.7 Hz, 1H), 5.05 (dd, J = 11.9, 7.8 Hz, 4H), 4.79 (s, 2H), 2.15 (s, 3H), 1.54 (s, 6H).31P NMR (202 MHz, CDCl3) δ 21.11 (tt, J = 13.9, 7.5 Hz). Synthesis of dibenzyl (4-hydroxy-3-(hydroxymethyl)-5-methylphenyl)phosphonate 1M aqueous HCl (10 mL, 10 to a stirring solution of 6- dibenzyloxyphosphoryl-2,2,8-trimethyl-4H-1,3-benzodioxine (1.46 g, 3.35 mmol) in acetone (40 mL) and left to stir at room temperature for 15 hours and then evaporated under reduced pressure to remove the acetone. The remaining aqueous phase was extracted with DCM, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (25 g SiO2, 0–10% methanol / EtOAc) provided the desired product (0.237 g, 14%) as a yellow solid.1H NMR (500 MHz, DMSO) δ 9.22 (s, 1H), 7.56 (d, J = 13.3 Hz, 1H), 7.40 – 7.29 (m, 11H), 5.36 (s, 1H), 4.98 (dd, J = 12.1, 8.1 Hz, 4H), 4.56 (s, 2H), 2.18 (s, 3H).31P NMR (202 MHz, DMSO) δ 21.15 (dq, J = 14.2, 6.9 Hz). LCMS (SQ) m / z = 399.2 [M+H] Synthesis of dibenzyl (4-(bis(benzyloxy)phosphoryl)-2-(hydroxymethyl)-6- methylphenyl) phosphate In a round bottom flask con L, 5.02 mmol), 4-DMAP (0.03 mL, 0.25 mmol), cooled to 5 ºC by ice / water, was added 4-dibenzyloxyphosphoryl-2- (hydroxymethyl)-6-methyl-phenol (500 mg, 1.26 mmol) followed by N,N- diisopropylethylamine (0.66 mL, 3.77 mmol). After stirring for 5 minutes, a solution of benzyloxyphosphonoyloxymethylbenzene (0.36 mL, 1.63 mmol) in MeCN (4.2 mL) was added dropwise over 5 min. The resulting mixture was stirred at room temperature for 16 h and then diluted with EtOAc, washed with 1 M aqueous HCl solution, brine, dried (MgSO4), and evaporated to dryness under reduced pressure. Chromatography (0–10 % MeOH in DCM) provided the desired product (105 mg, 11%) as a yellow oil.1H NMR (500 MHz, CDCl3) δ 7.45–7.22 (m, 22H), 5.12–4.97 (m, 4H), 4.93–4.88 (m, 2H), 4.79 (s, 2H), 4.70 (s, 2H), 2.15 (d, J = 0.8 Hz, 3H). Synthesis of dibenzyl (4-hydroxy-3-(hydroxymethyl)-5-methoxyphenyl)phosphonate 1M aqueous HCl solution (4 o a solution of 6- dibenzyloxyphosphoryl-8-methoxy-2,2-dimethyl-4H-1,3-benzodioxine (2.3 g, 5.06 mmol) dissolved in acetone (40 mL). After stirring at room temperature for 12 h, the reaction mixture was evaporated under reduced pressure to remove acetone. Extraction of the aqueous phase with EtOAc (250 ml) followed by washing with brine solution, dried (Na2SO4) and evaporated to dryness under reduced pressure gave the desired product (2.1 g, 100%) as a yellow oil.1H NMR (500 MHz, CDCl3) δ 7.36 – 7.28 (m, 10H), 7.18 (dt, J = 14.4, 1.8 Hz, 1H), 5.08 (dd, J = 11.8, 7.8 Hz, 2H), 5.01 (dd, J = 11.8, 8.1 Hz, 2H), 4.72 (s, 2H), 3.83 (d, J = 1.7 Hz, 3H). MS (ESI) m / z = 415.1 [M+H]+. Synthesis of dibenzyl (4-(bis(benzyloxy)phosphoryl)-2-(hydroxymethyl)-6- methoxyphenyl) phosphate A solution of 4-dibenzyloxyphosphoryl-2-(hydroxymethyl)-6-methoxy-phenol (1.87 g, 4.51 mmol) in MeCN (18 mL) was added dropwise to a cooled (5 ºC) solution of CCl4 (1.75 mL, 18.05 mmol), dibenzyl phosphonate (1.3 mL, 5.87 mmol) and DIPEA (2.35 mL, 13.54 mmol). The reaction mixture was stirred at room temperature for 12 h and then extracted into EtOAc, washed with 1M aq. HCl solution, brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (50–100% EtOAc in hexanes) provided the desired product (312 mg, 10%) as a yellow oil.1H NMR (500 MHz, CDCl3) δ 7.46 (dd, J = 13.6, 1.7 Hz, 1H), 7.36–7.27 (m, 20H), 7.22–7.15 (m, 1H), 5.16 (dt, J = 8.1, 3.7 Hz, 4H), 5.12–5.03 (m, 4H), 4.59 (d, J = 4.0 Hz, 2H), 3.63 (s, 3H). MS (ESI) m / z = 675.2 [M+H]+Synthesis of tert-butyl 3-acetyl-4-hydroxy-benzoate DCC (601 mg, 2.91 mmol) in as added to a mixture of 3-acetyl-4- hydroxy-benzoic acid (500 mg, 2.78 mmol), tert-butanol (34 mL) and 4- dimethylaminopyridine (138 mg, 1.13 mmol) in THF and left to stir at room temperature for 12 h. The resulting mixture was filtered and evaporated to dryness under reduced pressure. Chromatography (2–20% EtOAc in hexanes) provided the desired product (352 mg; 53%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 12.62 (s, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 8.8, 2.1 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 2.69 (s, 3H) and 1.60 (s, 9H). Synthesis of tert-butyl 4-hydroxy-3-(1-hydroxyethyl)benzoate Sodium borohydride (1.97 g, s slowly added to a solution of tert- butyl 3-acetyl-4-hydroxy-benzoate (2.46 g, 10.41 mmol) in THF (52 mL). The resulting mixture was heated at 80 ºC for 3 hours, cooled and then evaporated to dryness under reduced pressure. The residue was dissolved in water, acidified with 4N HCl solution and then extracted into EtOAc, washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (20%–60% EtOAc in hexanes) provide the desired product (1.76 g; 70%) as a white solid.1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 7.81 (dd, J = 8.4, 2.1 Hz, 1H), 7.64 (dd, J = 2.1, 0.6 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.14 (qd, J = 6.6, 3.6 Hz, 1H), 2.54 (d, J = 3.9 Hz, 1H), 1.61 (d, J = 6.6 Hz, 3H), 1.57 (s, 9H). Synthesis tert-butyl 4-diethoxyphosphoryloxy-3-(1-hydroxyethyl)benzoate Triethylamine (0.32 mL, 2.2 to a stirred mixture of tert-butyl 4- hydroxy-3-(1-hydroxyethyl)benzoate (181.mg, 0.76 mmol) and diethyl chlorophosphate (1.2 mL, 6.61 mmol) in CH2Cl2 (2.5 mL). The reaction was left to stir at room temperature for 12 h and then diluted with EtOAc and washed with aq.1M HCl solution, brine solution, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (40–80% EtOAc in hexanes) provided the desired product (2.76 g, 48%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 8.20 (dd, J = 2.2, 1.2 Hz, 1H), 7.88 (dd, J = 8.5, 2.2 Hz, 1H), 7.33–7.24 (m, 1H), 5.24 (q, J = 6.5 Hz, 1H), 4.33–4.14 (m, 4H), 1.59 (s, 9H), 1.53 (d, J = 6.5 Hz, 3H), 1.38 (td, J = 7.1, 1.1 Hz, 3H), 1.34 (td, J = 7.1, 1.1 Hz, 3H). Synthesis of tert-butyl 3-formyl-4-(hydroxymethyl)benzoate A mixture of 4-formyl-3-hy (3.0 g, 18.06 mmol) and 1,1-di-tert- butoxy-N,N-dimethyl-methanamine (13.89 mL, 60.19 mmol) in DMF (5 mL) was heated in a microwave at 120 ºC for 2 h and left to stir at room temp for 72 h. The resulting mixture was filtered and evaporated to dryness under reduced pressure. Chromatography (5–50% EtOAc in hexanes) provided the desired product (1.98 g; 49%) as a white solid.1H NMR (500 MHz, CDCl3) δ 10.94 (s, 2H), 9.98 (s, 2H), 7.64–7.46 (m, 3H), 1.60 (s, 11H). Synthesis of tert-butyl 3-hydroxy-4-(hydroxymethyl)benzoate Sodium borohydride (206 , . added to a solution of tert-butyl 4- formyl-3-hydroxy-benzoate (1.21 g, 5.44 mmol) in THF (20 mL) and then heated at 70 ºC for 2h. The cooled reaction mixture was evaporated to dryness under reduced pressure, diluted with water and acidified with 4N HCl solution, extracted with EtOAc, washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (5–50% EtOAc in hexanes) provided the title product (1.1 g; 90%) as a white solid.1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 7.5 Hz, 2H), 7.41 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 4.92 (d, J = 5.5 Hz, 2H), 2.31 (t, J = 5.7 Hz, 1H), 1.58 (s, 9H). Synthesis of tert-butyl 3-diethoxyoxyphosphoryloxy-4-(hydroxymethyl)benzoate Diethyl chlorophosphate (1 s added to a solution of tert-butyl 3- hydroxy-4-(hydroxymethyl)benzoate (1.1 g, 4.9 mmol) and DIPEA (2.5 mL, 14.6 mmol) in CH2Cl2 (24 mL) at 0 ºC. The reaction was allowed to warm up to room temperature and stirred for 15 hours and then quenched by water, extracted into CH2Cl2and evaporated to dryness under reduced pressure. Chromatography (10–50% EtOAc in hexanes) provided the desired product (2.77 g; 88%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J = 8.0, 1.4 Hz, 1H), 7.79 (t, J = 1.5 Hz, 1H), 7.53 (dd, J = 8.0, 0.9 Hz, 1H), 4.70 (d, J = 6.2 Hz, 2H), 4.28–4.23 (m, 4H), 1.59 (s, 9H) and 1.38 (m, J = 7.1, 1.2 Hz, 6H). Synthesis of tert-butyl 3-di-tert-butoxyphosphoryloxy-4-(hydroxymethyl)benzoate Di-tert-butoxyphosphine (1 as added to a cooled (5 ºC) solution of tert-butyl 3-hydroxy-4-(hydroxymethyl)benzoate (1.11 g; 4.95 mmol), DIPEA (2.53 mL; 14.58 mmol) and carbon tetrabromide (8.21 g; 24.75 mmol) and DMAP (100 mg; 0.81 mmol) in CH3CN (25 mL). After 2 h, the reaction mixture was quenched with water and extracted into EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (5–50% EtOAc in hexanes) provide the desired product (0.69 g; 33%) as a colorless solid.1H NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 7.6, 1.4 Hz, 2H), 7.51–7.45 (m, 1H), 4.65 (s, 2H), 1.59 (s, 9H) and 1.53 (s, 18H). Synthesis of methyl 3-dibenzyloxyphosphoryloxy-4-(hydroxymethyl)benzoate Benzyloxyphosphonoyloxy ane (513 mg, 1.84 mmol), carbon tetrabromide (3.06 g, 9.22 mmol), and DIPEA (0.96 mL, 5.53 mmol) were added to a cooled (0 ºC) solution of methyl 3-hydroxy-4-(hydroxymethyl)benzoate (336 mg, 1.84 mmol) was dissolved in acetonitrile (10 mL). The reaction was stirred at 0 ºC for 12 h and then diluted with EtOAc and quenched with 1M HCl solution. The organic phase was separated, washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (10–50% EtOAc in hexanes) provided the desired product (0.304 g; 37%) as a colorless oil).1H NMR (500 MHz, CDCl3) δ 7.86 (dt, J = 7.8, 1.4 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.37–7.28 (m, 10H), 5.13 (dd, J = 8.9, 1.8 Hz, 4H), 4.61 (s, 2H), 3.89 (s, 3H). Synthesis of tert-butyl 3-hydroxy-4-(1-hydroxyethyl)benzoate Bromo(methyl)magnesium ol) solution in THF was slowly added to a cooled (0 ºC) solution of tert-butyl 4-formyl-3-hydroxy-benzoate (3.09 g, 13.90 mmol) in THF (13.5 mL) and Et2O (13.5 mL). The reaction was stirred for 12 h and then quenched by the addition of sat’d aq. NH4Cl solution and extracted with EtOAc. The organic phase was separated, washed with brine solution, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (10–80% EtOAc in hexanes) provided the desired product (0.77 g, 23%) as a colorless oil.1H NMR (500 MHz, DMSO) δ 7.44 (d, J = 8.4 Hz, 1H), 7.38–7.32 (m, 2H), 4.99 (q, J = 6.4 Hz, 1H), 1.52 (s, 9H), 1.27 (d, J = 6.3 Hz, 3H). Synthesis of tert-butyl 4-diethoxyphosphoryloxy-3-(1-hydroxyethyl)benzoate Diethyl chlorophosphate (1.41 mL, 9.73 mmol) was added to a solution of tert-butyl 3-hydroxy-4-(hydroxymethyl)benzoate (1.09 g, 4.87 mmol) and DIPEA (2.54 mL, 14.60 mmol) in DCM (24 mL) cooled by an ice-bath. The reaction was left to stir for 15 h, and then quenched by the addition of water. The organic phase was extracted with further DCM, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (10–60% EtOAc in hexanes) gave the desired product (864 mg, 71%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.87–7.78 (m, 2H), 7.60 (dd, J = 8.1, 1.0 Hz, 1H), 5.26 (q, J = 6.6 Hz, 1H), 4.35–4.08 (m, 4H), 1.58 (s, 9H), 1.52 (d, J = 6.5 Hz, 3H), 1.39 (dtd, J = 29.0, 7.0, 1.1 Hz, 6H). Synthesis of tert-butyl 3-hydroxy-2-methyl-benzoate 1,1-Di-tert-butoxy-N,N-dimet ne (59.6 mL, 262.9 mmol) was added dropwise, via addition funnel, to a mixture of 3-hydroxy-2-methyl benzoic acid (10 g; 65.72 mmol) in toluene (130 mL) heated to 100 °C. The reaction was allowed to stir for another 15 minutes, cooled to room temperature and then quenched with water and extracted into EtOAc. The organic phase was washed with water, brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (0–40% EtOAc in hexanes) provided the desired product (6.5 g, 47%) as a white solid.1H NMR (500 MHz, CDCl3) δ 7.32 (dd, J = 7.8, 1.3 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.89 (dd, J = 8.0, 1.2 Hz, 1H), 2.42 (s, 3H), 1.59 (s, 9H). Synthesis of tert-butyl-formyl-3-hydroxy-2-methylbenzoate A solution of tert-butyl 3-hy nzoate (6.5 g, 31.21 mmol) in THF (20 mL) was added dropwise to a mixture of MgCl2 (5.94 g, 62.42 mmol), paraformaldehyde (2.8 g, 93.63 mmol), Et3N (8.7 mL, 62.42 mmol) and THF (84 mL). The resulting mixture was heated at 65°C for 12 h, cooled to room temperature and diluted with EtOAc (150 mL), washed with aqueous 1M HCl solution, then water and brine solution. The organic phase was dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (10–40% EtOAc in hexanes) afforded the desired product (5.1 g, 69%) as off-white crystals.1H NMR (500 MHz, CDCl3) δ 11.39 (s, 1H), 9.91 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 2.40 (s, 3H), 1.61 (s, 9H). Synthesis of tert-butyl 3-diethoxyphosphoryloxy-4-formyl-2-methyl-benzoate DIPEA (7.5 mL, 43.17 mm lution of tert-butyl-formyl-3- hydroxy-2-methylbenzoate (5.1 g, 21.58 mmol) DCM (108 mL) cooled to 0° C. Diethyl phosphochloridate (3.8 mL, 25.90 mmol) was added dropwise and the reaction mixture was allowed to stir for 72 hours. The reaction mixture was washed with water, sat’d aq. NH4Cl solution, and brine, then the organic phase was dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (10–80% EtOAc in hexanes) provided the desired product (5.89 g, 73%) as a white solid.1H NMR (500 MHz, CDCl3) δ 10.37 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 4.30–4.14 (m, 4H), 2.56 (s, 3H), 1.60 (s, 9H), 1.33 (td, J = 7.1, 1.1 Hz, 6H). Synthesis of tert-butyl 3-diethoxyphosphoryloxy-4-(hydroxymethyl)-2-methyl-benzoate NaBH4 (513 mg, 13.56 mm lution of tert-butyl 3- diethoxyphosphoryloxy-4-formyl-2-methyl-benzoate (5.05 g, 13.56 mmol) in EtOH (27 mL). After 15 minutes, the reaction was quenched with sat’d aq. NH4Cl solution and extracted in EtOAc, the organic phase was washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure to afford the desired product (4.90 g, 96%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 7.9, 1H), 7.34 (d, J = 7.9 Hz, 1H), 4.61 (s, 2H), 4.30– 4.15 (m, 4H), 2.49 (s, 3H), 1.59 (s, 9H), 1.34 (td, J = 7.1, 1.2 Hz, 6H) Synthesis of tert-butyl 3-hydroxy-2-fluoro-benzoate 1,1-Di-tert-butoxy-N,N-dimet ne (0.61 mL, 2.56 mmol) was added drop-wise via syringe to a suspension of 2-fluoro-3-hydroxybenzoic acid (100 mg, 0.64 mmol) in toluene (3.84 mL) heated at 90 ºC and under an atmosphere of argon. The mixture was then stirred at 90 ºC for another 45 minutes, cooled to room temperature and quenched by the addition of water. The organic phase was extracted into EtOAc, washed with brine solution, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (0–40% EtOAc in hexanes) provided the desired product (53 mg, 39%) as an off-white solid.1H NMR (500 MHz, CDCl3) δ 7.37 (ddd, J = 8.1, 6.5, 1.8 Hz, 1H), 7.15 (td, J = 7.9, 1.8 Hz, 1H), 7.04 (td, J = 8.0, 1.3 Hz, 1H), 1.59 (s, 9H). Synthesis of tert-butyl 3-fluoro-4-hydroxy-benzoate 1,1-Di-tert-butoxy-N,N-dimethyl mine (5.81 mL, 25.62 mmol) was slowly added to a heated (90 ºC) mixture of 3-fluoro-4-hydroxy-benzoic acid (2.0 g, 12.81 mmol) in toluene (25.62 mL). Heating continued for 4 h and then cooled to room temperature and evaporated to dryness under reduced pressure. Chromatography (0–20% EtOAc in hexanes) provided the desired product (0.27 g, 9%) as a white solid.1H NMR (500 MHz, CDCl3) δ 7.83–7.65 (m, 2H), 7.03 (t, J = 8.6 Hz, 1H), 1.60 (s, 9H). Synthesis of 7-di-ethoxyoxyphosphoryl-2,2-dimethyl-4H-1,3-benzodioxine n-BuLi solution (2.5 M in he , . as added to a cooled (–78 ºC) solution of 7-bromo-2,2-dimethyl-4H-1,3-benzodioxine (1.18 g, 4.88 mmol) in THF (24 mL). The mixture was stirred at –78 ºC for 1.5 h before the dropwise addition of a solution of diethoxy chlorophosphonate (1.26 g, 7.32 mmol) in THF (3.0 mL). The reaction mixture was allowed to warm to room temperature over 2 h and then quenched by the addition of sat. aq. NH4Cl solution. The mixture was diluted with water and extracted into diethyl ether, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (30% EtOAc in hexanes) provided the desired product (1.08 g; 73%) as a colorless oil.1H NMR (CDCl3, 500 MHz) δ 7.57 (ddd, J = 12.4, 8.4, 3.2, 1H), 7.48 (dd, J = 13.3, 3.0, 1H), 6.88 (dt, J = 8.4, 3.3 Hz, 1H), 4.86 (s, 2H), 4.15–4.05 (m, 4H), 1.55 (s, 6H), 1.33–1.30 (m, 6H). Synthesis of 5-diethoxyphosphoryl-2-(hydroxymethyl)phenol A mixture of 4-methylben -ium (256 mg, 1.03 mmol) and 7- diethoxyphosphoryl-2,2-dimethyl-4H-1,3-benzodioxine (3.09 g, 10.29 mmol) in MeCN - H2O (4:1, 248 mL) was stirred at 60 ºC overnight. The mixture was quenched with sat. aq. NaHCO3. And extracted into EtOAc, washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (10% MeOH in EtOAc) afforded the desired product (1.96 g, 73% yield) as a pale-yellow oil.1H NMR (500 MHz, CDCl3) δ 7.50 (ddd, J = 13.0, 8.3, 2.0 Hz, 1H), 7.40 (dd, J = 13.2, 1.9 Hz, 1H), 6.93 (dd, J = 8.3, 3.8 Hz, 1H), 4.78 (s.2H), 4.06–3.93 (m, 4H), 1.28 (t, J = 7.1 Hz, 6H). Synthesis of [5-diethoxyphosphoryl-2-(hydroxymethyl)phenyl] diethyl phosphate 1-[chloro(ethoxy)phospho , 46.115 mmol) dropwise was slowly added to a cooled (0 ºC) solution of 5-diethoxyphosphoryl-2-(hydroxymethyl)phenol (6.00 g, 23.057 mmol) and DIPEA (12.0 mL, 69.172 mmol) in CH2Cl2 (115 mL) under argon. The reaction mixture was stirred for 12 h and then quenched by the addition of water. The organic phase was extracted, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (0–10% MeOH in CH2Cl2) provide the desired product as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.67–7.61 (m, 1H), 7.60–7.57 (m, 2H), 4.69 (s, 2H), 4.27–4.20 (m, 4H), 4.15–4.06 (m, 4H), 1.38–1.34 (m, 6H), 1.33–1.27 (m, 6H). Synthesis of [5-diethoxyphosphoryl-2-(hydroxymethyl)-6-methyl-phenyl] diethyl phosphate Experimental procedure as [5-diet droxymethyl)phenyl] diethyl phosphate but starting with 6-methyl derivative.1H NMR (500 MHz, MeOD) δ 7.77 (ddd, J = 13.9, 8.0, 1.3 Hz, 1H), 7.56 (dd, J = 8.0, 5.0 Hz, 1H), 4.80 (s, 2H), 4.24 (hept, J = 7.2 Hz, 4H), 4.17–4.09 (m, 4H), 2.55 (s, 3H), 1.36–1.31 (m, 12H). Synthesis of tert-butyl 5-formyl-2-hydroxy-benzoate A mixture of 5-formyl-2-hy (3.5 g, 21.07 mmol) and 1,1-di-tert- butoxy-N,N-dimethyl-methanamine (10.1 mL, 42.14 mmol) was heated at 100 ºC in a microwave for 4h. The resulting mixture was filtered and evaporated to dryness under reduced pressure. Chromatography (2–20% EtOAc in hexanes) provided the desired product (1.35 g; 28%) as a white solid.1H NMR (500 MHz, CDCl3) δ 11.71 (s, 1H), 9.88 (s, 1H), 8.30 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 8.6, 2.1 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 1.65 (s, 9H). Synthesis of tert-butyl 2-hydroxy-5-(hydroxymethyl)benzoate Sodium borohydride (0.82 owly added to a stirred solution of tert-butyl 5-formyl-2-hydroxy-benzoate (2.42 g; 10.9 mmol) THF (20 mL). The resulting mixture was stirred at 70 ºC for 1h, cooled to room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in water, acidified with 2N HCl and extracted into EtOAc. The organic phase was separated, washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (2–20% EtOAc in hexanes).1H NMR (500 MHz, CDCl3) δ 11.04 (s, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.43 (dd, J = 8.5, 2.3 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 4.61 (s, 2H), 1.62 (s, 9H). Synthesis of tert-butyl 2-diethoxyphosphoryloxy-5-(hydroxymethyl)benzoate DIPEA (1.31 mL, 7.53 m ed solution of tert-butyl 2-hydroxy- 5-(hydroxymethyl)benzoate (844 mg, 3.76 mmol) and diethyl chlorophosphate (0.82 mL, 4.52 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred under argon for 12 h and then quenched with water. The organic phase was separated, washed with 1N HCl solution, brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (5– 50% EtOAc in hexanes) have the desired product (0.901 g; 30%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.73 (dd, J = 2.2, 1.1 Hz, 1H), 7.58–7.31 (m, 2H), 4.68 (s, 2H), 4.38 – 4.16 (m, 4H), 1.59 (s, 9H), 1.34 (td, J = 7.1, 1.1 Hz, 6H). Synthesis of 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-diethoxyphosphoryl-phenol n-BuLi [2.5M in hexa as added dropwise to a solution of [2-bromo-4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl] diethyl phosphate (4.77 g, 10.52 mmol) in THF (35 mL) cooled to –78 ºC under argon. The resulting mixture was allowed to warm to room temperature over 12 h and then quenched with 1N HCl solution and extracted into EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (2–20% EtOAc in hexanes) provided the desired product (2.57 g; 65%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 10.06 (d, J = 1.0 Hz, 1H), 7.33–7.27 (m, 1H), 7.27–7.21 (m, 1H), 6.85 (dd, J = 8.5, 6.7 Hz, 1H), 4.56 (d, J = 0.8 Hz, 2H), 4.13–4.00 (m, 2H), 3.95 (ddq, J = 10.1, 8.1, 7.0 Hz, 2H), 1.24 (td, J = 7.0, 0.6 Hz, 6H), 0.84 (s, 9H) 0.02 (s, 3H) and 0.01 (s, 3H). Synthesis of 2-diethoxyphosphoryl-4-(hydroxymethyl)phenol Tetrabutylammonium fluoride (2.29 mL, 6.86 mmol) was added to a stirred solution of 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-diethoxyphosphoryl-phenol (2.57 g, 6.86 mmol) in THF (17 mL). The reaction mixture was left to stir for 12 h and then evaporated to dryness under reduced pressure. Chromatography (30–80% EtOAc in hexanes) provided the desired product (1.18 g; 66%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 10.23 (s, 1H), 7.45 (dd, J = 8.4, 2.2 Hz, 1H), 7.37 (dd, J = 14.6, 2.2 Hz, 1H), 6.96 (dd, J = 8.6, 6.6 Hz, 1H), 4.62 (d, J = 3.9 Hz, 2H), 4.23–4.00 (m, 4H) and 1.33 (t, J = 7.0 Hz, 6H). Synthesis of [2-diethoxyphosphoryl-4-(hydroxymethyl)phenyl] diethyl phosphate Triethylamine (1.9 mL, 1 stirred solution of 2- diethoxyphosphoryl-4-(hydroxymethyl)phenol (1.18 g, 4.53 mmol) and diethyl chlorophosphate (0.98 mL, 6.8 mmol) in CH2Cl2 (15 mL). The resulting mixture was allowed to stir at room temperature for 16 h, diluted with EtOAc, washed with sat’d aq. Na2HCO3solution, 1M HCl solution, brine, dried (MgSO4) and evaporated to dryness. Chromatography (50% EtOAc in hexanes) provided the desired product as a colorless oil. LCMS m / z = 397.1 [M+H]+Synthesis of dibenzyl (2-hydroxy-5-(hydroxymethyl)-3-methylphenyl)phosphonate To a stirred solution of ethy sphoryl-4-hydroxy-5-methyl-benzoate (1.8 g, 4.09 mmol) in dichloromethane (40 mL) cooled –40 ºC was added DIBAL-H in 1M THF (19.4 mL). The resulting mixture was allowed to warm to room temperature over 5 h and the excess base quenched the by the addition of saturated aqueous NH4Cl solution, filtered through celite®and the organic phase extracted into EtOAc, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (SiO2; EtOAc in hexanes) gave the desired product (640 mg, 39%) as pale-yellow gum.1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.36–7.24 (m, 12H), 5.14–5.00 (m, 5H) 4.35 (d, J = 5.6 Hz, 2H), 2.18 (s, 3H). Synthesis of methyl 5-bromo-2-hydroxy-4-methoxybenzoate Br2 (3.1 mL, 60 mmol) was a stirred solution of methyl 2-hydroxy- 4-methoxy-benzoate (10 g, 55 mmol) in dichloromethane (100 mL) at 0 ºC. The resulting reaction was stirred at RT for 2h. The reaction mixture was quenched with sodium thiosulfate solution (300 ml) and extracted with dichloromethane. The combined organic layers were washed with brine solution, dried (Na2SO4), filtered and then evaporated to dryness under reduced pressure. Chromatography (SiO2; EtOAc in hexanes) provided the desired product (14 g, 97%).1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.88 (s, 1H), 6.72 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H). Synthesis of methyl 5-(bis(benzyloxy)phosphoryl)-2-hydroxy-4-methoxybenzoate Tetrakis(triphenylphosphin g, 1.92 mmol) was added to stirred a solution of methyl 5-bromo-2-hydroxy-4-methoxy-benzoate (10 g, 38 mmol), benzyloxyphosphonoyloxymethylbenzene (10.96 mL, 45.96 mmol), and DIPEA (10 mL, 57.46 mmol) in toluene (3 mL). The reaction was heated under microwave irradiation at 80 ºC for 16h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (SiO2, EtOAc in hexanes) provided the desired compound (7 g, 41%) as a yellow gum. LCMS m / z = 443.9 [M+H]+. Synthesis of dibenzyl (4-hydroxy-5-(hydroxymethyl)-2-methoxyphenyl)phosphonate 2N lithium aluminum hydride in THF (0.33 mL, 0.17 mmol) was added to stirred solution of methyl 5-dibenzyloxyphosphoryl-2-hydroxy-4-methoxy-benzoate (300 mg, 0.68 mmol) in THF (8 mL) at 0 ºC and allowed to stir for 1h. The reaction mixture was quenched with wet sodium sulphate, filtered through celite, and evaporated to dryness under reduced pressure. Chromatography (SiO2, methanol in dichloromethane) provides the desired product (60 mg, 21%).1H NMR (400 MHz, DMSO-d6) δ 10.28 (br. s, 1H), 7.68 (d, J = 15.6, 1H), 7.32–7.34 (m, 10H), 6.48 (d, J = 6H, 1H), 4.78-5.03 (m, 4H), 4.41 (s, 2H), 3.68 (s, 3H). LCMS m / z = 415.39 [M+H]+. Synthesis of dibenzyl (4-(bis(benzyloxy)phosphoryl)-2-(hydroxymethyl)-5- methoxyphenyl) phosphate DMAP (65 mg, 0.53 mmol) led (–10 ºC) solution of benzyloxyphosphonoyloxymethylbenzene (0.77 mL, 3.45 mmol), carbon tetrachloride (1.03 mL, 10.6 mmol), DIPEA (1.4 mL, 7.96 mmol) in acetonitrile (5.8 mL). The reaction solution was allowed to stir for 15 min at this temperature and then 4-dibenzyloxyphosphoryl-2- (hydroxymethyl)-5-methoxy-phenol (1.1 g, 2.65 mmol) in acetonitrile (3 mL) was added slowly as a suspension to the reaction solution. After stirring at room temperature for 7.5 hours the reaction mixture was evaporated to dryness. Chromatography (SiO2; EtOAc in hexanes) gave the desired product (0.76 g, 42%) as clear brown oil.1H NMR (500 MHz, CDCl3) δ 7.75 (dd, J = 15.2, 1.0 Hz, 1H), 7.31–7.22 (m, 20H), 6.55 (dd, J = 6.1, 1.2 Hz, 1H), 5.13–4.98 (m, 8H), 4.42 (d, J = 6.1 Hz, 2H), 3.46 (s, 3H). LCMS m / z = 675.1 [M+H]+. Synthesis of 6-bromo-4,4-dimethylchroman-2-one 3-Methylbut-2-enoic acid (3 , as added to a stirred solution of 4- bromophenol (50 g, 289 mmol) in methane sulfonic acid (500 mL). The resulting mixture was heated to 90º C for 12 h, cooled to room temperature and then poured onto ice water and then quenched by saturated aqueous NaHCO3 and then extracted with EtOAc, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (SiO2; EtOAc in hexanes) provided 6-bromo-4,4-dimethyl-chroman-2-one (30 g, 40%). MS (ESI) m / z = 257.0 [M + H]+. Synthesis of 6-dibenzyloxyphosphoryl-4,4-dimethyl-chroman-2-one Tetrakis (3.62 g, 3.14 mmo ture containing benzyloxyphosphonoyloxymethylbenzee (13.46 mL, 56.45 mmol), 6-bromo-4,4-dimethyl- chroman-2-one (16 g, 62.72 mmol) Cs2CO3 (30.88 mL, 68.99 mmol) in toluene (80 mL) was heated in a microwave at 120 ºC at 30 min. Reaction mixture quenched with water (500 mL) and extracted with EtOAc. Organic layer washed with brine solution and dried for Na2SO4 filter it and concentrate to under reduced pressure. Chromatography (EtOAc in hexanes) afforded 6-dibenzyloxyphosphoryl-4,4-dimethyl-chroman-2-one (3.8 g, 14%).1H NMR (400 MHz, DMSO-d6) δ 7.69 (m, 2H), 7.35 (s, 10H), 7.21 (dd, J= 3.6, 8 Hz, 1H), 5.07 (d, J = 8 Hz, 4H), 2.77 (s, 2H), and 1.24 (s, 6H). MS (ESI) m / z = 437.2 [M + H]+. Synthesis of tert-butyl 3-(5-dibenzyloxyphosphoryl-2-hydroxy-phenyl)-3-methyl- butanoate Potassium tert-butoxide (0.3 as added to a solution of 6- dibenzyloxyphosphoryl-4,4-dimethyl-chroman-2-one (0.88 g, 2.01 mmol) in THF (13 mL). after stirring at room temperature for 2 h, the excess base was quenched by the addition of 1N HCl (10 mL). The organic phase was extracted with EtOAc (75 mL), washed with and brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (SiO2; 20–70% EtOAc in hexanes) provided the desired product (528 mg, 51%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.70–7.59 (m, 1H), 7.55 (ddt, J = 13.0, 8.2, 2.1 Hz, 1H), 7.35 – 7.27 (m, 10H), 6.91 – 6.86 (m, 1H), 5.19–4.95 (m, 4H), 2.83 (d, J = 6.6 Hz, 2H), 1.44 (d, J = 1.9 Hz, 6H), 1.14 (d, J = 3.3 Hz, 9H). LRMS (ESI) m / z = 511.2 [M+H]+ Synthesis of tert-butyl 3-(5-dibenzyloxyphosphoryl-2-dibenzyloxyphosphoryloxy- phenyl)-3-methyl-butanoate DIPEA (0.61 mL, 3.53 mm cooled (5 ºC) solution of dibenzyl phosphonate (0.34 mL, 1.53 mmol) and DMAP (28 mg, 0.24 mmol) in carbon tetrachloride (0.46 mL, 4.71 mmol) under an argon atmosphere. After stirring for 10 min, a solution of tert-butyl 3-(5-dibenzyloxyphosphoryl-2-hydroxy-phenyl)-3-methyl-butanoate (0.6 g, 1.18 mmol) was added dropwise. After stirring for 1.5 h the reaction was diluted with EtOAc (75 mL), washed with 1N HCl (15 mL) and brine (15 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (25 g SiO2; 10-60% EtOAc in hexanes) to give the desired product (0.62 g, 68%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.71 (dt, J = 14.3, 1.8 Hz, 1H), 7.62 (ddd, J = 12.8, 8.4, 1.9 Hz, 1H), 7.53 (dd, J = 8.4, 4.1 Hz, 1H), 7.36–7.29 (m, 21H), 5.15 (d, J = 8.5 Hz, 4H), 5.12–4.99 (m, 5H), 2.66 (s, 2H), 1.40 (s, 6H), 1.09 (s, 9H). LRMS (ESI) m / z = 715.2 [M − t-butyl + H]+Synthesis of 3-(5-dibenzyloxyphosphoryl-2-dibenzyloxyphosphoryloxy-phenyl)-3- methyl-butanoic acid Tert-butyl 3-(5-dibenzyloxyphosphoryl-2-dibenzyloxyphosphoryloxy-phenyl)-3- methyl-butanoate (187 mg, 0.24 mmol) was dissolved in 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) and heated in microwave at 60 ºC for 30 min and then evaporated to dryness under reduced pressure. Chromatography (10 g SiO2; 0–10% methanol in dichloromethane) gave the desired product (60 mg, 34%) as a colorless oil.1H NMR (500 MHz, CDCl3) δ 7.78–7.70 (m, 1H), 7.53 (ddd, J = 12.7, 8.4, 1.9 Hz, 1H), 7.48–7.40 (m, 1H), 7.34–7.26 (m, 20H), 5.18– 5.06 (m, 5H), 5.06–4.94 (m, 4H), 1.39 (s, 6H). LRMS (ESI) m / z = 713.1 [M−H]– Example 2: Synthesis of Prodrug Building Blocks General synthetic procedure for substituted [2 or 4- bisalkoxyl(phosphoryloxy)]benzyl(4-nitrophenyl)carbonates: DIPEA (1.1 mol. equiv.) was added to a stirred solution of the substituted dialkyl[2- (hydroxymethyl)phenyl]phosphates (prepared as in Example 1) (1 mol. equiv.) and bis(4- nitrophenyl) carbonate or 4-nitrophenylchloroformate (1 mol. equiv.) in CH2Cl2(0.05 M). The reaction mixture was left overnight and then evaporated to dryness under reduced pressure. Chromatography (SiO220–80% EtOAc in hexanes) provided the desired carbonates. General synthetic procedure for substituted [2 or 4- bisalkoxyl(phosphoryloxy)]benzyl carbonchloridates: Triphosgene (1.1 mol. equiv.) in a solution in 1 mL of THF was added slowly to a cooled (0 ºC) solution of substituted dialkyl[2-(hydroxymethyl)phenyl]phosphates (prepared as in Example 1) (1 mol. equiv.) in THF (0.2 M). DIPEA (1.2 mol. equiv.) was added and the reaction mixture stirred for 1 h and then quenched with water, extracted into EtOAc, washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure to give the desired chloroformate. General synthetic procedure for [bisalkoxyl (2-(chloromethoxy)methyl)-4 or 5- substituted] phenyl phosphates or [bisalkoxyl (4-(chloromethoxy)methyl)-2 or 3- substituted] phenyl phosphates: A solution of substituted dialkyl[2- (hydroxymethyl)phenyl]phosphates (prepared as in Example 1) (1.0 mol. equiv.) and paraformaldehyde (1.0 mol. equiv.) in TMSCl (4 mol. equiv.) was stirred at room temperature for 6 h and then evaporated to dryness under reduced pressure to give the desired chloromethyl ether that was used without purification. General synthetic procedure for substituted [2 or 4-bisalkoxyl(phosphoryloxy)]- benzylbromides: Triphenylphosphine(2.5 mol. equiv.) was added to a stirred solution of the benzyl alcohol (1 mol. equiv.) in DCM (0.25 M). This was followed by the addition of CBr4(2.5 mol. equiv.). The reaction mixture was allowed to stir at room temperature for 45 min. and then diluted with water. The organic phase was extracted into DCM, washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (SiO2; EtOAc in Hexanes) provided the desired products. General synthetic procedure for substituted [2 or 4-bisalkoxyl(phosphoryloxy)]- benzyl mesylates: Triethylamine (0.26 mL, 1.87 mmol 2 mol. equiv.) is added to a solution of the benzyl Alcohol (1 mol. equiv.) in anhydrous DCM (0.2 M) at –10 °C under an atmosphere of nitrogen gas. Methanesulfonyl chloride (1.5 mol. equiv.) is then added dropwise and the reaction allowed to stir for 1 hour and then warmed to room temperature. The reaction mixture is diluted with EtOAc and then washed with aqueous saturated ammonium chloride, brine solution, dried (Na2SO4) and evaporated to dryness under reduced pressure. The desired product is isolated by column chromatography (0–10% methanol in DCM). Structures of products and characterization data are provided in Table 1. Table 1. Building Block Compounds and Characterization Data Entry Structure Mass / NMR 1H NMR (500 MHz CDCl3) δ , δ , 9 δ = , , 911H NMR (500 MHz, CDCl3) δ 8.31–8.21 (m, 2H), 8.15 (t, J = 18 Hz 1H) 795 (dd J = 86, δ = , , δ = 6– 93 δ d, 0 δ J δ 4 .9 ), 1H NMR (500 MHz, CDCl3) δ 7.72 (ddd, J = 13.0, 6.8, 2.0 Hz, 2H) 742 (dd J = 90 35 Hz, 7 δ 2 , δ 8– s, δ ), , 1H NMR (500 MHz, CDCl3) δ 8.32–8.24 (m, 2H), 8.03 (t, J = 13 Hz 1H) 783 (dd J = 79, J δ = 55 J δ , 5 585.1 [M+H]+1H NMR (500 MHz, CDCl3) δ 763 (dd J = 81 1.3 δ J δ δ z, , δ J 3, 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 9.2 Hz, 2H), 7.96 XXXVI (dd J = 24 10 Hz 1H) 740 ). δ 2 δ ), z, . δ 2 , δ δ = 60 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 9.2 Hz, 2H), 7.77– 769 (m 1H) 764 (d J = 19 ), 0 δ 1 ). δ z, , δ ), δ – , z, LXI δ ), δ 4 , δ ), δ 7 δ ), ,

[0305] δ – XCVI δ = , , δ J 37 δ , , 6 δ J δ 7 δ = z, ),

[0306] Example 3: Synthesis of Prodrug Compounds

[0307] General synthetic procedures for attaching building blocks to pharmaceutical compounds

[0308] Method A (attachment to an amide): LiHMDS IM in THF (0.22 g, 1.29 mmol) was added to a stirred solution of the carbonate or chloroformate building Block (1.1 mol. equiv.) and the drug compound (e.g., enzalutamide, apalutamide) (1 mol. equiv.) in THF (0.05 M) cooled to 5 °C. After stirring for 12 h, the reaction mixture is quenched by the addition of IM HC1 solution, washed with sat'd aq. NaHCCh solution, brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (10-80% EtOAc in hexanes).

[0309] Method B (attachment to an amide, aniline, or amine): Sodium hydride (1.5 mol. equiv.) was added to a stirred solution of the drug (e.g., nilotinib, apixaban, rivaroxaban) (1 mol. equiv.) in DMF (0.25 M). A solution of the carbonate or chloroformate building Block (1.1 mol. equiv.) in DMF was added. The reaction is monitored by TLC and, upon completion, is evaporated to dryness under reduced pressure. The residue is dissolved in EtOAc, washed with IM HC1 solution, brine, dried (MgSOA and evaporated to dryness under reduced pressure. Chromatography (10-80% EtOAc in hexanes).

[0310] Method C (attachment to a sulfonamide): DMAP (0.1 mol. equiv.) was added to a stirred solution of the drug compound (e.g., vemurafenib, dabrafenib) (1 mol. equiv.) and DIPEA (3 mol. equiv.) and the carbonate or chloroformate building Block (1.5 mol. equiv.) in 1,4-dioxane (0.2 M). The reaction mixture was then heated in a microwave at 100 °C for 3 h, quenched with water, extracted into EtOAc, washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (50-70% EtOAc in hexanes).

[0311] Method D (benzylation of amine): A mixture of the drug compound (e.g., Palbociclib) (1 mol. equiv.) and the benzyl bromide prodrug analog (1.1 mol. equiv.) in a solvent such as acetonitrile (0.05 M) was heated at 100 °C for 1 h, cooled, evaporated to dryness. The Crude material was dissolved in EtOAc, washed with sat’d ammonium chloride solution, water, brine solution, dried (MgSCb) and evaporated to dryness under reduced pressure. Chromatography (50-70% EtOAc in hexanes).

[0312] Method E (attachment to hydroxyl group): A solution of the chloroform ate (1.1 mol. equiv.) in dichloromethane (0.05 M) was added to stirred solution of drug (1 mol. equiv.) and DIPEA (2 mol. equiv.) in dichloromethane (0.05 M) cooled to 0 °C. The reaction is stirred at ambient temperature over 6 hours and then diluted with water. The organic phase is extracted with dichloromethane, washed with brine, dried (MgSCU) and evaporated to dryness under reduced pressure. Chromatography (SiCE; ethyl acetate in hexanes) was used to isolate the desired products.

[0313] General synthetic procedure to deprotect prodrug compounds after synthesis

[0314] Tert-Butyl deprotection. TFA was added to a solution of the protected prodrug compound in CH2CI2 (0.2 M). After 15 minutes, the reaction mixture was evaporated to dryness under reduced pressure. Chromatography (C-18 25-90% acetonitrile in water) provided the desired product.

[0315] Ethyl and tert- Butyl protecting groups. TMSBr (3-20 mol. equiv.) was added dropwise to a solution of the protected prodrug compound (1 mol. equiv.) in THF, DCM or MeCN (0.2 M). The reaction was allowed to warm up to room temperature over 12 hours. The reaction was placed in an ice bath (0 °C) and quenched with MeOH. The solution was then evaporated to dryness under reduced pressure. Chromatography (Cl 8 25-90% acetonitrile in water) provided the desired products.

[0316] Benzyl groups. A mixture containing Pd / C and the protected prodrug compound in EtOH was placed under an atmosphere of hydrogen and stirred for 12 h, filtered and evaporated to dryness.

[0317] General synthetic procedure for sodium salt formation.

[0318] To a solution of the deprotected Prodrug (1 mol. equiv.) in THF (0.2 M) is added sodium bicarbonate (2-4 mol. equiv.). The mixture is stirred for 4 hours and then evaporated to dryness under educed pressure. If needed, the product can be purified by reverse phase chromatography (30-70% MeCN in water).

[0319] Structures of products and characterization data are provided in Table 2. Table 2. Prodrug Compounds and Characterization Data

[0320]

[0321] Ill

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331] Hz, 1H), 5.44 (d, J = 13.3 Hz, 1H), 5.36 (d, J = 13.0 Hz, 1H), 5.00 (d, J = 9.6 Hz, 1H), 4.35 (dd, J = 110 66 Hz 1H) 419 (s 2H) 382 (d J = 72 , d, 4, R t- diacetoxy-12-(benzoyloxy)-4,11-dihydroxy- 4a,8,13,13-tetramethyl-5-oxo- 2a344a56910111212a12b-dodecahydro- t- – 8 .1 7 J ), J .4 δ 962a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro- 1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet- 9-yl)oxy)-3-oxo-1-phenylpropan-2- t- t-

[0332] t- t- t

[0333] , , , , , , , , 6,12b-diacetoxy-9-(((2R,3S)-3-benzamido-2- hydroxy-3-phenylpropanoyl)oxy)-12- (benzoyloxy)-11-hydroxy-4a,8,13,13-tetramethyl- Name 5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b- dodecahydro-1H-7,11- methanocyclodeca[3,4]benzo[1,2-b]oxet-4- yl)oxy)carbonyl)oxy)methyl)-3- (phosphonooxy)phenyl)phosphonic acid 141 Structure (4-(((((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)- 6,12b-diacetoxy-9-(((2R,3S)-3-benzamido-2- hydroxy-3-phenylpropanoyl)oxy)-12- l- l- l- yl)oxy)carbonyl)oxy)methyl)-4- (phosphonooxy)benzoic acid t- – , , (3-(4-(((1S,2R)-1-benzamido-3- (((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b- diacetoxy-12-(benzoyloxy)-411-dihydroxy- t- t- t-

[0334] 3- lit O) 3-

[0335] 4- 4- z

[0336] z, ), , methanol-d4) δ 168.63, 157.54 (d, J = 7.4 Hz), 157.33, 147.27, 141.40, 139.98, 137.87, 136.83, 13600 13593 13472 13438 13380 13131 3-((4-(6-hydroxy-3-(4-(2-(piperidin-1- Name yl)ethoxy)benzoyl)benzo[b]thiophen-2- yl)phenoxy)methyl)-4-(phosphonooxy)benzoic )- 2 -

[0337] )- 2 -

[0338] , , ,

[0339] - n-

[0340] - n- - n-

[0341] - n- - - a]pyrazin-8-yl)carbamoyl)oxy)methyl)-3- (phosphonooxy)phenyl)phosphonic acid l- - l-

[0342] - 1- - 1- , – , - dihydrophthalazine-2-carbonyl)oxy)methyl)-3- (phosphonooxy)benzoic acid 190 191 192 Name dihydrophthalazine-2-carbonyl)oxy)methyl)-5- chloro-4-(phosphonooxy)phenyl)phosphonic acid Structure 193 (3-(((4-(3-(4-(cyclopropanecarbonyl)piperazine-1- carbonyl)-4-fluorobenzyl)-1-oxo-1,2- Name dihydrophthalazine-2-carbonyl)oxy)methyl)-5- methoxy-4-(phosphonooxy)phenyl)phosphonic acid 1- d - t - ic

[0343] )- )- - ic

[0344] l)- l)- l)- -

[0345] l)- l)- 3-

[0346] 3- 4- 4-

[0347] 4- 4- -

[0348] - H- yl)oxy)carbonyl)oxy)methyl)-3- (phosphonooxy)phenyl)phosphonic acid H- e- e- - - 3-

[0349] 3- o-

[0350] -

[0351] l- yl)piperazin-1-yl)pyrimidin-5- yl)ethyl)carbamoyl)oxy)methyl)-4- (phosphonooxy)phenyl)phosphonodiperoxoic acid l- d yl)ethyl)carbamoyl)oxy)methyl)-4- (phosphonooxy)phenyl)phosphonic acid h - -

[0352] - -

[0353] - p methyl-1H-pyrazol-3-yl)carbamoyl)oxy)methyl)-3- (phosphonooxy)phenyl)phosphonic acid 4- 5- - n- c - n- c 1,6-naphthyridin-7-yl)(methyl)amino)methyl)-3- (phosphonooxy)phenyl)phosphonic acid h

[0354] - 2- - 2-

[0355] )- 3- )- 3-

[0356] - - - - - oxo-1,2-dihydropyridine-1-carbonyl)oxy)methyl)- 3-(phosphonooxy)phenyl)phosphonic acid ic ic (3-((((2-methyl-5-(4-((4-methylpiperazin-1- Name yl)methyl)benzamido)phenyl)(4-(pyridin-3- yl)pyrimidin-2-yl)carbamoyl)oxy)methyl)-4- - - - - methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- carbonyl)oxy)methyl)-3- (phosphonooxy)phenyl)phosphonic acid - - -

[0357] - o o (3-(((N-(cyclohexylcarbamoyl)-4-(2-(5- Name methylpyrazine-2- carboxamido)ethyl)phenyl)sulfonamido)methyl)- - - y - y

[0358] - - - - carbonyl)carbamoyl)oxy)methyl)-3- (phosphonooxy)benzoic acid 1H NMR (500 MHz, MeOD) δ 8.42 (d, J = 5.6 Hz, 1H), 7.96 (s, 1H), 7.85 (dd, J = 8.5, 2.2 Hz, 1H), 783 (d J = 26 Hz 1H) 769 (dd J = 88 27 Hz, oy oy e- (S)-(4-(((6-((1-(5-fluoro-4-oxo-3-phenyl-3,4- Name dihydroquinazolin-2-yl)propyl)amino)-7H-purine- 7-carbonyl)oxy)methyl)-3- n- dodecahydro-1H-7,11- methanocyclodeca[3,4]benzo[1,2-b]oxet- 9-yl)oxy)carbonyl)-1010-dimethyl-38- (phosphonooxy)phenyl)phosphonic acid

[0359] yl)methoxy)methyl)-4- (phosphonooxy)phenyl)phosphonic acid

[0360]

[0361] (S)-(3-(((3-(4-((2-fluoro-4-((3- morpholinoazetidin-1- yl)methyl)benzyl)amino)-13- (3-(((3-(5-(1-benzylpiperidin-4-yl)-1- Name oxoisoindolin-2-yl)-2,6-dioxopiperidine- 1-carbonyl)oxy)methyl)-5-methoxy-4- azaundecyl)-4- (phosphonooxy)phenyl)phosphonic acid (3-((((6R,7R)-7-((Z)-2-(2-aminothiazol-4- yl)-2-(methoxyimino)acetamido)-3-(((2- methyl-56-dioxo-1256-tetrahydro- yl]methoxycarbonyloxymethyl]-2-fluoro- 4-phosphonooxy-phenyl]phosphonic acid sodium salt 8.2, 4.7, 0.9 Hz, 1H), 7.31 (dd, J = 8.7, 0.9 Hz, 1H), 7.26 (dd, J = 8.2, 2.8 Hz, 1H) 722 (t J = 11 Hz 1H) 677 (d J = 1 yl)methoxy)carbonyl)oxy)methyl)-6-methoxy-3- (phosphonooxy)phenyl)phosphonic acid 1H NMR (500 MHz D2O) δ 863 (dd J = Example 4: Mouse Pharmacokinetic Assay Compounds were formulated using saline solution and administered via oral gavage. The compounds were dosed at 0.0107 mmol / kg in male C57BI / 6J mice (3 mice per dose 5 study). Plasma samples collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8h and 24 h. Analysis as performed to determine the concentration of the released active drug. No prodrug was observed in plasma. AUC µM.hr of released Compound No. Cmax µM of released drug drug 5 Example 4: Stability and Solubility Data Stability in simulated gastric fluid (SGF) and Hank’s balanced salt solution (HBSS).10 µM of test compound was placed in 500 µL of either SGF or HBSS and incubated for 2 hours at 37 ºC. Aliquots of 25 µL were removed at 0, 60, and 120 min.300 µL of acetonitrile was added along with an internal standard. The sample was vortexed for 3 10 minutes and then Sol-moiety-drug conjugate and released drug concentrations were measured by LC-MS / MS. The percentage of compound (Sol-moiety-drug conjugate) remaining as well as released drug was measured for each time point. Table 4. Stability of Sol-moiety-drug conjugates tested in SGF and HBSS. Compound SGF (pH 1.2) t1 / 2 min HBSS (pH 6.5) t1 / 2 min 7 >120 >120 u y u y u g u g u ed salt solution (HBSS). 10 mg / mL samples of each Sol-moiety-drug conjugate were prepared in 5 Hank’s balanced salt solution (HBSS) at a pH of 6.5. A series of dilutions were then performed to obtain concentrations of 8, 6, 4, and 2 mg / mL. A standard curve was generated using the peak area at each concentration by HPLC analysis. Λmax was measured for each prodrug utilizing UV-spec. Saturated solutions were prepared by dissolved prodrugs (1 mg) in HBSS (20 μL) or Simulated Gastric Fluid (SGF) (100 μL). The slurries were sonicated for 30 seconds 10 and then centrifuged at 14,000 RPM for 10 min to pellet the insoluble prodrug. The supernatant was analyzed on HPLC, and the product peaks were integrated and compared to calibration curves to quantify the level of prodrug in solution. Table 5. Solubility of Sol-moiety-drug conjugates tested in SGF and HBSS. Compound Solubility (mg / mL) in SGF Solubility (mg / mL) in HBSS 131 0.022 0.1 133 0.66 >49a Example 6: Hydrolysis in human placental alkaline phosphatase solution Human placental ALP (Sigma, 524604) (0.5 unit / mL) was incubated with prodrug 5 (100 μM) in Tris Buffer (50 mM, pH 7.6) at 37 ºC in a final volume of 1 mL. The prodrug in buffer was preincubated at 37 ºC for 5 minutes and reactions were initiated with the addition of 100× enzyme. Aliquots (50 μL) were taken at 0 (immediately after mixing), 2, 4, 8, 16, 32, and 64 minutes and quenched in an equal volume acetonitrile + 0.1% formic acid. Disappearance of the prodrug and appearance of the parent drug were monitored utilizing 10 low-resolution mass spectra on an Agilent LCMS iQ instrument and compared to standard curves for individual parent drugs. The hydrolysis and product formation rates were calculated from the slope of the linear portion of the plotted regression curve of product and converted to picomoles of parent drug available versus time. A control sample was incubated without enzyme and analyzed at the final timepoint. 15 Table 6. Hydrolysis rates of Sol-moiety-drug conjugates using human placental alkaline phosphatase (0.5 units / mL). Compound Drug formation rate (pmol / min) Example 7: Caco-2 permeability assays Caco-2 cells were maintained in DMEM in an atmosphere of 5% CO2. For transport experiments 50,000 cells / well were seeded on 12-well plate with polycarbonate filter inserts and allowed to grow and differentiate for 25 ±4 days before the cell monolayers were used for 5 experiments. Apparent permeability coefficients were determined for apical to basolateral and basolateral to apical directions. Test articles and reference compounds were dissolved in HBSS containing 25 mM HEPES to yield a final concentration of 10 µM. The assays were performed in HBSS at pH 7.4 for the basolateral side and pH 6.5 for apical side at 37 ºC. Prior to the study, the monolayers were washed in prewarmed HBSS. At the start of the experiments, pre-warmed 10 HBSS containing the test articles was added to the donor side of the monolayer and HBSS without test articles was added to the receiver side. Aliquots of the receiver side were taken over the 2 h incubation period; aliquots of the donor side were taken at 0 h and 2 h. Aliquots were diluted with an equal volume of methanol / water with 0.1% formic acid containing the internal standard. The mixture was analyzed by LCMS / MS. The apparent permeability 15 coefficients (Papp) were calculated using the formula: Papp 1∕4 (dCrec / dt) / (A C0,donor)] 106with dCrec / dt being the change in concentration in the receiver compartment with time; C0,donorthe concentration in the donor compartment at time 0; and A the area of the cells monolayer (Hidalgo et al. Gastroenterology 96, 736–749 (1989)). Data are shown in FIG.52 / The Caco2 assay h is known to display similar levels of alkaline phosphatases as that 20 found in the human intestine due to its derivation from human colorectal adenocarcinoma cancer cells (Heimbach et al. Int. J. Pharm.261, 81–92 (2003); Pinto et al. Biol. Cell.47, 323– 330 (1983)). When the Sol-moiety-drug conjugates were applied to the apical side of Caco-2 cells, no cell absorption was observed (FIG.52, box i) and only released drug was measured in the basolateral chamber (FIG. 52, box ii). The Sol-moiety by-products X and Y (structures 25 shown below) were poorly absorbed, if at all (Papp = 0.1 and 0.0 × 10–6cm / s respectively), suggesting these would display limited permeability and potentially avoid any in vivo toxicity concerns that a hydroxybenzyl alcohol might possess. Example 7: In vivo pharmacokinetic studies Methods Male C57BI / 6 mice were administered the Sol-moiety drug prototypes by oral gavage (18 / 22-gauge gavage needle with a rounded ball at the tip to prevent injury during insertion), 5 directly into the stomach using saline solution (0.9% NaCl) or deionized water as a vehicle (dose of 10 µl / g body weight). Microbleeds via the tail vein at indicated time points over 24 hours were performed on each mouse. IV injections were made using a 27 / 29- or 30-gauge insulin syringe, and the dose was injected into the right or left lateral tail vein or via the retro-orbital route. IV injection of 10 paclitaxel was dosed at a concentration of 0.2 mg / ml (5 µl / g body weight) using a formulation consisting of DMSO (10%), Tween 80 (10%), and water (80%). Enzalutamide and vemurafenib were formulated in DMSO (10%) and water (90%). Mice were maintained and experiments performed at UF Scripps Institute for Biomedical Innovation & Technology or at Stanford University. Parent drug concentration was analyzed by LC-MS / MS. P values 15 were determined using an ordinary One Way ANOVA in GraphPad Prism. Results and Discussion Sol-moiety compounds (7, 49, 62, 41, 148, 78, 155 and 131) were dosed via oral gavage using saline solution as the vehicle. Despite known limitations of cassette studies, due 20 to potential inhibition of transporters and metabolizing enzymes, excellent exposure of released drug was observed for Sol-enzalutamide 7 (AUC = 212.7 µM•hr), Sol-vemurafenib 49 (AUC = 74.7 µM•hr), and Sol-desloratadine 155 (AUC = 217.5 µM•hr). Moderate or low exposure was observed for Sol-dabrafenib 62 (AUC = 0.08 µM•hr), Sol-apixaban 41 (AUC = 2.75 µM•hr), Sol-carvedilol 148 (AUC = 0.87 µM•hr), Sol-lenalidomide 78 (AUC = 1.6125 µM•hr) and Sol-paclitaxel 131 (AUC = 0.27 µM•hr) (FIG.53). These data confirm that Sol- moiety-drug conjugates can be dosed via oral gavage in saline solution and provide good exposure levels, potentially replacing standard organic solvent-based formulations, such as DMSO or PEG, for highly water-insoluble preclinical compounds. Given the promising oral bioavailability observed for enzalutamide from the cassette 30 PK study, the PK profiles of Sol-enzalutamide 7 (formulated in water) to enzalutamide formulated in carboxymethylcellulose (CMC) / Tween 80 (Tran et al. Science 324, 787–790 (2009)) were directly compared. Both compounds were dosed via oral gavage at 0.0215 mmol / kg and 0.107 mmol / kg (10 mg / kg and 50 mg / kg equivalent of enzalutamide) respectively. Enzalutamide was found to have an oral bioavailability of 45% at the 0.0215 mmol / kg dose, that decreased to 33% upon dose escalation. In contrast, Sol-enzalutamide 7 displayed oral bioavailability of 64% at both dose levels, suggesting that solubility is potentially driving the lack of dose-proportional increase in exposure observed with the 5 standard CMC formulation of enzalutamide (FIG.54A). Thus, at the 50 mg / kg dose equivalent of enzalutamide, a ~50% improvement in oral bioavailability was achieved using the water- based Sol-moiety technology. Next, attention focused on modifying the electronic and / or steric bulk around the phosphate group, to see if reducing the Sol-moiety hydrolysis rate could enhance the exposure of enzalutamide. Sol-enzalutamide analogs 10, 11, and 13 were evaluated 10 in the human placental alkaline phosphatase stability assay. Herein, a decrease in the rate of alkaline phosphatase hydrolysis was observed in accordance with the increase in steric bulk around the phosphate group (FIG. 55). The compounds (10, 11, and 13) were then dosed at 0.0107 mmol / kg (5 mg / kg equivalent of enzalutamide), via oral gavage in a mouse PK experiment. Unfortunately, enzalutamide drug levels remained high at the 24-hour timepoint, 15 so we were unable to clearly distinguish the differences in the oral bioavailability between the Sol-moiety analogs. However, an extended mouse PK study (72 hours) with the methyl analog 10 at a dose of 0.021 mmol / kg (equivalent to a dose of 10 mg / kg enzalutamide) gave an AUC0–72 of 2133 µM•h that is equivalent to 86% oral bioavailability of enzalutamide (FIG. 54B), a notable improvement relative to 7 (64% F) and almost a 2-fold boost in bioavailability over the 20 standard CMC formulation of enzalutamide at the same dose. This indicates that modifying steric and / or electronic substituents on the Sol-moiety modulates the rate of phosphate hydrolysis and, consequently, oral bioavailability of the released drug. The highly insoluble and poorly permeable (BCS Class IV) BRAF mutant inhibitor, vemurafenib was then investigated. When Sol-vemurafenib 49 and 51 were dosed at 0.051 25 mmol / kg (25 mg / kg equivalent of vemurafenib), 96% and 113% oral bioavailability was observed, significantly higher (>10-fold) than a 25 mg / kg dose of vemurafenib, formulated using PEG 400 with vitamin E (emulsifier) in saline. Once again, the concentrations of vemurafenib in plasma at 24 h, following delivery with Sol-vemurafenib 49 and 51, remained high, preventing pharmacokinetic differences between the two Sol-vemurafenib analogs from 30 being fully distinguishable (FIG. 56). Interestingly, the Sol-vemurafenib analogs 49 and 51 displayed elongated Tmaxand t1 / 2relative to vemurafenib, suggesting non-linear kinetics. Regardless, the results demonstrate the pharmacokinetic benefits of the water-soluble Sol- moiety technology over a standard PEG-based formulation and confirmed vemurafenib to be readily absorbed into mouse plasma once soluble. Paclitaxel is a widely used chemotherapeutic that is highly insoluble in water and poorly absorbed (BCS Class IV), due to first-pass metabolism and efflux; consequently, it is 5 intravenously administered to patients using Cremophor®EL as a formulation vehicle. As shown earlier, Sol-paclitaxel 131 gave low to modest oral bioavailability following a dose of 0.004 mmol / kg (equivalent to 3.5 mg / kg of paclitaxel) (FIG.52). However, 131 was not particularly soluble (0.1 mg / ml) in its free acid form at pH 6.5 in HBSS. Therefore, to enhance solubility, the Sol-paclitaxel derivative 133 was prepared and found to be soluble 10 at >49 mg / ml in HBSS also in its free acid form. Dosed orally to mice, at 0.004 mmol / kg (3.5 mg / kg equivalent of paclitaxel), 133 displayed a significant improvement in exposure (AUC = 0.98 µM•hr) with bioavailability of ~36%, a >3-fold increase relative to 131 and a 7-fold improvement over a previously described phosphonooxymethyl prodrug of paclitaxel, Compound Z (Golik et al. Bioorg. Med. Chem.6, 1837–1842 (1996)) (FIG.57). The rate of 15 hydrolysis for 133 was also slightly lower (1.44 pmol / min) than 131 (2.13 pmol / min) and Compound Z (2.03 pmol / min). Although a slight decrease in dose proportionality was observed when 133 was administered by oral gavage in mice at 25 mg / kg and 75 mg / kg (18 and 55 mg / kg equivalent of paclitaxel) (FIG.57), the overall oral bioavailability of 133 remained between 5–7-fold higher than Compound Z and clearly demonstrates superiority of 20 the Sol-moiety technology over traditional water-soluble prodrugs. Example 8: In vivo efficacy studies using pancreatic cancer xenograft mouse tumor model Methods 25 Female Foxn nu / nu mice (4 weeks old at time of delivery) were procured through Jackson laboratory. Mice were housed in Optimice carousel sterile quarters with filtered air supply in disposable cages from Animal Care Systems, Inc. (Centennial, CO). A 12-hour light / 12-hour dark light cycle is observed, with animal handling only taking place during the light cycle. On the day of implantation, BxPC-3 cells were trypsinized and allowed to detach 30 from flasks. Trypsin was then neutralized with complete media and cells were spun at 400 x g. Media was aspirated and cells were resuspended in 50:50 *Cultrex BME, Type 3:DMEM (no supplementation) at a concentration of 3.5 × 107cells / mL. A volume of 100 µL was injected into the right hind flank of each animal (a total of 3.5 × 106cells). When mean tumor volume reached ~95 mm3, mice were stratified and placed into four treatment groups of eight mice for the efficacy study and four treatment groups of four mice for the plasma and tumor PK study. Treatments were administered by oral gavage (20-gauge 38 mm flexible nylon) or by tail vein injection (adjusted by mouse weight for 10 mL / kg 5 dosing). The PK mice were dosed with a single dose. Tumor volumes were measured by digital caliper by the same technician each time and volume was calculated using the formula [Width2x Length] / 2. Tumor volumes were analyzed in Prism 10.1.1 (GraphPad) using a mixed model and a Dunnett post hoc analysis for repeated measures with multiple comparisons. Mice were maintained and experiments were conducted at RinconBio, Utah. Plasma and tumor 10 concentrations of paclitaxel were analyzed at UF Scripps Institute for Biomedical Innovation & Technology. All statistical analysis was performed using independent experimental samples.. Results and Discussion 15 As the 75 mg / kg dose of Sol-paclitaxel (133) provided paclitaxel plasma concentrations over an extended time above the 0.05 µmol Ctrough levels needed for in vivo efficacy (Stage et al. Clin. Pharmacokinet. 57, 7–19 (2018)), a proof-of-concept study was conducted using a BxPC-3 xenograft mouse model for pancreatic cancer, following a similar protocol described for a lipid-based formulation of oral paclitaxel (Jang et al. PLoS One 14(11) e0225095 (2019)). 20 The experiment was conducted using a vehicle arm (saline solution), a paclitaxel positive control dosed IV at 12.5 mg / kg once a week (QWK) in Cremophor®EL, and Sol-paclitaxel 133 dosed PO at 25 mg / kg and 75 mg / kg every other day (QOD) in saline solution. Dosing was performed over 21 days and tumor growth monitored for an additional 25 days. Tumor volume and animal weight were monitored on a biweekly basis (FIGS. 58A-B). Following the dosing 25 period, the tumor growth inhibition (TGI) of the 25 mg / kg QOD dose of 133 was −15%, whereas the 75 mg / kg (55 mg / kg equivalent of paclitaxel) dose had a TGI of 91% that reduced to 84% following the 25-day observation period. The IV dose of 12.5 mg / kg paclitaxel had a TGI of 78% following the dosing period that reduced to 51% following the observation period. There was no appreciable toxicity reported during the dosing of Sol-paclitaxel 133. Tumor and 30 plasma concentrations of paclitaxel, measured at 6 and 24 h post-dose of 133, confirmed reasonable dose-proportional exposure of paclitaxel. Interestingly, accumulation of paclitaxel in the tumor was observed at both doses of 133 after 24 hours, with the 75 mg / kg dose being almost 10-fold higher than the desired trough level for efficacy (FIG. 58C). This is the first reported efficacy study using an orally bioavailable prodrug of paclitaxel and highlights the ability of the Sol-moiety technology to transform the route of drug administration from intravenous to oral. 5 Example 9: In vivo exposure of the major sol-moiety by-products, Compounds X and Y Compound X was detected in mouse plasma following an oral dose of 4 mg / kg (AUClast= 3.93 µM•hr and t1 / 2 = 1.24 h) whereas compound Y was not detectable following a dose of 25 mg / kg (FIG.53) This data correlates well with the results of the Caco-2 permeability assay (FIG.52) and supports the development of Sol-moieties possessing a phosphonate group given 10 their superior aqueous solubility and by-product profile.

Claims

CLAIMS 1. A compound of formula (I): (I) 5 or a salt thereof, wherein: R3aR3bZ is -C -O-CR4aR4b-LG, -(CR5aR5b)p-CO-E, -(CR6aR6b)-LG, or -CR7aR7b-O- CR8aR8b-O-CR9aR9b-LG; one of R1aand R1bis -OPO(ORa)2, and the other is selected from hydrogen, alkyl, halo, haloalkyl, and -(CRbRc)m-X; 10 R2a, R2b, and R2care each independently selected from hydrogen, alkyl, halo, haloalkyl, and -(CRdRe)n-Y; wherein, when R1ais -OPO(ORa)2, R1band R2a, together with the carbon atoms to which they are attached, are optionally taken together to form an optionally substituted ring; X and Y are each independently selected from cyano, nitro, -ORf, -NRgRh, -COORi, - 15 CONRjRk, -S(O)2NRlRm, -PO(ORn)2, and -PO(ORo)CH2PO(ORp)2; m, n, and p are each independently 0, 1, or 2; R3a, R3b, R6a, R6b, R7a, and R7bare each independently selected from hydrogen and alkyl; R4aand R4bare each hydrogen, or are taken together to form an oxo group; 20 R5aand R5bare each independently selected from hydrogen, alkyl, halo, and alkoxy; R8aand R8bare each hydrogen, or are taken together to form an oxo group; R9aand R9bare each selected from hydrogen and alkyl, or are taken together to form an oxo group; Ra, Rf, Rg, Rh, Ri, Rj, Rk, Rl, Rm, Rn, Ro, and Rpare each independently selected from 25 hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, and arylalkyl; wherein Rgand Rh, Rjand Rk, and Rland Rm, together with the nitrogen atoms to which they are attached, are optionally taken together to form an optionally substituted ring; Rb, Rc, Rd, and Reare each independently selected from hydrogen and alkyl; E is halo or OH; andLG is selected from -O-Q, halo, and hydroxy, wherein Q is optionally substituted aryl, optionally substituted heterocyclyl, or -SO2R8, wherein R8is selected from alkyl and optionally substituted aryl. 5 2. The compound of claim 1, or a salt thereof, wherein, when R1ais -OPO(ORa)2, then either: R1bis -(CRbRc)m-X, wherein X is -COORior -PO(ORn)2; or at least one of R2a, R2b, and R2cis -(CRdRe)n-Y, wherein Y is -COORior -PO(ORn)2.

3. The compound of claim 1, or a salt thereof, wherein, when R1bis -OPO(ORa)2, then 10 either: R1ais -(CRbRc)m-X, wherein X is -COORior -PO(ORn)2; or at least one of R2a, R2b, and R2cis -(CRdRe)n-Y, wherein Y is -COORior -PO(ORn)2.

4. The compound of any one of claims 1-3, or a salt thereof, wherein Z is -CR3aR3b-O- CR4aR4b-LG, -(CR5aR5b)p-CO-E, or -(CR6aR6b)-LG. 15 5. The compound of any one of claims 1-4, or a salt thereof, wherein Z is -CR3aR3b-O- CR4aR4b-LG.

6. The compound of claim 5, or a salt thereof, wherein R3aand R3bare each 20 independently selected from hydrogen and methyl.

7. The compound of claim 5 or claim 6, or a salt thereof, wherein R4aand R4bare taken together to form an oxo group. 25 8. The compound of claim 5 or claim 6, or a salt thereof, wherein R4aand R4bare each hydrogen.

9. The compound of any one of claims 1-4, or a salt thereof, wherein Z is -(CR5aR5b)p- CO-E. 30 10. The compound of claim 9, or a salt thereof, wherein p is 2, each R5aand R5bis independently selected from hydrogen and methyl, and E is selected from chloro and hydroxy.

11. The compound of any one of claims 1-4, or a salt thereof, wherein Z is -(CR6aR6b)- LG.

12. The compound of claim 11, or a salt thereof, wherein R6aand R6bare each 5 independently selected from hydrogen and methyl, and LG is halo or hydroxy.

13. The compound of claim 12, or a salt thereof, wherein LG is bromo or hydroxy.

14. The compound of any one of claims 1-4, or a salt thereof, wherein Z is -CR7aR7b-O- 10 CR8aR8b-O-CR9aR9b-LG.

15. The compound of claim 14, or a salt thereof, wherein R7aand R7bare each hydrogen.

16. The compound of claim 14 or claim 15, or a salt thereof, wherein R8aand R8bare each 15 hydrogen, and R9aand R9bare taken together to form an oxo group.

17. The compound of claim 14 or claim 15, or a salt thereof, wherein R8aand R8btaken together to form an oxo group, and R9aand R9bare each hydrogen. 20 18. The compound of any one of claims 1-17, or a salt thereof, wherein Ra, Rf, Rg, Rh, Ri, Rj, Rk, Rl, Rm, Rn, Ro, and Rpare each independently selected from hydrogen, C1-C4alkyl, phenyl, and phenyl-C1-C2-alkyl.

19. The compound of any one of claims 1-18, or a salt thereof, wherein Rb, Rc, Rd, and 25 Reare each independently selected from hydrogen and methyl.

20. The compound of any one of claims 1-19, or a salt thereof, wherein R2a, R2b, and R2care each independently selected from hydrogen, C1-C4alkyl, halo, and -(CRdRe)n-Y, wherein n is 0 or 1, Rdand Reare each hydrogen, and Y is selected from cyano, -ORf, -COORi, and - 30 PO(ORn)2, wherein each Rf, Ri, and Rnis independently selected from hydrogen and C1-C4alkyl.

21. The compound of any one of claims 1-20, or a salt thereof, wherein LG is -O-Q, wherein Q is optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S. 5 22. The compound of claim 21, or a salt thereof, wherein LG is -O-Q, wherein Q is phenyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from nitro and halo.

23. The compound of claim 11, or a salt thereof, wherein LG is -O-(4-nitrophenyl) or -O- 10 pentafluorophenyl.

24. The compound of claim 1`, or a salt thereof, wherein LG is -O-Q, wherein Q is an optionally substituted pyrrolidine-2,5-dione. 15 25. The compound of any one of claims 1-20, or a salt thereof, wherein LG is -O-Q, wherein Q is -SO2R8, wherein R8is methyl.

26. The compound of any one of claims 1-20, or a salt thereof, wherein LG is halo or hydroxy. 20 27. The compound of claim 1, or a salt thereof, wherein the compound has formula (Ia) or (Ib): Ib).25 28. The compound of claim 1, selected from the group consisting of:and salts thereo .

29. A compound of formula (II):II) or a pharmaceutically a in: Z’ is -CR3aR3b-O-CR4aR4b-, -(CR5aR5b)p-CO-, -(CR6aR6b)-, or -CR7aR7b-O- CR8aR8b-O- CR9aR9b-; 5 one of R1aand R1bis -OPO(ORa)2, and the other is selected from hydrogen, alkyl, halo, haloalkyl, and -(CRbRc)m-X; R2a, R2b, and R2care each independently selected from hydrogen, alkyl, halo, haloalkyl, and -(CRdRe)n-Y; wherein, when R1ais -OPO(ORa)2, R1band R2a, together with the carbon atoms to 10 which they are attached, are optionally taken together to form an optionally substituted ring X and Y are each independently selected from cyano, nitro, -ORf, -NRgRh, -COORi, - CONRjRk, -S(O)2NRlRm, -PO(ORn)2, and -PO(ORo)CH2PO(ORp)2; m, n, and p are each independently 0, 1, or 2; R3a, R3b, R6a, R6b, R7a, and R7bare each independently selected from hydrogen and 15 alkyl; R4aand R4bare each hydrogen, or are taken together to form an oxo group; R5aand R5bare each independently selected from hydrogen, alkyl, halo, and alkoxy; R8aand R8bare each hydrogen, or are taken together to form an oxo group; R9aand R9bare each selected from hydrogen and alkyl, or are taken together to form 20 an oxo group; Ra, Rf, Rg, Rh, Ri, Rj, Rk, Rl, Rm, Rn, Ro, and Rpare each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, and arylalkyl; wherein Rgand Rh, Rjand Rk, and Rland Rm, together with the nitrogen atoms to which they are attached, are optionally taken together to form an optionally substituted ring; 25 Rb, Rc, Rd, and Reare each independently selected from hydrogen and alkyl; and D is a pharmaceutically active compound.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein, when R1ais OPO(ORa) then either: R1bis (CRbRc) X wherein X is -COORior -PO(ORn)2; or at least one of R2a, R2b, and R2cis -(CRdRe)n-Y, wherein Y is -COORior - PO(ORn)2.

31. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein, 5 when R1bis -OPO(ORa)2, then either: R1ais -(CRbRc)m-X, wherein X is -COORior - PO(ORn)2; or at least one of R2a, R2b, and R2cis -(CRdRe)n-Y, wherein Y is -COORior - PO(ORn)2.

32. The compound of any one of claims 29-31, or a pharmaceutically acceptable salt 10 thereof, wherein Z’ is -CR3aR3b-O-CR4aR4b-, -(CR5aR5b)p-CO-, or -(CR6aR6b)-.

33. The compound of any one of claims 29-32, or a pharmaceutically acceptable salt thereof, wherein Z’ is -CR3aR3b-O-CR4aR4b-. 15 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R3aand R3bare each independently selected from hydrogen and methyl.

35. The compound of claim 33 or claim 34, or a pharmaceutically acceptable salt thereof, wherein R4aand R4bare each hydrogen. 20 36. The compound of claim 33 or claim 34, or a pharmaceutically acceptable salt thereof, wherein R4aand R4bare taken together to form an oxo group.

37. The compound of any one of claims 29-32, or a pharmaceutically acceptable salt 25 thereof, wherein Z’ is -(CR5aR5b)p-CO-.

38. The compound of claim 37, wherein p is 2, and R5aand R5bare each independently selected from hydrogen and methyl. 30 39. The compound of any one of claims 29-32, or a pharmaceutically acceptable salt thereof, wherein Z’ is -(CR6aR6b)-.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R6aand R6bare each independently selected from hydrogen and methyl.

41. The compound of any one of claims 29-32 or a salt thereof, wherein Z’ is -CR7aR7b- O- CR8aR8b-O-CR9aR9b-LG. 5 42. The compound of claim 41, or a salt thereof, wherein R7aand R7bare each hydrogen.

43. The compound of claim 41 or claim 42, or a salt thereof, wherein R8aand R8bare each hydrogen, and R9aand R9bare taken together to form an oxo group. 10 44. The compound of claim 41 or claim 42, or a salt thereof, wherein R8aand R8btaken together to form an oxo group, and R9aand R9bare each hydrogen.

45. The compound of any one of claims 29-44, or a pharmaceutically acceptable salt thereof, wherein Ra, Rf, Rg, Rh, Ri, Rj, Rk, Rl, Rm, Rn, Ro, and Rpare each independently 15 selected from hydrogen, C1-C4 alkyl, phenyl, and phenyl-C1-C2-alkyl.

46. The compound of any one of claims 29-45, or a pharmaceutically acceptable salt thereof, wherein Rb, Rc, Rd, and Reare each independently selected from hydrogen and methyl. 20 47. The compound of any one of claims 29-46, or a pharmaceutically acceptable salt thereof, wherein R2a, R2b, and R2care each independently selected from hydrogen, C1-C4 alkyl, halo, and -(CRdRe)n-Y, wherein n is 0 or 1, Rdand Reare each hydrogen, and Y is selected from cyano, -ORf, -COORi, and -PO(ORn)2, wherein each Rf, Ri, and Rnis 25 independently selected from hydrogen and C1-C4alkyl.

48. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIa) or (IIb): b).

49. The compound of any one of claims 29-48, or a pharmaceutically acceptable salt thereof, wherein group D is attached to the compound via a nitrogen atom or an oxygen atom. 5 50. The compound of any one of claims 29-49, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically active compound is selected from the group consisting of: analgesics; anesthetics; antibacterials; anticonvulsants; antidementia agents; antidepressants; antiemetics; antifungals; antigout agents; anti-inflammatories; antimigraine agents; antimyasthenic agents; antimycobacterials; antineoplastics; antiparasitics; 10 antiparkinson agents; antipsychotics; antispasticity agents; antivirals; anxiolytics; bipolar agents; blood glucose regulators; blood products / modifiers / volume expanders; cardiovascular agents; central nervous system agents; dental and oral agents; dermatological agents; enzyme replacements / modifiers; gastrointestinal agents; genitourinary agents; hormonal agents; immunological agents; inflammatory bowel disease agents; metabolic bone 15 disease agents; ophthalmic agents; otic agents; respiratory tract agents; sedatives / hypnotics; and skeletal muscle relaxants.

51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically active compound is an antineoplastic agent. 20 52. The compound of any one of claims 29-51, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically active compound is selected from the group consisting of abrocitinib, acalbrutinib, amisulpride, apalutamide, apixaban, aprepitant, ARV-766, asciminib, atorvastatin, avacopan, avapritinib, bavdegalutamide, bicalutamide, cabazitaxel, 25 carvedilol, cefdinir, cefprozil, celecoxib, clarithromycin, dabrafenib, desloratadine, docetaxel, doravirine, doxorubicin, DT2216, efavirenz, enzalutamide, eragidomide, etravirine, ezetimibe, FHD-609, glimepiride, glipizide, glyburide, golcadomide, hydrochlorothiazide, hydroxyzine pamoate, ibrutinib, idelalisib, imatinib, ivacaftor, lamotrigine, lenalidomide, linezolid, lopinavir, meloxicam, metaxalone, methylphenidate, mezigdomide, modafinil, N- 30 desalkylquetiapine, niclosamide, nilotinib, NX-2127, olanzapine, olaparib, oliceridine, osimertinib, oteseconazole, oxcarbazepine, paclitaxel, pacritinib, palbociclib, pioglitazone, pomalidomide, pralsetinib, quetiapine, raloxifene, rilpivirine, rilzabrutinib, rimegepant, ripretinib, ritonavir, rivaroxaban, selpercatinib, selumetinib, simvastatin, SN-38, sorafenib,sotorasib, tacrolimus, tazemetostat, tucatinib, valdecoxib, vemurafenib, vepdegestrant, vociprotafib, and zanubrutinib.

53. The compound of any one of claims 29-52, or a pharmaceutically acceptable salt 5 thereof, wherein the pharmaceutically active compound is selected from the group consisting of apixaban, carvedilol, dabrafenib, desloratadine, enzalutamide, lenalidomide, paclitaxel, and vemurafenib.

54. The compound of any one of claims 29-53, or a pharmaceutically acceptable salt 10 thereof, wherein the pharmaceutically active compound is paclitaxel.

55. The compound of claim 29, or a pharmaceutically acceptable salt thereof, selected from compounds shown in FIGS.1-51 and Table 2.

56. A method of preparing a prodrug of a pharmaceutically active compound, comprising: 15 reacting a compound of any one of claims 1-28 with a pharmaceutically active compound in the presence of a base to form a protected prodrug compound; and removing protecting groups from the protected prodrug compound, to thereby provide the prodrug of the pharmaceutically active compound. 20 57. The method of claim 44, wherein the reacting step comprises: (a) combining the compound of any one of claims 1-28 and the pharmaceutically active compound to form a mixture; and (b) adding the base to the mixture. 25 58. The method of claim 45, wherein the reacting step comprises: (a) reacting the pharmaceutically active compound with a base to form a mixture; and (b) adding the compound of any one of claims 1-28 to the mixture.

59. A method of treating a disorder in a subject in need of treatment, comprising 30 administering to the subject a therapeutically effective amount of a compound of any one of claims 29-55, or a pharmaceutically acceptable salt thereof.

60. A system or kit comprising a compound of any one of claims 1-28, or a salt thereof, and a pharmaceutically active compound61. A compound of any one of claims 1-28, or a salt thereof, for use in preparing a prodrug compound. 5 62. A compound of any one of claims 29-55, or a pharmaceutically acceptable salt thereof, for use as a medicament.