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WO2025106974A1 - Fractions de promédicament et composés les comprenant - Google Patents

Fractions de promédicament et composés les comprenant Download PDF

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Publication number
WO2025106974A1
WO2025106974A1 PCT/US2024/056391 US2024056391W WO2025106974A1 WO 2025106974 A1 WO2025106974 A1 WO 2025106974A1 US 2024056391 W US2024056391 W US 2024056391W WO 2025106974 A1 WO2025106974 A1 WO 2025106974A1
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compound
hydrogen
salt
independently selected
alkyl
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Mark Smith
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Leland Stanford Junior University
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Leland Stanford Junior University
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
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    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
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    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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Definitions

  • prodrugs 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.
  • 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.
  • 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.
  • 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.
  • the prodrugs can undergo controlled cleavage, so as to maximize oral bioavailability.
  • Z is -CR 3a R 3b -O-CR 4a R 4b -LG, -(CR 5a R 5b ) P -CO-E, -(CR 6a R 6b )-LG, or -CR 7a R 7b -O- CR 8a R 8b -O-CR 9a R 9b -LG; one of R la and R lb is -0P0(0R a )2, and the other is selected from hydrogen, alkyl, halo, haloalkyl, and -(CR b R c ) m -X;
  • R 2a , R 2b , and R 2c are each independently selected from hydrogen, alkyl, halo, haloalkyl, and -(CR d R e ) n -Y; wherein, when R la is -0P0(0R a )2, R lb and R 2a , 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, -OR f , -NR 8 R h , -COOR 1 , - CONR'R k , -S(O) 2 NR 1 R m , -PO(OR n ) 2 , and -PO(OR O )CH 2 PO(OR P ) 2 ; m, n, and p are each independently 0, 1, or 2;
  • R 3a , R 3b , R 6a , R 6b , R 7a , and R 7b are each independently selected from hydrogen and alkyl;
  • R 4a and R 4b are each hydrogen, or are taken together to form an oxo group
  • R 5a and R 5b are each independently selected from hydrogen, alkyl, halo, and alkoxy;
  • R 8a and R 8b are each hydrogen, or are taken together to form an oxo group
  • R 9a and R 9b are each selected from hydrogen and alkyl, or are taken together to form an oxo group
  • R a , R f , R g , R h , R 1 , RJ, R k , R 1 , R m , R n , R°, and R p are each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, and arylalkyl; wherein R g and R h , R' and R k , and R 1 and R m , together with the nitrogen atoms to which they are attached, are optionally taken together to form an optionally substituted ring;
  • R b , R c , R d , and R e are each independently selected from hydrogen and alkyl;
  • E is halo or -OH
  • LG is selected from -O-Q, halo, and hydroxy, wherein Q is optionally substituted aryl, optionally substituted heterocyclyl, or -SO2R 8 , wherein R 8 is selected from alkyl and optionally substituted aryl.
  • R la is -OPO(OR a )2
  • R lb is -(CR b R c ) m -X, wherein X is -COOR 1 or -PO(OR n )2; or at least one of R 2a , R 2b , and R 2c is -(CR d R e ) n -Y, wherein Y is -COOR 1 or -PO(OR n )2.
  • R lb when R lb is -OPO(OR a )2, then either: R la is -(CR b R c ) m -X, wherein X is -COOR 1 or -PO(OR n )2; or at least one of R 2a , R 2b , and R 2C is -(CR d R e ) n -Y, wherein Y is -COOR 1 or -PO(OR n ) 2 .
  • Z is -CR 3a R 3b -O-CR 4a R 4b -LG, -(CR 5a R 5b ) P -CO-E, or - (CR 6a R 6b )-LG.
  • Z is -CR 3a R 3b -O-CR 4a R 4b -LG.
  • R 3a and R 3b are each independently selected from hydrogen and methyl.
  • R 4a and R 4b are taken together to form an oxo group. In some embodiments, R 4a and R 4b are each hydrogen.
  • Z is -(CR 5a R 5b ) p -CO-E.
  • p is 2
  • each R 5a and R 5b is independently selected from hydrogen and methyl
  • E is selected from chloro and hydroxy.
  • Z is -(CR 6a R 6b )-LG.
  • R 6a and R 6b are each independently selected from hydrogen and methyl, and LG is halo or hydroxy. In some embodiments, LG is bromo or hydroxy.
  • Z is -CR 7a R 7b -O- CR 8a R 8b -O-CR 9a R 9b -LG.
  • R 7a and R 7b are each hydrogen.
  • R 8a and R 8b are each hydrogen, and R 9a and R 9b are taken together to form an oxo group.
  • R 8a and R 8b taken together to form an oxo group, and R 9a and R 9b are each hydrogen.
  • R a , R f , R g , R h , R 1 , R j , R k , R 1 , R m , R n , R°, and R p are each independently selected from hydrogen, C1-C4 alkyl, phenyl, and phenyl-Ci-C2-alkyl.
  • R b , R c , R d , and R e are each independently selected from hydrogen and methyl.
  • R 2a , R 2b , and R 2c are each independently selected from hydrogen, C1-C4 alkyl, halo, and -(CR d R e ) n -Y, wherein n is 0 or 1, R d and R e are each hydrogen, and Y is selected from cyano, -OR f , -COOR 1 , and -PO(OR n )2, wherein each R f , R 1 , and R n is independently selected from hydrogen and C1-C4 alkyl.
  • 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.
  • LG is -O-Q, wherein Q is phenyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from nitro and halo.
  • LG is -O-(4-nitrophenyl) or -O-pentafluorophenyl.
  • LG is -O-Q, wherein Q is an optionally substituted pyrrolidine-2, 5-dione.
  • LG is -O-Q, wherein Q is -SO2R 8 , wherein R 8 is methyl.
  • LG is halo or hydroxy.
  • the compound has formula (la) or (lb):
  • the compound has formula (la).
  • the compound is selected from the group consisting of:
  • Z’ is -CR 3a R 3b -O-CR 4a R 4b -, -(CR 5a R 5b ) P -CO-, -(CR 6a R 6b )- , or -CR 7a R 7b -O- CR 8a R 8b -
  • R la and R lb are -OPO(OR a )2, and the other is selected from hydrogen, alkyl, halo, haloalkyl, and -(CR b R c ) m -X;
  • R 2a , R 2b , and R 2c are each independently selected from hydrogen, alkyl, halo, haloalkyl, and -(CR d R e ) n -Y; wherein, when R la is -OPO(OR a )z, R lb and R 2a , 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, -OR f , -NR 8 R h , -COOR 1 , -
  • R 4a and R 4b are each hydrogen, or are taken together to form an oxo group
  • R 5a and R 5b are each independently selected from hydrogen, alkyl, halo, and alkoxy;
  • R 8a and R 8b are each hydrogen, or are taken together to form an oxo group
  • R 9a and R 9b are each selected from hydrogen and alkyl, or are taken together to form an oxo group
  • R a , R f , R s , R h , R 1 , R 1 , R k , R 1 , R m , R n , R°, and R p are each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, and arylalkyl; wherein R g and R h , R' and R k , and R 1 and R m , together with the nitrogen atoms to which they are attached, are optionally taken together to form an optionally substituted ring;
  • R b , R c , R d , and R e are each independently selected from hydrogen and alkyl
  • D is a pharmaceutically active compound.
  • R la when R la is -OPO(OR a )2, then either: R lb is -(CR b R c ) m -X, wherein X is -C00R 1 or -PO(OR n )2; or at least one of R 2a , R 2b , and R 2c is -(CR d R e ) n -Y, wherein Y is -C00R 1 or -PO(OR n )2.
  • R lb when R lb is -OPO(OR a )2, then either: R la is -(CR b R c ) m -X, wherein X is -C00R 1 or -PO(OR n )2; or at least one of R 2a , R 2b , and R 2C is -(CR d R e ) n -Y, wherein Y is -COOR 1 or -PO(OR") 2 .
  • Z’ is -CR 3a R 3b -O-CR 4a R 4b -, -(CR 5a R 5b ) P -CO-, or -(CR 6a R 6b )-.
  • Z’ is -CR 3a R 3b -O-CR 4a R 4b -.
  • R 3a and R 3b are each independently selected from hydrogen and methyl.
  • R 4a and R 4b are each hydrogen. In some embodiments, R 4a and R 4b are taken together to form an oxo group.
  • Z’ is -CH2-.
  • Z’ is -(CR 5a R 5b ) P -CO-.
  • p is 2, and R 5a and R 5b are each independently selected from hydrogen and methyl.
  • Z’ is -(CR 6a R 6b )-.
  • R 6a and R 6b are each independently selected from hydrogen and methyl.
  • Z’ is -CR 7a R 7b -O- CR 8a R 8b -O-CR 9a R 9b -LG.
  • R 7a and R 7b are each hydrogen.
  • R 8a and R 8b are each hydrogen, and R 9a and R 9b are taken together to form an oxo group.
  • R 8a and R 8b taken together to form an oxo group, and R 9a and R 9b are each hydrogen.
  • R a , R f , R g , R h , R 1 , R j , R k , R 1 , R m , R n , R°, and R p are each independently selected from hydrogen, C1-C4 alkyl, phenyl, and phenyl-Ci -Ch-alky 1.
  • R b , R c , R d , and R e are each independently selected from hydrogen and methyl.
  • R 2a , R 2b , and R 2c are each independently selected from hydrogen, C1-C4 alkyl, halo, and -(CR d R e ) n -Y, wherein n is 0 or 1, R d and R e are each hydrogen, and Y is selected from cyano, -OR f , -COOR 1 , and -PO(OR n )2, wherein each R f , R 1 , and R n is independently selected from hydrogen and C1-C4 alkyl.
  • the compound has formula (Ila) or (lib):
  • group D is attached to the compound via a nitrogen atom or an oxygen atom.
  • 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/hypn
  • 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, ibrut
  • 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.
  • the compound of formula (II) is a compound shown in FIGS. 1-51 and Table 2.
  • 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.
  • 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.
  • 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.
  • a system or kit comprising a compound of formula (I), or a salt thereof, and a pharmaceutically active compound.
  • a compound of formula (I), or a salt thereof, for use in preparing a prodrug compound is disclosed herein.
  • FIG. 1 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is apalutamide.
  • FIG. 2 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is apixaban.
  • FIG. 3 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is aprepitant.
  • FIGS. 4A-4C show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is atorvastatin.
  • FIG. 5 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is bicalutamide.
  • FIGS. 6A-6B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is carvedilol.
  • FIG. 7 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is cefdinir.
  • FIG. 8 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is cefprozil.
  • FIG. 9 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is celecoxib.
  • FIGS. 10A-10B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is clarithromycin.
  • FIG. 11 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is dabrafenib.
  • FIG. 13 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is efavirenz.
  • FIG. 14 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is enzalutamide.
  • FIG. 15 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is etravirine.
  • 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.
  • FIG. 18 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is glipizide.
  • FIG. 19 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is glyburide.
  • FIG. 20 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is hydrochlorothiazide.
  • FIG. 21 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is hydroxyzine pamoate.
  • FIG. 22 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is ibrutinib.
  • FIG. 23 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is imatinib.
  • FIG. 24 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is ivacaftor.
  • FIG. 25 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is lamotrigine.
  • FIG. 26 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is lenalidomide.
  • FIG. 27 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is lopinavir.
  • FIG. 28 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is desloratadine.
  • FIG. 29 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is meloxicam.
  • FIG. 30 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is metaxalone.
  • FIG. 31 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is methylphenidate.
  • FIG. 32 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is modafinil.
  • 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.
  • FIG. 35 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is olanzapine.
  • FIG. 36 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is oxcarbazepine.
  • FIG. 37 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is osimertinib.
  • FIGS. 38A-38B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is paclitaxel.
  • FIG. 39 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is palbociclib.
  • FIG. 40 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is pomalidomide.
  • FIG. 41 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is pioglitazone.
  • FIGS. 42A-42B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is quetiapine or its active metabolite, N- desalkylquetiapine.
  • FIG. 43 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is raloxifene.
  • FIG. 44 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is rilpivirine.
  • FIG. 45 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is ritonavir.
  • FIG. 46 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is rivaroxaban.
  • FIG. 47 shows structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is simvastatin.
  • FIGS. 48A-48B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is SN-38.
  • 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.
  • FIGS. 51A-51B show structures of exemplary prodrug compounds, wherein the pharmaceutically active compound is vemurafenib.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • each intervening number there between with the same degree of precision is explicitly contemplated.
  • 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.
  • 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).
  • 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.
  • 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”).
  • an aryl group has six ring carbon atoms (“Ce aryl,” i.e., phenyl).
  • an aryl group has ten ring carbon atoms (“C10 aryl,” e.g., naphthyl such as 1- naphthyl and 2-naphthyl).
  • an aryl group has fourteen ring carbon atoms (“C14 aryl,” e.g., anthracenyl and phenanthrenyl).
  • 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.
  • 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.
  • 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.
  • cyano refers to a -CN group.
  • halogen refers to F, Cl, Br, or I.
  • 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.
  • each hydrogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”).
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.
  • 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”).
  • 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.
  • 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”).
  • 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 include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 5-membered heterocyclyl groups fused to a 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 include, without limitation, diazaspirononanyl (e.g., 2,7- diazaspiro[3.5]nonanyl).
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl 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 include, without limitation, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).
  • nitro refers to an -NO2 group.
  • 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.
  • the indication represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the rest of the compound).
  • 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.
  • 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.
  • 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-.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition.
  • condition As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.
  • an “effective amount” of a compound or composition refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition).
  • 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.
  • an effective amount of a compound or composition may reduce tumor burden or stop the growth or spread of a tumor.
  • 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.
  • 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.
  • 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).
  • 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
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof.
  • “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • 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.
  • Z is -CR 3a R 3b -O-CR 4a R 4b -LG, -(CR 5a R Sb ) P -CO-E, -(CR 6a R 6b )-LG, or -CR 7a R 7b -O- CR 8a R 8b -O-CR 9a R 9b -LG; one of R la and R lb is -OPO(OR a )2, and the other is selected from hydrogen, alkyl, halo, haloalkyl, and -(CR b R c ) m -X;
  • R 2a , R 2b , and R 2c are each independently selected from hydrogen, alkyl, halo, haloalkyl, and -(CR d R e ) n -Y; wherein, when R la is -OPO(OR a )2, R lb and R 2a , 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, -OR f , -NR g R h , -COOR 1 , - CONR j R k , -S(O) 2 NR'R m , -PO(OR n ) 2 , and -PO(OR°)CH 2 PO(OR P )2; m, n, and p are each independently 0, 1, or 2;
  • R 3a , R 3b , R 6a , R 6b , R 7a , and R 7b are each independently selected from hydrogen and alkyl;
  • R 4a and R 4b are each hydrogen, or are taken together to form an oxo group
  • R 5a and R Sb are each independently selected from hydrogen, alkyl, halo, and alkoxy;
  • R Sa and R 8b are each hydrogen, or are taken together to form an oxo group
  • R 9a and R 9b are each selected from hydrogen and alkyl, or are taken together to form an oxo group
  • R a , R f , R g , R h , R 1 , R j , R k , R 1 , R m , R n , R°, and R p are each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, and arylalkyl; wherein R 8 and R b , R 1 and R k , and R 1 and R m , together with the nitrogen atoms to which they are attached, are optionally taken together to form an optionally substituted ring;
  • R b , R c , R d , and R e are each independently selected from hydrogen and alkyl;
  • 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 -SO2R 8 , wherein R 8 is selected from alkyl and optionally substituted aryl.
  • one of R la and R lb is -OPO(OR a )2, wherein each R a is independently selected from hydrogen, Ci-Ce alkyl (e.g., C1-C4 alkyl, such as ethyl or tertbutyl), and benzyl; and the other one of R la and R lb is selected from hydrogen and - (CR b R c ) m -X, wherein m is 0 or 1, R c and R d are each hydrogen, and X is selected from -OR f , -COOR 1 , and -PO(OR n )2, wherein each R f , R 1 , and R n is independently selected from hydrogen and C1-C4 alkyl.
  • each R a is independently selected from hydrogen, Ci-Ce alkyl (e.g., C1-C4 alkyl, such as ethyl or tertbutyl), and benzyl
  • R la is -OPO(OR a )2, and R lb and R 2a , together with the carbon atoms to which they are attached, form an optionally substituted ring.
  • the optionally substituted ring is a phenyl ring that is optionally substituted with at least one substituent selected from alkyl, -OR f , -COOR 1 , and -PO(OR n )2, wherein each R f , R 1 , and R 11 is independently selected from hydrogen and C1-C4 alkyl.
  • Z’ is -CR 3a R 3b -O-CR 4a R 4b -, -(CR 5a R 5b ) P -CO-, or -(CR 6a R 6b )-.
  • Z is -CR 3a R 3b -O-CR 4a R 4b -LG.
  • R 3a and R 3b are each independently selected from hydrogen and C1-C4 alkyl. In some embodiments, R 3a and R 3b are each independently selected from hydrogen and methyl. In some embodiments, R 3a and R 3b are each hydrogen. In some embodiments, R 3a is hydrogen and R 3b is methyl. In some embodiments, R 3a and R 3b are each methyl.
  • R 4a and R 4b are taken together to form an oxo group. In some embodiments, R 4a and R 4b are each hydrogen.
  • Z is -(CR 5a R Sb ) p -CO-E, wherein E is halo or -OH.
  • p is 2, each R ,a and R 5b is independently selected from hydrogen and methyl, and E is chloro or -OH.
  • Z is -CiCHshClLCOOH or - C(CH3)2CH 2 COC1.
  • Z is -(CR 6a R 6b )-LG.
  • R 6a and R 6b are each independently selected from hydrogen and hydrogen and C1-C4 alkyl.
  • R 6a and R 6b are each independently selected from hydrogen and methyl.
  • R 6a and R 6b are each hydrogen.
  • R 6a is hydrogen and R 6b is methyl.
  • R 6a and R 6b are each methyl.
  • Z’ is -CR 7a R 7b -O- CR 8a R 8b -O-CR 9a R 9b -LG.
  • R 7a and R 7b are each hydrogen.
  • R Sa and R 8b are each hydrogen, and R 9a and R 9b are taken together to form an oxo group.
  • R 8a and R 8b taken together to form an oxo group, and R 9a and R 9b are each hydrogen.
  • R a , R f , R g , R h , R 1 , R', R k , R 1 , R m , R n , R°, and R p are each independently selected from hydrogen, C1-C4 alkyl, phenyl, and phenyl-Ci-C 2 -alkyl.
  • R a , R f , R g , R h , R 1 , R 1 , R k , R 1 , R m , R n , R°, and R p are each independently selected from hydrogen, methyl, ethyl, iso-propyl, tert-butyl, phenyl, and benzyl.
  • R b , R c , R d , and R e are each independently selected from hydrogen and methyl.
  • R 2a , R 2b , and R 2c are each independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, -COOH, -COO(tBu), -CH2COOH, -CH2COOCH3, -P(O)(Oh) 2 , and -P(O)(OEt) 2 .
  • 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).
  • 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.
  • LG is halo. In some embodiments, LG is bromo.
  • the compound has formula (la) or (lb):
  • the compound has a structure selected from:
  • each R a , R 1 , and R n is independently selected from hydrogen, alkyl (e.g., C1-C4 alkyl), and benzyl.
  • R a , R 1 , and R 11 are 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.
  • the disclosure also provides the building blocks in their unprotected forms (i.e., wherein R a , R 1 , and R' 1 are 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.
  • the compound is selected from the group consisting of:
  • Additional compounds of formula (I) include:
  • Compounds of formula (I) 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.
  • Z’ is -CR 3a R 3b -O-CR 4a R 4b -, -(CR 5a R 5b ) P -CO-, -(CR 6a R 6b )- , or -CR 7a R 7b -O- CR Sa R 8b - O-CR 9a R 9b -; one of R la and R lb is -OPO(OR a ) 2 , and the other is selected from hydrogen, alkyl, halo, haloalkyl, and -(CR b R c ) m -X;
  • R 2a , R 2b , and R 2c are each independently selected from hydrogen, alkyl, halo, haloalkyl, and -(CR d R e ) n -Y; wherein, when R la is -OPO(OR a )2, R lb and R 2a , 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, -OR f , -NR s R h , -COOR 1 , - CONR J R k , -S(O) 2 NR'R m , -PO(OR n ) 2 , and -P0(0R o )CH 2 P0(0R p ) 2 ; m, n, and p are each independently 0, 1, or 2;
  • R 3a , R 3b , R 6a , R 6b , R 7a , and R 7b are each independently selected from hydrogen and alkyl;
  • R 4a and R 4b are each hydrogen, or are taken together to form an oxo group
  • R 5a and R 5b are each independently selected from hydrogen, alkyl, halo, and alkoxy;
  • R 8a and R 8b are each hydrogen, or are taken together to form an oxo group;
  • R 9a and R 9b are each selected from hydrogen and alkyl, or are taken together to form an oxo group
  • R a , R f , R s , R h , R 1 , R 1 , R k , R 1 , R m , R n , R°, and R p are each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, and arylalkyl; wherein R g and R h , R' and R k , and R 1 and R m , together with the nitrogen atoms to which they are attached, are optionally taken together to form an optionally substituted ring;
  • R b , R c , R d , and R e are each independently selected from hydrogen and alkyl
  • D is a pharmaceutically active compound.
  • one of R la and R lb is -0P0(0R a )2, wherein each R a is 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 R la and R lb is selected from hydrogen and - (CR b R c ) m -X, wherein m is 0 or 1, R c and R d are each hydrogen, and X is selected from -0R f , -C00R 1 , and -P0(0R n )2, wherein each R f , R 1 , and R n is independently selected from hydrogen and C1-C4 alkyl.
  • each R a is independently selected from hydrogen, Ci-Ce alkyl (e.g., C1-C4 alkyl, such as ethyl or tert- butyl), and benzyl
  • Z’ is -CR 3a R 3b -O-CR 4a R 4b -, -(CR 5a R 5b ) p -CO-, or -(CR 6a R 6b )-.
  • Z’ is -CR 3a R 3b -O-CR 4a R 4b -.
  • R 3a and R 3b are each independently selected from hydrogen and C1-C4 alkyl. In some embodiments, R 3a and R 3b are each independently selected from hydrogen and methyl. In some embodiments, R 3a and R 3b are each hydrogen. In some embodiments, R 3a is hydrogen and R 3b is methyl. In some embodiments, R 3a and R 3b are each methyl.
  • R 4a and R 4b are taken together to form an oxo group. In some embodiments, R 4a and R 4b are each hydrogen.
  • Z’ is -CH2-.
  • Z’ is -(CR 5a R 5b ) P -CO-.
  • p is 2, and R 5a and R 5b are each independently selected from hydrogen and methyl.
  • Z’ is -C(CH 3 ) 2 CH 2 CO-.
  • Z’ is -(CR 6a R 6b )-.
  • R 6a and R 6b are each independently selected from hydrogen and hydrogen and C1-C4 alkyl.
  • R 6a and R 6b are each independently selected from hydrogen and methyl.
  • R 6a and R 6b are each hydrogen.
  • R 6a is hydrogen and R 6b is methyl.
  • R 6a and R 6b are each methyl.
  • Z’ is -CR 7a R 7b -O- CR 8a R 8b -O-CR 9a R 9b -LG.
  • R 7a and R 7b are each hydrogen.
  • R a , R f , R g , R h , R 1 , R', R k , R 1 , R m , R n , R°, and R p are each independently selected from hydrogen, C1-C4 alkyl, phenyl, and phenyl-Ci-C2-alkyl.
  • R a , R f , R 8 , R h , R 1 , R J , R k , R 1 , R m , R n , R°, and R p are each independently selected from hydrogen, methyl, ethyl, iso-propyl, tert-butyl, phenyl, and benzyl.
  • R b , R c , R d , and R e are each independently selected from hydrogen and methyl.
  • R 2a , R 2b , and R 2c are each independently selected from hydrogen, C1-C4 alkyl, halo, and -(CR d R e ) n -Y, wherein n is 0 or 1, R d and R e are each hydrogen, and Y is selected from cyano, -OR f , -COOR 1 , and -PO(OR n )2, wherein each R f , R 1 , and R n is independently selected from hydrogen and C1-C4 alkyl.
  • R 2a , R 2b , and R 2c are each independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, -COOH, -COO(tBu), -CH2COOH, -CH2COOCH3, -P(O)(Oh) 2 , and -P(O)(OEt) 2 .
  • the compound has formula (Ila) or (lib):
  • D is a pharmaceutically active compound.
  • 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.
  • the pharmaceutically active compound is attached to the remainder of the compound via an oxygen atom, e.g., from an alcohol.
  • the group D can be any pharmaceutically active compound.
  • the group D is a small molecule therapeutic.
  • 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
  • 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
  • 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.
  • the pharmaceutically active compound is a BCS Class II compound or a BCS Class IV compound.
  • the pharmaceutically active compound is an anticoagulant (e.g., a factor Xa inhibitor such as apixaban or rivaroxaban).
  • 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,
  • 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).
  • an antiandrogen e.g., enzalutamide, apalutamide, bicalutamide
  • the pharmaceutically active compound is an antiemetic (e.g., aprepitant, amisulpride).
  • the pharmaceutically active compound is an antiparasitic, such as an anthelmintic (e.g., niclosamide).
  • 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).
  • the pharmaceutically active compound is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, such as ivacaftor.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • 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).
  • the pharmaceutically active compound is an anti-inflammatory, such as a nonsteroidal anti-inflammatory (e.g., celecoxib, meloxicam, valdecoxib).
  • 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).
  • the pharmaceutically active compound is a blood glucose regulator, such as an antidiabetic agent (e.g., ezetimibe, glimepiride, glipizide, glyburide, pioglitazone).
  • the pharmaceutically active compound is an anticonvulsant, such as lamotrigine or oxcarbazepine.
  • the pharmaceutically active compound is an antihistamine, such as desloratadine or hydroxyzine pamoate.
  • the pharmaceutically active compound is a skeletal muscle relaxant, such as metaxalone.
  • the pharmaceutically active compound is a central nervous system agent, such a CNS stimulant (e.g., methylphenidate, modafinil).
  • the pharmaceutically active compound is an antipsychotic, such as an atypical antipsychotic (e.g., olanzapine, quetiapine, //-desalkylquetiapine, amisulpride).
  • the pharmaceutically active compound is a hormonal agent, such as a selective estrogen receptor modifying agent (e.g., raloxifene).
  • the pharmaceutically active compound is an immunological agent, such as an immune suppressant (e.g., tacrolimus).
  • the pharmaceutically active compound is a cytochrome P450 3A4 inhibitor (e.g., avacopan).
  • 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.
  • opioid agonist e.g., oliceridine
  • the pharmaceutically active compound is an antifungal agent (e.g., oteseconazole).
  • 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.
  • 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.
  • compounds of formula (II) include groups such as R a , R 1 , and R n (among others) which in some embodiments are independently selected from hydrogen, alkyl (e.g., C1-C4 alkyl), and benzyl.
  • R a , R 1 , and R n are 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 R a , R 1 , and R n are hydrogen. All protected and deprotected forms of compounds of formula (II) are contemplated herein.
  • 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.
  • the compound of formula (II) is a compound shown in Table 2 herein, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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.
  • 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 to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 35 S, 18 F, and 36 C1, respectively.
  • the compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors.
  • positron-emitting isotopes that can be incorporated in compounds of formula (I) or (II) are n C, 13 N, 15 O, and 18 F.
  • 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.
  • 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.
  • 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.
  • 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 (4 th ed.), John Wiley & Sons, NY (2006).
  • an optically active form of a disclosed compound 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).
  • an optically active starting material prepared, for example, by asymmetric induction of a suitable reaction step
  • resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
  • a pure geometric isomer of a compound when 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.
  • the disclosed compounds may exist as salts, including pharmaceutically acceptable salts.
  • 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.
  • Salts may be prepared during the final isolation and purification of the compounds, or separately.
  • salts may be prepared by reacting an amino group of the compounds with a suitable acid.
  • 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.
  • the compound is in the form of a trifluoroacetate salt.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • the composition is in a form suitable for parenteral administration, e.g., intravenous, intramuscular, or subcutaneous administration.
  • the composition is in a form suitable for an implant, e.g., an ocular implant.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • 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.
  • 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.
  • 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.
  • the solvent is water.
  • the solvent is saline.
  • 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.
  • 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.
  • 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.
  • 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.
  • Compositions for oral administration can have various dosage forms.
  • 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.
  • Capsules 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.
  • 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.
  • 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.
  • compositions for oral administration can have liquid forms.
  • 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.
  • 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.
  • 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.
  • 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).
  • a carrier may include a single ingredient or a combination of two or more ingredients.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • the amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition.
  • 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.
  • 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.
  • 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).
  • a method of preparing a prodrug of a pharmaceutically active compound comprising reacting a compound of formula (I) with the pharmaceutically active compound in the presence of a suitable base.
  • 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.
  • 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.
  • 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.
  • a hydride-containing base e.g., sodium hydride
  • an organic base such as 4-dimethylaminopyridine, triethylamine, 2,6-lutidine, pyridine, or N,N- diisopropylethylamine
  • a lithium-containing base such as lithium bis(trimethylsilyl)amide or lithium diisopropylamide
  • an inorganic carbonate such as potassium carbonate or cesium carbonate.
  • the reactions can be carried out in any suitable solvent or solvent system.
  • 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.
  • 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).
  • room temperature i.e., in the presence of heat
  • the reaction is carried out at a temperature below room temperature (i.e., with cooling).
  • 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.
  • 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.
  • 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, pacritin
  • antineoplastic agent
  • 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).
  • 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
  • a leukemia e.g., chronic lymphocytic leukemia
  • 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).
  • an anticoagulant e.g., a factor Xa inhibitor such as apixaban or rivaroxaban.
  • 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).
  • the subject has cancer and the nausea and/or vomiting is chemotherapy induced.
  • 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).
  • 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).
  • 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).
  • the cardiovascular disorder is selected from high blood pressure, high cholesterol, stroke, or the like.
  • 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.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • 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).
  • a cephalosporin e.g., cefdinir, cefprozil
  • a macrolide e.g., clarithromycin
  • an oxazolidinone e.g., linezolid
  • 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).
  • a nonsteroidal anti-inflammatory e.g., celecoxib, meloxicam, valdecoxib.
  • 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).
  • a non-nucleoside reverse transcriptase inhibitor e.g., doravirine, efavirenz, etravirine, rilpivirine
  • a protease inhibitor e.g., lopinavir, nelfinavir, ritonavir.
  • 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).
  • an antidiabetic agent e.g., ezetimibe, glimepiride, glipizide, glyburide, pioglitazone.
  • 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.
  • the pharmaceutically active compound i.e., group D in the compound of formula (II)
  • an anticonvulsant such as lamotrigine or oxcarbazepine.
  • 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.
  • a pharmaceutically active compound i.e., group D in the compound of formula (II)
  • an antihistamine such as desloratadine or hydroxyzine pamoate.
  • 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.
  • a pharmaceutically active compound i.e., group D in the compound of formula (II)
  • metaxalone a skeletal muscle relaxant
  • 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).
  • a central nervous system agent such as a CNS stimulant (e.g., methylphenidate, modafinil).
  • 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).
  • a central nervous system agent such as a CNS stimulant (e.g., methylphenidate).
  • 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).
  • the mental disorder is selected from bipolar disorder, schizophrenia, and major depressive disorder.
  • 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).
  • a pharmaceutically active compound i.e., group D in the compound of formula (II)
  • a hormonal agent such as a selective estrogen receptor modifying agent (e.g., raloxifene).
  • 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).
  • the immune disorder comprises a transplant rejection.
  • 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).
  • the immune disorder is anti-neutrophil cytoplasmic autoantibody-associated vasculitis.
  • 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).
  • the pharmaceutically active compound i.e., group D in the compound of formula (II)
  • an opioid receptor agonist e.g., oliceridine
  • 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).
  • a pharmaceutically active compound i.e., group D in the compound of formula (II)
  • an antifungal agent e.g., oteseconazole
  • 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).
  • the pharmaceutically active compound i.e., group D in the compound of formula (II)
  • a calcitonin gene-related peptide receptor antagonist e.g., rimegepant
  • 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).
  • 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.
  • 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
  • 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.
  • 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.
  • 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).
  • kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.
  • 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.
  • 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.
  • 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
  • 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).
  • 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.
  • 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).
  • 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).
  • 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).
  • a solvent such as acetonitrile
  • 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.
  • 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 ⁇ M.hr of released Compound No. Cmax ⁇ M 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 ⁇ M of test compound was placed in 500 ⁇ L of either SGF or HBSS and incubated for 2 hours at 37 oC.
  • SGF gastric fluid
  • HBSS Hank’s balanced salt solution
  • the prodrug in buffer was preincubated at 37 oC for 5 minutes and reactions were initiated with the addition of 100 ⁇ enzyme. Aliquots (50 ⁇ L) 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.
  • Example 7 Caco-2 permeability assays Caco-2 cells were maintained in DMEM in an atmosphere of 5% CO 2 . 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 ⁇ M.
  • the assays were performed in HBSS at pH 7.4 for the basolateral side and pH 6.5 for apical side at 37 oC.
  • the monolayers were washed in prewarmed HBSS.
  • 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 were calculated using the formula: Papp 1 ⁇ 4 (dC rec/ dt)/(A C0,donor)] 10 6 with dC rec /dt being the change in concentration in the receiver compartment with time; C 0,donor the 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.
  • 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 ⁇ l/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.
  • 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.
  • vemurafenib The highly insoluble and poorly permeable (BCS Class IV) BRAF mutant inhibitor, vemurafenib was then investigated.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 [Width 2 x 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..
  • 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).
  • 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.
  • 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.

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Abstract

L'invention concerne des composés pouvant être utilisés pour préparer des promédicaments, des procédés de production de promédicaments à l'aide des composés, et des promédicaments produits au moyen de ces procédés. Les promédicaments produits à l'aide des composés de l'invention sont hautement solubles, ce qui permet une bonne biodisponibilité orale.
PCT/US2024/056391 2023-11-17 2024-11-18 Fractions de promédicament et composés les comprenant Pending WO2025106974A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025188941A1 (fr) * 2024-03-07 2025-09-12 Arvinas Operations, Inc. Procédés de fabrication d'un agent de dégradation de protéine de récepteur des androgènes

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Publication number Priority date Publication date Assignee Title
US4372894A (en) * 1977-12-22 1983-02-08 Astra Lakemedel Aktiebolag Phosphonoformic acid esters
US5132414A (en) * 1990-05-10 1992-07-21 Dana-Farber Cancer Institute, Inc. Dideoxynucleoside-5'-phosphonoformic acid compounds
US20160243137A1 (en) * 2007-08-10 2016-08-25 Basil Rigas Anti-Inflammatory Compounds and Use Thereof

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US4372894A (en) * 1977-12-22 1983-02-08 Astra Lakemedel Aktiebolag Phosphonoformic acid esters
US5132414A (en) * 1990-05-10 1992-07-21 Dana-Farber Cancer Institute, Inc. Dideoxynucleoside-5'-phosphonoformic acid compounds
US20160243137A1 (en) * 2007-08-10 2016-08-25 Basil Rigas Anti-Inflammatory Compounds and Use Thereof

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DATABASE PubChem 13 September 2017 (2017-09-13), XP009563761, Database accession no. 129811017 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025188941A1 (fr) * 2024-03-07 2025-09-12 Arvinas Operations, Inc. Procédés de fabrication d'un agent de dégradation de protéine de récepteur des androgènes

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