Selective delivery of agents to myeloid-derived suppressor cells with a dendrimer-based formulation

Abstract

The present disclosure provides compounds of the formulae herein (e.g., Formulae (I), (I'), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI)), and pharmaceutically acceptable salts thereof, and compositions and kits comprising the compounds, or pharmaceutically acceptable salts thereof, which are useful for the delivery of agents to immune cells (e.g., myeloid-derived suppressor cells (MDSCs)). The present disclosure also provides methods of treating or preventing diseases or disorders (e.g., diseases or disorders associated with MDSCs) by administering the compounds, or pharmaceutically acceptable salts thereof, or compositions thereof, to a subject in need thereof, and methods of preparing the compounds, or pharmaceutically acceptable salts thereof.

Description

SELECTIVE DELIVERY OF AGENTS TO MYELOID-DERIVED SUPPRESSOR CELLS WITH A DENDRIMER-BASED FORMULATION CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63 / 627,659, filed January 31, 2024, titled SELECTIVE DELIVERY OF AGENTS TO MYELOID-DERIVED SUPPRESSOR CELLS WITH A DENDRIMER-BASED FORMULATION, the contents of which are incorporated herewith by reference in their entirety. BACKGROUND OF THE INVENTION

[0002] Nanoparticles have been used to deliver therapeutic payload for disease treatment. While most in vivo biodistribution studies of nanoparticles have been focused on their tissue-level accumulation and clearance1, 2, recent progress in the nanomedicine field suggested that targeting nanoparticles to immune cells can be used to modulate the immune response and to enhance therapeutic delivery to the disease region3-5.

[0003] For example, monocytic-myeloid-derived suppressor cells (M-MDSCs) are important cellular targets in cancer6. M-MDSCs are pathologically activated monocytes with potent immunosuppressive activities. Clinically, a high burden of M-MDSCs is associated with poor prognosis of many solid tumors7. In cancer, M-MDSCs help create and maintain an immunosuppressive tumor microenvironment (TME)8, 9. These cells can suppress anti-tumor T cells and promote regulatory T cells and anti-inflammatory myeloid cells8, 9. As such, there is an urgent need to develop delivery strategies to target M-MDSCs for cancer treatment. M-MDSCs are also associated with sepsis.

[0004] In addition to their immunosuppressive features, M-MDSCs, as phagocytes, could also significantly affect the in vivo fate of nanoparticles. Historic studies have established the roles of myeloid cells in clearing nanoparticles10, 11, while emerging evidence has shown that myeloid cells in circulation can take up nanoparticles and actively transport them to the inflamed tissue4, 12, 13. M- MDSCs are significantly elevated in the peripheral blood of high-grade glioblastoma patients, accounting for as much as 10% of total cells in the peripheral blood and 30% of total peripheral blood mononuclear cells14, 15. In the presence of tumor lesions, the bone marrow accelerates monopoiesis and enhances the egress of M-MDSCs to the systemic circulation, leading to significant expansion of their population in the peripheral blood and in the spleen16. Tumor constantly recruits M-MDSCs in large amounts through CCR2-mediated chemotaxis to replenish the tumor-associated macrophages (TAMs)17, 18. Because of the abundance of M-MDSCs and their constant infiltration to the tumor sites, M-MDSCs have potential in mediating nanoparticle deposition at the tumors.

[0005] Given the roles of M-MDSCs in establishing TME and mediating nanoparticle tumor- targeting, many efforts have tried to establish the correlation between nanoparticle physiochemical properties, such as size, surface charge, and targeting ligand to their targeting of M-MDSCs19-22.U1197.70243WO00 1 / 193 #13587456v2However, a significant challenge in studying the cell targeting behaviors of nanoparticles is that when nanoparticles are injected into the blood, multiple serum proteins such as immunoglobulins, fibrinogen, complement proteins, and apolipoproteins readily adsorb to the nanoparticle surface, forming a ‘protein corona’23, 24. The protein corona masks nanoparticle interactions with the cell surface and alters the nanoparticle’s cellular tropism23, 24. The nanoparticle-associated proteins dictate nanoparticle interactions with cells and more broadly their in vivo targeting behaviors, while the physical properties of nanoparticles may play a secondary role in this process.

[0006] Dendrimers represent a class of ultra-small nanoparticles with sub-10nm size and carrying drug payload on their surfaces. About 26 dendrimer-based therapeutics with various types of payloads are currently under Phase I-III clinical trials25. Systemically administrated hydroxyl-terminated PAMAM dendrimer has been shown to selectively target TAMs in murine glioblastoma (glioma) models26, 27. However, given the heterogeneous nature of TAMs, it is unclear what subset(s) are being targeted and what mechanism mediates the selective cell-targeting.

[0007] Signal transducer and activator of transcription 3 (STAT3) is a transcription factor highly activated in MDSCs that promotes angiogenesis, host immunosuppression, and tumor invasion. Clinical translation of STAT3 inhibitors has been hampered because of poor solubility and bioavailability, off-target effects, and limited efficacy in clinical trials. SUMMARY OF THE INVENTION

[0008] The present disclosure provides an approach for the systemic delivery of agents, such as LLL12, a small molecule inhibitor of STAT3, by formulating the agents into dendrimer-based conjugates.

[0009] In one aspect, the present disclosure provides compounds of Formula (I):and pharmaceutically acceptable salts thereof, wherein L, X, Y, Z, n, p, and q are as defined herein.

[0010] In another aspect, the present disclosure provides a compound of Formula (I′):and pharmaceutically acceptable salts thereof, wherein L, X, Y, Z, n, p, and q are as defined herein.U1197.70243WO00 2 / 193 #13587456v2

[0011] In another aspect, the present disclosure provides compounds of Formula (II):and pharmaceutically acceptable salts thereof, wherein L, Y, Zn, n, p, and q are as defined herein.

[0012] In another aspect, the present disclosure provides compounds of Formula (III):and pharmaceutically acceptable salts thereof, wherein L, Y, Zn, n, p, and q are as defined herein.

[0013] In another aspect, the present disclosure provides compounds of Formula (IV):and pharmaceutically acceptable salts thereof, wherein L, Y, Zn, n, p, and q are as defined herein.

[0014] In another aspect, the present disclosure provides compounds of Formula (V):and pharmaceutically acceptable salts thereof, wherein L, Y, Zn, n, p, and q are as defined herein.

[0015] In another aspect, the present disclosure provides compounds of Formula (VI):and pharmaceutically acceptable salts thereof, wherein L, Y, Zn, n, p, and q are as defined herein.U1197.70243WO00 3 / 193 #13587456v2

[0016] In another aspect, the present disclosure provides compounds of Formula (VII):and pharmaceutically acceptable salts thereof, wherein L, Y, Zn, n, p, and q are as defined herein.

[0017] In another aspect, the present disclosure provides compounds of Formula (VIII):and pharmaceutically acceptable salts thereof, wherein L, Y, Zn, n, p, and q are as defined herein.

[0018] In another aspect, the present disclosure provides compounds of Formula (IX):and pharmaceutically acceptable salts thereof, wherein L, Y, Zn, n, p, and q are as defined herein.U1197.70243WO00 4 / 193 #13587456v2

[0019] In another aspect, the present disclosure provides compounds of Formula (X):and pharmaceutically acceptable salts thereof, wherein L, Y, Zn, n, p, and q are as defined herein.

[0020] In another aspect, the present disclosure provides compounds of Formula (XI):and pharmaceutically acceptable salts thereof, wherein L, Y, Zn, n, p, and q are as defined herein.

[0021] In another aspect, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formulae (I), (I′), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0022] In another aspect, the present disclosure provides a method of modulating a target protein, the method comprising administering to a subject in need thereof or contacting a cell, tissue, or biological sample with an effective amount of a compound of Formulae (I), (I′), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0023] In another aspect, the present disclosure provides kits comprising a provided compound or provided composition and instructions for its use.

[0024] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.U1197.70243WO00 5 / 193 #13587456v2BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIGs.1A-1D show that CCR2RFP / WTCX3CR1GFP / WTtransgenic mice enable direct surveillance of M-MDSCs in mouse glioma model. FIG.1A shows that in mice with established GL261 tumors, the pie graph shows the flow cytometry measurement of the average percentage of M-MDSCs that reside in the reservoir tissues such as bone marrow, spleen, and peripheral blood leukocytes. At 3-4 weeks after tumor initiation, tissues from 6 tumor-bearing mice were analyzed. FIG.1B shows a gating strategy for the M-MDSCs cells in each tissue: the M-MDSCs are defined as the CCR2+ / CX3CR1+ population. FIG.1C shows the gating strategy and the average percentage of major cell subsets in the GL261 tumor stroma. CCR2+ / CX3CR1+ cells: M-MDSCs; CCR2- / CX3CR1+ cells: likely representing the CNS tissue-resident microglia; CCR2- / CX3CR1meidumcells: CX3CR1int, likely represent immune cells infiltrate brain tumor from external sources; CCR2+ / CX3CR1- cells: CCR2+, likely represent other infiltrate myeloid cells originated outside of the CNS. CCR2- / CX3CR1- cells: other cells, a collection of tumor cells and other tumor stroma cells. At 3-4 weeks after tumor initiation, tissues from 6 tumor-bearing mice were analyzed. FIG.1D shows a confocal microscopy image of tumor (KR158). Arrow indicates the CCR2+ / CX3CR1+ M-MDSCs..

[0026] FIGs.2A-2H show that tumor M-MDSCs efficiently endocytose dendrimers with high capacity. Cy5-labeled OH dendrimers (50mg / kg) were systemically injected into GL261 and KR158 tumor bearing transgenic mice (CCR2WT / RFPCX3CR1WT / GFP) at 3-4 weeks post-implantation; at 24 hours post injection, OH dendrimers uptake in myeloid subsets (indicated by Cy5 Median Fluorescence Intensity (MFI)) and the composition of dendrimer-positive cells (indicated by percentage of dendrimer-positive subset) within the tumor were analyzed through flow cytometry. FIG.2A shows the capacity of each cell subsets to uptake OH dendrimers within the GL261 gliomas at 24 hours post-injection. This is indicated by the MFI, which representatively measures the median number of dendrimers deposited per single cell. FIG.2B shows the statistical analysis of FIG.2A. FIG.2C shows a representative density plot of GL261 tumor stromal cells (left panel) and in the same tumor, the density plot of OH dendrimer-positive cells (right panel). M-MDSCs are shown in the box. FIG.2D shows the statistical analysis of the density plot of dendrimer-positive cells in FIG. 2C (right panel), which shows the composition of dendrimer-positive cells in each cellular compart within the GL261 tumor as a percent of a whole (n=6). FIG.2E shows the comparison of the mean, upper and lower quartiles of OH dendrimer deposition in tumor as measured by MFI between GL261 and KR158 gliomas. FIG.2F shows the comparison of OH dendrimer uptake capacity (MFI) in each cell subsets between GL261 and KR158 tumors. FIG.2G shows the composition of dendrimer- positive cells in each cellular compart within the KR158 tumor as a percent of a whole (n=6). FIG. 2H shows the correlation analysis between the abundance of cell subset (indicated by the percentage of cell subset within all tumor stroma cells) and the dendrimer deposition within the tumor (indicated by Cy5 MFI of all tumor cells) for both GL261 and KR158 tumors. The Pearson correlation coefficient (R) is based on 95% confidence interval. Weak correlation, R>0.2 or R<-0.2; strongU1197.70243WO00 6 / 193 #13587456v2correlation, R>0.6 or R<-0.6. For all in vivo experiment, data were generated based on 6 mice of both male and female sexes, *p<0.05, **p<0.01, ***p<0.001, ns=not statistically significant.

[0027] FIGs.3A-3E show the trafficking kinetics of M-MDSC contributes to the dendrimer accumulation in the tumor. FIG.3A shows a graphical illustration shows the trafficking kinetics of M-MDSCs. M-MDSCs are recruited to the brain tumor from bone marrow (hematopoiesis organ) or spleen (temporary reservoir) through systemic circulation (blood). FIG.3B shows a heatmap that shows the OH dendrimer uptake capacity (indicated by Cy5 MFI) for M-MDSCs in bone marrow, spleen, blood, and tumor in GL261 glioma bearing mice (average MFI from 6 mice). FIG.3C shows a histogram that shows the overall OH dendrimer uptake capacity (indicated by Cy5 MFI) for white blood cells isolated from the peripheral blood of GL261 tumor-bearing mice. Control cells (no dendrimer injection). Cell subsets (lymphocytes, monocytes, granulocytes) were gated based on the scattered plot FSC vs. SSC. FIG.3D shows a comparison of the percentage of dendrimer-positive M- MDSCs between 24 hours vs.72 hours after dendrimer injection. Data was obtained from GL261 tumor-bearing mice. FIG.3E shows quantification of OH dendrimer concentrations in the plasma of GL261 tumor-bearing C57BL / 6 mice at 24 hours (n=7) and 72 hours (n=12) post-dendrimer injection. For all other experiments in this figure, flow cytometry analyses were based on 6 GL261 tumor- bearing mice that received systemic injection of 50 mg / kg OH dendrimers. *p<0.05, **p<0.01.

[0028] FIGs.4A-4J show that dendrimer surface chemistry affects their interactions with M-MDSC in vivo. To determine how dendrimer surface chemistry affect their interaction with M-MDSCs in vivo, dendrimers with different terminal groups (i.e. Succinamic acid: SA, hydroxyl: OH, and amine: NH2) were systemically injected into healthy (n=3) or tumor bearing mice (n=4) at tolerable doses (50mg / kg for SA and OH, 10mg / kg for NH2). At 24 hours after dendrimer injection, the bone marrow and tumor were isolated for flow cytometry analysis. FIG.4A shows a comparison of the percentage of dendrimer-positive M-MDSCs (% dendrimer+ M-MDSCs) in the bone marrow of healthy (left) and KR158 tumor-bearing mice (right) between SA, OH, and NH2 dendrimers. The % dendrimer+ M- MDSCs measure dendrimer’s ability to ‘target’ M-MDSCs in the tissue. FIG.4B shows comparison of the percentage of dendrimer-positive M-MDSCs in the KR158 tumor between SA, OH, and NH2 dendrimers. FIG.4C shows representative histograms comparing the Cy5 MFI of dendrimer-positive cells for OH, SA, and NH2 dendrimers in the bone marrow of KR158 tumor-bearing mice (top) and healthy mice (bottom) respectively. FIGs.4D-4E show a comparison of the M-MDSC’s capacity to endocytose SA, OH, and NH2 dendrimers (indicated by MFI). Plot shows M-MDSCs isolated from the bone marrow of healthy mice (left) and KR158 tumor bearing mice (right) (FIG.4D) and the KR158 tumors (FIG.4E). FIG.4F shows a comparison of SA and OH dendrimers for the composition of dendrimer-positive cells within the KR158 tumor. FIG.4G shows the heatmap shows the uptake capacity of SA and OH dendrimers (indicated by Cy5 MFI) by different cell subsets within the GL261 tumor. Data displayed is median. FIGs.4H-4I show statistical analysis comparing the SA and OH dendrimers in terms of their uptake capacity (indicated by Cy5 MFI of dendrimer-positiveU1197.70243WO00 7 / 193 #13587456v2cells) by M-MDSCs within the tumor (FIG.4H) and bone marrow (FIG.4I) of the GL261 tumor bearing mice. FIG.4J shows a comparison of SA and OH dendrimers for the composition of dendrimer-positive cells within the GL261 tumor. For all statistical analyses, *p<0.05, **p<0.01, ****p<0.0001.

[0029] FIGs.5A-5I show the serum proteins associated with dendrimers dictate the interaction between dendrimers and M-MDSCs. FIG.5A shows a schematic illustration of the generation of M- MDSC from the bone marrow of CCR2WT / RFPCX3CR1WT / GFPtransgenic mice. To generate the M- MDSCs, bone marrow cells were isolated and were cultured in KR158 conditioned media for 5 days. FIG.5B shows flow cytometry analysis shows that exposure of bone marrow cells to KR158 conditioned media for 5 days enriched the CCR2+ / CX3CR1+ cells (M-MDSCs) from less than 10% to approximately 59%. FIG.5C shows the histogram compares the uptake of OH, SA, and NH2 dendrimers (indicated by Cy5 MFI) by ex vivo generated M-MDSCs in the absence of mouse serum. To generate the plot, M-MDSCs were incubated with dendrimers at room temperature (RT) for 30 minutes. FIG.5D shows a comparison of ζ-potentials (zeta potentials) (mV) of serum proteins (triangle) and NH2, OH, and SA dendrimers before (circle) and after incubation with mouse serum (square). Dendrimers were incubated at 0.86 mg / mL in normal murine serum at 37°C for 30 minutes. ζ-potentials (mV) determined using DLS. The experiment was repeated for 3 times (n=3). FIG.5E shows a schematic illustration of the experiment flow that determines the influence of serum proteins on the dendrimer uptake by M-MDSCs. FIG.5F shows the plot based on the experiment flow in FIG.5E, which shows dose-dependent dendrimer uptake (indicated by Cy5 MFI) by M-MDSCs after co- incubation with either PBS (solid line) or mouse serum (dotted line) for NH2 (circle), OH (square), and SA (triangle) dendrimers. Each date point is an average of 3 independent experiment. FIG.5G shows a schematic illustration of the experiment flow that determines how heat-inactivation of serum affect the uptake of NH2, OH, and SA dendrimers by M-MDSCs. FIG.5H shows the plot based on the experiment flow in (FIG.5G), which shows the fold change of dendrimer uptake (x-axis) before and after heat-inactivation of mouse serum as a function of dendrimer dose (y-axis). NH2: circle, OH: square, SA: triangle. Negative fold change indicates heat inactivation of serum decreased dendrimer uptake. Positive fold change indicates heat inactivation of serum enhanced dendrimer uptake. Each data point is an average of 3 independent experiment. FIG.5I shows a representative scattered plot of heat inactivation of mouse serum enhanced the uptake of OH dendrimers by M-MDSCs. **p<0.01, ***p<0.005.

[0030] FIG.6A shows the capacity of each cell subsets to uptake OH dendrimers within the KR158 gliomas at 24 hours post-injection. This is indicated by the MFI, which representatively measures the median number of dendrimers deposited per single cell. FIG.6B shows the statistical analysis of FIG.6A. FIG.6C shows confocal microscopy image of dendrimer (white) distribution within the tumor (KR158) at 24 hours postinjection. Arrow and star indicate the intracellular localization of OH dendrimer with CCR2+ / CX3CR1+ M-MDSCs.U1197.70243WO00 8 / 193 #13587456v2

[0031] FIG.7 shows representative fluorescence image of GL261 and KR158 tumor. Arrow indicates the tumor stroma.

[0032] FIG.8A shows murine bone marrow sagittal cross section showing OH dendrimer (Cy5) signal 24 hours post 50mg / kg injection of (OH) dendrimer. Image generated by fluorescence microscopy 4X magnification panel and optimized for brightness and contrast using Fiji. Box highlighting image zoom panel. Below showing OH dendrimer in the monocyte rich red marrow of spongy bone (circle). FIG.8B shows murine spleen sagittal cross section showing dendrimer (Cy5) signal 24 hours post 50mg / kg injection of OH dendrimer. Image generated by fluorescence microscopy 10X magnification panel. Box highlighting image zoom panel. Below showing dendrimer deposition in monocyte rich red pulp and exclusion from lymphocyte white pulp zones. The Cy5 labelling of the G6 PAMAM dendrimer was carried out by following previously published work53. The amine surface G6 PAMAM dendrimer (50 mg) was dissolved in borate buffer (2 mL, pH 8.5) at room temperature. The reaction mixture was cooled to 0 ℃and Cy5 mono NHS ester (3.6 eq, 2.5 mg) in DMSO (1 mL) was added. The reaction mixture was allowed to stir overnight and lyophilized. The obtained crude product was dissolved in water and dialyzed (membrane MWCO = 12-14 kDa) against pure DI water for 24 h with successive change of water every 3 h. The collected water in dialysis bag was lyophilized to get the amine surface D-Cy5 (48 mg). The Cy5 labelling on hydroxyl surface dendrimer was conducted using bi-functional hydroxyl surface dendrimer by following the above procedure. The hydroxyl surface bi-functional dendrimer and acid surface bi-functional dendrimer were synthesized using literature method54. The acid surface bi-functional dendrimer (0.000590 mmol, 1.0 eq, 50 mg) was dissolved in DMSO (2 mL) at room temperature, to this solution was added Cy5 NHS ester (0.0022 mmol, 3.66 eq, 1.72 mg) and DIEA (0.0065 mmol, 11 eq, 1.5 uL). The resulting reaction mixture was allowed to stir overnight and dialyzed against DMSO for 8 h by changing the solvent at least two times, which was further dialyzed against DMF for 12 h by changing the solvent two times. The collected solvent was evaporated under high vacuum and compound was dissolved in water, dialyzed against pure DI water for 6 h by changing the solvent every 2 hours. The collected water was lyophilized for 24 h to get pure acid surface D-Cy5 (45 mg).

[0033] FIGs.9A-9B show flow cytometry analyses of dendrimer uptake in blood leukocytes. FIG. 9A shows a comparison of OH dendrimer uptake (MFI) in leukocyte subpopulations of GL261 and KR158 tumor-bearing mice. n=6. FIG.9B shows a comparison of the percent of dendrimer positive leukocytes by subpopulations of GL261 and KR158 tumorbearing mice. n=6. *p<0.05, **p<0.001, ***p=0.0001, ****p<0.0001.

[0034] FIGs 10A-10B show the number-average mean-based size (FIG.10A) and z-potential (mV) (FIG.10B) of hydroxyl (OH), succinamic acid (SA), and amine (NH2) dendrimers. The size and z- potential were measured by dynamic light scattering (DLS) and electrophoretic light scattering (ELS). FIG.10C shows a schematic illustration of the labeling of Cy5 to NH2 (top), OH (middle), and SA (bottom) dendrimers.U1197.70243WO00 9 / 193 #13587456v2

[0035] FIG.11A shows in vitro evaluation of the dose-dependent toxicity of NH2, OH, and SA dendrimers on primary M-MDSCs by cell-titer blue assay. Positive control: cells treated with 1% Triton-X, Negative control: cell without treatment. FIG.11B shows that at 24 hours after systemic injection, NH2 dendrimers (10mg / kg) co-localized with the endothelial cell (indicated by arrow) in tumor stroma of a KR158 glioma established from CCR2WT / RFPCX3CR1WT / GFPtransgenic mouse.

[0036] FIG.12A shows NH2 dendrimer distribution within the KR158 tumor at 24 hours post- injection (10mg / kg), Image based on the widefield fluorescence microscopy (left panel) with zoom (right panel). FIG.12B shows OH dendrimer distribution within the KR158 tumor at 24 hours post- injection (50mg / kg), Image based on widefield fluorescence microscopy (left panel) with zoom (right panel). FIG.12C shows SA dendrimer distribution within the KR158 tumor at 24 hours post-injection (50mg / kg), Image based on widefield fluorescence microscopy (left panel) with zoom (right panel). FIG.12D shows 10X merge confocal of tumor from FIG.12A. FIG.12E shows 10X merge confocal of tumor from tumor shown in FIG.12B. FIG.12F shows 10X merge confocal of tumor from tumor shown in FIG.12C. FIG.12G shows 60X merge confocal for amine dendrimer tumor shown in FIG. 12D. FIG.12H shows 60X merge confocal for amine dendrimer tumor shown in FIG.12E. FIG.12I shows 60X merge confocal for amine dendrimer tumor shown in FIG.12F.

[0037] FIGs.13A-13B show the comparison of overall tumor depositions of SA and OH dendrimers (indicated by Cy5 MFI) in KR158 tumor (FIG.13A) and GL261 tumor (FIG.13B). NS: no statistical significance.

[0038] FIG.14 shows a schematic of delivery of LLL12 via a dendrimer drug conjugate.

[0039] FIG.15 shows a schematic of characterization of the dendrimer drug conjugate by dynamic light scattering (DLS).

[0040] FIG.16 shows a schematic of characterization of drug release quantification using high pressure liquid chromatography (HPLC).

[0041] FIG.17 shows the zeta potential of PAMAM dendrimers (mV) using electrophoretic light scattering in 10 mM NaCl at 0.03 mg / mL. Positive (NH3) refers to a PAMAM dendrimer with positively charged amine surface groups. Neutral (OH) refers to a PAMAM dendrimer with neutral hydroxyl surface groups. Negative (SA) refers to a PAMAM dendrimer with negatively charged succinamic acid surface groups.

[0042] FIGs.18A-18H show HPLC studies of G6 PAMAM OH dendrimer at 210 nm (FIG.18A), LLL12 at 250 nm (FIG.18B), LLL12-linker at 250 nm (FIG.18C), dendrimer-LLL12 conjugate 12 at 250 nm (FIG.18D), dendrimer-LLL12 conjugate 17 at 250 nm (FIG.18E), dendrimer-LLL12 conjugate 17 release profile at pH 4.5 at 250 nm (FIG.18F), dendrimer-LLL12 conjugate 17 release profile at 210 nm (FIG.18G), and dendrimer-LLL12 conjugate 17 release profile at pH 7.4 at 250 nm (FIG.18H).

[0043] FIGs.19A-19G show IC50 efficacy and toxicity studies. FIG.19A shows a schematic for the IC50 studies. FIG.19B shows a THP-1STAT3-LucIL-6 response curve. FIG.19C shows a dose responseU1197.70243WO00 10 / 193 #13587456v2curve in THP-1STAT3-Luc. FIGs.19D-19E show the LLL12 IC50 mass. FIG.19F shows the IC50 for dendrimer-LLL12 conjugate 17. FIG.19G shows a comparison of toxicity between LLL12 and dendrimer-LLL12 conjugate 17.

[0044] FIGs.20A-20B show a UV-vis spectrum of LLL12 (FIG.20A) and a calibration curve (FIG. 20B).

[0045] FIGs.21A-21B show1H NMR (FIG.21A) and13C NMR (FIG.21B) spectra of 1.

[0046] FIGs.22A-22B show1H NMR (FIG.22A) and13C NMR (FIG.22B) spectra of 3.

[0047] FIGs.23A-23B show1H NMR (FIG.23A) and13C NMR (FIG.23B) spectra of 4.

[0048] FIG.24 shows1H NMR spectrum of 6.

[0049] FIG.25 shows1H NMR spectrum of 9.

[0050] FIG.26 shows1H NMR spectrum of 10.

[0051] FIG.27 shows1H NMR spectrum of 12.

[0052] FIGs.28A-28B show1H NMR (FIG.28A) and13C NMR (FIG.28B) spectra of 14.

[0053] FIG.29 shows1H NMR spectrum of 16.

[0054] FIG.30 shows1H NMR spectrum of 17.

[0055] FIGs.31A-31B show1H NMR (FIG.31A) and13C NMR (FIG.31B) spectra of 18.

[0056] FIGs.32A-32B show1H NMR (FIG.32A) and13C NMR (FIG.32B) spectra of 20.

[0057] FIGs.33A-33B show1H NMR spectra of 21 from 0 ppm to 14 ppm (FIG.33A) and 0 ppm to 9 ppm (FIG.32B).

[0058] FIGs.34A-34B show (FIG.34A) and Zeta Potential (FIG.34B) of dendrimer conjugates of the present disclosure, along with unfunctionalized G6-OH. Size and Zeta Potential were calculated in 10mM NaCl.

[0059] FIG.35 shows a schematic of efficacy (IC50) and toxicity analyses for dendrimer-drug conjugates.

[0060] FIGs.36A-36B show representative IC50 curves for free drug (LLL12), dendrimer-LLL12 conjugates D-LLL12C (17), D-LLL12S (12), and D- LLL12H (21) (FIG.36A) and average IC50 values from 3 repeated experiments (FIG.36B).

[0061] FIGs.37A-37C show toxicity (measured by cell viability) for 17 (FIG.37A), 12 (FIG.37B), and 21 (FIG.37C), with LLL12 as a control.

[0062] FIGs.38A-38E show the therapeutic window. FIGs.38A-38D show the overlays of the IC50 curve (bioluminescence; curve with open circles) and the viability curve (curve with shaded triangles) for LLL12 (FIG.38A), G6-LLL12C (D-LLL12C, 17) (FIG.38B), G6-LLL12S (D-LLL12S, 12) (FIG.38C), and G6-LLL12H (D-LLL12H, 21) (FIG.38D). FIG.38E shows the calculated therapeutic windows.U1197.70243WO00 11 / 193 #13587456v2DEFINITIONS

[0063] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0064] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0065] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C1-6 alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0066] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2U1197.70243WO00 12 / 193 #13587456v2carbon atoms (“C1–2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1–6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n- heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1–12 alkyl (such as unsubstituted C1–6 alkyl, e.g., −CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, – CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).

[0067] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.

[0068] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–20 heteroalkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–12 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–11 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–10heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–9heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–8heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–7heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–6heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1–5heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbonU1197.70243WO00 13 / 193 #13587456v2atoms and 1or 2 heteroatoms within the parent chain (“C1–4heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C1–3heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C1–2heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“C1 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C2-6heteroalkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted C1–12 heteroalkyl. In certain embodiments, the heteroalkyl group is a substituted C1–12 heteroalkyl.

[0069] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1–12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1–11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1–10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1–9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1–8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1–7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1–6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1–5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1–4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1–3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1–2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C1–4 alkenyl groups include methylidenyl (C1), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1–6 alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C1-20alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3 or) may be in the (E)- or (Z)-configuration.U1197.70243WO00 14 / 193 #13587456v2

[0070] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain.

[0071] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20alkynyl”).

[0072] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain.

[0073] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.

[0074] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”).

[0075] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ^ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”).

[0076] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ^ electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).

[0077] The term “unsaturated bond” refers to a double or triple bond.

[0078] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0079] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.

[0080] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, heteroalkylene is the divalent moiety of heteroalkyl, and heteroalkenylene is the divalent moiety of heteroalkenyl.

[0081] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, heteroalkyl, and heteroalkenyl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted”U1197.70243WO00 15 / 193 #13587456v2or “unsubstituted” alkenyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

[0082] Exemplary carbon atom substituents include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3 −C(=S)N(Rbb)2, −C(=O)SRaa, −C(=S)SRaa,−NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3+X−, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; wherein: each instance of Raais, independently, selected from C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroarylU1197.70243WO00 16 / 193 #13587456v2ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20alkyl, C1–20perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereinU1197.70243WO00 17 / 193 #13587456v2each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–10alkyl, C1–10perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6 alkyl, −ON(C1–6 alkyl)2, −N(C1–6 alkyl)2, −N(C1–6 alkyl)3+X−, −NH(C1–6 alkyl)2+X−, −NH2(C1–6 alkyl)+X−, −NH3+X−, −N(OC1–6 alkyl)(C1–6 alkyl), −N(OH)(C1–6 alkyl), −NH(OH), −SH, −SC1–6 alkyl, −SS(C1–6 alkyl), −C(=O)(C1–6 alkyl), −CO2H, −CO2(C1–6 alkyl), −OC(=O)(C1–6 alkyl), −OCO2(C1–6 alkyl), −C(=O)NH2, −C(=O)N(C1–6 alkyl)2, −OC(=O)NH(C1–6 alkyl), −NHC(=O)( C1–6 alkyl), −N(C1–6 alkyl)C(=O)( C1–6 alkyl), −NHCO2(C1–6 alkyl), −NHC(=O)N(C1–6 alkyl)2, −NHC(=O)NH(C1–6 alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6 alkyl), −OC(=NH)(C1–6 alkyl), −OC(=NH)OC1–6 alkyl, −C(=NH)N(C1–6 alkyl)2, −C(=NH)NH(C1–6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6 alkyl)2, −OC(NH)NH(C1– 6 alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6 alkyl), −SO2N(C1–6 alkyl)2, −SO2NH(C1–6 alkyl), −SO2NH2, −SO2C1–6 alkyl, −SO2OC1–6 alkyl, −OSO2C1–6 alkyl, −SOC1–6 alkyl, −Si(C1–6 alkyl)3, −OSi(C1–6 alkyl)3 −C(=S)N(C1–6 alkyl)2, C(=S)NH(C1–6 alkyl), C(=S)NH2, −C(=O)S(C1–6 alkyl), −C(=S)SC1–6 alkyl, −SC(=S)SC1–6 alkyl, −P(=O)(OC1–6 alkyl)2, −P(=O)(C1–6 alkyl)2, −OP(=O)(C1–6 alkyl)2, −OP(=O)(OC1–6 alkyl)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; and each X−is a counterion.

[0083] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0084] The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxy,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −ORaa, −ON(Rbb)2, −OC(=O)SRaa, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −OC(=NRbb)N(Rbb)2, −OS(=O)Raa, −OSO2Raa, −OSi(Raa)3,U1197.70243WO00 18 / 193 #13587456v2−OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, and −OP(=O)(N(Rbb))2, wherein X−, Raa, Rbb, and Rccare as defined herein.

[0085] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRbb)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1–20alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, hetero C1–20 alkyl, hetero C1–20 alkenyl, hetero C1– 20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0086] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1–10 alkyl, C1–20 alkenyl, C1–20 alkynyl, hetero C1–20 alkyl, hetero C1–20 alkenyl, hetero C1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0087] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or an oxygen protecting group.

[0088] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups includeU1197.70243WO00 19 / 193 #13587456v2−Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb)2)2, wherein X−, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0089] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−, HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5– sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−, B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0090] A “leaving group” (LG) is an art-understood term referring to an atomic or molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6th ed. (501–502). In some embodiments, the leaving group is an internal leaving group such as an epoxide.

[0091] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0092] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0093] The term “heteroatom” refers to an atom that is not hydrogen or carbon. In certain embodiments, the heteroatom is nitrogen. In certain embodiments, the heteroatom is oxygen. In certain embodiments, the heteroatom is sulfur.

[0094] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present disclosure is not limited in any manner by the above exemplary listing of substituents.U1197.70243WO00 20 / 193 #13587456v2

[0095] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0096] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate,U1197.70243WO00 21 / 193 #13587456v2methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0097] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0098] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0099] The terms “composition” and “formulation” are used interchangeably.

[0100] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non- human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0101] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitialU1197.70243WO00 22 / 193 #13587456v2fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0102] The term “target tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound, particle, and / or composition of the present disclosure is delivered. A target tissue may be an abnormal or unhealthy tissue, which may need to be treated. A target tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the target tissue is the liver. In certain embodiments, the target tissue is the lung. A “non-target tissue” is any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is not a target tissue.

[0103] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0104] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0105] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0106] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, theU1197.70243WO00 23 / 193 #13587456v2desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0107] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0108] In certain embodiments, the compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0109] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0110] A “therapeutically effective amount” of a compound described herein 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 of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which 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, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for modulating a target protein in a subject or a cell, tissue, or biological sample. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating cancer (e.g., a solid tumor (e.g., brain tumor (e.g., glioblastoma), pancreatic cancer, ovarian cancer)). In certain embodiments, a therapeutically effective amount is an amount sufficient for modulating a target protein in a subject or a cell, tissue, or biological sample and treating cancer (e.g., a solid tumor (e.g., brain tumor (e.g., glioblastoma), pancreatic cancer, ovarian cancer)).

[0111] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amountU1197.70243WO00 24 / 193 #13587456v2that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for modulating a target protein in a subject or a cell, tissue, or biological sample. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating cancer (e.g., a solid tumor (e.g., brain tumor (e.g., glioblastoma), pancreatic cancer, ovarian cancer)). In certain embodiments, a prophylactically effective amount is an amount sufficient for modulating a target protein in a subject or a cell, tissue, or biological sample and treating cancer (e.g., a solid tumor (e.g., brain tumor (e.g., glioblastoma), pancreatic cancer, ovarian cancer)).

[0112] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0113] The term “inhibit” or “inhibition” in the context of enzymes, for example, in the context of STAT3, IDO, NOS, arginase, PD-L1, protein kinase B, or CD73, refers to a reduction in the activity of the enzyme. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., STAT3, IDO, NOS, arginase, PD-L1, protein kinase B, or CD73 activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., STAT3, IDO, NOS, arginase, PD-L1, protein kinase B, or CD73 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.

[0114] The term “agonist” or “agonism” in the context of enzymes, for example, in the context of TLR7 or STING, refers to the activation of a receptor to produce an enzyme response. In some embodiments, the term refers to an increase of the level of enzyme response, e.g., TLR7 or STING response, to a level that is statistically significantly higher than an initial level, which may, for example, be a baseline level of enzyme response. In some embodiments, the term refers to an increase of the level of enzyme response, e.g., TLR7 or STING response, to a level that is greater than 100%, greater than 125%, greater than 150%, greater than 175%, greater than 200%, greater than 300%, greater than 400%, greater than 500%, greater than 600%, greater than 700%, greater than 800%, greater than 900%, or greater than 1000% of an initial level, which may, for example, be a baseline level of enzyme response.

[0115] The term “antagonist” or “antagonism” in the context of enzymes, for example, refers to blocking activation of a receptor to prevent an enzyme response. In some embodiments, the term refers to a reduction of the level of enzyme response, to a level that is statistically significantly lowerU1197.70243WO00 25 / 193 #13587456v2than an initial level, which may, for example, be a baseline level of enzyme response. In some embodiments, the term refers to a reduction of the level of enzyme response, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme response.

[0116] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0117] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0118] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumorsU1197.70243WO00 26 / 193 #13587456v2are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0119] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non- Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cellU1197.70243WO00 27 / 193 #13587456v2lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T- cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0120] The terms “inflammatory disease” and “inflammatory condition” are used interchangeably herein, and refer to a disease or condition caused by, resulting from, or resulting in inflammation. Inflammatory diseases and conditions include those diseases, disorders or conditions that areU1197.70243WO00 28 / 193 #13587456v2characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and / or loss of function (functio laesa, which can be partial or complete, temporary or permanent. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, andU1197.70243WO00 29 / 193 #13587456v2necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0121] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener’s granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. The compounds disclosed herein may also be useful in treating inflammation associated with cancer.U1197.70243WO00 30 / 193 #13587456v2

[0122] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, , psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0123] The term “liver disease” or “hepatic disease” refers to damage to or a disease of the liver. Non-limiting examples of liver disease include intrahepatic cholestasis (e.g., alagille syndrome, biliary liver cirrhosis), fatty liver (e.g., alcoholic fatty liver, Reye’s syndrome), hepatic vein thrombosis, hepatolenticular degeneration (i.e., Wilson’s disease), hepatomegaly, liver abscess (e.g., amebic liver abscess), liver cirrhosis (e.g., alcoholic, biliary, and experimental liver cirrhosis), alcoholic liver diseases (e.g., fatty liver, hepatitis, cirrhosis), parasitic liver disease (e.g., hepatic echinococcosis, fascioliasis, amebic liver abscess), jaundice (e.g., hemolytic, hepatocellular, cholestatic jaundice), cholestasis, portal hypertension, liver enlargement, ascites, hepatitis (e.g., alcoholic hepatitis, animal hepatitis, chronic hepatitis (e.g., autoimmune, hepatitis B, hepatitis C, hepatitis D, drug induced chronic hepatitis), toxic hepatitis, viral human hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), granulomatous hepatitis, secondary biliary cirrhosis, hepatic encephalopathy, varices, primary biliary cirrhosis, primary sclerosing cholangitis, hepatocellular adenoma, hemangiomas, bile stones, liver failure (e.g., hepatic encephalopathy, acute liver failure), angiomyolipoma, calcified liver metastases, cystic liver metastases, fibrolamellar hepatocarcinoma, hepatic adenoma, hepatoma, hepatic cysts (e.g., Simple cysts, Polycystic liver disease, hepatobiliary cystadenoma, choledochal cyst), mesenchymal tumors (mesenchymal hamartoma, infantile hemangioendothelioma, hemangioma, peliosis hepatis, lipomas, inflammatory pseudotumor), epithelial tumors (e.g., bile duct hamartoma, bile duct adenoma), focal nodular hyperplasia, nodular regenerative hyperplasia, hepatoblastoma, hepatocellular carcinoma, cholangiocarcinoma, cystadenocarcinoma, tumors of blood vessels, angiosarcoma, Karposi’s sarcoma, hemangioendothelioma, embryonal sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, carcinosarcoma, teratoma, carcinoid, squamous carcinoma, primary lymphoma, peliosis hepatis,U1197.70243WO00 31 / 193 #13587456v2erythrohepatic porphyria, hepatic porphyria (e.g., acute intermittent porphyria, porphyria cutanea tarda), and Zellweger syndrome.

[0124] Immune disorders, such as auto-immune disorders, include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren’s syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet’s disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), and disorders ameliorated by a gastroprokinetic agent (e.g., ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and food allergies and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costo-chondritis)).

[0125] A “microbial infection” refers to an infection with a microorganism, such as a fungus, bacteria or virus. In certain embodiments, the microbial infection is an infection with a fungus, i.e., a fungal infection. In certain embodiments, the microbial infection is an infection with a virus, i.e., a viral infection. In certain embodiments, the microbial infection is an infection with a bacteria, i.e., a bacterial infection. Various microbial infections include, but are not limited to, skin infections, GI infections, urinary tract infections, genito-urinary infections, sepsis, blood infections, and systemic infections.

[0126] The term “particle” refers to a small object, fragment, or piece of a substance that may be a single element, inorganic material, organic material, or mixture thereof. Examples of particles include polymeric particles, single-emulsion particles, double-emulsion particles, coacervates, liposomes, microparticles, nanoparticles, macroscopic particles, pellets, crystals, aggregates, composites, pulverized, milled or otherwise disrupted matrices, and cross-linked protein or polysaccharide particles, each of which have an average characteristic dimension of about less than about 1 mm and at least 1 nm, where the characteristic dimension, or “critical dimension,” of the particle is the smallest cross-sectional dimension of the particle. A particle may be composed of a single substance or multiple substances. In certain embodiments, the particle is not a viral particle. In other embodiments, the particle is not a liposome. In certain embodiments, the particle is not a micelle. InU1197.70243WO00 32 / 193 #13587456v2certain embodiments, the particle is substantially solid throughout. In certain embodiments, the particle is a nanoparticle. In certain embodiments, the particle is a microparticle.

[0127] The term “nanoparticle” refers to a particle having an average (e.g., mean) dimension (e.g., diameter) of between about 1 nanometer (nm) and about 1 micrometer (µm) (e.g., between about 1 nm and about 300 nm, between about 1 nm and about 100 nm, between about 1 nm and about 30 nm, between about 1 nm and about 10 nm, or between about 1 nm and about 3 nm), inclusive.

[0128] The term “microparticle” refers to a particle having an average (e.g., mean) dimension (e.g., diameter) of between about 1 micrometer (µm) and about 1 millimeter (mm) (e.g., between about 1 µm and about 100 µm, between about 1 µm and about 30 µm, between about 1 µm and about 10 µm, or between about 1 µm and about 3 µm), inclusive.

[0129] The “hydrodynamic diameter” of a particle refers to the diameter of a solid sphere that would exhibit the same hydrodynamic friction as the particle (e.g., the diameter of a solid sphere that diffuses at the same rate as the particle). Hydrodynamic diameter can be measured through various techniques including dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA).

[0130] The terms “polydispersity index” or “PDI” refer to the degree of non-uniformity of a size distribution of particles (e.g., the broadness of a molecular weight distribution). PDI can be measured through various techniques including dynamic light scattering (DLS).

[0131] The term “zeta potential” refers to the potential difference between the surface of a particle and the surrounding liquid the particles are dispersed in (e.g., the surface charge of nanoparticles in solution). Zeta potential can be measured through various techniques including electrophoretic light scattering and electroacoustic phenomenon.

[0132] The term “pKa” refers to the negative decadic logarithm of the ionization constant (Ka) of an acid; equal to the pH value at which equal concentrations of the acid and conjugate base forms of a substance (often a buffer) are present.

[0133] The term “about X,” where X is a number or percentage, refers to a number or percentage that is between 99.5% and 100.5%, between 99% and 101%, between 98% and 102%, between 97% and 103%, between 96% and 104%, between 95% and 105%, between 92% and 108%, or between 90% and 110%, inclusive, of X.

[0134] The term “dendrimer” refers to a molecular architecture with an interior core, interior layers (or “generations”) of repeating units which are attached to and extend from this interior core, each layer having one or more branching points, and the outermost generation having terminal functional groups on an exterior surface. Examples of dendrimers include, but are not limited to, poly(amidoamine) (PAMAM), polyester, polylysine, and poly(propylene imine) (PPI). In some embodiments, terminal functional groups of a dendrimer include one or more hydroxyl groups, one or more amine groups, and / or one or more carboxyl groups.

[0135] The term “PAMAM dendrimer” means poly(amidoamine) dendrimer, which may contain different cores, with amidoamine building blocks. The method for making them is known to those ofU1197.70243WO00 33 / 193 #13587456v2skill in the art and generally, involves a two-step iterative reaction sequence that produces concentric shells (generations) of dendritic 0-alanine units around a central initiator core. This PAMAM core- shell architecture grows linearly in diameter as a function of added shells (generations). Meanwhile, the surface groups amplify exponentially at each generation according to dendritic-branching mathematics. PAMAM dendrimers can have carboxylic acid, amine and / or hydroxyl terminations and can be any generation of dendrimers including, but not limited to, generation 1 PAMAM dendrimers, generation 2 PAMAM dendrimers, generation 3 PAMAM dendrimers, generation 4 PAMAM dendrimers, generation 5 PAMAM dendrimers, generation 6 PAMAM dendrimers, generation 7 PAMAM dendrimers, generation 8 PAMAM dendrimers, generation 9 PAMAM dendrimers, or generation 10 PAMAM dendrimers. In some embodiments, the number of terminal sites on a dendrimer can depend on the particular dendrimeric scaffold and its generation. For example, in some embodiments, a dendrimer is based on a generation 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PAMAM dendrimeric scaffold, which have 4, 8, 16, 32, 64, 128, 256, 512, 1024, 2048, and 4096 terminal sites, respectively. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0136] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting. Compounds

[0137] In one aspect, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substitutedU1197.70243WO00 34 / 193 #13587456v2heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; each instance of X is independently a conjugated agent; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0138] In another aspect, the present disclosure provides a compound of Formula (I′):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; each instance of X is independently selected from formulae (ii) to (xi):U1197.70243WO00 35 / 193 #13587456v2p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0139] In another aspect, the present disclosure provides a compound of Formula (I′):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;U1197.70243WO00 36 / 193 #13587456v2each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; each instance of X is independently selected from formulae (ii) to (x):p is an integer between 1 and 2(n+2), inclusive;U1197.70243WO00 37 / 193 #13587456v2q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0140] In another aspect, the present disclosure provides a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0141] In another aspect, the present disclosure provides a compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;U1197.70243WO00 38 / 193 #13587456v2each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0142] In another aspect, the present disclosure provides a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–,U1197.70243WO00 39 / 193 #13587456v2optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0143] In another aspect, the present disclosure provides a compound of Formula (V):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0144] In another aspect, the present disclosure provides a compound of Formula (VI):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;U1197.70243WO00 40 / 193 #13587456v2each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0145] In another aspect, the present disclosure provides a compound of Formula (VII):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–,U1197.70243WO00 41 / 193 #13587456v2optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0146] In another aspect, the present disclosure provides a compound of Formula (VIII):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).U1197.70243WO00 42 / 193 #13587456v2

[0147] In another aspect, the present disclosure provides a compound of Formula (IX):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).U1197.70243WO00 43 / 193 #13587456v2

[0148] In another aspect, the present disclosure provides a compound of Formula (X):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0149] In another aspect, the present disclosure provides a compound of Formula (XI):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer;U1197.70243WO00 44 / 193 #13587456v2n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2). Zn, n, p, and q

[0150] As generally described herein, Znis an nth generation polyamidoamine (PAMAM) dendrimer.

[0151] In some embodiments, the nth generation PAMAM dendrimer is prepared by a two-step iterative reaction sequence that produces concentric shells (generations) of dendritic 0-alanine units around a central initiator core. In some embodiments, the nth generation PAMAM dendrimer is a generation 1 PAMAM dendrimer, generation 2 PAMAM dendrimer, generation 3 PAMAM dendrimer, generation 4 PAMAM dendrimer, generation 5 PAMAM dendrimer, generation 6 PAMAM dendrimer, generation 7 PAMAM dendrimer, generation 8 PAMAM dendrimer, generation 9 PAMAM dendrimer, or generation 10 PAMAM dendrimer. In some embodiments, the nth generation PAMAM dendrimer is a generation 6 PAMAM dendrimer.

[0152] In some embodiments, Znis an nth generation PAMAM dendrimer (i.e., Znis the core of an nth generation PAMAM dendrimer, and does not include the terminal groups of the dendrimer). By means of non-limiting example, in some embodiments, Z0is a 0th generation dendrimer (i.e., Z0is the core of a 0th generation PAMAM dendrimer). In some embodiments, Z0is a 0th generation dendrimer (i.e., Z0is the core of a 0th generation PAMAM dendrimer) of formula:U1197.70243WO00 45 / 193 #13587456v2.

[0153] By means of an additional non-limiting example, in some embodiments, Z1is a 1st generation PAMAM dendrimer (i.e., Z1is the core of a 1st generation PAMAM dendrimer). In some embodiments, Z1is a 1st generation PAMAM dendrimer (i.e., Z1is the core of a 1st generation PAMAM dendrimer) of formula:.

[0154] As a further non-limiting example, the compound of Formula (I) or Formula (I′), wherein: Z1is an 1st generation polyamidoamine (PAMAM) dendrimer; n is 1; each instance of Y is independentlycan be represented by the formula:,U1197.70243WO00 46 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0155] As generally described herein, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0156] In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2 or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, n is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 2, 3, 4, 5, 6, or 7. In some embodiments, n is 2, 3, 4, 5, or 6. In some embodiments, n is 2, 3, 4, or 5. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3. In some embodiments, n is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is 3, 4, 5, 6, 7, 8, or 9. In some embodiments, n is 3, 4, 5, 6, 7, or 8. In some embodiments, n is 3, 4, 5, 6, or 7. In some embodiments, n is 3, 4, 5, or 6. In some embodiments, n is 3, 4, or 5. In some embodiments, n is 3 or 4.

[0157] In some embodiments, n is 4 or greater. In some embodiments, n is 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is 4, 5, 6, 7, 8, or 9. In some embodiments, n is 4, 5, 6, 7, or 8. In some embodiments, n is 4, 5, 6, or 7. In some embodiments, n is 4, 5, or 6. In some embodiments, n is 4 or 5. In some embodiments, n is 5 or greater. In some embodiments, n is 5, 6, 7, 8, 9, or 10. In some embodiments, n is 5, 6, 7, 8, or 9. In some embodiments, n is 5, 6, 7, or 8. In some embodiments, n is 5, 6, or 7. In some embodiments, n is 5 or 6. In some embodiments, n is 6 or greater. In some embodiments, n is 6, 7, 8, 9, or 10. In some embodiments, n is 6, 7, 8, or 9. In some embodiments, n is 6, 7, or 8. In some embodiments, n is 6 or 7. In some embodiments, n is 7 or greater. In some embodiments, n is 7, 8, 9, or 10. In some embodiments, n is 7, 8, or 9. In some embodiments, n is 7 or 8. In some embodiments, n is 8 or greater. In some embodiments, n is 8, 9, or 10. In some embodiments, n is 8 or 9. In some embodiments, n is 9 or greater. In some embodiments, n is 9 or 10.

[0158] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0159] In some embodiments, n is 0, such that Znis Z0, and Z0is a 0th generation PAMAM dendrimer. In some embodiments, n is 1, such that Znis Z1, and Z1is a 1st generation PAMAM dendrimer. In some embodiments, n is 2, such that Znis Z2, and Z2is a 2nd generation PAMAM dendrimer. In some embodiments, n is 3, such that Znis Z3, and Z3is a 3rd generation PAMAM dendrimer. In some embodiments, n is 4, such that Znis Z4, and Z4is a 4th generation PAMAMU1197.70243WO00 47 / 193 #13587456v2dendrimer. In some embodiments, n is 5, such that Znis Z5, and Z5is a 5th generation PAMAM dendrimer. In some embodiments, n is 6, such that Znis Z6, and Z6is a 6th generation PAMAM dendrimer. In some embodiments, n is 7, such that Znis Z7, and Z7is a 7th generation PAMAM dendrimer. In some embodiments, n is 8, such that Znis Z8, and Z8is a 8th generation PAMAM dendrimer. In some embodiments, n is 9, such that Znis Z9, and Z9is a 9th generation PAMAM dendrimer. In some embodiments, n is 10, such that Znis Z10, and Z10is a 10th generation PAMAM dendrimer.

[0160] In some embodiments, Znis Z4, Z5, Z6, Z7, Z8, Z9, or Z10. In some embodiments, Znis Z4, Z5, Z6, Z7, Z8, or Z9. In some embodiments, Znis Z4, Z5, Z6, Z7, or Z8. In some embodiments, Znis Z4, Z5, Z6, or Z7. In some embodiments, Znis Z4, Z5, or Z6. In some embodiments, Znis Z5, Z6, Z7, Z8, Z9, or Z10. In some embodiments, Znis Z5, Z6, Z7, Z8, or Z9. In some embodiments, Znis Z5, Z6, Z7, or Z8. In some embodiments, Znis Z5, Z6, or Z7. In some embodiments, Znis Z5or Z6. In some embodiments, Znis Z6, Z7, Z8, Z9, or Z10. In some embodiments, Znis Z6, Z7, Z8, or Z9. In some embodiments, Znis Z6, Z7, or Z8. In some embodiments, Znis Z6or Z7.

[0161] As generally described herein, p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

[0162] In some embodiments, n is 0, such that the sum of p and q is 4. In some embodiments, n is 1, such that the sum of p and q is 8. In some embodiments, n is 2, such that the sum of p and q is 16. In some embodiments, n is 3, such that the sum of p and q is 32.

[0163] In some embodiments, n is 4, such that the sum of p and q is 64. In some embodiments, the sum of p and q is 64. In some embodiments, the sum of p and q is 64, p is an integer between 1 and 10, inclusive, and q is an integer between 54 and 63, inclusive. In some embodiments, the sum of p and q is 64, p is an integer between 1 and 5, inclusive, and q is an integer between 59 and 63, inclusive.

[0164] In some embodiments, n is 5, such that the sum of p and q is 128. In some embodiments, the sum of p and q is 128. In some embodiments, the sum of p and q is 128, p is an integer between 1 and 20, inclusive, and q is an integer between 108 and 127, inclusive. In some embodiments, the sum of p and q is 128, p is an integer between 1 and 15, inclusive, and q is an integer between 113 and 127, inclusive. In some embodiments, the sum of p and q is 128, p is an integer between 1 and 10, inclusive, and q is an integer between 118 and 127, inclusive. In some embodiments, the sum of p and q is 128, p is an integer between 1 and 5, inclusive, and q is an integer between 123 and 127, inclusive.

[0165] In some embodiments, n is 6, such that the sum of p and q is 256. In some embodiments, the sum of p and q is 256. In some embodiments, the sum of p and q is 256, p is an integer between 1 and 40, inclusive, and q is an integer between 216 and 255, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 5 and 35, inclusive, and q is an integer between 221 and 251, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 8 and 32,U1197.70243WO00 48 / 193 #13587456v2inclusive, and q is an integer between 224 and 248, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 10 and 30, inclusive, and q is an integer between 226 and 246, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 12 and 28, inclusive, and q is an integer between 228 and 244, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 14 and 26, inclusive, and q is an integer between 230 and 242, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 15 and 25, inclusive, and q is an integer between 231 and 241, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 16 and 24, inclusive, and q is an integer between 232 and 240, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 17 and 23, inclusive, and q is an integer between 233 and 239, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 18 and 22, inclusive, and q is an integer between 234 and 238, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 19 and 21, inclusive, and q is an integer between 235 and 237, inclusive.

[0166] In some embodiments, the sum of p and q is 256, p is an integer between 1 and 30, inclusive, and q is an integer between 226 and 255, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 3 and 27, inclusive, and q is an integer between 229 and 253, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 5 and 25, inclusive, and q is an integer between 231 and 251, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 7 and 23, inclusive, and q is an integer between 233 and 249, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 9 and 21, inclusive, and q is an integer between 235 and 247, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 10 and 20, inclusive, and q is an integer between 236 and 246, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 11 and 19, inclusive, and q is an integer between 237 and 245, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 12 and 18, inclusive, and q is an integer between 238 and 244, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 13 and 17, inclusive, and q is an integer between 239 and 243, inclusive. In some embodiments, the sum of p and q is 256, p is an integer between 14 and 16, inclusive, and q is an integer between 240 and 242, inclusive.

[0167] In some embodiments, p is 1 and q is 255. In some embodiments, p is 2 and q is 254. In some embodiments, p is 3 and q is 253. In some embodiments, p is 4 and q is 252. In some embodiments, p is 5 and q is 251. In some embodiments, p is 6 and q is 250. In some embodiments, p is 7 and q is 249. In some embodiments, p is 8 and q is 248. In some embodiments, p is 9 and q is 247. In some embodiments, p is 10 and q is 246. In some embodiments, p is 11 and q is 245. In some embodiments, p is 12 and q is 244. In some embodiments, p is 13 and q is 243. In some embodiments, p is 14 and q is 242. In some embodiments, p is 15 and q is 241. In some embodiments, p is 16 and q is 240. In some embodiments, p is 17 and q is 239. In some embodiments, p is 18 and q is 238. In some embodiments, p is 19 and q is 237. In some embodiments, p is 20 and q is 236. In some embodiments,U1197.70243WO00 49 / 193 #13587456v2p is 21 and q is 235. In some embodiments, p is 22 and q is 234. In some embodiments, p is 23 and q is 233. In some embodiments, p is 24 and q is 232. In some embodiments, p is 25 and q is 231. In some embodiments, p is 26 and q is 230. In some embodiments, p is 27 and q is 229. In some embodiments, p is 28 and q is 228. In some embodiments, p is 29 and q is 227. In some embodiments, p is 30 and q is 226. In some embodiments, p is 31 and q is 225. In some embodiments, p is 32 and q is 224. In some embodiments, p is 33 and q is 223. In some embodiments, p is 34 and q is 222. In some embodiments, p is 35 and q is 221. In some embodiments, p is 36 and q is 220. In some embodiments, p is 37 and q is 219. In some embodiments, p is 38 and q is 218. In some embodiments, p is 39 and q is 217. In some embodiments, p is 40 and q is 216. In some embodiments, p is 15 and q is 241; or p is 20 and q is 236.

[0168] In some embodiments, n is 7, such that the sum of p and q is 512. In some embodiments, the sum of p and q is 512. In some embodiments, the sum of p and q is 512, p is an integer between 1 and 80, inclusive, and q is an integer between 432 and 511, inclusive. In some embodiments, the sum of p and q is 512, p is an integer between 1 and 40, inclusive, and q is an integer between 472 and 511, inclusive.

[0169] In some embodiments, n is 8, such that the sum of p and q is 1024. In some embodiments, the sum of p and q is 1024. In some embodiments, the sum of p and q is 1024, p is an integer between 1 and 160, inclusive, and q is an integer between 864 and 1023, inclusive. In some embodiments, the sum of p and q is 512, p is an integer between 1 and 80, inclusive, and q is an integer between 944 and 1023, inclusive.

[0170] In some embodiments, n is 9, such that the sum of p and q is 2048. In some embodiments, the sum of p and q is 2048. In some embodiments, the sum of p and q is 2048, p is an integer between 1 and 320, inclusive, and q is an integer between 1728 and 2047, inclusive. In some embodiments, the sum of p and q is 2048, p is an integer between 1 and 160, inclusive, and q is an integer between 1888 and 2047, inclusive.

[0171] In some embodiments, n is 10, such that the sum of p and q is 4096. In some embodiments, the sum of p and q is 4096. In some embodiments, the sum of p and q is 4096, p is an integer between 1 and 640, inclusive, and q is an integer between 3456 and 4095, inclusive. In some embodiments, the sum of p and q is 4096, p is an integer between 1 and 320, inclusive, and q is an integer between 3776 and 4095, inclusive.

[0172] In some embodiments, p is at least 1. In some embodiments, p is at least 2. In some embodiments, p is at least 3. In some embodiments, p is at least 4. In some embodiments, p is at least 5. In some embodiments, p is at least 6. In some embodiments, p is at least 7. In some embodiments, p is at least 8. In some embodiments, p is at least 9. In some embodiments, p is at least 10. In some embodiments, p is at least 11. In some embodiments, p is at least 12. In some embodiments, p is at least 13. In some embodiments, p is at least 14. In some embodiments, p is at least 15. In someU1197.70243WO00 50 / 193 #13587456v2embodiments, p is at least 16. In some embodiments, p is at least 17. In some embodiments, p is at least 18. In some embodiments, p is at least 19. In some embodiments, p is at least 20. L and R1

[0173] As generally described herein, each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, – S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0174] In some embodiments, at least one instance of L is optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, at least one instance of L is optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, at least one instance of L is optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0175] In some embodiments, at least one instance of L is optionally substituted C1-20 alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted 5- 6 membered heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, – C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, at least one instance of L is optionally substituted C1-20alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20alkylene or optionally substituted 5-6 membered heteroarylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, at least one instance of L is optionally substituted C1-20alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backboneU1197.70243WO00 51 / 193 #13587456v2carbon atoms in the optionally substituted C1-20alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0176] In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20alkylene or optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene or optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0177] In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–. In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20alkylene is replaced with –O–. In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–. In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–. In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof,U1197.70243WO00 52 / 193 #13587456v2wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–. In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–.

[0178] In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1- 20 alkylene are replaced with –NR1–. In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atoms in the optionally substituted linear C1-20 alkylene is replaced with –NR1–. In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1- 20 alkylene are replaced with –NR1–.

[0179] In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20alkylene is replaced with –C(=O)–. In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 3U1197.70243WO00 53 / 193 #13587456v2backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L is optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–.

[0180] In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1- 20 alkylene are replaced with optionally substituted heteroarylene. In some embodiments, at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20 alkylene is replaced with optionally substituted heteroarylene.

[0181] In some embodiments, at least one instance of L comprises optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0182] In some embodiments, at least one instance of L comprises optionally substituted C1-20alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20alkylene or optionally substituted 5-6 membered heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted C1-20alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms inU1197.70243WO00 54 / 193 #13587456v2the optionally substituted C1-20alkylene or optionally substituted 5-6 membered heteroarylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted C1-20alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with – O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0183] In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene or optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene or optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0184] In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20alkylene is replaced with –O–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–. In some embodiments, at least one instance of L comprises optionallyU1197.70243WO00 55 / 193 #13587456v2substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–.

[0185] In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atoms in the optionally substituted linear C1-20 alkylene is replaced with –NR1–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –NR1–.

[0186] In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1U1197.70243WO00 56 / 193 #13587456v2backbone carbon atom in the optionally substituted linear C1-20alkylene is replaced with –C(=O)–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–.

[0187] In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20 alkylene is replaced with optionally substituted heteroarylene.

[0188] In some embodiments, at least one instance of L comprises optionally substituted alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0189] In some embodiments, at least one instance of L comprises optionally substituted C1-20alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20alkylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted C1-20alkylene, optionally wherein one or more backbone carbon atoms in theU1197.70243WO00 57 / 193 #13587456v2optionally substituted C1-20alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0190] In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene are independently replaced with –O–, – NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0191] In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20 alkylene is replaced with –O–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with – O–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–.

[0192] In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –NR1–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, wherein at least 1 backbone carbon atoms in the optionally substituted linear C1-20alkylene is replaced with –NR1–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –NR1–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –NR1–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene,U1197.70243WO00 58 / 193 #13587456v2wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –NR1–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20alkylene, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –NR1–.

[0193] In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20 alkylene is replaced with –C(=O)–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–.

[0194] In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20 alkylene is replaced with optionally substituted heteroarylene.

[0195] In some embodiments, at least one instance of L comprises,U1197.70243WO00 59 / 193 #13587456v2, wherein each x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each y is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, at least one instance of L comprises10; and each y is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, at least one instance of L. In some embodiments, at least one instance of LU1197.70243WO00 60 / 193 #13587456v2

[0196] In some embodiments, at least one instance of L comprises optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heteroarylene are independently replaced with –O–, –NR1–, – C(=O)–, or optionally substituted heteroarylene.

[0197] In some embodiments, at least one instance of L comprises optionally substituted heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted 5-6 membered heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted 5 membered heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted 6 membered heteroarylene. In some embodiments, at least one instance of L comprises optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring heteroatoms selected from O, N, and S. In some embodiments, at least one instance of L comprises optionally substituted 5 membered heteroarylene having 1, 2, or 3 ring heteroatoms selected from O, N, and S. In some embodiments, at least one instance of L comprises optionally substituted 6 membered heteroarylene having 1, 2, or 3 ring heteroatoms selected from O, N, and S.

[0198] In some embodiments, at least one instance of L comprises optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms. In some embodiments, at least one instance of L comprises optionally substituted 5-6 membered heteroarylene having 1 ring N atom. In some embodiments, at least one instance of L comprises optionally substituted 5-6 membered heteroarylene having 2 ring N atoms. In some embodiments, at least one instance of L comprises optionally substituted 5-6 membered heteroarylene having 3 ring N atoms. In some embodiments, at least one instance of L comprises optionally substituted 5 membered heteroarylene having 1, 2, or 3 ring N atoms. In some embodiments, at least one instance of L comprises optionally substituted 5 membered heteroarylene having 1 ring N atom. In some embodiments, at least one instance of L comprises optionally substituted 5 membered heteroarylene having 2 ring N atoms. In some embodiments, at least one instance of L comprises optionally substituted 5 membered heteroarylene having 3 ring N atoms. In some embodiments, at least one instance of L comprises optionally substituted 6 membered heteroarylene having 1, 2, or 3 ring N atoms. In some embodiments, at least one instance of L comprises optionally substituted 6 membered heteroarylene having 1 ring N atom. In some embodiments, at least one instance of L comprises optionally substituted 6 membered heteroarylene having 2 ring N atoms. In some embodiments, at least one instance of L comprises optionally substituted 6 membered heteroarylene having 3 ring N atoms.U1197.70243WO00 61 / 193 #13587456v2

[0199] In some embodiments, at least one instance of L comprises , ,. In some embodiments, at least one instance of L comprises. In some embodiments, at least one instance of L comprises. In some embodiments, at least one instance of L comprises.In some embodiments, at least one instance of L is,

[0201] In some embodiments, at least one instance of L comprisesU1197.70243WO00 62 / 193 #13587456v2.

[0202] In some embodiments, each instance of L independently comprises optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene or optionally substituted heteroarylene are independently replaced with –O–, – NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0203] In some embodiments, each instance of L independently comprises optionally substituted C1- 20 alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted 5-6 membered heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted C1-20 alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted 5-6 membered heteroarylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted C1-20 alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0204] In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20alkylene or optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–,U1197.70243WO00 63 / 193 #13587456v2–C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene or optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0205] In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20 alkylene is replaced with –O–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–.U1197.70243WO00 64 / 193 #13587456v2

[0206] In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –NR1–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atoms in the optionally substituted linear C1-20alkylene is replaced with –NR1–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1- 20 alkylene are replaced with –NR1–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–.

[0207] In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20alkylene is replaced with –C(=O)–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or aU1197.70243WO00 65 / 193 #13587456v2combination thereof, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–.

[0208] In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms, or a combination thereof, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20 alkylene is replaced with optionally substituted heteroarylene.

[0209] In some embodiments, each instance of L independently comprises optionally substituted alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0210] In some embodiments, each instance of L independently comprises optionally substituted C1- 20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted C1-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20alkylene are independently replaced with –O–, –NR1–, – C(=O)–, or optionally substituted heteroarylene.

[0211] In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20alkylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, – S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.U1197.70243WO00 66 / 193 #13587456v2

[0212] In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, wherein one or more backbone carbon atoms in the optionally substituted linear C1-20alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –O–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20 alkylene is replaced with –O–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –O–.

[0213] In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 1 backbone carbon atoms in the optionally substituted linear C1-20 alkylene is replaced with –NR1–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –NR1–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –NR1–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –NR1–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –NR1–.

[0214] In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, wherein at least 1 backboneU1197.70243WO00 67 / 193 #13587456v2carbon atom in the optionally substituted linear C1-20alkylene is replaced with –C(=O)–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, wherein at least 2 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 3 backbone carbon atoms in the optionally substituted linear C1-20alkylene are replaced with –C(=O)–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20alkylene, wherein at least 4 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with –C(=O)–.

[0215] In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 1, 2, 3, 4, or 5 backbone carbon atoms in the optionally substituted linear C1-20 alkylene are replaced with optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted linear C1-20 alkylene, wherein at least 1 backbone carbon atom in the optionally substituted linear C1-20 alkylene is replaced with optionally substituted heteroarylene.

[0216] In some embodiments, each instance of L independently comprises, ,10; and each y is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each instance of L independently comprisesU1197.70243WO00 68 / 193 #13587456v2, , , , , , , , , , , , , , or 10; and each y is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each instance of L

[0217] In some embodiments, each instance of L independently comprises optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heteroarylene are independently replaced with –U1197.70243WO00 69 / 193 #13587456v2O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

[0218] In some embodiments, each instance of L independently comprises optionally substituted heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted 5-6 membered heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted 5 membered heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted 6 membered heteroarylene. In some embodiments, each instance of L independently comprises optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring heteroatoms selected from O, N, and S. In some embodiments, each instance of L independently comprises optionally substituted 5 membered heteroarylene having 1, 2, or 3 ring heteroatoms selected from O, N, and S. In some embodiments, each instance of L independently comprises optionally substituted 6 membered heteroarylene having 1, 2, or 3 ring heteroatoms selected from O, N, and S.

[0219] In some embodiments, each instance of L independently comprises optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring N atoms. In some embodiments, each instance of L independently comprises optionally substituted 5-6 membered heteroarylene having 1 ring N atom. In some embodiments, each instance of L independently comprises optionally substituted 5-6 membered heteroarylene having 2 ring N atoms. In some embodiments, each instance of L independently comprises optionally substituted 5-6 membered heteroarylene having 3 ring N atoms. In some embodiments, each instance of L independently comprises optionally substituted 5 membered heteroarylene having 1, 2, or 3 ring N atoms. In some embodiments, each instance of L independently comprises optionally substituted 5 membered heteroarylene having 1 ring N atom. In some embodiments, each instance of L independently comprises optionally substituted 5 membered heteroarylene having 2 ring N atoms. In some embodiments, each instance of L independently comprises optionally substituted 5 membered heteroarylene having 3 ring N atoms. In some embodiments, each instance of L independently comprises optionally substituted 6 membered heteroarylene having 1, 2, or 3 ring N atoms. In some embodiments, each instance of L independently comprises optionally substituted 6 membered heteroarylene having 1 ring N atom. In some embodiments, each instance of L independently comprises optionally substituted 6 membered heteroarylene having 2 ring N atoms. In some embodiments, each instance of L independently comprises optionally substituted 6 membered heteroarylene having 3 ring N atoms.

[0220] In some embodiments, each instance of L independently comprises,, , . In some embodiments, each instance of L independentlyU1197.70243WO00 70 / 193 #13587456v2comprises . In some embodiments, each instance of L independently comprises. In some embodiments, each instance of L independentlycomprises.

[0221] In some embodiments, each instance of L independently comprises

[0222] As generally described herein, each instance of R1is independently hydrogen or optionally substituted alkyl.

[0223] In some embodiments, at least one instance of R1is hydrogen.

[0224] In some embodiments, at least one instance of R1is optionally substituted alkyl. In some embodiments, at least one instance of R1is optionally substituted C1-12 alkyl. In some embodiments, at least one instance of R1is optionally substituted C1-6 alkyl. In some embodiments, at least one instance of R1is optionally substituted C1-3 alkyl. In some embodiments, at least one instance of R1is unsubstituted alkyl. In some embodiments, at least one instance of R1is unsubstituted C1-12 alkyl. In some embodiments, at least one instance of R1is unsubstituted C1-6 alkyl. In some embodiments, at least one instance of R1is unsubstituted C1-3 alkyl. In some embodiments, at least one instance of R1isU1197.70243WO00 71 / 193 #13587456v2unsubstituted linear alkyl. In some embodiments, at least one instance of R1is unsubstituted linear C1-12alkyl. In some embodiments, at least one instance of R1is unsubstituted linear C1-6alkyl. In some embodiments, at least one instance of R1is unsubstituted linear C1-3alkyl.

[0225] In some embodiments, each instance of R1is independently hydrogen.

[0226] In some embodiments, each instance of R1is independently optionally substituted alkyl. In some embodiments, each instance of R1is independently optionally substituted C1-12alkyl. In some embodiments, each instance of R1is independently optionally substituted C1-6alkyl. In some embodiments, each instance of R1is independently optionally substituted C1-3 alkyl. In some embodiments, each instance of R1is independently unsubstituted alkyl. In some embodiments, each instance of R1is independently unsubstituted C1-12 alkyl. In some embodiments, each instance of R1is independently unsubstituted C1-6 alkyl. In some embodiments, each instance of R1is independently unsubstituted C1-3 alkyl. In some embodiments, each instance of R1is independently unsubstituted linear alkyl. In some embodiments, each instance of R1is independently unsubstituted linear C1-12 alkyl. In some embodiments, each instance of R1is independently unsubstituted linear C1-6 alkyl. In some embodiments, each instance of R1is independently unsubstituted linear C1-3 alkyl. X

[0227] As generally described herein, each instance of X is independently a conjugated agent. In some embodiments, the conjugated agent is a radical of an agent. In some embodiments, each instance of X is independently a radical of an agent.

[0228] In some embodiments, the agent is a small molecule compound (e.g., a small molecule organic compound). In some embodiments, the conjugated agent is a radical of a small molecule compound (e.g., a small molecule organic compound). In some embodiments, each instance of X is independently a radical of a small molecule compound (e.g., a small molecule organic compound). In some embodiments, an agent is a small molecule compound having a molecular weight of less than 2,000 daltons (Da), less than 1,500 Da, less than 1,000 Da, or less than 500 Da. In some embodiments, an agent is a small-molecule compound having a molecular weight of between about 100 and about 2,000 Da. For example, in some embodiments, the small-molecule compound has a molecular weight of between about 100 and about 1,500 Da, between about 100 and about 1,000 Da, between about 100 and about 750 Da, between about 100 and about 500 Da, between about 500 and about 2,000 Da, between about 500 and about 1,500 Da, or between about 500 and about 1,000 Da.

[0229] In some embodiments, the conjugated agent is a radical of an agent selected from:U1197.70243WO00 72 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the conjugated agent is a radical of LLL12-Hydrazone (18):Hydrazone, 18),U1197.70243WO00 73 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0231] LLL12 refers to 5-hydroxy-9,10-dioxo-9,10-dihydroanthracene-1-sulfonamide (CAS No. 1260247-42-4), or a pharmaceutically acceptable salt thereof, which is a signal transducer and activator of transcription 3 (STAT3) inhibitor. Imiquimod refers to 1-isobutyl-1H-imidazo[4,5- c]quinolin-4-amine (CAS No.99011-02-6), or a pharmaceutically acceptable salt thereof, which is a Toll-like receptor 7 (TLR7) agonist. NLG-919 (IDO-IN-7) refers to 1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethan-1-ol (CAS No.1402836-58-1), or a pharmaceutically acceptable salt thereof, which is an indoleamine 2,3-dioxygenase (IDO) inhibitor. L-NMMA refers to N5- [imino(methylamino)methyl]-L-ornithine (L-NG-monomethyl Arginine) (CAS No.53308-83-1, acetate salt), or a pharmaceutically acceptable salt thereof, which is a nitric oxide synthase (NOS) inhibitor. Nor-NOHA refers to (S)-2-amino-4-(3-hydroxyguanidino)butanoic acid (Nω-Hydroxy-nor- L-arginine) (CAS No.291758-32-2, dichloride salt), or a pharmaceutically acceptable salt thereof, which is an arginase inhibitor. CA-170 refers to (((S)-3-amino-1-(3-((R)-1-amino-2-hydroxyethyl)- 1,2,4-oxadiazol-5-yl)-3-oxopropyl)carbamoyl)-L-threonine (CAS No.1673534-76-3), or a pharmaceutically acceptable salt thereof, which is a programmed death-ligand 1 (PD-L1) inhibitor. Triciribine phosphate refers to ((2S,3R,4S,5S)-5-(3-amino-5-methyl-1,4,5,6,8-pentaazaacenaphthylen- 1(5H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl dihydrogen phosphate (CAS No.61966-08-3), or a pharmaceutically acceptable salt thereof, which is a protein kinase B inhibitor. AB-680 refers to (((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-fluorophenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid (CAS No.2105904-82-1), or a pharmaceutically acceptable salt thereof, which is a cluster of differentiation 73 (CD73) inhibitor.2′,3′-cGAMP (2′,3′-cyclic GMP-AMP) refers to 2-amino-9- ((5R,7R,8R,12aR,14R,15R,15aS,16R)-14-(6-amino-9H-purin-9-yl)-2,10,15,16-tetrahydroxy-2,10- dioxidooctahydro-12H-5,8-methanofuro[3,2-l][1,3,6,9,11]pentaoxa[2,10]diphosphacyclotetradecin-7- yl)-3,9-dihydro-6H-purin-6-one (CAS No.1441190-66-4), or a pharmaceutically acceptable salt thereof, which is a stimulator of interferon genes (STING) agonist.

[0232] In some embodiments, the conjugated agent is a radical of an agent selected from LLL12, imiquimod, and NLG-919. In some embodiments, the conjugated agent is a radical of LLL12. In some embodiments, the conjugated agent is a radical of imiquimod. In some embodiments, the conjugated agent is a radical of NLG-919. In some embodiments, the conjugated agent is a radical of an agent selected from L-NMMA, nor-NOHA, and CA-170. In some embodiments, the conjugated agent is a radical of L-NMMA. In some embodiments, the conjugated agent is a radical of nor-NOHA. In some embodiments, the conjugated agent is a radical of CA-170. In some embodiments, the conjugated agent is a radical of an agent selected from triciribine phosphate, AB-680, and 2′,3′-cGAMP. In some embodiments, the conjugated agent is a radical of triciribine phosphate. In some embodiments, the conjugated agent is a radical of AB-680. In some embodiments, the conjugated agent is a radical ofU1197.70243WO00 74 / 193 #13587456v22′,3′-cGAMP. In some embodiments, the conjugated agent is a radical of an agent selected from LLL12 and LLL12-Hydrazone.

[0233] In some embodiments, at least one instance of X is a radical of an agent selected from LLL12, imiquimod, NLG-919, L-NMMA, nor-NOHA, CA-170, triciribine phosphate, AB-680, and 2′,3′- cGAMP. In some embodiments, at least one instance of X is a radical of an agent selected from LLL12, imiquimod, and NLG-919. In some embodiments, at least one instance of X is a radical of LLL12. In some embodiments, at least one instance of X is a radical of imiquimod. In some embodiments, at least one instance of X is a radical of NLG-919. In some embodiments, at least one instance of X is a radical of an agent selected from L-NMMA, nor-NOHA, and CA-170. In some embodiments, at least one instance of X is a radical of L-NMMA. In some embodiments, at least one instance of X is a radical of nor-NOHA. In some embodiments, at least one instance of X is a radical of CA-170. In some embodiments, at least one instance of X is a radical of an agent selected from triciribine phosphate, AB-680, and 2′,3′-cGAMP. In some embodiments, at least one instance of X is a radical of triciribine phosphate. In some embodiments, at least one instance of X is a radical of AB- 680. In some embodiments, at least one instance of X is a radical of 2′,3′-cGAMP.

[0234] In some embodiments, at least one instance of X is a radical of an agent selected from LLL12, imiquimod, NLG-919, L-NMMA, nor-NOHA, CA-170, triciribine phosphate, AB-680, 2′,3′-cGAMP, and LLL12-Hydrazone. In some embodiments, at least one instance of X is a radical of an agent selected from LLL12 and LLL12-Hydrazone. In some embodiments, at least one instance of X is a radical of LLL12-Hydrazone.

[0235] In some embodiments, each instance of X is independently a radical of an agent selected from LLL12, imiquimod, NLG-919, L-NMMA, nor-NOHA, CA-170, triciribine phosphate, AB-680, and 2′,3′-cGAMP. In some embodiments, each instance of X is independently a radical of an agent selected from LLL12, imiquimod, and NLG-919. In some embodiments, each instance of X is independently a radical of LLL12. In some embodiments, each instance of X is independently a radical of imiquimod. In some embodiments, each instance of X is independently a radical of NLG- 919. In some embodiments, each instance of X is independently a radical of an agent selected from L- NMMA, nor-NOHA, and CA-170. In some embodiments, each instance of X is independently a radical of L-NMMA. In some embodiments, each instance of X is independently a radical of nor- NOHA. In some embodiments, each instance of X is independently a radical of CA-170. In some embodiments, each instance of X is independently a radical of an agent selected from triciribine phosphate, AB-680, and 2′,3′-cGAMP. In some embodiments, each instance of X is independently a radical of triciribine phosphate. In some embodiments, each instance of X is independently a radical of AB-680. In some embodiments, each instance of X is independently a radical of 2′,3′-cGAMP.

[0236] In some embodiments, each instance of X is independently a radical of an agent selected from LLL12, imiquimod, NLG-919, L-NMMA, nor-NOHA, CA-170, triciribine phosphate, AB-680, 2′,3′- cGAMP, and LLL12-Hydrazone. In some embodiments, each instance of X is independently a radicalU1197.70243WO00 75 / 193 #13587456v2of an agent selected from LLL12 and LLL12-Hydrazone. In some embodiments, each instance of X is independently a radical of LLL12-Hydrazone.

[0237] In some embodiments, the agent is a hydrophobic agent, a cationic agent, or an anionic agent. In some embodiments, the agent is a hydrophobic agent. In some embodiments, the hydrophobic agent has a logP value of greater than 0. In some embodiments, the hydrophobic agent is selected from LLL12, imiquimod, and NLG-919, and pharmaceutically acceptable salts thereof.

[0238] In some embodiments, the agent is a cationic agent. In some embodiments, the cationic agent is positively charged at physiological pH. In some embodiments, the cationic agent is selected from L- NMMA, nor-NOHA, and CA-170, and pharmaceutically acceptable salts thereof.

[0239] In some embodiments, the agent is an anionic agent. In some embodiments, the anionic agent is negatively charged at physiological pH. In some embodiments, the anionic agent is selected from triciribine phosphate, AB-680, and 2′,3′-cGAMP, and pharmaceutically acceptable salts thereof.

[0240] In some embodiments, the agent is a STAT3 inhibitor, a TLR7 agonist, an IDO inhibitor, an NOS inhibitor, an arginase inhibitor, a PD-L1 inhibitor, a protein kinase B inhibitor, a CD73 inhibitor, or a STING agonist. In some embodiments, the agent is a STAT3 inhibitor, a TLR7 agonist, or an IDO inhibitor. In some embodiments, the agent is a STAT3 inhibitor. In some embodiments, the agent is a TLR7 agonist. In some embodiments, the agent is an IDO inhibitor. In some embodiments, the agent is an NOS inhibitor, an arginase inhibitor, a PD-L1 inhibitor. In some embodiments, the agent is an NOS inhibitor. In some embodiments, the agent is an arginase inhibitor. In some embodiments, the agent is a PD-L1 inhibitor. In some embodiments, the agent is a protein kinase B inhibitor, a CD73 inhibitor, or a STING agonist. In some embodiments, the agent is a protein kinase B inhibitor. In some embodiments, the agent is a CD73 inhibitor. In some embodiments, the agent is a STING agonist.

[0241] In some embodiments, the STAT3 inhibitor is LLL12. In some embodiments, the STAT3 inhibitor is LLL12-Hydrazone. In some embodiments, the TLR7 agonist is imiquimod. In some embodiments, the IDO inhibitor is NLG-919. In some embodiments, the NOS inhibitor is L-NMMA. In some embodiments, the arginase inhibitor is nor-NOHA. In some embodiments, the PD-L1 inhibitor is CA-170. In some embodiments, the protein kinase B inhibitor is triciribine phosphate. In some embodiments, the CD73 inhibitor is AB-680. In some embodiments, the STING agonist is 2′,3′- cGAMP.U1197.70243WO00 76 / 193 #13587456v2

[0242] In some embodiments, at least one instance of X is selected from formulae (ii), (iii), (iv), (v), (vi), (vii), (viii)U1197.70243WO00 77 / 193 #13587456v2

[0243] In some embodiments, at least one instance of X is selected from formulae (ii), (iii), (iv), (v), (vi), (vii), (viii)

[0244] In some embodiments, at least one instance of X is selected from formulae (ii), (iii), and (iv). In some embodiments, at least one instance of X is of formula (ii). In some embodiments, at least one instance of X is of formula (iii). In some embodiments, at least one instance of X is of formula (iv). In some embodiments, at least one instance of X is selected from formulae (v), (vi), and (vii). In some embodiments, at least one instance of X is of formula (v). In some embodiments, at least one instance of X is of formula (vi). In some embodiments, at least one instance of X is of formula (vii). In some embodiments, at least one instance of X is selected from formulae (viii), (ix), and (x). In some embodiments, at least one instance of X is of formula (viii). In some embodiments, at least oneU1197.70243WO00 78 / 193 #13587456v2instance of X is of formula (ix). In some embodiments, at least one instance of X is of formula (x). In some embodiments, at least one instance of X is selected from formulae (ii) and (xi). In some embodiments, at least one instance of X is of formula (xi).

[0245] In some embodiments, each instance of X is independently selected from formulae (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), and (x). In some embodiments, each instance of X is independently selected from formulae (ii), (iii), and (iv). In some embodiments, each instance of X is independently of formula (ii). In some embodiments, each instance of X is independently of formula (iii). In some embodiments, each instance of X is independently of formula (iv). In some embodiments, each instance of X is independently selected from formulae (v), (vi), and (vii). In some embodiments, each instance of X is independently of formula (v). In some embodiments, each instance of X is independently of formula (vi). In some embodiments, each instance of X is independently of formula (vii). In some embodiments, each instance of X is independently selected from formulae (viii), (ix), and (x). In some embodiments, each instance of X is independently of formula (viii). In some embodiments, each instance of X is independently of formula (ix). In some embodiments, each instance of X is independently of formula (x). In some embodiments, each instance of X is independently selected from formulae (ii) and (xi). In some embodiments, each instance of X is independently of formula (xi).

[0246] In some embodiments, the compound of Formula (I) or Formula (I′) is selected fromU1197.70243WO00 79 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the compound of Formula (I) or Formula (I′) is selected from FormulaeU1197.70243WO00 80 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the compound of Formula (I) or Formula (I′) is selected from Formulae (II), (III), (IV), and (XI). In some embodiments, the compound of Formula (I) or Formula (I′) is selected from Formulae (II), (III), and (IV). In some embodiments, the compound of Formula (I) or Formula (I′) is of Formula (II). In some embodiments, the compound of Formula (I) or Formula (I′) is of Formula (III). In some embodiments, the compound of Formula (I) or Formula (I′) is of Formula (IV). In some embodiments, the compound of Formula (I) or Formula (I′) is selected from Formulae (V), (VI), and (VII). In some embodiments, the compound of Formula (I) or Formula (I′) isU1197.70243WO00 81 / 193 #13587456v2of Formula (V). In some embodiments, the compound of Formula (I) or Formula (I′) is of Formula (VI). In some embodiments, the compound of Formula (I) or Formula (I′) is of Formula (VII). In some embodiments, the compound of Formula (I) or Formula (I′) is selected from Formulae (VIII), (IX), and (X). In some embodiments, the compound of Formula (I) or Formula (I′) is of Formula (VIII). In some embodiments, the compound of Formula (I) or Formula (I′) is of Formula (IX). In some embodiments, the compound of Formula (I) or Formula (I′) is of Formula (X). In some embodiments, the compound of Formula (I) or Formula (I′) is selected from Formulae (II) and (XI). In some embodiments, the compound of Formula (I) or Formula (I′) is of Formula (XI).

[0249] In some embodiments, the compound of Formula (I) is selected from Formulae (II), (III), (IV), and (XI). In some embodiments, the compound of Formula (I) is selected from Formulae (II), (III), and (IV). In some embodiments, the compound of Formula (I) is of Formula (II). In some embodiments, the compound of Formula (I) is of Formula (III). In some embodiments, the compound of Formula (I) is of Formula (IV). In some embodiments, the compound of Formula (I) is selected from Formulae (V), (VI), and (VII). In some embodiments, the compound of Formula (I) is of Formula (V). In some embodiments, the compound of Formula (I) is of Formula (VI). In some embodiments, the compound of Formula (I) is of Formula (VII). In some embodiments, the compound of Formula (I) is selected from Formulae (VIII), (IX), and (X). In some embodiments, the compound of Formula (I) is of Formula (VIII). In some embodiments, the compound of Formula (I) is of Formula (IX). In some embodiments, the compound of Formula (I) is of Formula (X). In some embodiments, the compound of Formula (I) is selected from Formulae (II) and (XI). In some embodiments, the compound of Formula (I) is of Formula (XI).

[0250] In some embodiments, the compound of Formula (I′) is selected from Formulae (II), (III), (IV), and (XI). In some embodiments, the compound of Formula (I′) is selected from Formulae (II), (III), and (IV). In some embodiments, the compound of Formula (I′) is of Formula (II). In some embodiments, the compound of Formula (I′) is of Formula (III). In some embodiments, the compound of Formula (I′) is of Formula (IV). In some embodiments, the compound of Formula (I′) is selected from Formulae (V), (VI), and (VII). In some embodiments, the compound of Formula (I′) is of Formula (V). In some embodiments, the compound of Formula (I′) is of Formula (VI). In some embodiments, the compound of Formula (I′) is of Formula (VII). In some embodiments, the compound of Formula (I′) is selected from Formulae (VIII), (IX), and (X). In some embodiments, the compound of Formula (I′) is of Formula (VIII). In some embodiments, the compound of Formula (I′) is of Formula (IX). In some embodiments, the compound of Formula (I′) is of Formula (X). In some embodiments, the compound of Formula (I′) is selected from Formulae (II) and (XI). In some embodiments, the compound of Formula (I′) is of Formula (XI).

[0251] In some embodiments, the compound of Formula (I) can be characterized in terms of mass percentage (e.g., % by mass (m / m)) of X (e.g., of conjugated agent). In some embodiments, mass percentage refers to a molecular weight (Da) percentage of X (e.g., of conjugated agent) in theU1197.70243WO00 82 / 193 #13587456v2compound of Formula (I). In some embodiments, mass percentage can be determined by the general formula of: (X (e.g., conjugated agent) MW) / (compound of Formula (I) MW) × 100. For example, in some embodiments, (X (e.g., conjugated agent) MW) can be determined by calculating or approximating the molecular weight of X (e.g., of a conjugated agent) as a single molecule or compound (conjugated or unconjugated), and multiplying this value by the number of terminal sites at which X (e.g., of conjugated agent) is present in the compound of Formula (I) (e.g., multiplying by p). In some embodiments, (X (e.g., conjugated agent) MW) can be determined by calculating or approximating the sum of the atomic mass of all atoms which form X (e.g., conjugated agent) in the compound of Formula (I). The value for (X (e.g., conjugated agent) MW) can be taken as a fraction of total molecular weight of the compound of Formula (I) (compound of Formula (I) MW), and multiplied by 100 to provide a mass percentage. In some embodiments, mass percentage can be determined by experimental or empirical means. For example, in some embodiments, mass percentage can be determined using proton nuclear magnetic resonance (1H NMR) or other analytical methods known in the art.

[0252] In some embodiments, the compound of Formula (I′) can be characterized in terms of mass percentage (e.g., % by mass (m / m)) of X. In some embodiments, mass percentage refers to a molecular weight (Da) percentage of X in the compound of Formula (I′). In some embodiments, mass percentage can be determined by the general formula of: (X MW) / (compound of Formula (I′) MW) × 100. For example, in some embodiments, (X MW) can be determined by calculating or approximating the molecular weight of X as a single molecule or compound (conjugated or unconjugated), and multiplying this value by the number of terminal sites at which X is present in the compound of Formula (I′) (e.g., multiplying by p). In some embodiments, (X MW) can be determined by calculating or approximating the sum of the atomic mass of all atoms which form X in the compound of Formula (I′). The value for (X MW) can be taken as a fraction of total molecular weight of the compound of Formula (I′) (compound of Formula (I′) MW), and multiplied by 100 to provide a mass percentage. In some embodiments, mass percentage can be determined by experimental or empirical means. For example, in some embodiments, mass percentage can be determined using proton nuclear magnetic resonance (1H NMR) or other analytical methods known in the art.

[0253] In some embodiments, the compound of Formula (I) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of X (e.g., of conjugated agent). In some embodiments, the compound of Formula (I) comprises between about 1% and about 20% by mass of X (e.g., of conjugated agent). In some embodiments, the compound of Formula (I) comprisesU1197.70243WO00 83 / 193 #13587456v2between about 1% and about 10% by mass of X (e.g., of conjugated agent). In some embodiments, the compound of Formula (I) comprises between about 5% and about 10% by mass of X (e.g., of conjugated agent).

[0254] In some embodiments, the compound of Formula (I′) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of X. In some embodiments, the compound of Formula (I′) comprises between about 1% and about 20% by mass of X. In some embodiments, the compound of Formula (I′) comprises between about 1% and about 10% by mass of X. In some embodiments, the compound of Formula (I′) comprises between about 5% and about 10% by mass of X.

[0255] In some embodiments, the compound of Formula (II) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of formula (ii). In some embodiments, the compound of Formula (II) comprises between about 1% and about 20% by mass of formula (ii). In some embodiments, the compound of Formula (II) comprises between about 1% and about 10% by mass of formula (ii). In some embodiments, the compound of Formula (II) comprises between about 5% and about 10% by mass of formula (ii).

[0256] In some embodiments, the compound of Formula (III) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of formula (iii). In some embodiments, the compound of Formula (III) comprises between about 1% and about 20% by mass of formula (iii). In some embodiments, the compound of Formula (III) comprises between about 1% and about 10% by mass of formula (iii). In some embodiments, the compound of Formula (III) comprises between about 5% and about 10% by mass of formula (iii).U1197.70243WO00 84 / 193 #13587456v2

[0257] In some embodiments, the compound of Formula (IV) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of formula (iv). In some embodiments, the compound of Formula (IV) comprises between about 1% and about 20% by mass of formula (iv). In some embodiments, the compound of Formula (IV) comprises between about 1% and about 10% by mass of formula (iv). In some embodiments, the compound of Formula (IV) comprises between about 5% and about 10% by mass of formula (iv).

[0258] In some embodiments, the compound of Formula (V) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of formula (v). In some embodiments, the compound of Formula (V) comprises between about 1% and about 20% by mass of formula (v). In some embodiments, the compound of Formula (V) comprises between about 1% and about 10% by mass of formula (v). In some embodiments, the compound of Formula (V) comprises between about 5% and about 10% by mass of formula (v).

[0259] In some embodiments, the compound of Formula (VI) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of formula (vi). In some embodiments, the compound of Formula (VI) comprises between about 1% and about 20% by mass of formula (vi). In some embodiments, the compound of Formula (VI) comprises between about 1% and about 10% by mass of formula (vi). In some embodiments, the compound of Formula (VI) comprises between about 5% and about 10% by mass of formula (vi).

[0260] In some embodiments, the compound of Formula (VII) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, aboutU1197.70243WO00 85 / 193 #13587456v22% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of formula (vii). In some embodiments, the compound of Formula (VII) comprises between about 1% and about 20% by mass of formula (vii). In some embodiments, the compound of Formula (VII) comprises between about 1% and about 10% by mass of formula (vii). In some embodiments, the compound of Formula (VII) comprises between about 5% and about 10% by mass of formula (vii).

[0261] In some embodiments, the compound of Formula (VIII) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of formula (viii). In some embodiments, the compound of Formula (VIII) comprises between about 1% and about 20% by mass of formula (viii). In some embodiments, the compound of Formula (VIII) comprises between about 1% and about 10% by mass of formula (viii). In some embodiments, the compound of Formula (VIII) comprises between about 5% and about 10% by mass of formula (viii).

[0262] In some embodiments, the compound of Formula (IX) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of formula (ix). In some embodiments, the compound of Formula (IX) comprises between about 1% and about 20% by mass of formula (ix). In some embodiments, the compound of Formula (IX) comprises between about 1% and about 10% by mass of formula (ix). In some embodiments, the compound of Formula (IX) comprises between about 5% and about 10% by mass of formula (ix).

[0263] In some embodiments, the compound of Formula (X) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of formula (x). In some embodiments, the compound of Formula (X) comprises between about 1% and about 20% by mass ofU1197.70243WO00 86 / 193 #13587456v2formula (x). In some embodiments, the compound of Formula (X) comprises between about 1% and about 10% by mass of formula (x). In some embodiments, the compound of Formula (X) comprises between about 5% and about 10% by mass of formula (x).

[0264] In some embodiments, the compound of Formula (XI) comprises between about 1% and about 20%, about 1% and about 15%, about 1% and about 14%, about 1% and about 13%, about 1% and about 12%, about 1% and about 11%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 2% and about 15%, about 2% and about 10%, about 3% and about 15%, about 3% and about 10%, about 4% and about 15%, about 5% and about 10%, about 6% and about 15%, about 7% and about 10%, about 8% and about 15%, or about 9% and about 10% by mass (m / m) of formula (xi). In some embodiments, the compound of Formula (XI) comprises between about 1% and about 20% by mass of formula (xi). In some embodiments, the compound of Formula (XI) comprises between about 1% and about 10% by mass of formula (xi). In some embodiments, the compound of Formula (XI) comprises between about 5% and about 10% by mass of formula (xi). Y and RA

[0265] As generally described herein, each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA.

[0266] In some embodiments, at least one instance of Y is –ORA. In some embodiments, each instance of Y is independently –ORA.

[0267] In some embodiments, at least one instance of Y is –OH. In some embodiments, each instance of Y is independently –OH.

[0268] In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, optionally substituted alkyl, optionally substituted alkynyl, or optionally substituted heteroalkyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen or optionally substituted alkyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen or optionally substituted alkynyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen or optionally substituted heteroalkyl. In some embodiments, at least one instance of Y is – ORA, wherein RAis hydrogen, optionally substituted alkyl, or optionally substituted alkynyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, optionally substituted alkynyl, or optionally substituted heteroalkyl.

[0269] In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, optionally substituted alkyl, optionally substituted alkynyl, or optionally substituted heteroalkyl. In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen or optionally substituted alkyl. In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen or optionally substituted alkynyl. In some embodiments, each instance of Y isU1197.70243WO00 87 / 193 #13587456v2independently –ORA, wherein RAis hydrogen or optionally substituted heteroalkyl. In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, optionally substituted alkyl, or optionally substituted alkynyl. In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, optionally substituted alkynyl, or optionally substituted heteroalkyl.

[0270] In some embodiments, at least one instance of Y is –ORA, wherein RAis optionally substituted alkyl, optionally substituted alkynyl, or optionally substituted heteroalkyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis optionally substituted alkyl or optionally substituted alkynyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis optionally substituted alkyl or optionally substituted heteroalkyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis optionally substituted alkynyl or optionally substituted heteroalkyl.

[0271] In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkynyl, or optionally substituted C1-10 heteroalkyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, optionally substituted linear C1-10 alkyl, optionally substituted linear C1-10 alkynyl, or optionally substituted linear C1-10 heteroalkyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkynyl, or optionally substituted C1-6 heteroalkyl. In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, optionally substituted linear C1-6 alkyl, optionally substituted linear C1-6 alkynyl, or optionally substituted linear C1-6 heteroalkyl.

[0272] In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, C1-10 alkyl, C1-10 alkynyl, or C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, C1-10 alkyl, C1-10 alkynyl, or C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, linear C1-10alkyl, linear C1-10alkynyl, or linear C1-10heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, linear C1-10alkyl, linear C1-10alkynyl, or linear C1-10heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, C1-6alkyl, C1-6alkynyl, or C1-6heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, C1-6alkyl, C1-6alkynyl, or C1-6heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, linear C1-6alkyl,U1197.70243WO00 88 / 193 #13587456v2linear C1-6alkynyl, or linear C1-6heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of Y is –ORA, wherein RAis hydrogen, linear C1-6alkyl, linear C1-6alkynyl, or linear C1-6heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O).

[0273] In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, optionally substituted C1-10alkyl, optionally substituted C1-10alkynyl, or optionally substituted C1-10heteroalkyl. In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, optionally substituted linear C1-10 alkyl, optionally substituted linear C1-10 alkynyl, or optionally substituted linear C1-10 heteroalkyl. In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkynyl, or optionally substituted C1-6 heteroalkyl. In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, optionally substituted linear C1-6 alkyl, optionally substituted linear C1-6 alkynyl, or optionally substituted linear C1-6 heteroalkyl.

[0274] In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, C1-10 alkyl, C1-10 alkynyl, or C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, C1-10 alkyl, C1-10 alkynyl, or C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, linear C1-10 alkyl, linear C1-10 alkynyl, or linear C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of Y is independently – ORA, wherein RAis hydrogen, linear C1-10 alkyl, linear C1-10 alkynyl, or linear C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, C1-6 alkyl, C1-6 alkynyl, or C1-6 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of Y is independently – ORA, wherein RAis hydrogen, C1-6 alkyl, C1-6 alkynyl, or C1-6 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, linear C1-6alkyl, linear C1-6alkynyl, or linear C1-6heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of Y is independently –ORA, wherein RAis hydrogen, linear C1-6alkyl, linear C1-6alkynyl, or linear C1-6heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O).U1197.70243WO00 89 / 193 #13587456v2

[0275] In some embodiments, at least one instance of Y is –OH, or

[0276] In some embodiments, at least one instance of Y is –N(RA)2. In some embodiments, each instance of Y is independently –N(RA)2. In some embodiments, at least one instance of Y is –NHRA. In some embodiments, each instance of Y is independently –NHRA. In some embodiments, at least one instance of Y is –NH2. In some embodiments, each instance of Y is independently –NH2.

[0277] In some embodiments, at least one instance of Y is –C(=O)ORA. In some embodiments, each instance of Y is independently –C(=O)ORA. In some embodiments, at least one instance of Y is – C(=O)OH. In some embodiments, each instance of Y is independently –C(=O)OH.

[0278] As generally described herein, each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0279] In some embodiments, at least one instance of RAis hydrogen, optionally substituted alkyl, optionally substituted alkynyl, or optionally substituted heteroalkyl. In some embodiments, at least one instance of RAis hydrogen or optionally substituted alkyl. In some embodiments, at least one instance of RAis hydrogen or optionally substituted alkynyl. In some embodiments, at least one instance of RAis hydrogen or optionally substituted heteroalkyl. In some embodiments, at least one instance of RAis hydrogen, optionally substituted alkyl, or optionally substituted alkynyl. In some embodiments, at least one instance of RAis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, at least one instance of RAis hydrogen, optionally substituted alkynyl, or optionally substituted heteroalkyl.

[0280] In some embodiments, each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkynyl, or optionally substituted heteroalkyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted alkyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted alkynyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted heteroalkyl. In someU1197.70243WO00 90 / 193 #13587456v2embodiments, each instance of RAis independently hydrogen, optionally substituted alkyl, or optionally substituted alkynyl. In some embodiments, each instance of RAis independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, each instance of RAis independently hydrogen, optionally substituted alkynyl, or optionally substituted heteroalkyl.

[0281] In some embodiments, at least one instance of RAis optionally substituted alkyl, optionally substituted alkynyl, or optionally substituted heteroalkyl.

[0282] In some embodiments, at least one instance of RAis hydrogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkynyl, or optionally substituted C1-10 heteroalkyl. In some embodiments, at least one instance of RAis hydrogen, optionally substituted linear C1-10 alkyl, optionally substituted linear C1-10 alkynyl, or optionally substituted linear C1-10 heteroalkyl. In some embodiments, at least one instance of RAis hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkynyl, or optionally substituted C1-6 heteroalkyl. In some embodiments, at least one instance of RAis hydrogen, optionally substituted linear C1-6 alkyl, optionally substituted linear C1-6 alkynyl, or optionally substituted linear C1-6 heteroalkyl.

[0283] In some embodiments, at least one instance of RAis hydrogen, C1-10 alkyl, C1-10 alkynyl, or C1- 10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis hydrogen, C1-10 alkyl, C1- 10 alkynyl, or C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, at least one instance of RAis hydrogen, linear C1-10 alkyl, linear C1-10 alkynyl, or linear C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis hydrogen, linear C1-10 alkyl, linear C1-10 alkynyl, or linear C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, at least one instance of RAis hydrogen, C1-6 alkyl, C1-6 alkynyl, or C1-6 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis hydrogen, C1-6 alkyl, C1-6 alkynyl, or C1-6 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, at least one instance of RAis hydrogen, linear C1-6alkyl, linear C1-6alkynyl, or linear C1-6heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis hydrogen, linear C1-6alkyl, linear C1-6alkynyl, or linear C1-6heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O).

[0284] In some embodiments, each instance of RAis independently hydrogen, optionally substituted C1-10alkyl, optionally substituted C1-10alkynyl, or optionally substituted C1-10heteroalkyl. In some embodiments, each instance of RAis independently hydrogen, optionally substituted linear C1-10alkyl, optionally substituted linear C1-10alkynyl, or optionally substituted linear C1-10heteroalkyl. In someU1197.70243WO00 91 / 193 #13587456v2embodiments, each instance of RAis independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6alkynyl, or optionally substituted C1-6heteroalkyl. In some embodiments, each instance of RAis independently hydrogen, optionally substituted linear C1-6alkyl, optionally substituted linear C1-6alkynyl, or optionally substituted linear C1-6heteroalkyl.

[0285] In some embodiments, each instance of RAis independently hydrogen, C1-10 alkyl, C1-10 alkynyl, or C1-10heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen, C1-10 alkyl, C1-10 alkynyl, or C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen, linear C1-10 alkyl, linear C1-10 alkynyl, or linear C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen, linear C1-10 alkyl, linear C1-10 alkynyl, or linear C1-10 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen, C1-6 alkyl, C1- 6 alkynyl, or C1-6 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen, C1-6 alkyl, C1-6 alkynyl, or C1-6 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen, linear C1-6 alkyl, linear C1-6 alkynyl, or linear C1-6 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen, linear C1-6 alkyl, linear C1-6 alkynyl, or linear C1-6 heteroalkyl, wherein the alkyl, alkynyl, or heteroalkyl is substituted with an oxo group (=O).

[0286] In some embodiments, at least one instance of RAis hydrogen,or

[0287] In some embodiments, at least one instance of RAis of formula: (i), wherein RA1is optionally substituted alkyl, optionally substituted alkynyl, or optionally substituted heteroalkyl. InU1197.70243WO00 92 / 193 #13587456v2some embodiments, at least one instance of RAis of formula (i), wherein RA1is optionally substituted C1-10alkyl, optionally substituted C1-10alkynyl, or optionally substituted C1-10heteroalkyl. In some embodiments, at least one instance of RAis of formula (i), wherein RA1is optionally substituted linear C1-10alkyl, optionally substituted linear C1-10alkynyl, or optionally substituted linear C1-10heteroalkyl. In some embodiments, at least one instance of RAis of formula (i), wherein RA1is optionally substituted C1-6alkyl, optionally substituted C1-6alkynyl, or optionally substituted C1-6heteroalkyl. In some embodiments, at least one instance of RAis of formula (i), wherein RA1is optionally substituted linear C1-6 alkyl, optionally substituted linear C1-6 alkynyl, or optionally substituted linear C1-6 heteroalkyl. In some embodiments, at least one instance of RAis of formula (i), wherein RA1is

[0288] In some embodiments, at least one instance of RAis hydrogen. In some embodiments, each instance of RAis hydrogen.

[0289] In some embodiments, at least one instance of RAis optionally substituted alkyl. In some embodiments, at least one instance of RAis optionally substituted C1-10 alkyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-10 alkyl. In some embodiments, at least one instance of RAis optionally substituted C1-6alkyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-6 alkyl.

[0290] In some embodiments, at least one instance of RAis C1-10 alkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis C1-10alkyl substituted with an oxo group (=O). In some embodiments, at least one instance of RAis linear C1-10alkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis linear C1-10alkyl substituted with an oxo group (=O). In some embodiments, at least one instance of RAis C1-6alkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis C1-6alkyl substituted with an oxo group (=O). In some embodiments, at least one instance of RAis linear C1-6alkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis linear C1-6alkyl substituted with an oxo group (=O). In some embodiments, at least one instance

[0291] In some embodiments, each instance of RAis independently hydrogen or optionally substituted alkyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-10 alkyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-10 alkyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-6 alkyl.U1197.70243WO00 93 / 193 #13587456v2

[0292] In some embodiments, each instance of RAis independently hydrogen or C1-10alkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or C1-10alkyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or linear C1-10alkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or linear C1-10alkyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or C1-6alkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or C1-6 alkyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or linear C1-6 alkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or linear C1-6 alkyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or.

[0293] In some embodiments, at least one instance of RAis optionally substituted alkenyl. In some embodiments, at least one instance of RAis optionally substituted C1-10 alkenyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-10alkenyl. In some embodiments, at least one instance of RAis optionally substituted C1-6alkenyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-6alkenyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted alkenyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-10alkenyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-10alkenyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-6alkenyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-6alkenyl.

[0294] In some embodiments, at least one instance of RAis optionally substituted alkynyl. In some embodiments, at least one instance of RAis optionally substituted C1-10alkynyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-10alkynyl. In some embodiments, at least one instance of RAis optionally substituted C1-6alkynyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-6alkynyl.

[0295] In some embodiments, at least one instance of RAis C1-10alkynyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis C1-10alkynyl substituted with an oxo group (=O). In some embodiments, at least one instance of RAis linear C1-10 alkynyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis linear C1-10 alkynyl substituted with an oxo group (=O). In some embodiments, at least one instance of RAis C1-6 alkynyl substituted with an oxo group (=O)U1197.70243WO00 94 / 193 #13587456v2and / or an amino group (–NH2). In some embodiments, at least one instance of RAis C1-6alkynyl substituted with an oxo group (=O). In some embodiments, at least one instance of RAis linear C1-6alkynyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis linear C1-6alkynyl substituted with an oxo group (=O). In some embodiments, at least one instance of RAis.

[0296] In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-10alkynyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-10alkynyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-6alkynyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-6alkynyl.

[0297] In some embodiments, each instance of RAis independently hydrogen or C1-10alkynyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or C1-10alkynyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or linear C1-10 alkynyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or linear C1-10 alkynyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or C1-6 alkynyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or C1-6 alkynyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or linear C1-6 alkynyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or linear C1-6 alkynyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or

[0298] In some embodiments, at least one instance of RAis optionally substituted heteroalkyl. In some embodiments, at least one instance of RAis optionally substituted C1-10 heteroalkyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-10 heteroalkyl. In some embodiments, at least one instance of RAis optionally substituted C1-6 heteroalkyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-6 heteroalkyl.

[0299] In some embodiments, at least one instance of RAis C1-10 heteroalkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis C1-10 heteroalkyl substituted with an oxo group (=O). In some embodiments, at least one instance of RAis linear C1-10 heteroalkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis linear C1-10 heteroalkyl substituted with an oxo groupU1197.70243WO00 95 / 193 #13587456v2(=O). In some embodiments, at least one instance of RAis C1-6heteroalkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis C1-6heteroalkyl substituted with an oxo group (=O). In some embodiments, at least one instance of RAis linear C1-6heteroalkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, at least one instance of RAis linear C1-6 heteroalkyl substituted with an oxo group (=O). In some embodiments, at least one instance of RAis.

[0300] In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-10 heteroalkyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-10 heteroalkyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-6 heteroalkyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-6 heteroalkyl.

[0301] In some embodiments, each instance of RAis independently hydrogen or C1-10 heteroalkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or C1-10 heteroalkyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or linear C1-10 heteroalkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or linear C1-10heteroalkyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or C1-6heteroalkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or C1-6heteroalkyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or linear C1-6heteroalkyl substituted with an oxo group (=O) and / or an amino group (–NH2). In some embodiments, each instance of RAis independently hydrogen or linear C1-6heteroalkyl substituted with an oxo group (=O). In some embodiments, each instance of RAis independently hydrogen or.

[0302] In some embodiments, at least one instance of RAis optionally substituted heteroalkenyl. In some embodiments, at least one instance of RAis optionally substituted C1-10 heteroalkenyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-10 heteroalkenyl. In some embodiments, at least one instance of RAis optionally substituted C1-6 heteroalkenyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-6 heteroalkenyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted heteroalkenyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-10 heteroalkenyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-10 heteroalkenyl. In some embodiments, each instance of RAis independentlyU1197.70243WO00 96 / 193 #13587456v2hydrogen or optionally substituted C1-6heteroalkenyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-6heteroalkenyl.

[0303] In some embodiments, at least one instance of RAis optionally substituted heteroalkynyl. In some embodiments, at least one instance of RAis optionally substituted C1-10heteroalkynyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-10 heteroalkynyl. In some embodiments, at least one instance of RAis optionally substituted C1-6heteroalkynyl. In some embodiments, at least one instance of RAis optionally substituted linear C1-6heteroalkynyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted heteroalkynyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-10 heteroalkynyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-10 heteroalkynyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C1-6 heteroalkynyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted linear C1-6 heteroalkynyl.

[0304] In some embodiments, at least one instance of RAis optionally substituted carbocyclyl. In some embodiments, at least one instance of RAis optionally substituted C3-10 carbocyclyl. In some embodiments, at least one instance of RAis optionally substituted C4-6 carbocyclyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted carbocyclyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C3-10 carbocyclyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted C4-6 carbocyclyl.

[0305] In some embodiments, at least one instance of RAis optionally substituted heterocyclyl. In some embodiments, at least one instance of RAis optionally substituted 3-10 membered heterocyclyl. In some embodiments, at least one instance of RAis optionally substituted 4-6 membered heterocyclyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted heterocyclyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted 3-10 membered heterocyclyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted 4-6 membered heterocyclyl.

[0306] In some embodiments, at least one instance of RAis optionally substituted aryl. In some embodiments, at least one instance of RAis optionally substituted phenyl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted aryl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted phenyl.

[0307] In some embodiments, at least one instance of RAis optionally substituted heteroaryl. In some embodiments, at least one instance of RAis optionally substituted 5-10 membered heteroaryl. In some embodiments, at least one instance of RAis optionally substituted 5-6 membered heteroaryl. In some embodiments, at least one instance of RAis optionally substituted 5-6 monocyclic membered heteroaryl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted heteroaryl. In some embodiments, each instance of RAis independently hydrogen orU1197.70243WO00 97 / 193 #13587456v2optionally substituted 5-10 membered heteroaryl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted 5-6 membered heteroaryl. In some embodiments, each instance of RAis independently hydrogen or optionally substituted 5-6 monocyclic membered heteroaryl.

[0308] In some embodiments, the compound of Formula (I) comprises an effective number of instances of Y for targeting a specific cell type. In some embodiments, the compound of Formula (I) comprises an effective number of instances of Y for targeting myeloid-derived suppressor cells (MDSCs). In some embodiments, the compound of Formula (I′) comprises an effective number of instances of Y for targeting a specific cell type. In some embodiments, the compound of Formula (I′) comprises an effective number of instances of Y for targeting myeloid-derived suppressor cells (MDSCs). Subgeneric Embodiments

[0309] In some embodiments, the compound of Formula (I) or Formula (I′) is of Formula (I-a):or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (I-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (I-a), or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, the compound of Formula (II) is of Formula (II-a):or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the compound of Formula (II) is of Formula (II-b):or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the compound of Formula (II) is of Formula (II-c):U1197.70243WO00 98 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the compound of Formula (II) is of Formula (II-d) or Formula (II-e):or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the compound of Formula (II) is of Formula (II-d-i) or Formula (II-e-U1197.70243WO00 99 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the compound of Formula (II) is of formula:, or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the compound of Formula (III) is of Formula (III-a):or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the compound of Formula (III) is of Formula (III-b):U1197.70243WO00 100 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, the compound of Formula (III) is of Formula (III-c):or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, the compound of Formula (IV) is of Formula (IV-a):or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, the compound of Formula (IV) is of Formula (IV-b):or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, the compound of Formula (IV) is of Formula (IV-c):or a pharmaceutically acceptable salt thereof.

[0322] In some embodiments, the compound of Formula (V) is of Formula (V-a):or a pharmaceutically acceptable salt thereof.U1197.70243WO00 101 / 193 #13587456v2

[0323] In some embodiments, the compound of Formula (V) is of Formula (V-b):or a pharmaceutically acceptable salt thereof.

[0324] In some embodiments, the compound of Formula (V) is of Formula (V-c):or a pharmaceutically acceptable salt thereof.

[0325] In some embodiments, the compound of Formula (VI) is of Formula (VI-a):or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the compound of Formula (VI) is of Formula (VI-b):or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, the compound of Formula (VI) is of Formula (VI-c):or a pharmaceutically acceptable salt thereof.

[0328] In some embodiments, the compound of Formula (VII) is of Formula (VII-a):or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the compound of Formula (VII) is of Formula (VII-b):U1197.70243WO00 102 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0330] In some embodiments, the compound of Formula (VII) is of Formula (VII-c):or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the compound of Formula (VIII) is of Formula (VIII-a):or a pharmaceutically acceptable salt thereof.

[0332] In some embodiments, the compound of Formula (VIII) is of Formula (VIII-b):or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments, the compound of Formula (VIII) is of Formula (VIII-c):U1197.70243WO00 103 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0334] In some embodiments, the compound of Formula (IX) is of Formula (IX-a):or a pharmaceutically acceptable salt thereof.

[0335] In some embodiments, the compound of Formula (IX) is of Formula (IX-b):or a pharmaceutically acceptable salt thereof.

[0336] In some embodiments, the compound of Formula (IX) is of Formula (IX-c):U1197.70243WO00 104 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, the compound of Formula (X) is of Formula (X-a):or a pharmaceutically acceptable salt thereof.

[0338] In some embodiments, the compound of Formula (X) is of Formula (X-b):or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the compound of Formula (X) is of Formula (X-c):or a pharmaceutically acceptable salt thereof.

[0340] In some embodiments, the compound of Formula (XI) is of Formula (XI-a):U1197.70243WO00 105 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0341] In some embodiments, the compound of Formula (XI) is of Formula (XI-b):or a pharmaceutically acceptable salt thereof.

[0342] In some embodiments, the compound of Formula (XI) is of Formula (XI-c):or a pharmaceutically acceptable salt thereof.

[0343] In some embodiments, the compound of Formula (XI) is of Formula (XI-d):U1197.70243WO00 106 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

[0344] In some embodiments, the compound of Formula (XI) is of Formula (XI-e):or a pharmaceutically acceptable salt thereof.

[0345] In some embodiments, the compound of Formula (XI) is of formula:, or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, a provided compound (a compound described herein, a compound of the present disclosure) is a compound of any of the formulae disclosed herein (e.g., Formulae (I), (I′), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI)), or a pharmaceutically acceptable salt thereof. In some embodiments, a provided compound is a compound of any of the Formulae disclosed herein (e.g., Formulae (I), (I′), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI)), or a salt thereof. In some embodiments, a provided compound is a compound of any of the Formulae disclosed herein (e.g., Formulae (I), (I′), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI)). Compositions and Kits

[0347] In some embodiments, the provided compound is provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is an amount effective for modulating a target protein in a subject or a cell, tissue, or biological sample.

[0348] In some embodiments, the composition is formulated as a particle. In some embodiments, the composition is formulated as a nanoparticle or microparticle. In some embodiments, the particle is a microparticle (i.e., particle having a characteristic dimension of less than about 1 millimeter and atU1197.70243WO00 107 / 193 #13587456v2least about 1 micrometer, where the characteristic dimension of the particle is the smallest cross- sectional dimension of the particle). In some embodiments, the particle is a nanoparticle (i.e., a particle having a characteristic dimension of less than about 1 micrometer and at least about 1 nanometer, where the characteristic dimension of the particle is the smallest cross-sectional dimension of the particle).

[0349] The particles described herein may include additional materials such as polymers (e.g., synthetic polymers (e.g., PEG, PLGA) and natural polymers (e.g., phospholipids)). In some embodiments, the additional materials are approved by a regulatory agency, such as the U.S. FDA, for human and veterinary use.

[0350] The particles may be prepared using any method known in the art, such as precipitation, milling, spray drying, single and double emulsion solvent evaporation, solvent extraction, phase separation, and simple and complex coacervation. The conditions used in preparing the particles may be altered to yield particles of a desired size or property (e.g., hydrophobicity, hydrophilicity, external morphology, “stickiness”, shape, polydispersity, etc.). The method of preparing the particle and the conditions (e.g., solvent, temperature, concentration, and air flow rate, etc.) used may also depend on the agent being complexed, encapsulated, or mixed, and / or the composition of the matrix.

[0351] Methods developed for making particles for delivery of agents that are included in the particles are described in the literature. See, e.g., Doubrow, M., Ed., “Microcapsules and Nanoparticles in Medicine and Pharmacy,” CRC Press, Boca Raton, 1992; Mathiowitz and Langer, J. Controlled Release 5:13-22, 1987; Mathiowitz et al., Reactive Polymers 6:275-283, 1987; Mathiowitz et al., J. Appl. Polymer Sci.35:755-774, 1988, which are incorporated by reference herein.

[0352] If the particles prepared by any of the above methods have a size range outside of the desired range, the particles can be sized, for example, using a sieve. The particles may also be coated. In some embodiments, the particles are coated with a targeting agent. In some embodiments, the particles are coated with a surface-altering agent. In some embodiments, the particles are coated to achieve desirable surface properties (e.g., a particular charge).

[0353] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0354] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.U1197.70243WO00 108 / 193 #13587456v2

[0355] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0356] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents or fillers, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0357] Exemplary diluents or fillers include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, starches (such as dry starch, cornstarch), sugars (such as powdered sugar), calcium trisulfate, carboxymethylcellulose calcium, dextrate, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium, maltitol, maltodextrin, maltose, sucrose, glucose, mannitol, silicic acid, xylitol, and mixtures thereof.

[0358] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0359] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween®20), polyoxyethylene sorbitan (Tween®60), polyoxyethylene sorbitanU1197.70243WO00 109 / 193 #13587456v2monooleate (Tween®80), sorbitan monopalmitate (Span®40), sorbitan monostearate (Span®60), sorbitan tristearate (Span®65), glyceryl monooleate, sorbitan monooleate (Span®80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj®45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij®30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic®F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0360] Exemplary disintegrating agents or disintegrants include agar, algin, alginic acid, sodium alginate, silicates, sodium carbonate, calcium carbonate, carboxymethylcellulose, cellulose, clay, colloidal silicon dioxide, croscarmellose sodium, crospovidone, rubber, magnesium silicate, methylcellulose, potassium krillin, hydroxypropylcellulose (e.g., low substituted Hydroxypropylcellulose), crosslinked polyvinylpyrrolidone, hydroxypropylcellulose, and starch (e.g., sodium glycolate starch, potato or tapioca starch).

[0361] Exemplary binding agents include starch (e.g., glycolate starch, cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0362] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0363] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0364] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.

[0365] Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol,U1197.70243WO00 110 / 193 #13587456v2chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0366] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0367] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0368] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0369] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall®115, Germaben®II, Neolone®, Kathon®, and Euxyl®.

[0370] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0371] Exemplary lubricating agents include agar, ethyl oleate, ethyl laurate, glycerin, blyceryl palmitostearate, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycol, sodium stearyl, sorbitol, zinc stearate, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0372] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn,U1197.70243WO00 111 / 193 #13587456v2sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0373] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0374] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0375] In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a ready-to-use (“RTU”) preparation that can be directly administered to a subject. In some embodiments, the RTU preparation is a suspension. In some embodiments, the RTU preparation is a solution. In some embodiments, the RTU preparation is an emulsion. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a solid that is reconstituted prior to administration. In some embodiments, the solid is a lyophilized solid. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a liquid or suspension that is diluted prior to administration.

[0376] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.U1197.70243WO00 112 / 193 #13587456v2

[0377] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0378] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0379] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0380] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0381] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can beU1197.70243WO00 113 / 193 #13587456v2admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0382] Dosage forms for topical and / or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0383] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0384] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0385] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powderU1197.70243WO00 114 / 193 #13587456v2reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self- propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0386] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0387] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0388] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0389] Formulations for nasal administration may, for example, comprise...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; each instance of X is independently a conjugated agent; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

2. A compound of Formula (I′):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionallyU1197.70243WO00 168 / 193 #13587456v2substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; each instance of X is independently selected from formulae (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), and (xi):U1197.70243WO00 169 / 193 #13587456v2p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

3. A compound of Formula (I′):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; each instance of X is independently selected from formulae (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), and (x):U1197.70243WO00 170 / 193 #13587456v2p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

4. The compound of any one of claims 1-3, wherein the compound is of Formula (I-a):or a pharmaceutically acceptable salt thereof.U1197.70243WO00 171 / 193 #13587456v25. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) comprises between about 2% and about 15% by weight of X.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) comprises between about 5% and about 10% by weight of X.

7. The compound of any one of claims 1 or 4-6, or a pharmaceutically acceptable salt thereof, wherein the conjugated agent is a radical of an agent.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein the agent is a hydrophobic agent, an anionic agent, or a cationic agent.

9. The compound of any one of claims 7 or 8, or a pharmaceutically acceptable salt thereof, wherein the agent is a STAT3 inhibitor, a TLR7 agonist, an IDO inhibitor, an NOS inhibitor, an arginase inhibitor, a PD-L1 inhibitor, a protein kinase B inhibitor, a CD73 inhibitor, or a STING agonist.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each instance of X is selected from formulae (ii), (iii), and (iv).

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each instance of X is selected from formulae (v), (vi), and (vii).

12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each instance of X is selected from formulae (viii), (ix), and (x).

13. The compound of any one of claims 1-12, wherein the compound is selected from Formulae (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and (XI):U1197.70243WO00 172 / 193 #13587456v2U1197.70243WO00 173 / 193 #13587456v2or a pharmaceutically acceptable salt thereof:

14. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).U1197.70243WO00 174 / 193 #13587456v215. A compound of Formul or a pharmaceutically acceptable salt thereof, wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of Y is independently –ORA, –N(RA)2, or –C(=O)ORA; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of L is independently optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R1is independently hydrogen or optionally substituted alkyl; p is an integer between 1 and 2(n+2), inclusive; q is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p and q is 2(n+2).

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein each instance of Y is independently –ORA.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkynyl, or optionally substituted heteroalkyl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof,U1197.70243WO00 175 / 193 #13587456v2wherein at least one instance of RAis hydrogen.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein at least one instance of RAis optionally substituted alkyl, optionally substituted alkynyl, or optionally substituted heteroalkyl.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein at least one instance of RAis of formula:(i), wherein RA1is optionally substituted alkyl, optionally substituted alkynyl, or optionally substituted heteroalkyl.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein at least one instance of RAis of formula:(i), wherein RA1is optionally substituted C1-10alkyl, optionally substituted C1-10alkynyl, or optionally substituted C1-10heteroalkyl.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof,23. The compound of any one of claims 1-22, wherein the compound is of Formula (II-a):or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 1-23, wherein the compound is of Formula (II-b):U1197.70243WO00 176 / 193 #13587456v2or a pharmaceutically acceptable salt thereof.

25. The compound of any one of claims 1-22, wherein the compound is of Formula (XI-a):or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1-22 or 25, wherein the compound is of Formula (XI-b):or a pharmaceutically acceptable salt thereof.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein n is 4, 5, 6, 7, 8, 9, or 10.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein n is 6.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L is optionally substituted alkylene, optionally substitutedU1197.70243WO00 177 / 193 #13587456v2heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L is optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L is optionally substituted C1-20 alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted 5-6 membered heteroarylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L is optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene containing 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene or optionally substituted 5-6 membered heteroarylene containing 1, 2, or 3 ring N atoms are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L comprises optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted alkylene or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L comprises optionally substituted alkylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms inU1197.70243WO00 178 / 193 #13587456v2the optionally substituted alkylene or optionally substituted heteroarylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L comprises optionally substituted C1-20 alkylene, optionally substituted 5-6 membered heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20alkylene or optionally substituted 5-6 membered heteroarylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L comprises optionally substituted linear C1-20 alkylene, optionally substituted 5-6 membered heteroarylene containing 1, 2, or 3 ring N atoms, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene or optionally substituted 5-6 membered heteroarylene containing 1, 2, or 3 ring N atoms are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L comprises optionally substituted C1-20 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L comprises optionally substituted linear C1-20 alkylene, wherein one or more backbone carbon atoms in the optionally substituted linear C1-20 alkylene are independently replaced with –O–, –NR1–, –C(=O)–, or optionally substituted heteroarylene.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, ,,U1197.70243WO00 179 / 193 #13587456v2, wherein each x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each y is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof,41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L comprises optionally substituted heteroarylene.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L comprises optionally substituted 5-6 membered heteroarylene.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L comprises optionally substituted 5-6 membered heteroarylene having 1, 2, or 3 ring heteroatoms selected from O, N, and S.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein at least one instance of L comprises optionally substituted 5-6 membered heteroarylene having 3 ring N atoms.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof,U1197.70243WO00 180 / 193 #13587456v2wherein at least one instance of L comprises46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof,wherein at least one instance of L comprises.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof,48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, wherein the sum of p and q is 256.

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, wherein p is an integer between 1 and 40, inclusive, and q is an integer between 216 and 255, inclusive.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, wherein p is an integer between 10 and 30, inclusive, and q is an integer between 226 and 246, inclusive.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein p is an integer between 17 and 23, inclusive, and q is an integer between 233 and 239, inclusive; or p is an integer between 12 and 18, inclusive, and q is an integer between 238 and 244, inclusive.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, U1197.70243WO00 181 / 193 #13587456v2wherein p is 20 and q is 236; or p is 15 and q is 241.

53. The compound of any one of claims 14, 16-24, or 27-52, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) comprises between about 2% and about 15% by54. The compound of any one of claims 14, 16-24, or 27-53, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) comprises between about 5% and about 10% by mass55. The compound of any one of claims 1-14, 16-24, or 27-54, wherein the compound is of56. The compound of any one of claims 1-14, 16-24, or 27-55, wherein the compound is ofU1197.70243WO00 182 / 193 #13587456v2Formula (II-c-i) or Formula (II-d-i):

57. The compound of any one of claims 1-14, 16-24, or 27-56, wherein the compound is of formula:, or a pharmaceutically acceptable salt thereof.

58. The compound of any one of claims 15-22 or 25-52, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (XI) comprises between about 2% and about 15% by massU1197.70243WO00 183 / 193 #13587456v259. The compound of any one of claims 15-22, 25-52, or 58, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (XI) comprises between about 5% and about 10% by mass60. The compound of any one of claims 1, 2, 4-13, 15-22, 25-52, 58, or 59, wherein the compound is ofor a pharmaceutically acceptable salt thereof.

61. The compound of any one of claims 1, 2, 4-13, 15-22, 25-52, or 58-60, wherein theU1197.70243WO00 184 / 193 #13587456v2compound is ofor a pharmaceutically acceptable salt thereof.

62. The compound of any one of claims 1, 2, 4-13, 15-22, 25-52, or 58-61, wherein the compound is of formula:, or a pharmaceutically acceptable salt thereof.

63. A pharmaceutical composition comprising a compound any one of claims 1-62, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

64. A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-62, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 63.

65. The method of claim 64, wherein the disease or disorder is a proliferative disease.

66. The method of claim 65, wherein the proliferative disease is cancer.

67. The method of claim 66, wherein the cancer comprises a solid tumor.U1197.70243WO00 185 / 193 #13587456v268. The method of any one of claims 66 or 67, wherein the cancer is brain tumor (e.g., glioma, glioblastoma), pancreatic cancer, or ovarian cancer.

69. A method of modulating a target protein, the method comprising administering to a subject in need thereof or contacting a cell, tissue, or biological sample with an effective amount of the compound of any one of claims 1-62, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 63.

70. The method of claim 69, wherein modulating the target protein comprises inhibition of the target protein.

71. The method of claim 69, wherein modulating the target protein comprises agonism of the target protein.

72. The method of any one of claims 69-71, wherein the target protein is signal transducer and activator of transcription 3 (STAT3), Toll-like receptor 7 (TLR7), indoleamine 2,3-dioxygenase (IDO), nitric oxide synthase (NOS), arginase, programmed death-ligand 1 (PD-L1), protein kinase B, cluster of differentiation 73 (CD73), or stimulator of interferon genes (STING).

73. The method of any one of claims 69-72, wherein the cell is a myeloid derived suppressor cell (MDSC).

74. The method of any one of claims 69-72, wherein the cell is a tumor-infiltrating monocyte (TIM).

75. The method of any one of claims 64-74, wherein the administration is by injection.

76. A method of preparing a compound of Formula (II-c):U1197.70243WO00 186 / 193 #13587456v2or a pharmaceutically acceptable salt thereof, the method comprising: providing a reaction vessel; adding to the reaction vessel a compound of Formula (XIII-a):(XIII-a), or a salt thereof; adding to the reaction vessel a compound of Formula (XIV-a):or a salt thereof; and obtaining the compound of Formula (II-c), or pharmaceutically acceptable salt thereof; wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each of p and p1 is independently an integer between 1 and 2(n+2), inclusive; each of q and q1 is independently an integer between 0 and 2(n+2)-1, inclusive; the sum of p and q is 2(n+2); the sum of p1 and q1 is 2(n+2); p is less than or equal to p1; and q is greater than or equal to q1.U1197.70243WO00 187 / 193 #13587456v277. A method of preparing a compound of Formula (II-d):or a pharmaceutically acceptable salt thereof, the method comprising: providing a reaction vessel; adding to the reaction vessel a compound of Formula (XIII-b):or a salt thereof; adding to the reaction vessel a compound of Formula (XIV-b):or a salt thereof; and obtaining the compound of Formula (II-d), or pharmaceutically acceptable salt thereof; wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each of p and p2 is independently an integer between 1 and 2(n+2), inclusive; each of q and q2 is independently an integer between 0 and 2(n+2)-1, inclusive; the sum of p and q is 2(n+2); the sum of p2 and q2 is 2(n+2); p is less than or equal to p2; and q is greater than or equal to q2.U1197.70243WO00 188 / 193 #13587456v278. A method of preparing a compound of Formula (XI-d):or a pharmaceutically acceptable salt thereof, the method comprising: providing a reaction vessel; adding to the reaction vessel a compound of Formula (XIII-b):or a salt thereof; adding to the reaction vessel a compound of Formula (XIV-c):or a salt thereof; and obtaining the compound of Formula (XI-d), or pharmaceutically acceptable salt thereof; wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each of p and p2 is independently an integer between 1 and 2(n+2), inclusive; each of q and q2 is independently an integer between 0 and 2(n+2)-1, inclusive; the sum of p and q is 2(n+2); the sum of p2 and q2 is 2(n+2);U1197.70243WO00 189 / 193 #13587456v2p is less than or equal to p2; and q is greater than or equal to q2.

79. A compound made by the method of any one of claims 76-78.

80. A compound, or a pharmaceutically acceptable salt thereof, made by the method comprising: providing a reaction vessel; adding to the reaction vessel a compound of Formula (III-a):or a salt thereof; adding to the reaction vessel a compound of Formula (IV-a):or a salt thereof; and obtaining the compound, or pharmaceutically acceptable salt thereof; wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; p1 is an integer between 1 and 2(n+2), inclusive; q1 is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p1 and q1 is 2(n+2).

81. A method of preparing a compound, or a pharmaceutically acceptable salt thereof, the method comprising: providing a reaction vessel; adding to the reaction vessel a compound of Formula (III-b):U1197.70243WO00 190 / 193 #13587456v2or a salt thereof; adding to the reaction vessel a compound of Formula (IV-b):or a salt thereof; and obtaining the compound, or pharmaceutically acceptable salt thereof; wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; p2 is an integer between 1 and 2(n+2), inclusive; q2 is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p2 and q2 is 2(n+2).

82. A method of preparing a compound, or a pharmaceutically acceptable salt thereof, the method comprising: providing a reaction vessel; adding to the reaction vessel a compound of Formula (XIII-b):or a salt thereof; adding to the reaction vessel a compound of Formula (XIV-c):U1197.70243WO00 191 / 193 #13587456v2or a salt thereof; and obtaining the compound, or pharmaceutically acceptable salt thereof; wherein: Znis an nth generation polyamidoamine (PAMAM) dendrimer; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; p2 is an integer between 1 and 2(n+2), inclusive; q2 is an integer between 0 and 2(n+2)-1, inclusive; and the sum of p2 and q2 is 2(n+2).

83. A kit comprising: the compound of any one of claims 1-62, or the pharmaceutical composition of claim 63; and instructions for its use.U1197.70243WO00 192 / 193 #13587456v2

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