Ionizable lipids for messenger RNA delivery

Abstract

Provided herein are compounds, such as compounds of Formula (I), and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, and isotopically labeled derivatives thereof, and compositions, methods, uses, and kits thereof. The compounds provided herein are lipids useful for delivery of agents, including polynucleotides such as mRNA, for the treatment and / or prevention of various diseases and conditions (e.g., genetic diseases, proliferative diseases, hematological diseases, neurological diseases, liver diseases, spleen diseases, lung diseases, painful conditions, psychiatric disorders, musculoskeletal diseases, metabolic disorders, inflammatory diseases, and autoimmune diseases).

Description

IONIZABLE LIPIDS FOR MESSENGER RNA DELIVERYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U. S. C. § 119(e) to U. S. Provisional Application, U. S. S. N. 63 / 560,991, filed March 4, 2024, titled “Ionizable Lipids for Messenger RNA Delivery,” which is incorporated herein by reference.GOVERNMENT SUPPORT

[0002] This invention was made with government support under HL162564 and AI161805 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Lipid nanoparticles (LNPs) for RNA delivery have recently begun to demonstrate their potential for improving human health.1,2mRNA vaccines for COVID-19 have provided exceptional protection against severe disease,3,4and hepatic RNA delivery has yielded the FDA approved Onpattro and other promising clinical programs.1,5,6Despite this, more potent and targeted LNPs are required to achieve enable the broadest application of RNA therapies for genetic diseases, reduce side effects,7improve shelf stability,8,9deliver to extrahepatic tissue such as the lung epithelium,10-13and improve control over inflammation.14Lung-targeted gene therapy is particularly challenging13but has the potential to treat a range of diseases including cystic fibrosis (CF),13idiopathic pulmonary fibrosis,15alpha-1 antitrypsin deficiency,18chronic obstructive pulmonary disease (COPD),19primary ciliary dyskinesia (PCD),20asthma,21,22and more.

[0004] To date, ionizable lipids for LNP-based delivery have been designed via experimental screening, rational design,23-25or a combination of the two.14,26Screens generally rely on high-yield combinatorial chemistry to generate chemically diverse lipid libraries, while rational design leverages features of potent ionizable lipids such as inclusion of biodegradable groups and branched tails.23,24,26SUMMARY OF THE INVENTION

[0005] The present disclosure describes the development of a novel 4-component reaction (4CR) that allowed for synthesis of a library of ionizable lipids, and screening for their ability to deliver mRNA locally and to specific organs in mice. Lipids were identified that are efficient at delivering mRNA to the muscle, lung, and nose.

[0006] In one aspect, provided herein is a compound of Formula (I):O NHRR2O2C- L2— L3-CO2R3°YN'R’X (I).1 / 232M1237.70152US0012225011.1or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically labeled derivative thereof, wherein R, R1, R2, R3, L2, L3, and X are as defined herein.

[0007] In another aspect, provided herein is a composition comprising a compound provided herein, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.

[0008] In another aspect, provided herein is a method of delivering an agent to a subject or a cell, comprising administering to the subject or contacting the cell with a composition comprising an agent and a compound provided herein, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically labeled derivative thereof.

[0009] In another aspect, provided herein is a method of treating and / or preventing a disease, disorder, or condition in a subject, comprising administering to the subject a composition comprising an agent and a compound provided herein, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically labeled derivative thereof.

[0010] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims. It should be understood that the aspects described herein are not limited to specific embodiments, methods, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, provide non-limiting examples of the invention.

[0012] FIGs. 1A-1G show workflow for LiON, deep learning-based LNP design. FIG. 1A shows collection of available LNP data, typically collected from a screen generated via combinatorial synthesis. FIG. 1B shows training predictive MPNN-based DL model on training data. Inputs are the chemical structure of the ionizable lipid along with metadata (formulation details, cargo, target of LNP). FIG. 1C shows rank of lipids from novel library using trained model. FIG. 1D shows screen of top candidates in vivo. FIG. 1E shows follow up and structurally optimize individual promising LNPs. FIGs. 1F-1G show performance of model as measured by correlation between predicted and experimental delivery results on held-out test set using a random training test split (FIG. 1F) and an amine-based training-test split (FIG. 1G).

[0013] FIGs.2A-2H show LiON for optimizing IV liver delivery of branched ester-based library. FIG. 2A shows Michael addition chemistry for generation of branched-tail ionizable lipids. FIGs. 2B-2F show FFL mRNA delivery testing to the liver, 1ug dose delivered IV, imaging after 6 h. FIG. 2B 2 / 232M1237.70154WO0012225011.1shows screen of top DL candidates with EPA (T08) and DHA (T16) tails. n=3 for RM-2-133-3 control, n=l-2 for rest of screen. FIG. 2C shows RJ-A03-T16 has improved liver delivery compared to RM-2-133-3 (which according to this work’s nomenclature would be designated RJ-A03-T08). FIG. 2D shows screen of top DL candidates with ALA (T30) and GLA (T34) tails. FIG. 2E shows evaluation of top candidates RJ-A14-T30 and RJ-A14-T34 relative to controls. FIG. 2F shows screening of candidates with tail T01, with RJ-A30-T01 as top candidate. FIG. 2G shows testing of top candidates relative to controls shows RJ-A30-T01 appears to be the top performer. FIG. 2H shows serum Epo 6 h after Epo mRNA delivery. All doses for this figure are 1 pg.

[0014] FIGs.3A-3K show combining LiON with 4-component reaction chemistry. FIG.3A shows 4-component reaction scheme to generate novel ionizable lipids. FIGs. 3B-3K show intramuscular (IM) FFL mRNA delivery testing, imaged 6 h after injection in BALB / C mice unless otherwise indicated. FIG.3B shows initial IM delivery testing with ML3 and ML5 (lug dose, BL / 6 mice) compared to cKK-E12. FIG. 3C shows structures of ML3 and ML3Me. FIG. 3D shows delivery of ML3Me is better than delivery of ML3 (lug dose). FIG.3E shows testing of top DL candidates against SM-102 and cKK-E12 controls (5ug dose) shows promise for some candidates. FIG. 3F shows IM delivery of FO-32 compared to cKK-E12 and SM-102 (lug dose). FIG.3G shows structures of top candidates FO-32, FO-35, and EB-66. FIGs. 3H-3K show comparison of delivery of formulation-optimized DL-designed lipids compared to cKK-E12 (formulation-matched and with original KK formulation) and SM-102 (clinical vaccine formulation with DMPE-PEG2000 instead of DMG-PEG2000), at 0.01 (FIG. 3H), 0.1 (FIG. 31), 1 (FIG. 3J), and lOug (FIG.3K) doses.

[0015] FIGs. 4A-4F show respiratory tract delivery. FIG. 4A shows IN FFL delivery (1.5ug dose) comparison between lead DL candidates (FO-32, FO-35, EB-66) and controls (cKK-E12, SM-102, Lipid 331). FIG. 4B shows OPA FFL delivery comparison (1ug dose) between lead DL candidates and controls. FIGs. 4C-4E show OPA FFL delivery (lug dose) for FO-32 compared to top control cKK-E12. FIG. 4C shows representative lung image, FIG. 4D shows lung luminescence, FIG.4E shows tracheal luminescence quantified following background subtraction due to low signal. FIG. 4F shows nebulized FFL delivery (500ug dose) for FO-32 compared to top control IR-117-17 for nose, lung, and trachea. IN delivery is in BALB / C, all OPA and nebulized testing in BL / 6 mice.

[0016] FIG. 5 shows representative structures from each of the datasets used to train the model.

[0017] FIGs.6A-6D show strategies for training-test split. FIG. 6A shows a schematic of a toy combinatorially synthesized library between three headgroups and three tails. FIG. 6B shows standard random training-test split will result in a test set where each tail, and each headgroup, will be present in the training set, so predictions are more akin to interpolation. FIG. 6C shows amine-based training-test split will result in a test set with a fully new amine headgroup, forcing model extrapolation to a new component (here, amine A2). FIG. 6D shows generating a test set with both amines and tails unseen in the training data requires discarding a large fraction of the available data.

[0018] FIG. 7 shows the top 3 predicted branched ester structures for mRNA delivery.3 / 232M1237.70154WO0012225011.1

[0019] FIG. 8 shows testing of arachidonic acid (T15)-containing lipids for liver mRNA delivery. FFL mRNA delivery testing to the liver, 1ug dose delivered IV, imaging after 6 h.

[0020] FIG. 9 shows components for initial 4CR in silico screen.

[0021] FIG. 10 shows the structure of ML5.

[0022] FIGs. 11A-11B show the testing of ML3 analogues. FIG. 11A shows testing of LNPs with DL-driven ionizable lipids and analogues. “Relative total flux” refers to luminescence relative to a cKK-E12-treated mouse tested on the same day. All data generated from BALB / C mice, 5|lg dose using handmixed undialyzed LNPs, except for initial testing with ML3 and ML3Me 11 pg dose, microfluidically synthesized and dialyzed LNPs, C57BL / 6 mice). FIG. 11B shows structures of tested ionizable lipids.

[0023] FIGs. 12A-12B show testing of LiON-designed lipids. FIG. 12A shows testing of LNPs with LiON-driven ionizable lipids from large-scale in silico screen. “Relative total flux” refers to luminescence relative to a cKK-E12-treated mouse tested on the same day. BALB / C mice, 5pg dose using handmixed undialyzed LNPs. FIG. 12B shows structures of tested ionizable lipids.

[0024] FIGs. 13A-13B show testing of top ionizable lipid analogues. FIG. 13A shows testing of LNPs with analogues of DL-driven ionizable lipids. “Relative total flux” refers to luminescence relative to a cKK-E12-treated mouse tested on the same day. BALB / C mice, 5pg dose using handmixed undialyzed LNPs. FIG. 13B shows structures of tested ionizable lipids.

[0025] FIGs. 14A-14B show systematic testing of analogues of FO-32. FIG. 14A shows intramuscular FFL delivery. “Relative total flux” refers to luminescence relative to a cKK-E12-treated mouse tested on the same day. BALB / C mice, 5pg dose using handmixed undialyzed LNPs for FO-37-FO-43, BALB / C mice, Ipg dose using microfluidically synthesized dialyzed LNPs for FO-45, FO-46, and FO-47. FIG. 14B shows structures of tested ionizable lipids.

[0026] FIGs. 15A-15C show formulation screening. See Tables 5-6 for formulation parameters. FIG. 15A shows a formulation screen for FO-16 and FO-32. FIG. 15B shows follow-up screen of formulations to further optimize F10 for FO-32. FIG. 15C shows testing of F17 and F3, chosen as alternative F17 while retaining good activity for both FO-16 and FO-32, against FO-32 KK and cKK-E12 controls suggests F3 is superior, lug FFL dose for all experiments delivered IM to BALB / C mice.

[0027] FIGs. 16A-16B show IM delivery testing. FIG. 16A shows representative IVIS images of LNPs tested at lug dose (FIG. 3J). Only 5 mice can be imaged at once on IVIS so the representative cKK-E12 mouse was imaged separately, but the scale is the same. FIG. 16B shows encapsulation efficiency of LNPs tested in FIGs. 3H-3K.

[0028] FIG. 17 shows combined dose curve LNPs tested.

[0029] FIGs. 18A-18F show extended data from intranasal delivery experiment shown in FIG. 4A.FIGs. 18A-18C show representative IVIS images of nasal (FIG. 18A), lung (FIG. 18B), trachea4 / 232M1237.70154WO0012225011.1(FIG. 18C) luminescence (regions without tracheas are used for background subtraction, required only for trachea due to extremely low tracheal signal). FIG. 18D shows quantified lung luminescence.FIG. 18E shows quantified background-subtracted tracheal luminescence. FIG. 18F shows encapsulation efficiencies for LNPs tested intranasally.

[0030] FIGs. 19A-19F show extended data from OPA delivery experiments. FIG. 19A shows OPA FFL delivery comparison (lug dose, BL / 6 mice) between lead DL candidates and controls. FIGs. 19B-19C show tracheal delivery quantification for experiments in FIG. 4B and FIG.15 A. FIG. 19D shows representative tracheal delivery for FO-32 and cKK-E12 for FIG. 4D. FIGs. 19E-19F show encapsulation efficiencies for experiments in FIG. 4B and FIG. 19A.

[0031] FIGs.20A-20C show freeze-thaw stability studies for FO-32. FIGs. 20A-20B show intranasal mRNA delivery of FO-32 LNPs formulated with Tl-5 formulation after a freeze-thaw (flash frozen with 5% sucrose cryoprotectant) or fresh, 5ug dose, BL / 6 mice: nasal luminescence (FIG. 20A), lung luminescence (FIG. 20B). FIG. 20C shows mRNA encapsulation efficiency of fresh and freeze-thawed LNP after storage for 1 week at -80 or in liquid nitrogen (LN2), without (-Sue) or with (+Suc) cryoprotectant.

[0032] FIGs.21A-21C show closest analogues (by Tanimoto similarity) between top lipids and structures from the training dataset. FIG. 21A shows i) FO-32 and closest analogue, ii) Ketone extension of FO-32 and closest analogue showing presence of this alkyne in the training set. FIG. 21B shows i) FO-35 and closest analogue, ii) Ketone extension of FO-35 and closest analogue, showing that this structure is highly unique. FIG. 21C shows i) EB-66 and closest analogue, ii) Ketone extension of EB-66 and closest analogue, showing that this structure is highly unique.

[0033] FIG. 22 shows the comparison of EB-59 and FO-32 to cKK-E12. I pg mRNA dose.

[0034] FIGs.23A-23B show OPA delivery (I pg dose) to BL / 6 mice with 35:28:34.5:2.5 ionizable lipid: DOTAP:cholesterol: PEG-lipid formulation (FIG. 23A) and BL / 6 mice with 30:39:30:1 ionizable lipid: DOTAP: cholesterol: PEG-lipid formulation (FIG. 23B).

[0035] FIG. 24 shows the structures of lipids EB-59, EB-66, and EB-64.

[0036] FIG. 25 shows results of IM delivery screening of additional lipids. All LNPs were handmixed and delivery was normalized to cKK-E12 run on the same day.

[0037] FIG. 26 shows IV FFL mRNA delivery to the liver and spleen (5pg dose).

[0038] FIGs.27A-27B show respiratory tract mRNA delivery showing that ML3-Me-DHA is comparable to cKK-E12 for respiratory tract delivery. FIG. 27A shows intranasal FFL mRNA delivery (Ipg / mouse), imaged 6h after administration. FIG. 27B shows intratracheal FFL mRNA delivery (4pg / mouse), lungs imaged 6h after administration.

[0039] FIG. 28 shows ALI culture screen of LNPs (primary human bronchial epithelial cells grown in 96-well 0.4pm pore Transwell inserts for 4 weeks, cultured with PneumaCult-ALI media, treated5 / 232M1237.70154WO0012225011.1with 500ng handmixed LNP / insert, n=2 wells / LNP) prepared using 35:28:34.5:2.5 ionizable lipid: DOTAP:cholesterol: PEG-lipid formulation. Black arrows indicate alkyne ketone group.

[0040] FIGs.29A-29B show intranasal FFL delivery (1µg in 15µL) to the nose (FIG. 29 A) and the lung (FIG. 29B). FO-32 significantly outperforms cKK-E12. KK formulation used (35:16:46.5:2.5 ionizable lipid: DOPE: cholesterol: PEG-lipid).

[0041] FIG. 30 shows oropharyngeal aspiration-based delivery to the lung. FO-22 and FO-32 are not significantly different from cKK-E12.

[0042] FIG. 31 shows the structures of additional lipids.

[0043] FIGs.32A-32F show ’H and13C NMR spectra of lipids FO-32 (FIGs. 32A-32B), FO-35(FIGs. 32C-32D), and EB-66 (FIGs. 32E-32F).

[0044] FIGs.33A-33D show further characterization of RJ-A30-T01 LNPs. FIG. 33A shows biodistribution of luciferase expression in liver, spleen, and lung following IV administration of 1 µg total mRNA to BL / 6 mice (n=4). FIG. 33B shows the size of RJ-A30-T01 LNPs following freezethaw cycle using 5% sucrose as a cryoprotectant. Diameters average across 5-10 repeated measurements. FIG. 33C shows pro-inflammatory cytokine concentrations (comparisons used two-sided unpaired t-test assuming equal variance). FIG.33D shows liver enzyme concentrations in serum 6 h following IV administration of 1 pg total mRNA (comparisons used 2-way ANOVA, no significant difference between PBS and RJ-A30-T01, F(l,10)=0.0006, p=0.98). n=4 for FIGs. 33C and 33D.

[0045] FIGs.34A-34D show the uptake mechanism for LNPs. HeLa cells were treated with approximately 10 ng of total RNA in tetramethylindocarbocyanine perchlorate (Dil)-labeled fluorescent LNPs (0.5 mol% Dil), and either PBS or one of two uptake inhibitors: 5-(N-Ethyl-Nisopropyl) amiloride (EIPA, 50 pM) or Dynasore (Dyn, 100 pM). Dil interfered with Ribogreen assay so RNA concentration was estimated based on previous concentrations from comparable LNP syntheses; comparisons between LNPs are therefore not valid but comparisons between the same LNP are since dose was consistent. LNP uptake was measured using flow cytometry. FIG. 34A shows gating strategy for flow cytometry. FIG. 34B shows representative flow cytometry plots for LNP uptake in the presence of no inhibitor, Dyn or EIPA. FIG. 34C shows Dil-i- percentages and FIG. 34D shows mean Dil uptake for each LNP and each inhibitor. Statistical tests for FIGs. 34C and 34D: two-way ANOVA (all interactions, row factor, column factors significant, p<0.01) followed by Dunnett’s multiple comparison test using the “no inhibitor” condition as control, for each LNP. n=3 wells / condition except 2 wells for cKK-E12 EIPA condition. Error bars, mean + / - SEM.

[0046] FIGs.35A-35E show LNP pKa. FIG. 35A shows pKa of cKK-E12 (KK formulation). FIG.35B shows pKa of SM-102 (DSPC formulation). FIG.35C shows pKa of FO-32. FIG. 35D shows pKa of FO-35. FIG. 35E shows pKa of EB-66. n=2 separate LNP syntheses and pKa measurements. pKa values are indicated on the x axes and were determined via 4-parameter logistic curve (4PL) using GraphPad Prism 9 by averaging the two LogIC50’s (one from each replicate).6 / 232M1237.70154WO0012225011.1

[0047] FIGs.36A-36B show inflammation and biodistribution of intramuscularly administered LNPs. FIG. 36A shows pro-inflammatory cytokine concentrations in serum 6 h following IM administration of 1 pg total mRNA (n=4 BL / 6 mice). PBS control is same as for other cytokine quantifications (all cytokine quantification experiments were done at the same time on the same day). Groups were compared via 1-way ANOVA; only IL-6 showed significant difference among means (F(5,18)=4.883, p=0.0054). Individual statistical comparisons were performed between all three control conditions (PBS, cKK-E12, SM-102) and all 3 new lipid conditions (FO-32, FO-35, EB-66) via Sidak's multiple comparisons test. The outlier points found in multiple EB-66 cytokine observations were all from the same mouse. FIG. 36B shows luminescence in different organs following IM administration of 1 pg total mRNA. FIGs. 36A and 36B used the same n=4 (BL / 6) mice; blood collection and luminescence measurement were performed consecutively. All error bars: mean + / - SEM.

[0048] FIGs.37A-37B show inflammation and biodistribution of intranasally administered LNPs.FIG. 37A shows pro-inflammatory cytokine concentrations in serum 6 h following intranasal (IN) administration of 1 pg total mRNA (n=4 BL / 6 mice). PBS control is same as for other cytokine quantifications (all cytokine quantification experiments were done at the same time on the same day). Groups were compared via 1-way ANOVA; only IL-6 showed significant difference among means (F(7,22)=3.019, p=0.022). Individual statistical comparisons were performed between all three control conditions (PBS, cKK-E12, SM-102) and all 5 new lipid conditions (FO-32 DOTAP and DOPE, FO-35 DOTAP and DOPE, EB-66) via Sidak's multiple comparisons test; none were significant in any condition. FIG. 37B shows luminescence in different organs following IN administration of 1 pg total mRNA. FIGs. 37A and 37B used the same n=4 (BL / 6) mice; blood collection and luminescence measurement were performed consecutively. FO-32 and FO-35 DOPE formulations refer to formulation F3. All error bars, mean + / - SEM.

[0049] FIGs.38A-38E show freeze-thaw stability studies for LNP candidates. FIG. 38A shows nasal luminescence and FIG. 38B shows lung luminescence following intranasal mRNA delivery of FO-32 LNPs formulated with Tl-5 formulation after a freeze-thaw (flash frozen with 5% sucrose cryoprotectant) or fresh, 5 ug dose, n=4 BL / 6 mice. Error bars: mean + / - SEM. Statistical tests: unpaired equal-variance two-sided t tests. FIG. 38C mRNA encapsulation efficiency of fresh and freeze-thawed LNP. FIGs.38D and 38E show diameter of LNPs formulated according to Tl-5 formulation (FIG. 38D) and intranasal formulation (FIG.38E), encapsulating Cre (FIG. 38D) and FFL (FIG. 38E) mRNA. Diameters are average across 8-10 repeated measurements.

[0050] FIGs. 39A-39B show cross-validation performance of LiON 2.0 by correlating predicted and experimental delivery for fully random (FIG. 39A) and amine-based (FIG. 39B) splitting using fivefold cross validation. Error bars, mean + / - SEM. N values are average number of datapoints in each training set. Correlations with <10 measurements were discarded (hence why 4CR aid IM only7 / 232M1237.70154WO0012225011.1has 3-4 points per plot). “RJ Liver” and “RJ Spleen” contain the results from RJ series screening (see FIG. 2).

[0051] FIGs.40A-40C show luminescence of LNPs in muscle (FIG. 40A), nasal (FIG. 40B), or lung (FIG. 40C).

[0052] FIGs.41A-41B show LNP performance in either the KK formulation (FIG. 41 A) or T 1-5 formulation (FIG. 41B) in HeLa cells.

[0053] FIGs.42A-42D show flux after intramuscular administration of LNP at 0.01 pg (FIG. 42A), 0.1 pg (FIG.42B), 1 pg (FIG. 42C), or 10 pg (FIG. 42D).

[0054] FIG. 43 provides various formulations of DOPE, cholesterol, ionizable lipid, and PEG-lipid.

[0055] FIGs.44A-44F show luminescence in HeLa cells (15k cells) for formulations prepared according to FIG. 43 comprising various ionizable lipids at 100 ng per well. FIG. 44A compares formulations of EB-A2. FIG. 44B compares formulations of EB-C1. FIG. 44C compares formulations of EB-E1. FIG. 44D compares formulations of EB-E2. FIG. 44E compares formulations of EB-E3. FIG. 44F compares formulations of EB-F1.

[0056] FIG. 45 shows flux in lungs of 1 pg of ionizable lipids dosed intratracheally.

[0057] FIG. 46 shows flux after administration of 0.1 pg of ionizable lipid dosed intramuscularly.

[0058] FIG. 47 shows a schematic of a vaccine model for assessing ionizable lipids.

[0059] FIG. 48 shows a schematic of an immunogenicity assessment of ionizable lipids in a primeboost H3 vaccine model.DEFINITIONS

[0060] 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.

[0061] 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 8 / 232M1237.70154WO0012225011.1the 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 invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0062] When a range of values is listed, it is intended to encompass 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 “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, Ce, Ci-6, C1-5, Ci^t, C1-3, C1-2, C2-6, C2-5, C2 4, C2-3, C3-6, C3-5, C3–4, C4-6, C4-5, and C5-6 alkyl.

[0063] In a formula, the bond is a single bond, the dashed line — is a single bond or absent, and the bond = or is a single or double bond.

[0064] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0065] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of Ci-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., zz-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (Ce) e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs), 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 Ci-12 alkyl (such as unsubstituted Ci-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z'-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted zz-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z'-Bu)). In certain embodiments, the9 / 232M1237.70154WO0012225011.1alkyl group is a substituted Ci-12 alkyl (such as substituted Ci-6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0066] 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 (“heteroCi-20 alkyl”). 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 (“heteroCi-12 alkyl”). 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 (“heteroCi-n alkyl”). 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 (“heteroCi-10 alkyl”). 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 (“heteroCi-9 alkyl”). 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 (“heteroCi-s alkyl”). 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 (“heteroCi-7 alkyl”). 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 (“heteroCi-6 alkyl”). 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 (“heteroCi-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“hctcroCi 4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). 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 (“heteroC26 alkyl”). 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 heteroCi-12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-12 alkyl.

[0067] 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 (“Ci-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“Ci-12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“Ci-11 alkenyl”). In some embodiments, an10 / 232M1237.70154WO0012225011.1alkenyl group has 1 to 10 carbon atoms (“Ci-io 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 (“Ci-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 (“Ci^t 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 (“Ci 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 C2-4 alkenyl 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 C1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20 alkenyl. 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 (£)- or (Z)-configuration.

[0068] 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. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-s alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkenyl”). In some embodiments, a heteroalkenyl group has Ito 6 carbon atoms, at11 / 232M1237.70154WO0012225011.1least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“hctcroCi 4 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC1-20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1-20 alkenyl.

[0069] 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) (“Ci -20 alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“Ci-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“Ci-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“Ci-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“CM alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“Ci alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C1-4 alkynyl groups include, without limitation, methylidynyl (Ci), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.

[0070] 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. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 2012 / 232M1237.70154WO0012225011.1carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi- 20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi- io alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-s alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“hctcroCi 4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC1-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1-20 alkynyl.

[0071] 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. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3 -14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3 -13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3 -11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3 -10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3 -7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5 -10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3),13 / 232M1237.70154WO0012225011.1cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-14 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0072] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3 -10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.14 / 232M1237.70154WO0012225011.1

[0073] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered nonaromatic 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”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0074] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 -ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0075] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,15 / 232M1237.70154WO0012225011.1pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5 -membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo-[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0076] 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 (“Ctu aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.

[0077] “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0078] 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,16 / 232M1237.70154WO0012225011.1wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.“Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5 -indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0079] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system 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 (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system 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 (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system 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 (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0080] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include 17 / 232M1237.70154WO0012225011.1imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl.Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0081] “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0082] The term “unsaturated bond” refers to a double or triple bond.

[0083] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0084] 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.

[0085] 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, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0086] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term 18 / 232M1237.70154WO0012225011.1“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 invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, 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 invention is not limited in any manner by the exemplary substituents described herein.

[0087] 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, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -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), Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-20 alkenyl, Ci-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, 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 =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC;wherein:each instance of Raais, independently, selected from Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-2o alkenyl, Ci-20 alkynyl, heteroCi-2o alkyl, heteroC1-20alkenyl, heteroC1-20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,19 / 232M1237.70154WO0012225011.1carbocyclyl, 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, C1-20 alkyl, C1-20 perhaloalkyl, Ci-2o alkenyl, Ci-2o 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, Ci-2o alkyl, Ci-2o perhaloalkyl, Ci-2o alkenyl, Ci-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, C1-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroC1-10alkyl, heteroC1-10alkenyl, heteroC1-10alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 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 =0 or =S; wherein X“ is a counterion;each instance of Reeis, independently, selected from Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,20 / 232M1237.70154WO0012225011.1heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;each instance of Rffis, independently, selected from hydrogen, Ci-io alkyl, Ci-io perhaloalkyl, Ci-io alkenyl, Ci-io alkynyl, heteroCi-io alkyl, heteroCi-io alkenyl, heteroCi-io alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 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, -OCi_6 alkyl, — ON(CI-6alkyl)2, -N(CI-6 alkyl)2, -N(CI-6 alkyl)3+X“, -NH(Ci- _6alkyl)2+X“, -NH2(CI_6 alkyl)+X. -NH3+X“, -N(OCiGalkyl)(Ci^ alkyl), -N(OH)(Ci^ alkyl), -NH(OH), -SH, -SCi^ alkyl, -SSlCiGalkyl), -C(=O)(Ci^ alkyl), -CO2H, -CChlCiGalkyl), -OC(=O)(Ci_6 alkyl), -OCO2(Ci6alkyl), -C(=O)NH2, -C(=O)N(Ci-6 alkyl)2, -OC(=O)NH(Ci-6 alkyl), -NHC(=O)( CiGalkyl), -N(Ci^ alkyl)C(=O)( Cm; alkyl), -NHCO2(CI_6 alkyl), -NHC(=O)N(CI_6alkyl)2, — NHC(=O)NH(CI-6 alkyl), -NHC(=O)NH2, -C(=NH)O(Ci-6 alkyl), -OC(=NH)(Ci^ alkyl), — OC(=NH)OCi <, alkyl, -C(=NH)N(CI_6alkyl)2, -C(=NH)NH(CI_6 alkyl), -C(=NH)NH2, — OC(=NH)N(Ci-6 alkyl)2, -OC(NH)NH(C,_ 6 alkyl), -OC(NH)NH2, -NHC(NH)N(CI-6 alkyl)2, -NHC(=NH)NH2, — NHSO2(CI-6alkyl), -SO2N(CI -6 alkyl)2, -SO2NH(CIGalkyl), -SO2NH2, -SO2C1 <> alkyl, -SO2OC1 <> alkyl, -OSO2C1 <> alkyl, -SOCiGalkyl, -Si(Ci-6 alkyl)3, -OSilCiGalkyl)3-C(=S)N(Ci^ alkyl)2, C(=S)NH(CI-6alkyl), C(=S)NH2, -C(=O)S(Ci-6 alkyl), -C(=S)SCi^ alkyl, -SC(=S)SCi. _6alkyl, -P(=O)(OC« alkyl)2, -P(=O)(Ci-6 alkyl)2, -OP(=O)(C« alkyl)2, -OP(=O)(OC« alkyl)2, Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-io alkyl, heteroCi-io alkenyl, heteroCi-io alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; andeach X" is a counterion.

[0088] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO^, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa.-C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES,21 / 232M1237.70154WO0012225011.1TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted Ci-10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0089] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0090] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxyl,” 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, -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.

[0091] The term “thiol” or “thio” refers to the group -SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -SRaa, -S=SRCC, -SC(=S)SRaa, -SC(=S)ORaa, -SC(=S) N(Rbb)2, -SC(=O)SRaa, -SC(=O)ORaa, -SC(=O)N(Rbb)2, and -SC(=O)Raa, wherein Raaand Rccare as defined herein.

[0092] The term “amino” refers to the group -NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0093] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa, -NHCO2Raa.-NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORCC)2, and22 / 232M1237.70154WO0012225011.1-NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group -NH(Rbb) is not hydrogen.

[0094] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbSO2Raa, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0095] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(Rbb)3 and -N(Rbb)3+X“, wherein Rbband X“ are as defined herein.

[0096] The term “acyl” refers to a group having the general formula -C(=O)Raa, -C(=O)ORaa, -C(=O)-O-C(=O)Raa, -C(=O)SRaa, -C(=O)N(Rbb)2, -C(=S)Raa, -C(=S)N(Rbb)2, and -C(=S)S(Raa), -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)SRaa, and -C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0097] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (-C(=O)Raa), carboxylic acids (-CO2H), aldehydes (-CHO), esters (-CO2Raa, -C(=O)SRaa, -C(=S)SRaa), amides (-C(=O)N(Rbb)2, -C(=O)NRbbSO2Raa, -C(=S)N(Rbb)2), and imines (-C(=NRbb)Raa, -C(=NRbb)ORaa), -C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0098] 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, CI 20 alkyl, C 1-20 perhaloalkyl, C 1-20 alkenyl, Ci-20 alkynyl, hetero C 1-20 alkyl, hetero C 1-20 alkenyl, hetero Ci-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.

[0099] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais23 / 232M1237.70154WO0012225011.1hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, 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 Ci-io alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a nitrogen protecting group.

[0100] 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, -SOFT. -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, Ci-io alkyl (e.g., aralkyl, heteroaralkyl), Ci-2o alkenyl, Ci-20 alkynyl, hetero Ci-2o alkyl, hetero Ci-2o alkenyl, hetero Ci-2o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce 14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, 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.

[0101] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3 -pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, -acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0102] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl 24 / 232M1237.70154WO0012225011.1carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), I J -dimcthyl-2-halocthyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'~ and 4'-pyridy l)cthy 1 carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cy anoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, 5-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(A2V-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-( / V,. A-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1-(3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1-methyl-l-phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0103] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- 25 / 232M1237.70154WO0012225011.1methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4 / ,8 / -dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0104] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A’-p-toluenesulfonylaminoacyl derivatives, N’-phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, A-acctylmcthioninc derivatives, 4,5-diphenyl-3-oxazolin-2-one, A-phthalimidc, A-dithiasuccinimidc (Dts), A-2,3-diphcnylmalcimidc, A-2,5-dimethylpyrrole, N-l, 1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1, 3 -dibenzyl- 1,3,5 -triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, A-methylamine, A-allylamine, A-[2-(trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, A-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, A-di(4-methoxyphenyl)methylamine, A-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), A-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenylfluorenylamine (PhF), A-2,7-dichloro-9-fluorenylmethyleneamine, A-ferrocenylmethylamino (Fem), A-2-picolylamino A’-oxide, N-l, 1-dimethylthiomethyleneamine, A-benzylideneamine, A-p-methoxybenzylideneamine, A-diphenylmethyleneamine, A-[(2-pyridyl)mesityl]methyleneamine, A-(A’, A’-dimethylaminomethylene) amine, A-p-nitrobenzylideneamine, A-salicylideneamine, A-5-chlorosalicylideneamine, A-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, A-cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, A-borane derivatives, A-diphenylborinic acid derivatives, A-[phenyl(pentaacylchromium- or tungsten)acyl]amine, A-copper chelate, A-zinc chelate, A-nitroamine, A-nitrosoamine, amine A-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are A, A’-isopropylidenediamine.

[0105] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0106] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CCER”, -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 Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais 26 / 232M1237.70154WO0012225011.1hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, 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 Ci-io alkyl, 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 Ci-6 alkyl or an oxygen protecting group.

[0107] 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 include -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.

[0108] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxy cyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl. S'.. S'-dioxidc, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1-methyl-l-methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn),p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl A-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’ -bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"’-[N-(imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4’-Dimethoxy-3"’-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), l,l-bis(4-methoxyphenyl)-r-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl 27 / 232M1237.70154WO0012225011.1. S'.. S'-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxy acetate, triphenylmethoxy acetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(l,l,3,3-tetramethylbutyl)phenoxy acetate, 2,4-bis( 1, 1 -dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl A^A / '-tctramcthylphosphorodiamidatc, alkyl / V-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0109] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0110] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, 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 Ci-io alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a sulfur protecting group.

[0111] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa,28 / 232M1237.70154WO0012225011.1-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 Raa, Rbb, and Rccare as defined herein. Sulfur 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.

[0112] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0113] 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.

[0114] 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 this invention 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+(G i 4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include29 / 232M1237.70154WO0012225011.1ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0115] 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 this invention 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, 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 salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci-4 alkyljT 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.

[0116] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.30 / 232M1237.70154WO0012225011.1

[0117] The term “stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent molecules are an integral part of the crystal lattice, in which they interact strongly with the compound and each other. The removal of the solvent molecules will cause instability of the crystal network, which subsequently collapses into an amorphous phase or recrystallizes as a new crystalline form with reduced solvent content.

[0118] The term “non-stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent content may vary without major changes in the crystal structure. The amount of solvent in the crystal lattice only depends on the partial pressure of solvent in the surrounding atmosphere. In the fully solvated state, non-stoichiometric solvates may, but not necessarily have to, show an integer molar ratio of solvent to the compound. During drying of a non-stoichiometric solvate, a portion of the solvent may be removed without significantly disturbing the crystal network, and the resulting solvate can subsequently be resolvated to give the initial crystalline form. Unlike stoichiometric solvates, the desolvation and resolvation of non-stoichiometric solvates is not accompanied by a phase transition, and all solvation states represent the same crystal form.

[0119] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R·x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R·0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2 H2O) and hexahydrates (R·6 H2O)).

[0120] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0121] The term “co-crystal” refers to a crystalline structure comprising at least two different components e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid. In the salt, a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature. In the co-crystal, however, a compound disclosed herein is complexed31 / 232M1237.70154WO0012225011.1with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.

[0122] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0123] 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”.

[0124] 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”.

[0125] The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0126] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0127] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester 32 / 232M1237.70154WO0012225011.1derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred.

[0128] The terms “phosphorylethanolamine” and “phosphoethanolamine” are used interchangeably.

[0129] The term “sterol” refers to a subgroup of steroids also known as steroid alcohols, i.e., a steroid containing at least one hydroxyl group. Sterols are usually divided into two classes: (1) plant sterols also known as “phytosterols,” and (2) animal sterols also known as “zoosterols.” The term “sterol” includes, but is not limited to, cholesterol, sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrassicasterol), desmosterol, chalinosterol, poriferasterol, clionasterol, ergosterol, coprosterol, codisterol, isofucosterol, fucosterol, clerosterol, nervisterol, lathosterol, stellasterol, spinasterol, chondrillasterol, peposterol, avenasterol, isoavenasterol, fecosterol, pollinastasterol, and all natural or synthesized forms and derivatives thereof, including isomers.

[0130] As used here, the term “PEG-lipid” refers to a PEGylated lipid.

[0131] An “amino acid” refers to natural and unnatural D / L alpha-amino acids, as well as natural and unnatural beta- and gamma- amino acids. A “peptide” refers to two amino acids joined by a peptide bond. A “polypeptide” refers to three or more amino acids joined by peptide bonds. An “amino acid side chain” refers to the group(s) pended to the alpha carbon (if an alpha amino acid), alpha and beta carbon (if a beta amino acid), or the alpha, beta, and gamma carbon (if a gamma amino acid). Exemplary amino acid side chains are depicted herein.

[0132] A “protein,” “peptide,” or “polypeptide” comprises a polymer of amino acid residues linked together by peptide bonds. The term, as used herein, refers to proteins, polypeptides, and peptides of any size, structure, or function. Typically, a protein will be at least three amino acids long. A protein may refer to an individual protein or a collection of proteins. Inventive proteins preferably contain only natural amino acids, although non-natural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and / or amino acid analogs as are known in the art may alternatively be employed. Also, one or more of the amino acids in a protein may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for 33 / 232M1237.70154WO0012225011.1conjugation or functionalization, or other modification. A protein may also be a single molecule or may be a multi-molecular complex. A protein may be a fragment of a naturally occurring protein or peptide. A protein may be naturally occurring, recombinant, synthetic, or any combination of these.

[0133] The term “apolipoprotein” refers to a protein that binds a lipid (e.g., triacylglycerol or cholesterol) to form a lipoprotein. Apolipoproteins also serve as enzyme cofactors, receptor ligands, and lipid transfer carriers that regulate the metabolism of lipoproteins and their uptake in tissues. Major types of apolipoproteins include integral and non-integral apolipoproteins. Exemplary apolipoproteins include apoA (e.g., apoA-I, apoA-II, apoA-IV, and apoA-V); apoB (e.g., apoB48 and apoB 100); apoC (e.g., apoC-I, apoC-II, apoC-III, and apoC-IV); apoD; apoE; apoH; and apoJ.

[0134] The term “gene” refers to a nucleic acid fragment that expresses a specific protein, including regulatory sequences preceding (5’ non-coding sequences) and following (3’ non-coding sequences) the coding sequence. “Native gene” refers to a gene as found in nature with its own regulatory sequences. “Chimeric gene” or “chimeric construct” refers to any gene or a construct, not a native gene, comprising regulatory and coding sequences that are not found together in nature.Accordingly, a chimeric gene or chimeric construct may comprise regulatory sequences and coding sequences that are derived from different sources, or regulatory sequences and coding sequences derived from the same source, but arranged in a manner different than that found in nature.“Endogenous gene” refers to a native gene in its natural location in the genome of an organism. A “foreign” gene refers to a gene not normally found in the host organism, but which is introduced into the host organism by gene transfer. Foreign genes can comprise native genes inserted into a nonnative organism, or chimeric genes. A “transgene” is a gene that has been introduced into the genome by a transformation procedure.

[0135] The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid”, “nucleic acid molecule”, “nucleic acid sequence”, and “oligonucleotide” refer to a series of nucleotide bases (also called “nucleotides”) in DNA and RNA, and mean any chain of two or more nucleotides. The polynucleotides can be chimeric mixtures or derivatives or modified versions thereof, singlestranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, its hybridization parameters, etc. The oligonucleotide may comprise a modified base moiety which is selected from the group including, but not limited to, 5-fluorouracil, 5 -bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1 -methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5- methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5- methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5’ -methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2- 34 / 232M1237.70154WO0012225011.1thiouracil, 4-thiouracil, 5-methyluracil, uracil- 5-oxyacetic acid methylester, uracil-5 -oxy acetic acid, 5-methyl-2- thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, a thio-guanine, and 2,6-diaminopurine. The oligonucleotide may comprise one or more locked nucleic acid (LNA) moieties. A nucleotide sequence typically carries genetic information, including the information used by cellular machinery to make proteins and enzymes. These terms include double- or single-stranded genomic and cDNA, RNA, any synthetic and genetically manipulated polynucleotide, and both sense and antisense polynucleotides. This includes single- and double-stranded molecules, i.e., DNA-DNA, DNA-RNA and RNA-RNA hybrids, as well as “protein nucleic acids” (PNAs) formed by conjugating bases to an amino acid backbone. This also includes nucleic acids containing carbohydrate or lipids. Exemplary DNAs include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), a provirus, a lysogen, repetitive DNA, satellite DNA, and viral DNA. Exemplary RNAs include single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), a polyinosinic acid, a ribozyme, a flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, and viral satellite RNA.

[0136] Polynucleotides described herein may be synthesized by standard methods known in the art, e.g., by use of an automated DNA synthesizer (such as those that are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides may be synthesized by the method of Stein et al., Nucl. Acids Res., 16, 3209, (1988), methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., Proc. Natl. Acad. Sci. U. S. A. 85, 7448-7451, (1988)). A number of methods have been developed for delivering antisense DNA or RNA to cells, e.g., antisense molecules can be injected directly into the tissue site, or modified antisense molecules, designed to target the desired cells (antisense linked to peptides or antibodies that specifically bind receptors or antigens expressed on the target cell surface) can be administered systemically. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines. However, it is often difficult to achieve intracellular 35 / 232M1237.70154WO0012225011.1concentrations of the antisense sufficient to suppress translation of endogenous mRNAs. Therefore a preferred approach utilizes a recombinant DNA construct in which the antisense oligonucleotide is placed under the control of a strong promoter. The use of such a construct to transfect target cells in the patient will result in the transcription of sufficient amounts of single stranded RNAs that will form complementary base pairs with the endogenous target gene transcripts and thereby prevent translation of the target gene mRNA. For example, a vector can be introduced in vivo such that it is taken up by a cell and directs the transcription of an antisense RNA. Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in mammalian cells. Expression of the sequence encoding the antisense RNA can be by any promoter known in the art to act in mammalian, preferably human, cells. Such promoters can be inducible or constitutive. Such promoters include, but are not limited to: the SV40 early promoter region (Bernoist et al., Nature, 290, 304-310, (1981); Yamamoto et al., Cell, 22, 787-797, (1980); Wagner et al., Proc. Natl. Acad. Sci. U. S. A. 78, 1441-1445, (1981); Brinster et al., Nature 296, 39-42, (1982)). Any type of plasmid, cosmid, yeast artificial chromosome or viral vector can be used to prepare the recombinant DNA construct that can be introduced directly into the tissue site.Alternatively, viral vectors can be used which selectively infect the desired tissue, in which case administration may be accomplished by another route (e.g., systemically).

[0137] The polynucleotides may be flanked by natural regulatory (expression control) sequences, or may be associated with heterologous sequences, including promoters, internal ribosome entry sites (IRES) and other ribosome binding site sequences, enhancers, response elements, suppressors, signal sequences, polyadenylation sequences, introns, 5'- and 3 '-non-coding regions, and the like. The nucleic acids may also be modified by many means known in the art. Non-limiting examples of such modifications include methylation, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, and internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.). Polynucleotides may contain one or more additional covalently linked moieties, such as, for example, proteins e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), intercalators (e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, iron, oxidative metals, etc.), and alkylators. The polynucleotides may be derivatized by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage. Furthermore, the polynucleotides herein may also be modified with a label capable of providing a detectable signal, either directly or indirectly. Exemplary labels include radioisotopes, fluorescent molecules, biotin, and the like.

[0138] A “recombinant nucleic acid molecule” is a nucleic acid molecule that has undergone a molecular biological manipulation, i.e., non-naturally occurring nucleic acid molecule or genetically 36 / 232M1237.70154WO0012225011.1engineered nucleic acid molecule. Furthermore, the term “recombinant DNA molecule” refers to a nucleic acid sequence which is not naturally occurring, or can be made by the artificial combination of two otherwise separated segments of nucleic acid sequence, i.e., by ligating together pieces of DNA that are not normally continuous. By “recombinantly produced” is meant artificial combination often accomplished by either chemical synthesis means, or by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques using restriction enzymes, ligases, and similar recombinant techniques as described by, for example, Sambrook et al., Molecular Cloning, second edition, Cold Spring Harbor Laboratory, Plainview, N. Y.; (1989), or Ausubel et al., Current Protocols in Molecular Biology, Current Protocols (1989), and DNA Cloning: A Practical Approach, Volumes I and II (ed. D. N. Glover) IREL Press, Oxford, (1985); each of which is incorporated herein by reference.

[0139] Such manipulation may be done to replace a codon with a redundant codon encoding the same or a conservative amino acid, while typically introducing or removing a sequence recognition site. Alternatively, it may be performed to join together nucleic acid segments of desired functions to generate a single genetic entity comprising a desired combination of functions not found in nature. Restriction enzyme recognition sites are often the target of such artificial manipulations, but other site specific targets, e.g., promoters, DNA replication sites, regulation sequences, control sequences, open reading frames, or other useful features may be incorporated by design. Examples of recombinant nucleic acid molecule include recombinant vectors, such as cloning or expression vectors which contain DNA sequences encoding Ror family proteins or immunoglobulin proteins which are in a 5' to 3' (sense) orientation or in a 3' to 5' (antisense) orientation.

[0140] The term “pDNA,” “plasmid DNA,” or “plasmid” refers to a small DNA molecule that is physically separate from, and can replicate independently of, chromosomal DNA within a cell. Plasmids can be found in all three major domains: Archaea, Bacteria, and Eukarya. In nature, plasmids carry genes that may benefit survival of the subject e.g., antibiotic resistance) and can frequently be transmitted from one bacterium to another (even of another species) via horizontal gene transfer. Artificial plasmids are widely used as vectors in molecular cloning, serving to drive the replication of recombinant DNA sequences within host subjects. Plasmid sizes may vary from 1 to over 1,000 kbp. Plasmids are considered replicons, capable of replicating autonomously within a suitable host.

[0141] “RNA transcript” refers to the product resulting from RNA polymerase-catalyzed transcription of a DNA sequence. When the RNA transcript is a complementary copy of the DNA sequence, it is referred to as the primary transcript or it may be an RNA sequence derived from post-transcriptional processing of the primary transcript and is referred to as the mature RNA.“Messenger RNA (mRNA)” refers to the RNA that is without introns and can be translated into polypeptides by the cell. “cRNA” refers to complementary RNA, transcribed from a recombinant cDNA template. “cDNA” refers to DNA that is complementary to and derived from an mRNA 37 / 232M1237.70154WO0012225011.1template. The cDNA can be single-stranded or converted to double-stranded form using, for example, the Klenow fragment of DNA polymerase I.

[0142] A sequence “complementary” to a portion of an RNA, refers to a sequence having sufficient complementarity to be able to hybridize with the RNA, forming a stable duplex; in the case of double-stranded antisense nucleic acids, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the longer the hybridizing nucleic acid, the more base mismatches with an RNA it may contain and still form a stable duplex (or triplex, as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex.

[0143] The terms “nucleic acid” or “nucleic acid sequence”, “nucleic acid molecule”, “nucleic acid fragment” or “polynucleotide” may be used interchangeably with “gene”, “mRNA encoded by a gene” and “cDNA”.

[0144] The term “mRNA” or “mRNA molecule” refers to messenger RNA, or the RNA that serves as a template for protein synthesis in a cell. The sequence of a strand of mRNA is based on the sequence of a complementary strand of DNA comprising a sequence coding for the protein to be synthesized.

[0145] The term “siRNA” or “siRNA molecule” refers to small inhibitory RNA duplexes that induce the RNA interference (RNAi) pathway, where the siRNA interferes with the expression of specific genes with a complementary nucleotide sequence. siRNA molecules can vary in length (e.g., between 18-30 or 20-25 basepairs) and contain varying degrees of complementarity to their target mRNA in the antisense strand. Some siRNA have unpaired overhanging bases on the 5’ or 3’ end of the sense strand and / or the antisense strand. The term siRNA includes duplexes of two separate strands, as well as single strands that can form hairpin structures comprising a duplex region.

[0146] The term “gene silencing” refers to an epigenetic process of gene regulation where a gene is “switched off’ by a mechanism other than genetic modification. That is, a gene which would be expressed (i.e., “turned on”) under normal circumstances is switched off by machinery in the cell. Gene silencing occurs when RNA is unable to make a protein during translation. Genes are regulated at either the transcriptional or post-transcriptional level. Transcriptional gene silencing is the result of histone modifications, creating an environment of heterochromatin around a gene that makes it inaccessible to transcriptional machinery (e.g., RNA polymerase and transcription factors). Post-transcriptional gene silencing is the result of mRNA of a particular gene being destroyed or blocked. The destruction of the mRNA prevents translation and thus the formation of a gene product (e.g., a protein). A common mechanism of post-transcriptional gene silencing is RNAi.

[0147] 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,38 / 232M1237.70154WO0012225011.1microparticles, nanoparticles (e.g., lipid 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. In certain embodiments, the particle is substantially solid throughout. In certain embodiments, the particle is a nanoparticle. In certain embodiments, the particle is a microparticle.

[0148] The terms “composition” and “formulation” are used interchangeably.

[0149] 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 nonhuman 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.

[0150] 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, interstitial fluid, 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.

[0151] 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 invention 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.39 / 232M1237.70154WO0012225011.1

[0152] 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.

[0153] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0154] 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.

[0155] 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.

[0156] An “effective amount” of a compound or agent described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound or agent 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 or agent, 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 prophylactically effective amount. In certain embodiments, an effective amount is the amount of a compound or agent described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound or agent 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, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0157] 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 about40 / 232M1237.70154WO0012225011.1100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0158] In certain embodiments, the compounds of the invention may be 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.

[0159] 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.

[0160] A “therapeutically effective amount” of a compound or agent 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 or agent 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 delivering an agent to a subject or a cell. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering a polynucleotide to a subject or a cell. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering mRNA to a subject or a cell. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease, disorder, or condition. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering an agent to a subject or a cell and treating a disease, disorder, or condition. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering a polynucleotide to a subject or a cell and treating a disease, disorder, or condition. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering mRNA to a subject or a cell and treating a disease, disorder, or condition.

[0161] A “prophylactically effective amount” of a compound or agent 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 or agent 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 amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount 41 / 232M1237.70154WO0012225011.1sufficient for delivering an agent to a subject or a cell. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering a polynucleotide to a subject or a cell. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering mRNA to a subject or a cell. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease, disorder, or condition. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering an agent to a subject or a cell and preventing a disease, disorder, or condition. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering a polynucleotide to a subject or a cell and preventing a disease, disorder, or condition. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering mRNA to a subject or a cell and preventing a disease, disorder, or condition.

[0162] The term “genetic disease” refers to a disease caused by one or more abnormalities in the genome of a subject, such as a disease that is present from birth of the subject. Genetic diseases may be heritable and may be passed down from the parents’ genes. A genetic disease may also be caused by mutations or changes of the DNAs and / or RNAs of the subject. In such cases, the genetic disease will be heritable if it occurs in the germline. Exemplary genetic diseases include, but are not limited to, Aarskog-Scott syndrome, Aase syndrome, achondroplasia, acrodysostosis, addiction, adrenoleukodystrophy, albinism, ablepharon-macrostomia syndrome, alagille syndrome, alkaptonuria, alpha-1 antitrypsin deficiency, Alport’s syndrome, Alzheimer’s disease, asthma, autoimmune polyglandular syndrome, androgen insensitivity syndrome, Angelman syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention deficit hyperactivity disorder (ADHD), autism, baldness, Batten disease, Beckwith- Wiedemann syndrome, Best disease, bipolar disorder, br achy dactyl), breast cancer, Burkitt lymphoma, chronic myeloid leukemia, Charcot-Marie-Tooth disease, Crohn’s disease, cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer, congenital adrenal hyperplasia, Cornelia de Lange syndrome, Costello syndrome, Cowden syndrome, craniofrontonasal dysplasia, Crigler-Najjar syndrome, Creutzfeldt- Jakob disease, cystic fibrosis, deafness, depression, diabetes, diastrophic dysplasia, DiGeorge syndrome, Down’s syndrome, dyslexia, Duchenne muscular dystrophy, Dubowitz syndrome, ectodermal dysplasia Ellis-van Creveld syndrome, Ehlers-Danlos, epidermolysis bullosa, epilepsy, essential tremor, familial hypercholesterolemia, familial Mediterranean fever, fragile X syndrome, Friedreich’s ataxia, Gaucher disease, glaucoma, glucose galactose malabsorption, glutaricaciduria, gyrate atrophy, Goldberg Shprintzen syndrome (velocardiofacial syndrome), Gorlin syndrome, Hailey-Hailey disease, hemihypertrophy, hemochromatosis, hemophilia, hereditary motor and sensory neuropathy (HMSN), hereditary non polyposis colorectal cancer (HNPCC), Huntington’s disease, immunodeficiency with hyper-IgM, juvenile onset diabetes, Klinefelter’s syndrome, Kabuki syndrome, Leigh’s disease, long QT syndrome, lung cancer, malignant melanoma, manic depression, Marfan syndrome, Menkes syndrome, miscarriage, mucopolysaccharide disease, multiple endocrine neoplasia, multiple sclerosis, muscular dystrophy, myotrophic lateral sclerosis, myotonic dystrophy,42 / 232M1237.70154WO0012225011.1neurofibromatosis, Niemann-Pick disease, Noonan syndrome, obesity, ovarian cancer, pancreatic cancer, Parkinson’s disease, paroxysmal nocturnal hemoglobinuria, Pendred syndrome, peroneal muscular atrophy, phenylketonuria (PKU), polycystic kidney disease, Prader-Willi syndrome, primary biliary cirrhosis, prostate cancer, REAR syndrome, Refsum disease, retinitis pigmentosa, retinoblastoma, Rett syndrome, Sanfilippo syndrome, schizophrenia, severe combined immunodeficiency, sickle cell anemia, spina bifida, spinal muscular atrophy, spinocerebellar atrophy, sudden adult death syndrome, Tangier disease, Tay-Sachs disease, thrombocytopenia absent radius syndrome, Townes-Brocks syndrome, tuberous sclerosis, Turner syndrome, Usher syndrome, von Hippel-Lindau syndrome, Waardenburg syndrome, Weaver syndrome, Werner syndrome, Williams syndrome, Wilson’s disease, xeroderma piginentosum, and Zellweger syndrome.

[0163] 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.

[0164] 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.

[0165] 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 43 / 232M1237.70154WO0012225011.1to 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 tumors are 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.

[0166] 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- 44 / 232M1237.70154WO0012225011.1Hodgkin 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-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom’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 carcinoma45 / 232M1237.70154WO0012225011.1(PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0167] A “hematological disease” includes a disease which affects a hematopoietic cell or tissue. Hematological diseases include diseases associated with aberrant hematological content and / or function. Examples of hematological diseases include diseases resulting from bone marrow irradiation or chemotherapy treatments for cancer, diseases such as pernicious anemia, hemorrhagic anemia, hemolytic anemia, aplastic anemia, sickle cell anemia, sideroblastic anemia, anemia associated with chronic infections such as malaria, trypanosomiasis, HTV, hepatitis virus or other viruses, myelophthisic anemias caused by marrow deficiencies, renal failure resulting from anemia, anemia, polycythemia, infectious mononucleosis (EVI), acute non-lymphocytic leukemia (ANLL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), polycythemia ver a, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, Wilm’s tumor, Ewing’s sarcoma, retinoblastoma, hemophilia, disorders associated with an increased risk of thrombosis, herpes, thalassemia, antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red blood cells such as micro-angiopathic hemolytic anemias, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation, infections by parasites such as Plasmodium, chemical injuries from, e.g., lead poisoning, and hypersplenism.

[0168] The term “neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease. Examples of neurological diseases include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s 46 / 232M1237.70154WO0012225011.1disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; bbrain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt- Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome;Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTEV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Eeigh’s disease; Eennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis;47 / 232M1237.70154WO0012225011.1myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0169] 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 (z.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.,48 / 232M1237.70154WO0012225011.1alcoholic 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, erythrohepatic porphyria, hepatic porphyria (e.g., acute intermittent porphyria, porphyria cutanea tarda), and Zellweger syndrome.

[0170] The term “spleen disease” refers to a disease of the spleen. Example of spleen diseases include, but are not limited to, splenomegaly, spleen cancer, asplenia, spleen trauma, idiopathic purpura, Felty’s syndrome, Hodgkin’s disease, and immune-mediated destruction of the spleen.

[0171] The term “lung disease” or “pulmonary disease” refers to a disease of the lung. Examples of lung diseases include, but are not limited to, bronchiectasis, bronchitis, bronchopulmonary dysplasia, interstitial lung disease, occupational lung disease, emphysema, cystic fibrosis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), asthma (e.g., intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma), chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, interstitial lung disease, sarcoidosis, asbestosis, aspergilloma, aspergillosis, pneumonia (e.g., lobar pneumonia, multilobar pneumonia, bronchial pneumonia, interstitial pneumonia), pulmonary fibrosis, pulmonary tuberculosis, rheumatoid lung disease, pulmonary embolism, and lung cancer (e.g., non-small-cell lung carcinoma (e.g., adenocarcinoma, squamous-cell lung carcinoma, large-cell lung carcinoma), small-cell lung carcinoma).

[0172] A “painful condition” includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post-operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre-operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual 49 / 232M1237.70154WO0012225011.1dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre-term labor, pain associated with withdrawl symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter’s arthritis), lumbosacral pain, musculo-skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental / maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g., nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[0173] In certain embodiments, the painful condition is neuropathic pain. The term “neuropathic pain” refers to pain resulting from injury to a nerve. Neuropathic pain is distinguished from nociceptive pain, which is the pain caused by acute tissue injury involving small cutaneous nerves or small nerves in muscle or connective tissue. Neuropathic pain typically is long-lasting or chronic and often develops days or months following an initial acute tissue injury. Neuropathic pain can involve persistent, spontaneous pain as well as allodynia, which is a painful response to a stimulus that normally is not painful. Neuropathic pain also can be characterized by hyperalgesia, in which there is an accentuated response to a painful stimulus that usually is trivial, such as a pin prick. Neuropathic pain conditions can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain conditions include, but are not limited to, diabetic neuropathy (e.g., peripheral diabetic neuropathy); sciatica; non-specific lower back pain; multiple sclerosis pain; carpal tunnel syndrome, fibromyalgia; HIV-related neuropathy; neuralgia (e.g., post-herpetic neuralgia, trigeminal neuralgia); pain resulting from physical trauma e.g., amputation; surgery, invasive medical procedures, toxins, burns, infection), pain resulting from cancer or chemotherapy (e.g., chemotherapy-induced pain such as chemotherapy- induced peripheral neuropathy), and pain resulting from an inflammatory condition (e.g., a chronic inflammatory condition). Neuropathic pain can result from a peripheral nerve disorder such as neuroma; nerve compression; nerve crush, nerve stretch or incomplete nerve transsection; mononeuropathy or polyneuropathy. Neuropathic pain can also result from a disorder such as dorsal root ganglion compression; inflammation of the spinal cord; contusion, tumor or hemisection of the spinal cord; tumors of the brainstem, thalamus or cortex; or trauma to the brainstem, thalamus or cortex.

[0174] The symptoms of neuropathic pain are heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as “pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation50 / 232M1237.70154WO0012225011.1(dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).

[0449] In certain embodiments, the painful condition is non-inflammatory pain. The types of non-inflammatory pain include, without limitation, peripheral neuropathic pain (e.g., pain caused by a lesion or dysfunction in the peripheral nervous system), central pain (e.g., pain caused by a lesion or dysfunction of the central nervous system), deafferentation pain (e.g., pain due to loss of sensory input to the central nervous system), chronic nociceptive pain (e.g., certain types of cancer pain), noxious stimulus of nociceptive receptors (e.g., pain felt in response to tissue damage or impending tissue damage), phantom pain (e.g., pain felt in a part of the body that no longer exists, such as a limb that has been amputated), pain felt by psychiatric subjects (e.g., pain where no physical cause may exist), and wandering pain (e.g., wherein the pain repeatedly changes location in the body).

[0175] The term “psychiatric disorder” refers to a disease of the mind and includes diseases and disorders listed in the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV), published by the American Psychiatric Association, Washington D. C. (1994). Psychiatric disorders include, but are not limited to, anxiety disorders (e.g., acute stress disorder agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, and specific phobia), childhood disorders, (e.g., attention-deficit / hyperactivity disorder, conduct disorder, and oppositional defiant disorder), eating disorders e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g., depression, bipolar disorder, cyclothymic disorder, dysthymic disorder, and major depressive disorder), personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, and shared psychotic disorder), substance -related disorders (e.g., alcohol dependence, amphetamine dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, and sedative dependence), adjustment disorder, autism, delirium, dementia, multi-infarct dementia, learning and memory disorders (e.g., amnesia and age-related memory loss), and Tourette’s disorder.

[0176] The term “musculoskeletal disease” or “MSD” refers to an injury and / or pain in a subject’s joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck, and back. In certain embodiments, an MSD is a degenerative disease. In certain embodiments, an MSD includes an inflammatory condition. Body parts of a subject that may be associated with MSDs include upper and lower back, neck, shoulders, and extremities (arms, legs, feet, and hands). In certain embodiments, an MSD is a bone disease, such as achondroplasia, acromegaly, bone callus, bone demineralization, bone 51 / 232M1237.70154WO0012225011.1fracture, bone marrow disease, bone marrow neoplasm, dyskeratosis congenita, leukemia (e.g., hairy cell leukemia, lymphocytic leukemia, myeloid leukemia, Philadelphia chromosome -positive leukemia, plasma cell leukemia, stem cell leukemia), systemic mastocytosis, myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, myeloid sarcoma, myeloproliferative disorders, multiple myeloma, polycythemia vera, pearson marrow-pancreas syndrome, bone neoplasm, bone marrow neoplasm, Ewing sarcoma, osteochondroma, osteoclastoma, osteosarcoma, brachydactyly, Camurati-Engelmann syndrome, Craniosynostosis, Crouzon craniofacial dysostosis, dwarfism, achondroplasia, bloom syndrome, Cockayne syndrome, Ellis-van Creveld syndrome, Seckel syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, Werner syndrome, hyperostosis, osteophyte, Klippel-Trenaunay- Weber syndrome, Marfan syndrome, McCune-Albright syndrome, osteitis, osteoarthritis, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, Leri-Weill dyschondrosteosis, osteochondrosis, osteodystrophy, osteogenesis imperfecta, osteolysis, Gorham-Stout syndrome, osteomalacia, osteomyelitis, osteonecrosis, osteopenia, osteopetrosis, osteoporosis, osteosclerosis, otospondylomegaepiphyseal dysplasia, pachydermoperiostosis, Paget disease of bone, Polydactyly, Meckel syndrome, rickets, Rothmund-Thomson syndrome, Sotos syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, syndactyly, Apert syndrome, syndactyly type II, or Werner syndrome. In certain embodiments, an MSD is a cartilage disease, such as cartilage neoplasm, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, or Leri-Weill dyschondrosteosis. In certain embodiments, an MSD is hernia, such as intervertebral disk hernia. In certain embodiments, an MSD is a joint disease, such as arthralgia, arthritis (e.g., gout e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan syndrome), Lyme disease, osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatic fever, rheumatoid arthritis, Felty syndrome, synovitis, Blau syndrome, nail-patella syndrome, spondyloarthropathy, reactive arthritis, Stickler syndrome, synovial membrane disease, synovitis, or Blau syndrome. In certain embodiments, an MSD is Langer-Giedion syndrome. In certain embodiments, an MSD is a muscle disease, such as Barth syndrome, mitochondrial encephalomyopathy, MELAS syndrome, MERRF syndrome, MNGIE syndrome, mitochondrial myopathy, Kearns-Sayre syndrome, myalgia, fibromyalgia, polymyalgia rheumatica, myoma, myositis, dermatomyositis, neuromuscular disease, Kearns-Sayre syndrome, muscular dystrophy, myasthenia, congenital myasthenic syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis, myotonia, myotonia congenita, spinal muscular atrophy, tetany, ophthalmoplegia, or rhabdomyolysis. In certain embodiments, an MSD is Proteus syndrome. In certain embodiments, an MSD is a rheumatic diseases, such as arthritis (e.g., gout (e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan lyme disease)), osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatic fever, rheumatoid arthritis, Felty syndrome, synovitis, Blau syndrome, gout (e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan syndrome), polymyalgia rheumatica, rheumatic fever, rheumatic heart disease, or Sjogren syndrome. In certain embodiments, an MSD is Schwartz-Jampel syndrome. In certain embodiments, an MSD is a skeleton disease, such as Leri-Weill dyschondrosteosis, skeleton malformations,52 / 232M1237.70154WO0012225011.1Melnick-Needles syndrome, pachydermoperiostosis, Rieger syndrome, spinal column disease, intervertebral disk hernia, scoliosis, spina bifida, spondylitis, ankylosing spondylitis, spondyloarthropathy, reactive arthritis, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, or spondylosis.

[0177] The term “metabolic disorder” refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

[0178] In certain embodiments, the metabolic disorder is a wasting condition. A “wasting condition” includes but is not limited to, anorexia and cachexias of various natures (e.g., weight loss associated with cancer, weight loss associated with other general medical conditions, weight loss associated with failure to thrive, and the like). In certain embodiments, the metabolic disorder is an obesity-related condition or a complication thereof. An “obesity-related condition” includes, but is not limited to, obesity, undesired weight gain (e.g., from medication-induced weight gain, from cessation of smoking) and an over-eating disorder (e.g., binge eating, bulimia, compulsive eating, or a lack of appetite control each of which can optionally lead to undesired weight gain or obesity). “Obesity” and “obese” refers to class I obesity, class II obesity, class III obesity and pre-obesity (e.g., being “overweight”) as defined by the World Health Organization.

[0179] Reduction of storage fat is expected to provide various primary and / or secondary benefits in a subject (e.g., in a subject diagnosed with a complication associated with obesity) such as, for example, an increased insulin responsiveness (e.g., in a subject diagnosed with Type II diabetes mellitus); a reduction in elevated blood pressure; a reduction in elevated cholesterol levels; and / or a reduction (or a reduced risk or progression) of ischemic heart disease, arterial vascular disease, angina, myocardial infarction, stroke, migraines, congestive heart failure, deep vein thrombosis, pulmonary embolism, gall stones, gastroesophagael reflux disease, obstructive sleep apnea, obesity hypoventilation syndrome, asthma, gout, poor mobility, back pain, erectile dysfunction, urinary incontinence, liver injury (e.g., fatty liver disease, liver cirrhosis, alcoholic cirrhosis, endotoxin mediated liver injury) or chronic renal failure.

[0180] 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 are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation 53 / 232M1237.70154WO0012225011.1of 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, and54 / 232M1237.70154WO0012225011.1necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0181] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anaemia), 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, ischaemic 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, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia, 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, schleroderma, scierodoma, 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 prostatistis. 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).

[0182] 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 55 / 232M1237.70154WO0012225011.1be 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, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis e.g., Wegener’s granulomatosis, microscopic poly angiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0183] In certain embodiments, the inflammatory disorder and / or the immune disorder is a gastrointestinal disorder. In some embodiments, the gastrointestinal disorder is selected from 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)). In certain embodiments, the gastrointestinal disorder is inflammatory bowel disease (IBD).

[0184] In certain embodiments, the inflammatory condition and / or immune disorder is a skin condition. In some embodiments, the skin condition is pruritus (itch), psoriasis, eczema, burns or dermatitis. In certain embodiments, the skin condition is psoriasis. In certain embodiments, the skin condition is pruritis.

[0185] Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, or more typically, within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0186] Unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0187] Provided herein are compounds (e.g., compounds of Formula (I)), and pharmaceutically acceptable salts thereof, and compositions and kits thereof. The compounds provided herein can form particles and may therefore be used to deliver agents (e.g., a polynucleotide) to a subject, target tissue,56 / 232M1237.70154WO0012225011.1or cell. Also provided herein are methods of delivery and methods of treating a disease, disorder, or condition, comprising administering to the subject a composition comprising a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof.Compounds

[0188] Provided herein are compounds of Formula (I):O NHRR2O2C- L2— L3-CO2R3X(I),or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein:R is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;R1is optionally substituted aliphatic or optionally substituted heteroaliphatic;each of R2and R3is independently optionally substituted aliphatic, optionally substituted heteroaliphatic, or optionally substituted carbocyclyl; wherein at least one of R2and R3is optionally substituted alkynyl, optionally substituted C10-C20 branched alkyl, or -(CH2)m-R4;each R4is independently optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;each m is independently an integer from 0-10, inclusive;each of L2and L3is independently optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C1-C10 heteroalkylene, optionally substituted C2-C10 heteroalkenylene, or optionally substituted C2-C10 heteroalkynylene; andX is optionally substituted aliphatic, optionally substituted heteroaliphatic, or optionally substituted carbocyclyl.R

[0189] As defined herein, R is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In some embodiments, R is optionally substituted aliphatic. In some embodiments, R is substituted aliphatic. In some embodiments, R is unsubstituted aliphatic. In some embodiments, R is optionally substituted alkyl. In some embodiments, R is unsubstituted alkyl. In some embodiments, R is substituted alkyl. In some embodiments, R is optionally substituted C1-C20 alkyl. In some embodiments, R is substituted C1-C20 alkyl. In some embodiments, R is unsubstituted C1-C20 alkyl. In some embodiments, R is optionally substituted Ci-Ce alkyl. In some embodiments, R is substituted Ci-Ce alkyl. In some embodiments, R57 / 232M1237.70154WO0012225011.1is unsubstituted Ci-Ce alkyl. In some embodiments, R is optionally substituted C2-C4 alkyl. In some embodiments, R is substituted C2-C4 alkyl. In some embodiments, R is unsubstituted C2-C4 alkyl. In some embodiments, R is n-butyl or t-butyl. In some embodiments, R is of the formula:In some embodiments, R is of the formula:. In some embodiments, R is of the formula:. In some embodiments, R is optionally substituted alkenyl. In some embodiments, R is unsubstituted alkenyl. In some embodiments, R is substituted alkenyl. In some embodiments, R is optionally substituted C2-C20 alkenyl. In some embodiments, R is substituted C2-C20 alkenyl. In some embodiments, R is unsubstituted C2-C20 alkenyl. In some embodiments, R is optionally substituted C10-C20 alkenyl. In some embodiments, R is substituted C10-C20 alkenyl. In some embodiments, R is unsubstituted C10-C20 alkenyl. In some embodiments, R is unsubstituted linear C10-C20 alkenyl. Insome embodiments, R is of the formula:someembodiments, R is optionally substituted alkynyl. In some embodiments, R is unsubstituted alkynyl. In some embodiments, R is substituted alkynyl. In some embodiments, R is optionally substituted C2- C20 alkynyl. In some embodiments, R is substituted C2-C20 alkynyl. In some embodiments, R is unsubstituted C2-C20 alkynyl.

[0190] In some embodiments, R is optionally substituted heteroaliphatic. In some embodiments, R is substituted heteroaliphatic. In some embodiments, R is unsubstituted heteroaliphatic. In some embodiments, R is optionally substituted heteroalkyl. In some embodiments, R is unsubstituted heteroalkyl. In some embodiments, R is substituted heteroalkyl. In some embodiments, R is optionally substituted C1-C20 heteroalkyl. In some embodiments, R is substituted C1-C20 heteroalkyl. In some embodiments, R is unsubstituted C1-C20 heteroalkyl. In some embodiments, R is of the formula:. In some embodiments, R is of the formula:embodiments, R is of the formula:I. In some embodiments, R is optionally substituted heteroalkenyl. In some embodiments, R is unsubstituted heteroalkenyl. In some embodiments, R is substituted heteroalkenyl. In some embodiments, R is optionally substituted C2-C20 heteroalkenyl. In some embodiments, R is substituted C2-C20 heteroalkenyl. In some embodiments, R is unsubstituted C2-C20 heteroalkenyl. In some embodiments, R is optionally substituted heteroalkynyl. In some embodiments, R is unsubstituted heteroalkynyl. In some embodiments, R is substituted heteroalkynyl. In some embodiments, R is optionally substituted C2-C20 heteroalkynyl. In some embodiments, R is substituted C2-C20 heteroalkynyl. In some embodiments, R is unsubstituted58 / 232M1237.70154WO0012225011.1C2-C20 heteroalkynyl. In some embodiments, any of the above heteroaliphatic moieties comprises a disulfide moiety.

[0191] In some embodiments, R is optionally substituted carbocyclyl. In some embodiments, R is substituted carbocyclyl. In some embodiments, R is unsubstituted carbocyclyl. In some embodiments, R is optionally substituted C3-C10 carbocyclyl. In some embodiments, R is substituted C3-C10 carbocyclyl. In some embodiments, R is unsubstituted C3-C10 carbocyclyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is substituted cyclohexyl. In some embodiments, R is unsubstituted cyclohexyl. In some embodiments, R is optionally substitutedadamantyl. In some embodiments, R is of the formula:|n SOme embodiments, R is optionally substituted heterocyclyl. In some embodiments, R is substituted heterocyclyl. In some embodiments, R is unsubstituted heterocyclyl. In some embodiments, R is optionally substituted 3-10 membered heterocyclyl. In some embodiments, R is substituted 3-10 membered heterocyclyl. In some embodiments, R is unsubstituted 3-10 membered heterocyclyl. In some embodiments, R is optionally substituted 5-6 membered heterocyclyl. In some embodiments, R is substituted 5-6 membered heterocyclyl. In some embodiments, R is unsubstituted 5-6 membered heterocyclyl.R1

[0192] As defined herein, R1is optionally substituted aliphatic or optionally substituted heteroaliphatic. In some embodiments, R1is optionally substituted aliphatic. In some embodiments, R1is substituted aliphatic. In some embodiments, R1is unsubstituted aliphatic. In some embodiments, R1is optionally substituted alkyl. In some embodiments, R1is unsubstituted alkyl. In some embodiments, R1is substituted alkyl. In some embodiments, R1is optionally substituted C1-C20 alkyl. In some embodiments, R1is substituted C1-C20 alkyl. In some embodiments, R1is unsubstituted Ci-C20 alkyl. In some embodiments, R1is optionally substituted Ci-Ce alkyl. In some embodiments, R1is substituted Ci-Ce alkyl. In some embodiments, R1is unsubstituted Ci-Ce alkyl. In some embodiments, R1is optionally substituted C2-C4 alkyl. In some embodiments, R1is substituted C2-C4 alkyl. In some embodiments, R1is unsubstituted C2-C4 alkyl. In some embodiments, R1is optionally substituted alkenyl. In some embodiments, R1is unsubstituted alkenyl. In some embodiments, R1is substituted alkenyl. In some embodiments, R1is optionally substituted C2-C20 alkenyl. In some embodiments, R1is substituted C2-C20 alkenyl. In some embodiments, R1is unsubstituted C2-C20 alkenyl. In some embodiments, R1is optionally substituted alkynyl. In some embodiments, R1is unsubstituted alkynyl. In some embodiments, R1is substituted alkynyl. In some embodiments, R1is optionally substituted C2-C20 alkynyl. In some embodiments, R1is substituted C2-C20 alkynyl. In some embodiments, R1is unsubstituted C2-C20 alkynyl.59 / 232M1237.70154WO0012225011.1

[0193] In some embodiments, R1is optionally substituted heteroaliphatic. In some embodiments, R1is substituted heteroaliphatic. In some embodiments, R1is unsubstituted heteroaliphatic. In some embodiments, R1is optionally substituted heteroalkyl. In some embodiments, R1is unsubstituted heteroalkyl. In some embodiments, R1is substituted heteroalkyl. In some embodiments, R1is optionally substituted C1-C20 heteroalkyl. In some embodiments, R1is substituted C1-C20 heteroalkyl. In some embodiments, R1is unsubstituted C1-C20 heteroalkyl. In some embodiments, R1is optionally substituted Ci-Ce heteroalkyl. In some embodiments, R1is substituted Ci-Ce heteroalkyl. In some embodiments, R1is unsubstituted Ci-Ce heteroalkyl. In some embodiments, R1is optionally substituted C2-C4 heteroalkyl. In some embodiments, R1is substituted C2-C4 heteroalkyl. In some embodiments, R1is unsubstituted C2-C4 heteroalkyl. In some embodiments, R1is optionally substituted heteroalkenyl. In some embodiments, R1is unsubstituted heteroalkenyl. In some embodiments, R1is substituted heteroalkenyl. In some embodiments, R1is optionally substituted C2-C20 heteroalkenyl. In some embodiments, R1is substituted C2-C20 heteroalkenyl. In some embodiments, R1is unsubstituted C2-C20 heteroalkenyl. In some embodiments, R1is optionally substituted heteroalkynyl. In some embodiments, R1is unsubstituted heteroalkynyl. In some embodiments, R1is substituted heteroalkynyl. In some embodiments, R1is optionally substituted C2-C20 heteroalkynyl. In some embodiments, R1is substituted C2-C20 heteroalkynyl. In some embodiments, R1is unsubstituted C2-C20 heteroalkynyl.Rp1b ib R

[0194] In some embodiments, R1is of the formula:Ra(i-a) or ' (i-b), wherein: each of Rlaand Rlbis independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or Rlaand Rlbare joined together to form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring. In some embodiments, R1is of the Formula (i-a). In some embodiments, R1is of the Formula (i-b). In some embodiments, at least one of Rlaand Rlbis optionally substituted acyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted alkenyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted alkynyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted heterocyclyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted aryl. In some embodiments, at least one of Rlaand Rlbis optionally substituted heteroaryl.

[0195] In some embodiments, at least one of Rlaand Rlbis hydrogen. In some embodiments, at least one of Rlaand Rlbis optionally substituted alkyl. In some embodiments, at least one of Rlaand Rlbis substituted alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted Ci-Ce alkyl. In some embodiments,60 / 232M1237.70154WO0012225011.1at least one of Rlaand Rlbis substituted Ci-Ce alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted Ci-Ce alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, or optionally substituted n-butyl. In some embodiments, at least one of Rlaand Rlbis methyl, ethyl, n-propyl, or n-butyl.

[0196] In some embodiments, each of Rlaand Rlbis independently hydrogen. In some embodiments, each of Rlaand Rlbis independently optionally substituted alkyl. In some embodiments, each of Rlaand Rlbis independently substituted alkyl. In some embodiments, each of Rlaand Rlbis independently unsubstituted alkyl. In some embodiments, each of Rlaand Rlbis independently optionally substituted Ci-Ce alkyl. In some embodiments, each of Rlaand Rlbis independently substituted Ci-Ce alkyl. In some embodiments, each of Rlaand Rlbis independently unsubstituted Ci-Ce alkyl. In some embodiments, each of Rlaand Rlbis independently optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, or optionally substituted n-butyl. In some embodiments, each of Rlaand Rlbis independently methyl, ethyl, n-propyl, or n-butyl.

[0197] In some embodiments, R1is of the Formula (i-a), and at least one of Rlaand Rlbis hydrogen or optionally substituted alkyl. In some embodiments, R1is of the Formula (i-a), and at least one of Rlaand Rlbis hydrogen or optionally substituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-a), and at least one of Rlaand Rlbis hydrogen or unsubstituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-a), and at least one of Rlaand Rlbis hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, or optionally substituted n-butyl. In some embodiments, R1is of the Formula (i-a), and at least one of Rlaand Rlbis hydrogen, methyl, ethyl, n-propyl, or n-butyl. In some embodiments, R1is of the Formula (i-a), and each of Rlaand Rlbis independently hydrogen or optionally substituted alkyl. In some embodiments, R1is of the Formula (i-a), and each of Rlaand Rlbis independently hydrogen or optionally substituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-a), and each of Rlaand Rlbis independently hydrogen or unsubstituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-a), and each of Rlaand Rlbis independently hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, or optionally substituted n-butyl. In some embodiments, R1is of the Formula (i-a), and each of Rlaand Rlbis independently hydrogen, methyl,ethyl, n-propyl, or n-butyl. In some embodiments, R1is of the formula:HN isome embodiments, R1is of the formula:In some embodiments, R is of theformula:. In some embodiments, R1is of the formula:. In some61 / 232M1237.70154WO0012225011.1embodiments, R1is of the formula:N. In some embodiments, R1is of theformula: " —zx— In some embodiments, R1is of the formula:OH

[0198] In some embodiments, Rlaand Rlbare joined together to form an optionally substituted heterocyclic ring. In some embodiments, Rlaand Rlbare joined together to form a substituted heterocyclic ring. In some embodiments, Rlaand Rlbare joined together to form an unsubstituted heterocyclic ring. In some embodiments, Rlaand Rlbare joined together to form an optionally substituted 3-10 membered heterocyclic ring. In some embodiments, Rlaand Rlbare joined together to form a substituted 3-10 membered heterocyclic ring. In some embodiments, Rlaand Rlbare joined together to form an unsubstituted 3-10 membered heterocyclic ring. In some embodiments, Rlaand Rlbare joined together to form an optionally substituted 5- to 6-membered heterocyclic ring. In some embodiments, Rlaand Rlbare joined together to form an optionally substituted 5-membered heterocyclic ring. In some embodiments, Rlaand Rlbare joined together to form an optionally substituted 6-membered heterocyclic ring.(Ra)xi

[0199] In some embodiments, R1is of the formula:(i-c); wherein each Rais independently optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and xl is 0, 1, 2, 3, or 4. In someembodiments, the R1of Formula (i-c) is of the formula:* * — (i-c-1). In some embodiments, at least one Rais independently optionally substituted acyl. In some embodiments, at least one Rais optionally substituted alkenyl. In some embodiments, at least one Rais optionally substituted alkynyl. In some embodiments, at least one Rais optionally substituted carbocyclyl. In some embodiments, at least one Rais optionally substituted heterocyclyl. In some embodiments, at least one Rais optionally substituted aryl. In some embodiments, at least one Rais optionally substituted heteroaryl. In some embodiments, xl is 0. In some embodiments, xl is 1. In some embodiments, xl is 2. In some embodiments, xl is 3. In some embodiments, xl is 4.

[0200] In some embodiments, at least one Rais optionally substituted alkyl. In some embodiments, at least one Rais substituted alkyl. In some embodiments, at least one Rais unsubstituted alkyl. In some embodiments, at least one Rais optionally substituted Ci-Ce alkyl. In some embodiments, at least one62 / 232M1237.70154WO0012225011.1Rais substituted Ci-Ce alkyl. In some embodiments, at least one Rais unsubstituted Ci-Ce alkyl. In some embodiments, at least one Rais optionally substituted C1-C3 alkyl. In some embodiments, at least one Rais substituted C1-C3 alkyl. In some embodiments, at least one Rais unsubstituted C1-C3 alkyl. In some embodiments, at least one Rais optionally substituted ethyl. In some embodiments, at least one Rais ethyl.

[0201] In some embodiments, R1is of the Formula (i-c), and at least one Rais optionally substituted alkyl. In some embodiments, R1is of the Formula (i-c), and at least one Rais unsubstituted alkyl. In some embodiments, R1is of the Formula (i-c), and at least one Rais optionally substituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-c), and at least one Rais unsubstituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-c), and at least one Rais optionally substituted C1-C3 alkyl. In some embodiments, R1is of the Formula (i-c), and at least one Rais unsubstituted Ci-C3 alkyl. In some embodiments, R1is of the Formula (i-c), and at least one Rais optionally substituted ethyl. In some embodiments, R1is of the Formula (i-c), and at least one Rais ethyl. In someembodiments, R1is of the formula:

[0202] In some embodiments, Rlaand Rlbare joined together to form an optionally substituted heteroaryl ring. In some embodiments, Rlaand Rlbare joined together to form an optionally substituted 5- to 7-membered heteroaryl ring. In some embodiments, Rlaand Rlbare joined together to form an optionally substituted 5-membered heteroaryl ring. In some embodiments, Rla and Rlb are joined together to form an optionally substituted 6-membered heteroaryl ring.

[0203] In some embodiments, R1is of the Formula (i-a), and Rlaand Rlbare joined together to form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring. In some embodiments, R1is of the Formula (i-a), and Rlaand Rlbare joined together to form an optionally substituted 5- to 7-membered heterocyclic ring. In some embodiments, R1is of the Formula (i-a), and Rlaand Rlbare joined together to form an optionally substituted 5- to 6-membered heteroaryl ring. In some embodiments, R1is of the Formula (i-a), and Rlaand Rlbare joined together to form an optionally substituted 5-membered heteroaryl ring. In some embodiments, R1 is of the Formula (i-a), and Rla and Rlb are joined together to form an optionally substituted 6-membered heteroaryl ring. InNsome embodiments, R1is of the formula:(i-e); each Rais independently optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and x2 is 0, 1, 2, or 3. In some embodiments, at least one Rais independently optionally substituted acyl. In some embodiments, at least one Rais optionally substituted alkyl. In some embodiments, at least one Rais optionally substituted alkenyl. In some embodiments, at least one Rais optionally substituted alkynyl.63 / 232M1237.70154WO0012225011.1In some embodiments, at least one Rais optionally substituted carbocyclyl. In some embodiments, at least one Rais optionally substituted heterocyclyl. In some embodiments, at least one Rais optionally substituted aryl. In some embodiments, at least one Rais optionally substituted heteroaryl. In some embodiments, x2 is 0. In some embodiments, x2 is 1. In some embodiments, x2 is 2. In someembodiments, x2 is 3. In some embodiments, R1is of the formula:. In someembodiments, R1is of the formula:

[0204] In some embodiments, R1is of the formula:(i-f),hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and xl is 1, 2, 3, or 4. In some embodiments, R1is of the Formula (i-f). In some embodiments, R1is of the formula:. In some embodiments, R1is of the Formula (i-g). In some embodiments, R1is of(i-g-1). In some embodiments, R1is of the formula:. In some embodiments, R1is of the Formula (i-h). In some embodiments, R1is ofthe formula:. In some embodiments, R1is of the Formula (i-i). In someembodiments, R1is of the formula:. In some embodiments, R1is of theformula:. In some embodiments, R1is of the Formula (i-j). In64 / 232M1237.70154WO0012225011.1some embodiments, R1is of the formula:. In some embodiments, R1is of thezNx^Formula (i-k). In some embodiments, R1is of the formula:Rd(i-k-1). In some, N^embodiments, R1is of the formula:'

[0205] In some embodiments, R1is of the Formula (i-b), and at least one of Rlaand Rlbis hydrogen or optionally substituted alkyl. In some embodiments, R1is of the Formula (i-b), and at least one of Rlaand Rlbis hydrogen or optionally substituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-b), and at least one of Rlaand Rlbis hydrogen or unsubstituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-b), and at least one of Rlaand Rlbis hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, or optionally substituted n-butyl. In some embodiments, R1is of the Formula (i-b), and at least one of Rlaand Rlbis hydrogen, methyl, ethyl, n-propyl, or n-butyl. In some embodiments, R1is of the Formula (i-b), and each of Rlaand Rlbis independently hydrogen or optionally substituted alkyl. In some embodiments, R1is of the Formula (i-b), and each of Rlaand Rlbis independently hydrogen or optionally substituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-b), and each of Rlaand Rlbis independently hydrogen or unsubstituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-b), and each of Rlaand Rlbis independently hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, or optionally substituted n-butyl. In some embodiments, R1is of the Formula (i-b), and each of Rlaand Rlbis independently hydrogen, methyl,ethyl, n-propyl, or n-butyl. In some embodiments, R1is of the formula:|nsomeembodiments, R1is of the formula:.

[0206] In some embodiments, R1is of the Formula (i-b), and Rlaand Rlbare joined together to form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring. In some embodiments, R1is of the Formula (i-b), and Rlaand Rlbare joined together to form an optionally substituted 5- to 7-membered heterocyclic ring. In some embodiments, R1is of the Formula (i-b), and Rlaand Rlbare joined together to form an optionally substituted 5- to 6-membered heteroaryl ring. In some embodiments, R1is of the Formula (i-b), and Rlaand Rlbare joined together to form an optionally substituted 5-membered heteroaryl ring. In some embodiments, R1is of the formula:65 / 232M1237.70154WO0012225011.1wherein each Rais independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and xl is 1, 2, 3, or 4. In some embodiments, R1is of the Formula (i-1). In some embodiments, R1is ofthe formula:. In some embodiments, R1is of the Formula (i-m). In someembodiments, R1is of the formula:(i-m-1). In some embodiments, R1is of theformula:. In some embodiments, R1is of the Formula (i-n). In some embodiments,R1is of the formula:. In some embodiments, R1is of the Formula (i-o). In someembodiments, R1is of the formula:. In some embodiments, R1is of the Formula(i-p). In some embodiments, R1is of the formula:. In some embodiments, R1is ofthe Formula (q). In some embodiments, R1is of the formula:(i-q-1). In someembodiments, R1is of the formula:. In some embodiments, R1is of theFormula (i-r). In some embodiments, R1is of the formula:. In some embodiments,66 / 232M1237.70154WO0012225011.1

[0207] In some embodiments, R1is of the formula: R1d(i-t), wherein: each of R1cand R1dis independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or R1cand R1dare joined together to form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring. In some embodiments, at least one of R1cand R1dis optionally substituted acyl. In some embodiments, at least one of R1cand R1dis optionally substituted alkenyl. In some embodiments, at least one of R1cand R1dis optionally substituted alkynyl. In some embodiments, at least one of R1cand R1dis optionally substituted carbocyclyl. In some embodiments, at least one of R1cand R1dis optionally substituted heterocyclyl. In some embodiments, at least one of R1cand R1dis optionally substituted aryl. In some embodiments, at least one of R1cand R1dis optionally substituted heteroaryl.

[0208] In some embodiments, at least one of R1cand R1dis hydrogen. In some embodiments, at least one of R1cand R1dis optionally substituted alkyl. In some embodiments, at least one of R1cand R1dis substituted alkyl. In some embodiments, at least one of R1cand R1dis unsubstituted alkyl. In some embodiments, at least one of R1cand R1dis optionally substituted Ci-Ce alkyl. In some embodiments, at least one of R1cand R1dis substituted Ci-Ce alkyl. In some embodiments, at least one of R1cand R1dis unsubstituted Ci-Ce alkyl. In some embodiments, at least one of R1cand R1dis optionally substituted methyl or optionally substituted ethyl. In some embodiments, at least one of R1cand R1dis methyl or ethyl.

[0209] In some embodiments, each of R1cand R1dis independently hydrogen. In some embodiments, each of R1cand R1dis independently optionally substituted alkyl. In some embodiments, each of R1cand R1dis independently substituted alkyl. In some embodiments, each of R1cand R1dis independently unsubstituted alkyl. In some embodiments, each of R1cand R1dis independently optionally substituted Ci-Ce alkyl. In some embodiments, each of R1cand R1dis independently substituted Ci-Ce alkyl. In some embodiments, each of R1cand R1dis independently unsubstituted Ci-Ce alkyl. In some embodiments, each of R1cand R1dis independently optionally substituted methyl or optionally substituted ethyl. In some embodiments, each of R1cand R1dis independently methyl or ethyl.

[0210] In some embodiments, R1is of the Formula (i-t), and at least one of R1cand R1dis hydrogen or optionally substituted alkyl. In some embodiments, R1is of the Formula (i-t), and at least one of R1cand R1dis hydrogen or optionally substituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-t), and at least one of R1cand R1dis hydrogen or unsubstituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-t), and at least one of R1cand R1dis hydrogen, optionally substituted methyl, or optionally substituted ethyl. In some embodiments, R1is of the Formula (i-t), and at least one of R1cand R1dis hydrogen, methyl, or ethyl. In some embodiments, R1is of the67 / 232M1237.70154WO0012225011.1Formula (i-t), and each of R1cand R1dis independently hydrogen or optionally substituted alkyl. In some embodiments, R1is of the Formula (i-t), and each of R1cand R1dis independently hydrogen or optionally substituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-t), and each of R1cand R1dis independently hydrogen or unsubstituted Ci-Ce alkyl. In some embodiments, R1is of the Formula (i-t), and each of R1cand R1dis independently hydrogen, optionally substituted methyl, or optionally substituted ethyl. In some embodiments, R1is of the Formula (i-t), and each of R1cand R1dis independently hydrogen, methyl, or ethyl. In some embodiments, R1is of the formula:L2and L3

[0211] As defined herein, each of L2and L3is independently optionally substituted Ci-Cio alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C1-C10 heteroalkylene, optionally substituted C2-C10 heteroalkenylene, or optionally substituted C2-C10 heteroalkynylene. In some embodiments, L2and L3are the same. In some embodiments, L2and L3are different.

[0212] In some embodiments, at least one of L2and L3is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, or optionally substituted C2-C10 alkynylene. In some embodiments, at least one of L2and L3is optionally substituted C1-C10 alkylene. In some embodiments, at least one of L2and L3is optionally substituted Ci-Ce alkylene. In some embodiments, at least one of L2and L3is optionally substituted C1-C3 alkylene. In some embodiments, at least one of L2and L3is substituted C1-C10 alkylene. In some embodiments, at least one of L2and L3is substituted Ci-Ce alkylene. In some embodiments, at least one of L2and L3is substituted C1-C3 alkylene. In some embodiments, at least one of L2and L3is unsubstituted C1-C10 alkylene. In some embodiments, at least one of L2and L3is unsubstituted Ci-Ce alkylene. In some embodiments, at least one of L2and L3is unsubstituted C1-C3 alkylene.

[0213] In some embodiments, at least one of L2and L3is optionally substituted linear C1-C10 alkylene. In some embodiments, at least one of L2and L3is optionally substituted linear Ci-Ce alkylene. In some embodiments, at least one of L2and L3is optionally substituted linear C1-C3 alkylene. In some embodiments, at least one of L2and L3is substituted linear C1-C10 alkylene. In some embodiments, at least one of L2and L3is substituted linear Ci-Ce alkylene. In some embodiments, at least one of L2and L3is substituted linear C1-C3 alkylene. In some embodiments, at least one of L2and L3is unsubstituted linear C1-C10 alkylene. In some embodiments, at least one of L2and L3is unsubstituted linear Ci-Ce alkylene. In some embodiments, at least one of L2and L3is unsubstituted linear C1-C3 alkylene. In some embodiments, at least one of L2and L3is methylene, ethylene, or n-propylene. In some embodiments, at least one of L2and L3is methylene. In some68 / 232M1237.70154WO0012225011.1embodiments, at least one of L2and L3is ethylene. In some embodiments, at least one of L2and L3is / / -propylene.

[0214] In some embodiments, each of L2and L3is independently optionally substituted Ci-Cio alkylene, optionally substituted C2-C10 alkenylene, or optionally substituted C2-C10 alkynylene. In some embodiments, each of L2and L3is independently optionally substituted C1-C10 alkylene. In some embodiments, each of L2and L3is independently optionally substituted Ci-Ce alkylene. In some embodiments, each of L2and L3is independently optionally substituted C1-C3 alkylene. In some embodiments, each of L2and L3is independently substituted C1-C10 alkylene. In some embodiments, each of L2and L3is independently substituted Ci-Ce alkylene. In some embodiments, each of L2and L3is independently substituted C1-C3 alkylene. In some embodiments, each of L2and L3is independently unsubstituted C1-C10 alkylene. In some embodiments, each of L2and L3is independently unsubstituted Ci-Ce alkylene. In some embodiments, each of L2and L3is independently unsubstituted C1-C3 alkylene.

[0215] In some embodiments, each of L2and L3is independently optionally substituted linear C1-C10 alkylene. In some embodiments, each of L2and L3is independently optionally substituted linear Ci-Ce alkylene. In some embodiments, each of L2and L3is independently optionally substituted linear C1-C3 alkylene. In some embodiments, each of L2and L3is independently substituted linear C1-C10 alkylene. In some embodiments, each of L2and L3is independently substituted linear Ci-Ce alkylene. In some embodiments, each of L2and L3is independently substituted linear C1-C3 alkylene. In some embodiments, each of L2and L3is independently unsubstituted linear C1-C10 alkylene. In some embodiments, each of L2and L3is independently unsubstituted linear Ci-Ce alkylene. In some embodiments, each of L2and L3is independently unsubstituted linear C1-C3 alkylene. In some embodiments, each of L2and L3is independently methylene, ethylene, or / / -propylene. In some embodiments, each of L2and L3is independently methylene. In some embodiments, each of L2and L3is independently ethylene. In some embodiments, each of L2and L3is independently / / -propylene.

[0216] In some embodiments, at least one of L2and L3is of the formula:wherein:each R' is independently -H, -F, or optionally substituted Ci-Ce alkyl; andeach n is independently an integer from 1-10, inclusive.

[0217] In some embodiments, each of L2and L3is independently of the Formula (ii-a).

[0218] In some embodiments, at least one R' is -H. In some embodiments, at least one R' is -F. In some embodiments, at least one R' is optionally substituted Ci-Ce alkyl. In some embodiments, at least one R' is optionally substituted C1-C3 alkyl. In some embodiments, at least one R' is substituted Ci-Ce alkyl. In some embodiments, at least one R' is substituted C1-C3 alkyl. In some embodiments, at69 / 232M1237.70154WO0012225011.1least one R' is unsubstituted Ci-Ce alkyl. In some embodiments, at least one R' is unsubstituted C1-C3 alkyl.

[0219] In some embodiments, each R' is independently -H. In some embodiments, each R' is independently -F. In some embodiments, each R' is independently optionally substituted Ci-Ce alkyl. In some embodiments, each R' is independently optionally substituted C1-C3 alkyl. In some embodiments, each R' is independently substituted Ci-Ce alkyl. In some embodiments, each R' is independently substituted C1-C3 alkyl. In some embodiments, each R' is independently unsubstituted Ci-Ce alkyl. In some embodiments, each R' is independently unsubstituted C1-C3 alkyl.

[0220] In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one R' is -H. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one R' is -F. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one R' is optionally substituted Ci-Ce alkyl. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one R' is optionally substituted C1-C3 alkyl. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one R' is substituted Ci-Ce alkyl. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one R' is substituted C1-C3 alkyl. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one R' is unsubstituted Ci-Ce alkyl. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one R' is unsubstituted C1-C3 alkyl.

[0221] In some embodiments, each of L2and L3is independently of the Formula (ii-a). In some embodiments, each of L2and L3is independently of the Formula (ii-a), and at least one R' is independently -H. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and at least one R' is independently -F. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and at least one R' is independently optionally substituted Ci-Ce alkyl. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and at least one R' is independently optionally substituted C1-C3 alkyl. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and at least one R' is independently substituted Ci-Ce alkyl. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and at least one R' is independently substituted C1-C3 alkyl. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and at least one R' is independently unsubstituted Ci-Ce alkyl. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and at least one R' is independently unsubstituted C1-C3 alkyl.

[0222] In some embodiments, each of L2and L3is independently of the Formula (ii-a), and each R' is independently -H. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and each R' is independently -F. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and each R' is independently optionally substituted Ci-Ce alkyl. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and each R' is independently optionally substituted C1-C3 alkyl. In some embodiments, each of L2and L3is independently of the Formula (ii-70 / 232M1237.70154WO0012225011.1a), and each R' is independently substituted Ci-Ce alkyl. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and each R' is independently substituted C1-C3 alkyl. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and each R' is independently unsubstituted Ci-Ce alkyl. In some embodiments, each of L2and L3is independently of the Formula (ii-a), and each R' is independently unsubstituted C1-C3 alkyl.

[0223] In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 1, 2, 3, 4, 5, 6, or 7. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 1, 2, 3, 4, 5, or 6. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 1, 2, 3, 4, or 5. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 1, 2, 3, or 4. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 1, 2, or 3. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 2, 3, 4, 5, or 6. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 2, 3, 4, or 5. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 2, 3, or 4.

[0224] In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 1. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 2. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 3. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 4. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 5. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 6. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 7. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 8. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 9. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 10. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and at least one n is 2; at least one n is 3; at least one n is 4; at least one n is 5; or at least one n is 6.

[0225] In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is the same. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 1. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 2. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 3. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 4. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is 71 / 232M1237.70154WO0012225011.1independently 5. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 6. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 7. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 8. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 9. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 10. In some embodiments, at least one of L2and L3is of the Formula (ii-a), and each n is independently 2; each n is independently 3; each n is independently 4; each n is independently 5; or each n is independently 6.

[0226] In some embodiments, each of L2and L3is independently of the Formula (ii-a), each R' is independently -H, and each n is independently 2, 3, 4, 5, or 6. In some embodiments, each of L2and L3is independently of the Formula (ii-a), each R' is independently -H, and at least one n is 3. In some embodiments, each of L2and L3is independently of the Formula (ii-a), each R' is independently -H, and each n is independently 3.

[0227] In some embodiments, at least one of L2and L3is optionally substituted C2-C10 alkenylene. In some embodiments, at least one of L2and L3is optionally substituted C2-C6 alkenylene. In some embodiments, at least one of L2and L3is optionally substituted C2-C3 alkenylene. In some embodiments, at least one of L2and L3is substituted C2-C10 alkenylene. In some embodiments, at least one of L2and L3is substituted C2-C6 alkenylene. In some embodiments, at least one of L2and L3is substituted C2-C3 alkenylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C10 alkenylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C6 alkenylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C3 alkenylene.

[0228] In some embodiments, at least one of L2and L3is optionally substituted linear C2-C10 alkenylene. In some embodiments, at least one of L2and L3is optionally substituted linear C2-C6 alkenylene. In some embodiments, at least one of L2and L3is optionally substituted linear C2-C3 alkenylene. In some embodiments, at least one of L2and L3is substituted linear C2-C10 alkenylene. In some embodiments, at least one of L2and L3is substituted linear C2-C6 alkenylene. In some embodiments, at least one of L2and L3is substituted linear C2-C3 alkenylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C10 alkenylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C6 alkenylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C3 alkenylene.

[0229] In some embodiments, each of L2and L3is independently optionally substituted C2-C10 alkenylene. In some embodiments, each of L2and L3is independently optionally substituted C2-C6 alkenylene. In some embodiments, each of L2and L3is independently optionally substituted C2-C3 alkenylene. In some embodiments, each of L2and L3is independently substituted C2-C10 alkenylene. In some embodiments, each of L2and L3is independently substituted C2-C6 alkenylene. In some embodiments, each of L2and L3is independently substituted C2-C3 alkenylene. In some embodiments, each of L2and L3is independently unsubstituted C2-C10 alkenylene. In some embodiments, each of L272 / 232M1237.70154WO0012225011.1and L3is independently unsubstituted C2-C6 alkenylene. In some embodiments, each of L2and L3is independently unsubstituted C2-C3 alkenylene.

[0230] In some embodiments, each of L2and L3is independently optionally substituted linear C2-C10 alkenylene. In some embodiments, each of L2and L3is independently optionally substituted linear C2-Ce alkenylene. In some embodiments, each of L2and L3is independently optionally substituted linear C2-C3 alkenylene. In some embodiments, each of L2and L3is independently substituted linear C2-C10 alkenylene. In some embodiments, each of L2and L3is independently substituted linear C2-C6 alkenylene. In some embodiments, each of L2and L3is independently substituted linear C2-C3 alkenylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C10 alkenylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C6 alkenylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C3 alkenylene.

[0231] In some embodiments, at least one of L2and L3is optionally substituted C2-C10 alkynylene. In some embodiments, at least one of L2and L3is optionally substituted C2-C6 alkynylene. In some embodiments, at least one of L2and L3is optionally substituted C2-C3 alkynylene. In some embodiments, at least one of L2and L3is substituted C2-C10 alkynylene. In some embodiments, at least one of L2and L3is substituted C2-C6 alkynylene. In some embodiments, at least one of L2and L3is substituted C2-C3 alkynylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C10 alkynylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C6 alkynylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C3 alkynylene.

[0232] In some embodiments, at least one of L2and L3is optionally substituted linear C2-C10 alkynylene. In some embodiments, at least one of L2and L3is optionally substituted linear C2-C6 alkynylene. In some embodiments, at least one of L2and L3is optionally substituted linear C2-C3 alkynylene. In some embodiments, at least one of L2and L3is substituted linear C2-C10 alkynylene. In some embodiments, at least one of L2and L3is substituted linear C2-C6 alkynylene. In some embodiments, at least one of L2and L3is substituted linear C2-C3 alkynylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C10 alkynylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C6 alkynylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C3 alkynylene.

[0233] In some embodiments, each of L2and L3is independently optionally substituted C2-C10 alkynylene. In some embodiments, each of L2and L3is independently optionally substituted C2-C6 alkynylene. In some embodiments, each of L2and L3is independently optionally substituted C2-C3 alkynylene. In some embodiments, each of L2and L3is independently substituted C2-C10 alkynylene. In some embodiments, each of L2and L3is independently substituted C2-C6 alkynylene. In some embodiments, each of L2and L3is independently substituted C2-C3 alkynylene. In some embodiments, each of L2and L3is independently unsubstituted C2-C10 alkynylene. In some73 / 232M1237.70154WO0012225011.1embodiments, each of L2and L3is independently unsubstituted C2-C6 alkynylene. In some embodiments, each of L2and L3is independently unsubstituted C2-C3 alkynylene.

[0234] In some embodiments, each of L2and L3is independently optionally substituted linear C2-C10 alkynylene. In some embodiments, each of L2and L3is independently optionally substituted linear C2-Ce alkynylene. In some embodiments, each of L2and L3is independently optionally substituted linear C2-C3 alkynylene. In some embodiments, each of L2and L3is independently substituted linear C2-C10 alkynylene. In some embodiments, each of L2and L3is independently substituted linear C2-C6 alkynylene. In some embodiments, each of L2and L3is independently substituted linear C2-C3 alkynylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C10 alkynylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C6 alkynylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C3 alkynylene.

[0235] In some embodiments, at least one of L2and L3is optionally substituted C1-C10 heteroalkylene, optionally substituted C2-C10 heteroalkenylene, or optionally substituted C2-C10 heteroalkynylene. In some embodiments, at least one of L2and L3is optionally substituted C1-C10 heteroalkylene. In some embodiments, at least one of L2and L3is optionally substituted Ci-Ce heteroalkylene. In some embodiments, at least one of L2and L3is optionally substituted C1-C3 heteroalkylene. In some embodiments, at least one of L2and L3is substituted C1-C10 heteroalkylene. In some embodiments, at least one of L2and L3is substituted Ci-Ce heteroalkylene. In some embodiments, at least one of L2and L3is substituted C1-C3 heteroalkylene. In some embodiments, at least one of L2and L3is unsubstituted C1-C10 heteroalkylene. In some embodiments, at least one of L2and L3is unsubstituted Ci-Ce heteroalkylene. In some embodiments, at least one of L2and L3is unsubstituted C1-C3 heteroalkylene. In some embodiments, at least one of L2and L3is optionally substituted C1-C10 heteroalkylene comprising a disulfide.

[0236] In some embodiments, at least one of L2and L3is optionally substituted linear C1-C10 heteroalkylene. In some embodiments, at least one of L2and L3is optionally substituted linear Ci-Ce heteroalkylene. In some embodiments, at least one of L2and L3is optionally substituted linear C1-C3 heteroalkylene. In some embodiments, at least one of L2and L3is substituted linear C1-C10 heteroalkylene. In some embodiments, at least one of L2and L3is substituted linear Ci-Ce heteroalkylene. In some embodiments, at least one of L2and L3is substituted linear C1-C3 heteroalkylene. In some embodiments, at least one of L2and L3is unsubstituted linear C1-C10 heteroalkylene. In some embodiments, at least one of L2and L3is unsubstituted linear Ci-Ce heteroalkylene. In some embodiments, at least one of L2and L3is unsubstituted linear C1-C3 heteroalkylene. In some embodiments, at least one of L2and L3is optionally substituted linear C1-C10 heteroalkylene comprising a disulfide.

[0237] In some embodiments, each of L2and L3is independently optionally substituted C1-C10 heteroalkylene, optionally substituted C2-C10 heteroalkenylene, or optionally substituted C2-C1074 / 232M1237.70154WO0012225011.1heteroalkynylene. In some embodiments, each of L2and L3is independently optionally substituted Ci-Cio heteroalkylene. In some embodiments, each of L2and L3is independently optionally substituted Ci-Ce heteroalkylene. In some embodiments, each of L2and L3is independently optionally substituted C1-C3 heteroalkylene. In some embodiments, each of L2and L3is independently substituted C1-C10 heteroalkylene. In some embodiments, each of L2and L3is independently substituted Ci-Ce heteroalkylene. In some embodiments, each of L2and L3is independently substituted C1-C3 heteroalkylene. In some embodiments, each of L2and L3is independently unsubstituted C1-C10 heteroalkylene. In some embodiments, each of L2and L3is independently unsubstituted Ci-Ce heteroalkylene. In some embodiments, each of L2and L3is independently unsubstituted C1-C3 heteroalkylene.

[0238] In some embodiments, each of L2and L3is independently optionally substituted linear C1-C10 heteroalkylene. In some embodiments, each of L2and L3is independently optionally substituted linear Ci-Ce heteroalkylene. In some embodiments, each of L2and L3is independently optionally substituted linear C1-C3 heteroalkylene. In some embodiments, each of L2and L3is independently substituted linear C1-C10 heteroalkylene. In some embodiments, each of L2and L3is independently substituted linear Ci-Ce heteroalkylene. In some embodiments, each of L2and L3is independently substituted linear C1-C3 heteroalkylene. In some embodiments, each of L2and L3is independently unsubstituted linear C1-C10 heteroalkylene. In some embodiments, each of L2and L3is independently unsubstituted linear Ci-Ce heteroalkylene. In some embodiments, each of L2and L3is independently unsubstituted linear C1-C3 heteroalkylene.

[0239] In some embodiments, at least one of L2and L3is optionally substituted C2-C10 heteroalkenylene. In some embodiments, at least one of L2and L3is optionally substituted C2-C6 heteroalkenylene. In some embodiments, at least one of L2and L3is optionally substituted C2-C3 heteroalkenylene. In some embodiments, at least one of L2and L3is substituted C2-C10 heteroalkenylene. In some embodiments, at least one of L2and L3is substituted C2-C6 heteroalkenylene. In some embodiments, at least one of L2and L3is substituted C2-C3 heteroalkenylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C10 heteroalkenylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C6 heteroalkenylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C3 heteroalkenylene.

[0240] In some embodiments, at least one of L2and L3is optionally substituted linear C2-C10 heteroalkenylene. In some embodiments, at least one of L2and L3is optionally substituted linear C2-Ce heteroalkenylene. In some embodiments, at least one of L2and L3is optionally substituted linear C2-C3 heteroalkenylene. In some embodiments, at least one of L2and L3is substituted linear C2-C10 heteroalkenylene. In some embodiments, at least one of L2and L3is substituted linear C2-C6 heteroalkenylene. In some embodiments, at least one of L2and L3is substituted linear C2-C3 heteroalkenylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C1075 / 232M1237.70154WO0012225011.1heteroalkenylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C6 heteroalkenylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C3 heteroalkenylene.

[0241] In some embodiments, each of L2and L3is independently optionally substituted C2-C10 heteroalkenylene. In some embodiments, each of L2and L3is independently optionally substituted C2-Ce heteroalkenylene. In some embodiments, each of L2and L3is independently optionally substituted C2-C3 heteroalkenylene. In some embodiments, each of L2and L3is independently substituted C2-C10 heteroalkenylene. In some embodiments, each of L2and L3is independently substituted C2-C6 heteroalkenylene. In some embodiments, each of L2and L3is independently substituted C2-C3 heteroalkenylene. In some embodiments, each of L2and L3is independently unsubstituted C2-C10 heteroalkenylene. In some embodiments, each of L2and L3is independently unsubstituted C2-C6 heteroalkenylene. In some embodiments, each of L2and L3is independently unsubstituted C2-C3 heteroalkenylene.

[0242] In some embodiments, each of L2and L3is independently optionally substituted linear C2-C10 heteroalkenylene. In some embodiments, each of L2and L3is independently optionally substituted linear C2-C6 heteroalkenylene. In some embodiments, each of L2and L3is independently optionally substituted linear C2-C3 heteroalkenylene. In some embodiments, each of L2and L3is independently substituted linear C2-C10 heteroalkenylene. In some embodiments, each of L2and L3is independently substituted linear C2-C6 heteroalkenylene. In some embodiments, each of L2and L3is independently substituted linear C2-C3 heteroalkenylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C10 heteroalkenylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C6 heteroalkenylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C3 heteroalkenylene.

[0243] In some embodiments, at least one of L2and L3is optionally substituted C2-C10 heteroalkynylene. In some embodiments, at least one of L2and L3is optionally substituted C2-C6 heteroalkynylene. In some embodiments, at least one of L2and L3is optionally substituted C2-C3 heteroalkynylene. In some embodiments, at least one of L2and L3is substituted C2-C10 heteroalkynylene. In some embodiments, at least one of L2and L3is substituted C2-C6 heteroalkynylene. In some embodiments, at least one of L2and L3is substituted C2-C3 heteroalkynylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C10 heteroalkynylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C6 heteroalkynylene. In some embodiments, at least one of L2and L3is unsubstituted C2-C3 heteroalkynylene.

[0244] In some embodiments, at least one of L2and L3is optionally substituted linear C2-C10 heteroalkynylene. In some embodiments, at least one of L2and L3is optionally substituted linear C2-Ce heteroalkynylene. In some embodiments, at least one of L2and L3is optionally substituted linear C2-C3 heteroalkynylene. In some embodiments, at least one of L2and L3is substituted linear C2-C1076 / 232M1237.70154WO0012225011.1heteroalkynylene. In some embodiments, at least one of L2and L3is substituted linear C2-C6 heteroalkynylene. In some embodiments, at least one of L2and L3is substituted linear C2-C3 heteroalkynylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C10 heteroalkynylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C6 heteroalkynylene. In some embodiments, at least one of L2and L3is unsubstituted linear C2-C3 heteroalkynylene.

[0245] In some embodiments, each of L2and L3is independently optionally substituted C2-C10 heteroalkynylene. In some embodiments, each of L2and L3is independently optionally substituted C2-Ce heteroalkynylene. In some embodiments, each of L2and L3is independently optionally substituted C2-C3 heteroalkynylene. In some embodiments, each of L2and L3is independently substituted C2-C10 heteroalkynylene. In some embodiments, each of L2and L3is independently substituted C2-C6 heteroalkynylene. In some embodiments, each of L2and L3is independently substituted C2-C3 heteroalkynylene. In some embodiments, each of L2and L3is independently unsubstituted C2-C10 heteroalkynylene. In some embodiments, each of L2and L3is independently unsubstituted C2-C6 heteroalkynylene. In some embodiments, each of L2and L3is independently unsubstituted C2-C3 heteroalkynylene.

[0246] In some embodiments, each of L2and L3is independently optionally substituted linear C2-C10 heteroalkynylene. In some embodiments, each of L2and L3is independently optionally substituted linear C2-C6 heteroalkynylene. In some embodiments, each of L2and L3is independently optionally substituted linear C2-C3 heteroalkynylene. In some embodiments, each of L2and L3is independently substituted linear C2-C10 heteroalkynylene. In some embodiments, each of L2and L3is independently substituted linear C2-C6 heteroalkynylene. In some embodiments, each of L2and L3is independently substituted linear C2-C3 heteroalkynylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C10 heteroalkynylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C6 heteroalkynylene. In some embodiments, each of L2and L3is independently unsubstituted linear C2-C3 heteroalkynylene.

[0247] In some embodiments, at least one of L2and L3comprises a disulfide. In some embodiments, at least one of L2and L3is optionally substituted C1-C10 heteroalkylene comprising a disulfide. In some embodiments, at least one of L2and L3is optionally substituted C2-C10 heteroalkenylene comprising a disulfide. In some embodiments, at least one of L2and L3is optionally substituted C2-C10 heteroalkynylene comprising a disulfide.

[0248] In some embodiments, each of L2and L3comprises a disulfide. In some embodiments, each of L2and L3is independently optionally substituted C1-C10 heteroalkylene comprising a disulfide. In some embodiments, each of L2and L3is independently optionally substituted C2-C10 heteroalkenylene comprising a disulfide. In some embodiments, each of L2and L3is independently optionally substituted C2-C10 heteroalkynylene comprising a disulfide.77 / 232M1237.70154WO0012225011.1R2and R3

[0249] As defined herein, each of R2and R3is independently optionally substituted aliphatic, optionally substituted heteroaliphatic, or optionally substituted carbocyclyl; wherein at least one of R2and R3is optionally substituted alkynyl, optionally substituted branched C10-C20 alkyl, or -(CH2)m-R4- In some embodiments, R2and R3are the same. In some embodiments, R2and R3are different.

[0250] In some embodiments, at least one of R2and R3is optionally substituted alkynyl, optionally substituted branched C10-C20 alkyl, or -(CH2)m-R4- In some embodiments, each of R2and R3is independently optionally substituted alkynyl, optionally substituted branched C10-C20 alkyl, or -(CH2)m-R4.

[0251] In some embodiments, at least one of R2and R3is optionally substituted aliphatic. In some embodiments, at least one of R2and R3is substituted aliphatic. In some embodiments, at least one of R2and R3is unsubstituted aliphatic.

[0252] In some embodiments, at least one of R2and R3is optionally substituted alkyl. In some embodiments, at least one of R2and R3is optionally substituted C1-C20 alkyl. In some embodiments, at least one of R2and R3is optionally substituted branched C1-C20 alkyl. In some embodiments, at least one of R2and R3is optionally substituted C10-C20 alkyl. In some embodiments, at least one of R2and R3is optionally substituted branched C10-C20 alkyl. In some embodiments, at least one of R2and R3is substituted alkyl. In some embodiments, at least one of R2and R3is substituted C1-C20 alkyl. In some embodiments, at least one of R2and R3is substituted branched C1-C20 alkyl. In some embodiments, at least one of R2and R3is substituted C10-C20 alkyl. In some embodiments, at least one of R2and R3is substituted branched C10-C20 alkyl. In some embodiments, at least one of R2and R3is unsubstituted alkyl. In some embodiments, at least one of R2and R3is unsubstituted C1-C20 alkyl. In some embodiments, at least one of R2and R3is unsubstituted branched C1-C20 alkyl. In some embodiments, at least one of R2and R3is unsubstituted C10-C20 alkyl. In some embodiments, at least one of R2and R3is unsubstituted branched C10-C20 alkyl. In some embodiments, at least one of R2andR3isor. insome embodiments, at least one of R2and R3is. In some embodiments, at least one of R2and R3is.

[0253] In some embodiments, each of R2and R3is independently optionally substituted alkyl. In some embodiments, each of R2and R3is independently optionally substituted C1-C20 alkyl. In some embodiments, each of R2and R3is independently optionally substituted branched C1-C20 alkyl. In some embodiments, each of R2and R3is independently optionally substituted C10-C20 alkyl. In some embodiments, each of R2and R3is independently optionally substituted branched C10-C20 alkyl. In some embodiments, each of R2and R3is independently substituted alkyl. In some embodiments, each78 / 232M1237.70154WO0012225011.1of R2and R3is independently substituted C1-C20 alkyl. In some embodiments, each of R2and R3is independently substituted branched C1-C20 alkyl. In some embodiments, each of R2and R3is independently substituted C10-C20 alkyl. In some embodiments, each of R2and R3is independently substituted branched C10-C20 alkyl. In some embodiments, each of R2and R3is independently unsubstituted alkyl. In some embodiments, each of R2and R3is independently unsubstituted C1-C20 alkyl. In some embodiments, each of R2and R3is independently unsubstituted branched C1-C20 alkyl. In some embodiments, each of R2and R3is independently unsubstituted C10-C20 alkyl. In some embodiments, each of R2and R3is independently unsubstituted branched C10-C20 alkyl. In someembodiments, each of R2and R3is independentlyor \. Insome embodiments, each of R2and R3is independently. In someembodiments, each of R2and R3is independently

[0254] In some embodiments, at least one of R2and R3is optionally substituted alkenyl. In some embodiments, at least one of R2and R3is optionally substituted C2-C20 alkenyl. In some embodiments, at least one of R2and R3is optionally substituted C10-C20 alkenyl. In some embodiments, at least one of R2and R3is substituted alkenyl. In some embodiments, at least one of R2and R3is substituted C2-C20 alkenyl. In some embodiments, at least one of R2and R3is substituted C10-C20 alkenyl. In some embodiments, at least one of R2and R3is unsubstituted alkenyl. In some embodiments, at least one of R2and R3is unsubstituted C2-C20 alkenyl. In some embodiments, at least one of R2and R3is unsubstituted C10-C20 alkenyl. In some embodiments, at least one of R2and R3is. In some embodiments, at least one of R2and R3is. In some embodiments, at least one of R2and

[0255] In some embodiments, at least one of R2and R3is optionally substituted alkynyl. In some embodiments, at least one of R2and R3is optionally substituted C2-C20 alkynyl. In some embodiments, at least one of R2and R3is optionally substituted C10-C20 alkynyl. In some embodiments, at least one of R2and R3is substituted alkynyl. In some embodiments, at least one of R2and R3is substituted C2-C20 alkynyl. In some embodiments, at least one of R2and R3is substituted C10-C20 alkynyl. In some embodiments, at least one of R2and R3is unsubstituted alkynyl. In some embodiments, at least one of R2and R3is unsubstituted C2-C20 alkynyl. In some embodiments, at least79 / 232M1237.70154WO0012225011.1one of R2and R3is unsubstituted C10-C20 alkynyl. In some embodiments, at least one of R2and R3is, or. Insome embodiments, at least one of R2and R3is. In some embodiments, at least oneof R2and R3is. In some embodiments, at least one of R2and R3is. In some embodiments, at least one of R2and R3is. Insome embodiments, at least one of R2and R3is. In some embodiments, atleast one of R2and R3is. In some embodiments, at least one of R2andR3is \

[0256] In some embodiments, each of R2and R3is independently optionally substituted alkynyl. In some embodiments, each of R2and R3is independently optionally substituted C2-C20 alkynyl. In some embodiments, each of R2and R3is independently optionally substituted C10-C20 alkynyl. In some embodiments, each of R2and R3is independently substituted alkynyl. In some embodiments, each of R2and R3is independently substituted C2-C20 alkynyl. In some embodiments, each of R2and R3is independently substituted C10-C20 alkynyl. In some embodiments, each of R2and R3is independently unsubstituted alkynyl. In some embodiments, each of R2and R3is independently unsubstituted C2-C20 alkynyl. In some embodiments, each of R2and R3is independently unsubstituted C10-C20 alkynyl. Insome embodiments, each of R2and R3is independently. In some embodiments, each of R2and R3is independently. In some embodiments, each of R2and R3is independently80 / 232M1237.70154WO0012225011.1. In some embodiments, each of R2and R3is independentlyIn some embodiments, each of R2and R3is independently. In someembodiments, each of R2and R3is independently. In some embodiments,each of R2and R3is independently. In some embodiments, each of R2and R3is independently

[0257] In some embodiments, at least one of R2and R3is of the formula:|—(CH2)p≡—R5(iii-a),wherein:each R5is independently optionally substituted aliphatic or optionally substituted heteroaliphatic; andeach p is independently an integer from 1-10, inclusive.

[0258] In some embodiments, each of R2and R3is independently of the Formula (iii-a).

[0259] In some embodiments, at least one R5is optionally substituted aliphatic. In some embodiments, at least one R5is substituted aliphatic. In some embodiments, at least one R5is unsubstituted aliphatic.

[0260] In some embodiments, at least one R5is optionally substituted alkyl. In some embodiments, at least one R5is optionally substituted C1-C20 alkyl. In some embodiments, at least one R5is optionally substituted C1-C10 alkyl. In some embodiments, at least one R5is optionally substituted Ci-Ce alkyl. In some embodiments, at least one R5is optionally substituted linear C1-C20 alkyl. In some embodiments, at least one R5is optionally substituted linear C1-C10 alkyl. In some embodiments, at least one R5is optionally substituted linear Ci-Ce alkyl. In some embodiments, at least one R5is substituted alkyl. In some embodiments, at least one R5is substituted C1-C20 alkyl. In some embodiments, at least one R5is substituted C1-C10 alkyl. In some embodiments, at least one R5is substituted Ci-Ce alkyl. In some embodiments, at least one R5is substituted linear C1-C20 alkyl. In some embodiments, at least one R5is substituted linear C1-C10 alkyl. In some embodiments, at least one R5is substituted linear Ci-Ce alkyl. In some embodiments, at least one R5is unsubstituted alkyl. In some embodiments, at least one R5is unsubstituted C1-C20 alkyl. In some embodiments, at least one R5is unsubstituted C1-C10 alkyl. In some embodiments, at least one R5is unsubstituted Ci-Ce alkyl. In some embodiments, at least one R5is unsubstituted linear C1-C20 alkyl. In some embodiments, at least one R5is unsubstituted linear C1-C10 alkyl. In some embodiments, at least one R5is unsubstituted linear Ci-Ce alkyl. In some81 / 232M1237.70154WO0012225011.1embodiments, at least one R5is methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl. In some embodiments, at least one R5is methyl. In some embodiments, at least one R5is ethyl. In some embodiments, at least one R5is n-propyl. In some embodiments, at least one R5is n-butyl. In some embodiments, at least one R5is n-pentyl. In some embodiments, at least one R5is n-hexyl.

[0261] In some embodiments, each R5is independently optionally substituted alkyl. In some embodiments, each R5is independently optionally substituted C1-C20 alkyl. In some embodiments, each R5is independently optionally substituted C1-C10 alkyl. In some embodiments, each R5is independently optionally substituted Ci-Ce alkyl. In some embodiments, each R5is independently optionally substituted linear C1-C20 alkyl. In some embodiments, each R5is independently optionally substituted linear C1-C10 alkyl. In some embodiments, each R5is independently optionally substituted linear Ci-Ce alkyl. In some embodiments, each R5is independently substituted alkyl. In some embodiments, each R5is independently substituted C1-C20 alkyl. In some embodiments, each R5is independently substituted C1-C10 alkyl. In some embodiments, each R5is independently substituted Ci-Ce alkyl. In some embodiments, each R5is independently substituted linear C1-C20 alkyl. In some embodiments, each R5is independently substituted linear C1-C10 alkyl. In some embodiments, each R5is independently substituted linear Ci-Ce alkyl. In some embodiments, each R5is independently unsubstituted alkyl. In some embodiments, each R5is independently unsubstituted C1-C20 alkyl. In some embodiments, each R5is independently unsubstituted C1-C10 alkyl. In some embodiments, each R5is independently unsubstituted Ci-Ce alkyl. In some embodiments, each R5is independently unsubstituted linear C1-C20 alkyl. In some embodiments, each R5is independently unsubstituted linear C1-C10 alkyl. In some embodiments, each R5is independently unsubstituted linear Ci-Ce alkyl. In some embodiments, each R5is independently methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl. In some embodiments, each R5is independently methyl. In some embodiments, each R5is independently ethyl. In some embodiments, each R5is independently n-propyl. In some embodiments, each R5is independently n-butyl. In some embodiments, each R5is independently n-pentyl. In some embodiments, each R5is independently n-hexyl.

[0262] In some embodiments, at least one R5is optionally substituted alkenyl. In some embodiments, at least one R5is optionally substituted C1-C20 alkenyl. In some embodiments, at least one R5is optionally substituted C1-C10 alkenyl. In some embodiments, at least one R5is optionally substituted Ci-Ce alkenyl. In some embodiments, at least one R5is substituted alkenyl. In some embodiments, at least one R5is substituted C1-C20 alkenyl. In some embodiments, at least one R5is substituted C1-C10 alkenyl. In some embodiments, at least one R5is substituted Ci-Ce alkenyl. In some embodiments, at least one R5is unsubstituted alkenyl. In some embodiments, at least one R5is unsubstituted C1-C20 alkenyl. In some embodiments, at least one R5is unsubstituted C1-C10 alkenyl. In some embodiments, at least one R5is unsubstituted Ci-Ce alkenyl.

[0263] In some embodiments, each R5is independently optionally substituted alkenyl. In some embodiments, each R5is independently optionally substituted C1-C20 alkenyl. In some embodiments,82 / 232M1237.70154WO0012225011.1each R5is independently optionally substituted C1-C10 alkenyl. In some embodiments, each R5is independently optionally substituted Ci-Ce alkenyl. In some embodiments, each R5is independently substituted alkenyl. In some embodiments, each R5is independently substituted C1-C20 alkenyl. In some embodiments, each R5is independently substituted C1-C10 alkenyl. In some embodiments, each R5is independently substituted Ci-Ce alkenyl. In some embodiments, each R5is independently unsubstituted alkenyl. In some embodiments, each R5is independently unsubstituted C1-C20 alkenyl. In some embodiments, each R5is independently unsubstituted C1-C10 alkenyl. In some embodiments, each R5is independently unsubstituted Ci-Ce alkenyl.

[0264] In some embodiments, at least one R5is optionally substituted alkynyl. In some embodiments, at least one R5is optionally substituted C1-C20 alkynyl. In some embodiments, at least one R5is optionally substituted C1-C10 alkynyl. In some embodiments, at least one R5is optionally substituted Ci-Ce alkynyl. In some embodiments, at least one R5is substituted alkynyl. In some embodiments, at least one R5is substituted C1-C20 alkynyl. In some embodiments, at least one R5is substituted C1-C10 alkynyl. In some embodiments, at least one R5is substituted Ci-Ce alkynyl. In some embodiments, at least one R5is unsubstituted alkynyl. In some embodiments, at least one R5is unsubstituted C1-C20 alkynyl. In some embodiments, at least one R5is unsubstituted C1-C10 alkynyl. In some embodiments, at least one R5is unsubstituted Ci-Ce alkynyl.

[0265] In some embodiments, each R5is independently optionally substituted alkynyl. In some embodiments, each R5is independently optionally substituted C1-C20 alkynyl. In some embodiments, each R5is independently optionally substituted C1-C10 alkynyl. In some embodiments, each R5is independently optionally substituted Ci-Ce alkynyl. In some embodiments, each R5is independently substituted alkynyl. In some embodiments, each R5is independently substituted C1-C20 alkynyl. In some embodiments, each R5is independently substituted C1-C10 alkynyl. In some embodiments, each R5is independently substituted Ci-Ce alkynyl. In some embodiments, each R5is independently unsubstituted alkynyl. In some embodiments, each R5is independently unsubstituted C1-C20 alkynyl. In some embodiments, each R5is independently unsubstituted C1-C10 alkynyl. In some embodiments, each R5is independently unsubstituted Ci-Ce alkynyl.

[0266] In some embodiments, at least one R5is optionally substituted heteroaliphatic. In some embodiments, at least one R5is substituted heteroaliphatic. In some embodiments, at least one R5is unsubstituted heteroaliphatic.

[0267] In some embodiments, at least one R5is optionally substituted heteroalkyl. In some embodiments, at least one R5is optionally substituted C1-C20 heteroalkyl. In some embodiments, at least one R5is optionally substituted C1-C10 heteroalkyl. In some embodiments, at least one R5is optionally substituted Ci-Ce heteroalkyl. In some embodiments, at least one R5is substituted heteroalkyl. In some embodiments, at least one R5is substituted C1-C20 heteroalkyl. In some embodiments, at least one R5is substituted C1-C10 heteroalkyl. In some embodiments, at least one R5is substituted Ci-Ce heteroalkyl. In some embodiments, at least one R5is unsubstituted heteroalkyl. In83 / 232M1237.70154WO0012225011.1some embodiments, at least one R5is unsubstituted C1-C20 heteroalkyl. In some embodiments, at least one R5is unsubstituted C1-C10 heteroalkyl. In some embodiments, at least one R5is unsubstituted Ci-Ce heteroalkyl.

[0268] In some embodiments, each R5is independently optionally substituted heteroalkyl. In some embodiments, each R5is independently optionally substituted C1-C20 heteroalkyl. In some embodiments, each R5is independently optionally substituted C1-C10 heteroalkyl. In some embodiments, each R5is independently optionally substituted Ci-Ce heteroalkyl. In some embodiments, each R5is independently substituted heteroalkyl. In some embodiments, each R5is independently substituted C1-C20 heteroalkyl. In some embodiments, each R5is independently substituted C1-C10 heteroalkyl. In some embodiments, each R5is independently substituted Ci-Ce heteroalkyl. In some embodiments, each R5is independently unsubstituted heteroalkyl. In some embodiments, each R5is independently unsubstituted C1-C20 heteroalkyl. In some embodiments, each R5is independently unsubstituted C1-C10 heteroalkyl. In some embodiments, each R5is independently unsubstituted Ci-Ce heteroalkyl.

[0269] In some embodiments, at least one R5is optionally substituted heteroalkenyl. In some embodiments, at least one R5is optionally substituted C1-C20 heteroalkenyl. In some embodiments, at least one R5is optionally substituted C1-C10 heteroalkenyl. In some embodiments, at least one R5is optionally substituted Ci-Ce heteroalkenyl. In some embodiments, at least one R5is substituted heteroalkenyl. In some embodiments, at least one R5is substituted C1-C20 heteroalkenyl. In some embodiments, at least one R5is substituted C1-C10 heteroalkenyl. In some embodiments, at least one R5is substituted Ci-Ce heteroalkenyl. In some embodiments, at least one R5is unsubstituted heteroalkenyl. In some embodiments, at least one R5is unsubstituted C1-C20 heteroalkenyl. In some embodiments, at least one R5is unsubstituted C1-C10 heteroalkenyl. In some embodiments, at least one R5is unsubstituted Ci-Ce heteroalkenyl.

[0270] In some embodiments, each R5is independently optionally substituted heteroalkenyl. In some embodiments, each R5is independently optionally substituted C1-C20 heteroalkenyl. In some embodiments, each R5is independently optionally substituted C1-C10 heteroalkenyl. In some embodiments, each R5is independently optionally substituted Ci-Ce heteroalkenyl. In some embodiments, each R5is independently substituted heteroalkenyl. In some embodiments, each R5is independently substituted C1-C20 heteroalkenyl. In some embodiments, each R5is independently substituted C1-C10 heteroalkenyl. In some embodiments, each R5is independently substituted Ci-Ce heteroalkenyl. In some embodiments, each R5is independently unsubstituted heteroalkenyl. In some embodiments, each R5is independently unsubstituted C1-C20 heteroalkenyl. In some embodiments, each R5is independently unsubstituted C1-C10 heteroalkenyl. In some embodiments, each R5is independently unsubstituted Ci-Ce heteroalkenyl.

[0271] In some embodiments, at least one R5is optionally substituted heteroalkynyl. In some embodiments, at least one R5is optionally substituted C1-C20 heteroalkynyl. In some embodiments, at 84 / 232M1237.70154WO0012225011.1least one R5is optionally substituted C1-C10 heteroalkynyl. In some embodiments, at least one R5is optionally substituted Ci-Ce heteroalkynyl. In some embodiments, at least one R5is substituted heteroalkynyl. In some embodiments, at least one R5is substituted C1-C20 heteroalkynyl. In some embodiments, at least one R5is substituted C1-C10 heteroalkynyl. In some embodiments, at least one R5is substituted Ci-Ce heteroalkynyl. In some embodiments, at least one R5is unsubstituted heteroalkynyl. In some embodiments, at least one R5is unsubstituted C1-C20 heteroalkynyl. In some embodiments, at least one R5is unsubstituted C1-C10 heteroalkynyl. In some embodiments, at least one R5is unsubstituted Ci-Ce heteroalkynyl.

[0272] In some embodiments, each R5is independently optionally substituted heteroalkynyl. In some embodiments, each R5is independently optionally substituted C1-C20 heteroalkynyl. In some embodiments, each R5is independently optionally substituted C1-C10 heteroalkynyl. In some embodiments, each R5is independently optionally substituted Ci-Ce heteroalkynyl. In some embodiments, each R5is independently substituted heteroalkynyl. In some embodiments, each R5is independently substituted C1-C20 heteroalkynyl. In some embodiments, each R5is independently substituted C1-C10 heteroalkynyl. In some embodiments, each R5is independently substituted Ci-Ce heteroalkynyl. In some embodiments, each R5is independently unsubstituted heteroalkynyl. In some embodiments, each R5is independently unsubstituted C1-C20 heteroalkynyl. In some embodiments, each R5is independently unsubstituted C1-C10 heteroalkynyl. In some embodiments, each R5is independently unsubstituted Ci-Ce heteroalkynyl.

[0273] In some embodiments, at least one p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, at least one p is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, at least one p is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, at least one p is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, at least one p is 1, 2, 3, 4, 5, or 6. In some embodiments, at least one p is 1, 2, 3, 4, or 5. In some embodiments, at least one p is 1, 2, 3, or 4. In some embodiments, at least one p is 2, 3, 4, or 5. In some embodiments, at least one p is 2, 3, or 4. In some embodiments, at least one p is 2; or at least one p is 4. In some embodiments, at least one p is 1. In some embodiments, at least one p is 2. In some embodiments, at least one p is 3. In some embodiments, at least one p is 4. In some embodiments, at least one p is 5. In some embodiments, at least one p is 6. In some embodiments, at least one p is 7. In some embodiments, at least one p is 8. In some embodiments, at least one p is 9. In some embodiments, at least one p is 10.

[0274] In some embodiments, each p is independently 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, each p is independently 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, each p is independently 1, 2, 3, 4, 5, 6, or 7. In some embodiments, each p is independently 1, 2, 3, 4, 5, or 6. In some embodiments, each p is independently 1, 2, 3, 4, or 5. In some embodiments, each p is independently 1, 2, 3, or 4. In some embodiments, each p is independently 2, 3, 4, or 5. In some embodiments, each p is independently 2, 3, or 4. In some embodiments, each p is independently 2; or each p is independently 4. In some embodiments, each p is independently 1. In some embodiments,85 / 232M1237.70154WO0012225011.1each p is independently 2. In some embodiments, each p is independently 3. In some embodiments, each p is independently 4. In some embodiments, each p is independently 5. In some embodiments, each p is independently 6. In some embodiments, each p is independently 7. In some embodiments, each p is independently 8. In some embodiments, each p is independently 9. In some embodiments, each p is independently 10.

[0275] In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is optionally substituted alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is optionally substituted C1-C20 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is optionally substituted C1-C10 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is optionally substituted Ci-Ce alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is optionally substituted linear C1-C20 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is optionally substituted linear C1-C10 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is optionally substituted linear Ci-Ce alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is substituted alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is substituted C1-C20 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is substituted C1-C10 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is substituted Ci-Ce alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is substituted linear C1-C20 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is substituted linear C1-C10 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is substituted linear Ci-Ce alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is unsubstituted alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is unsubstituted C1-C20 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is unsubstituted C1-C10 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is unsubstituted Ci-Ce alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is unsubstituted linear C1-C20 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is unsubstituted linear C1-C10 alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is unsubstituted linear Ci-Ce alkyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is methyl, ethyl, n-propyl, n-butyl, n-pentyl, or / z-hcxyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is methyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is ethyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is n-propyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is n-butyl.86 / 232M1237.70154WO0012225011.1In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is n-pentyl. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one R5is n-hexyl.

[0276] In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is optionally substituted alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is optionally substituted C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is optionally substituted C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is optionally substituted C1-C6 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is optionally substituted linear C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is optionally substituted linear C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is optionally substituted linear Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is substituted alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is substituted C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is substituted C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is substituted Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is substituted linear C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is substituted linear C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is substituted linear Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is unsubstituted alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is unsubstituted C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is unsubstituted C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is unsubstituted Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is unsubstituted linear C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is unsubstituted linear C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is unsubstituted linear Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is methyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is ethyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is n-propyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a),87 / 232M1237.70154WO0012225011.1and at least one R5is n-butyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is n-pentyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one R5is n-hexyl.

[0277] In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently optionally substituted alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently optionally substituted C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently optionally substituted C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently optionally substituted Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently optionally substituted linear C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently optionally substituted linear C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently optionally substituted linear Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently substituted alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently substituted C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently substituted C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently substituted Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently substituted linear C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently substituted linear C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently substituted linear Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently unsubstituted alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently unsubstituted C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently unsubstituted C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently unsubstituted Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently unsubstituted linear C1-C20 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently unsubstituted linear C1-C10 alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently unsubstituted linear Ci-Ce alkyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently methyl, ethyl, n-propyl, n-butyl, n-pentyl, or / z-hcxyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently methyl. In some embodiments, each of R2and R3is independently of the88 / 232M1237.70154WO0012225011.1Formula (iii-a), and each R5is independently ethyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently n-propyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently n-butyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently n-pentyl. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each R5is independently n-hexyl.

[0278] In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 1, 2, 3, 4, 5, or 6. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 1, 2, 3, 4, or 5. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 1, 2, 3, or 4. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 2, 3, 4, or 5. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 2, 3, or 4. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 2; or at least one p is 4. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 1. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 2. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 3. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 4. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 5. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 6. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 7. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 8. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 9. In some embodiments, at least one of R2and R3is of the Formula (iii-a), and at least one p is 10.

[0279] In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 1, 2, 3, 4, 5, or 6. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 1, 2, 3, 4, or 5. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 1, 2, 3, or 4. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 2, 3, 4, or 5. In some embodiments, each of 89 / 232M1237.70154WO0012225011.1R2and R3is independently of the Formula (iii-a), and at least one p is 2, 3, or 4. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 2; or at least one p is 4. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 1. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 2. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 3. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 4. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 5. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 6. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 7. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 8. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 9. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and at least one p is 10.

[0280] In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 1, 2, 3, 4, 5, 6, or 7. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 1, 2, 3, 4, 5, or 6. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 1, 2, 3, 4, or 5. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 1, 2, 3, or 4. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 2, 3, 4, or 5. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 2, 3, or 4. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 2; or each p is independently 4. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 1. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 2. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 3. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 4. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 5. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 6. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 7. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 8. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 9. In some embodiments, each of R2and R3is independently of the Formula (iii-a), and each p is independently 10.90 / 232M1237.70154WO0012225011.1

[0281] In some embodiments, at least one of R2and R3is of the Formula (iii-a), at least one R5is optionally substituted aliphatic, and at least one p is 2, 3, 4, 5, or 6. In some embodiments, at least one of R2and R3is of the Formula (iii-a), at least one R5is optionally substituted Ci-Cio alkyl, and at least one p is 2, 3, 4, 5, or 6. In some embodiments, at least one of R2and R3is of the Formula (iii-a), at least one R5is optionally substituted linear Ci-Ce alkyl, and at least one p is 2, 3, 4, 5, or 6. In some embodiments, at least one of R2and R3is of the Formula (iii-a), at least one R5is methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl, and at least one p is 2, 3, 4, 5, or 6. In some embodiments, at least one of R2and R3is of the Formula (iii-a), at least one R5is n-hexyl, and at least one p is 2, 3, 4, 5, or 6. In some embodiments, at least one of R2and R3is of the Formula (iii-a), at least one R5is n-hexyl, and at least one p is 2.

[0282] In some embodiments, each of R2and R3is independently of the Formula (iii-a), each R5is independently optionally substituted aliphatic, and each p is independently 2, 3, 4, 5, or 6. In some embodiments, each of R2and R3is independently of the Formula (iii-a), each R5is independently optionally substituted Ci-Cio alkyl, and each p is independently 2, 3, 4, 5, or 6. In some embodiments, each of R2and R3is independently of the Formula (iii-a), each R5is independently optionally substituted linear Ci-Ce alkyl, and each p is independently 2, 3, 4, 5, or 6. In some embodiments, each of R2and R3is independently of the Formula (iii-a), each R5is independently methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl, and each p is independently 2, 3, 4, 5, or 6. In some embodiments, each of R2and R3is independently of the Formula (iii-a), each R5is independently n-hexyl, and each p is independently 2, 3, 4, 5, or 6. In some embodiments, each of R2and R3is independently of the Formula (iii-a), each R5is independently n-hexyl, and each p is independently 2.

[0283] In some embodiments, at least one of R2and R3is optionally substituted heteroaliphatic. In some embodiments, at least one of R2and R3is substituted heteroaliphatic. In some embodiments, at least one of R2and R3is unsubstituted heteroaliphatic. In some embodiments, at least one of R2and R3comprises a disulfide. In some embodiments, each of R2and R3independently comprises a disulfide.

[0284] In some embodiments, at least one of R2and R3is optionally substituted heteroalkyl. In some embodiments, at least one of R2and R3is optionally substituted C1-C20 heteroalkyl. In some embodiments, at least one of R2and R3is optionally substituted branched C1-C20 heteroalkyl. In some embodiments, at least one of R2and R3is optionally substituted C10-C20 heteroalkyl. In some embodiments, at least one of R2and R3is optionally substituted branched C10-C20 heteroalkyl. In some embodiments, at least one of R2and R3is substituted heteroalkyl. In some embodiments, at least one of R2and R3is substituted C1-C20 heteroalkyl. In some embodiments, at least one of R2and R3is substituted branched C1-C20 heteroalkyl. In some embodiments, at least one of R2and R3is substituted C10-C20 heteroalkyl. In some embodiments, at least one of R2and R3is substituted branched C10-C20 heteroalkyl. In some embodiments, at least one of R2and R3is unsubstituted heteroalkyl. In some embodiments, at least one of R2and R3is unsubstituted C1-C20 heteroalkyl. In some embodiments, at91 / 232M1237.70154WO0012225011.1least one of R2and R3is unsubstituted branched C1-C20 heteroalkyl. In some embodiments, at least one of R2and R3is unsubstituted C10-C20 heteroalkyl. In some embodiments, at least one of R2and R3is unsubstituted branched C10-C20 heteroalkyl. In some embodiments, at least one of R2and R3is optionally substituted heteroalkyl comprising a disulfide.

[0285] In some embodiments, at least one of R2and R3is optionally substituted heteroalkenyl. In some embodiments, at least one of R2and R3is optionally substituted C2-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is optionally substituted branched C2-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is optionally substituted C10-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is optionally substituted branched C10-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is substituted heteroalkenyl. In some embodiments, at least one of R2and R3is substituted C2-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is substituted branched C2-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is substituted C10-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is substituted branched C10-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is unsubstituted heteroalkenyl. In some embodiments, at least one of R2and R3is unsubstituted C2-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is unsubstituted branched C2-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is unsubstituted C10-C20 heteroalkenyl. In some embodiments, at least one of R2and R3is unsubstituted branched C10-C20 heteroalkenyl.

[0286] In some embodiments, at least one of R2and R3is optionally substituted heteroalkynyl. In some embodiments, at least one of R2and R3is optionally substituted C2-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is optionally substituted branched C2-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is optionally substituted C10-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is optionally substituted branched C10-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is substituted heteroalkynyl. In some embodiments, at least one of R2and R3is substituted C2-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is substituted branched C2-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is substituted C10-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is substituted branched C10-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is unsubstituted heteroalkynyl. In some embodiments, at least one of R2and R3is unsubstituted C2-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is unsubstituted branched C2-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is unsubstituted C10-C20 heteroalkynyl. In some embodiments, at least one of R2and R3is unsubstituted branched C10-C20 heteroalkynyl.

[0287] In some embodiments, at least one of R2and R3is optionally substituted carbocyclyl. In some embodiments, at least one of R2and R3is optionally substituted C3-C10 carbocyclyl. In some embodiments, at least one of R2and R3is optionally substituted monocyclic C3-C10 carbocyclyl. In some embodiments, at least one of R2and R3is optionally substituted C5-C7 carbocyclyl. In some embodiments, at least one of R2and R3is substituted carbocyclyl. In some embodiments, at least one92 / 232M1237.70154WO0012225011.1of R2and R3is substituted C3-C10 carbocyclyl. In some embodiments, at least one of R2and R3is substituted monocyclic C3-C10 carbocyclyl. In some embodiments, at least one of R2and R3is substituted C5-C7 carbocyclyl. In some embodiments, at least one of R2and R3is of the formula:. In some embodiments, at least one of R2and R3is of the formula:In some embodiments, at least one of R2and R3is of the formula:. In some embodiments, at least one of R2and R3is of the formula: / , or. In some embodiments, at least one of R2and R3is unsubstituted carbocyclyl. In some embodiments, at least one of R2and R3is unsubstituted C3-C10 carbocyclyl. In some embodiments, at least one of R2and R3is unsubstituted monocyclic C...

Claims

1. CLAIMSWhat is claimed is:

1. A compound of Formula (I):O NHRR2O2C— L2- L3— CO2R3x(I),or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein:R is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;R1is optionally substituted aliphatic or optionally substituted heteroaliphatic;each of R2and R3is independently optionally substituted aliphatic, optionally substituted heteroaliphatic, or optionally substituted carbocyclyl; wherein at least one of R2and R3is optionally substituted alkynyl, optionally substituted C10-C20 branched alkyl, or -(CH2)m-R4;each R4is independently optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;each m is independently an integer from 0-10, inclusive;each of L2and L3is independently optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C1-C10 heteroalkylene, optionally substituted C2-C10 heteroalkenylene, or optionally substituted C2-C10 heteroalkynylene; andX is optionally substituted aliphatic, optionally substituted heteroaliphatic, or optionally substituted carbocyclyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one of L2and L3is of the formula:-(CR'2)n—wherein:each R' is independently -H, -F, or optionally substituted Ci-Ce alkyl; andeach n is independently an integer from 1-10, inclusive.211 / 232M1237.70154WO0012225011.

13. The compound of claim 2, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each of L2and L3is independently of the formula:-(CR'2)n—4. The compound of any one of claims 2 and 3, wherein the compound is of Formula (II):CX. NHRR2O2C-(CR'2)n— P(CR'2)n-CO2R3°y%,X (II).or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

5. The compound of any one of claims 2-4, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each R' is H.

6. The compound of any one of claims 2-5, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each n is independently 2, 3, 4, 5, or 6.

7. The compound of any one of claims 2-6, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each n is 2; each n is 3; each n is 4; each n is 5; or each n is 6.

8. The compound of any one of claims 2-7, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each n is 3.

9. The compound of any one of claims 1-8, wherein the compound is of Formula (III):CK -NHRR2O2C — CO2R3°VN-R,X (HI)or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.212 / 232M1237.70154WO0012225011.

110. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one of R2and R3is of the formula:j-(CH2)p^^R5wherein:each R5is independently optionally substituted aliphatic or optionally substituted heteroaliphatic; andeach p is independently an integer from 1-10, inclusive.

11. The compound of claim 10, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each of R2and R3is independently of the formula:HCH2)P^^R5.

12. The compound of any one of claims 10 and 11, wherein the compound is of Formula (II-A):O NHRR5-^^- (CH2)pO2C-(CR'2)n— (CR'2)n— CO2(CH2)p— R5°YN'R1X (II-A), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

13. The compound of any one of claims 10-12, wherein the compound is of Formula (III- A):O NHR R5^^(CH2)pO2C^^yx^X'CO2(CH2)p^^R5°YN'R1x (III- A), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

14. The compound of any one of claims 10-13, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one R5is optionally substituted aliphatic.213 / 232M1237.70154WO0012225011.

115. The compound of any one of claims 10-14, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one R5is optionally substituted Ci-Cio alkyl.

16. The compound of any one of claims 10-15, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one R5is optionally substituted linear Ci-Ce alkyl.

17. The compound of any one of claims 10-16, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one R5is methyl, ethyl, n-propyl, n-butyl, n-pentyl, or / z-hcxyl.

18. The compound of any one of claims 10-17, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one R5is / z-hcxyl.

19. The compound of any one of claims 10-13, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each R5is independently optionally substituted aliphatic.

20. The compound of claim 19, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each R5is independently optionally substituted Ci-Cio alkyl.

21. The compound of any one of claims 19 and 20, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each R5is independently optionally substituted linear Ci-Ce alkyl.

22. The compound of any one of claims 19-21, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each R5is independently methyl, ethyl, n-propyl, n-butyl, n-pentyl, or / z-hcxyl.

23. The compound of any one of claims 19-22, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each R5is independently / z-hcxyl.214 / 232M1237.70154WO0012225011.

124. The compound of any one of claims 10-23, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each p is independently 2, 3, 4, 5, or 6.

25. The compound of any one of claims 10-24, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each p is 2; or each p is 4.

26. The compound of any one of claims 2-25, wherein the compound is of Formula (II-A-iii):X (II-A-iii), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

27. The compound of any one of claims 1-26, wherein the compound is of Formula (III- A-iii):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

28. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one of R2and R3is of the formula:wherein:= is a single bond or a double bond;each R6is independently halo, -OH, -O(optionally substituted Ci-Ce alkyl), -O(optionally substituted Ci-Ce haloalkyl), optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally215 / 232M1237.70154WO0012225011.1substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C2-C6 heteroalkynyl, or two R6are joined together to form an optionally substituted carbocyclic ring;each m is independently an integer from 0-6, inclusive; andeach q is independently an integer from 1-10, inclusive.

29. The compound of claim 28, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each of R2and R3is independently of the formula:

30. The compound of claim 28, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each of R2and R3is independently of the formula:The compound of any one of claims 28 and 29, wherein the compound is of Formula (II-B):(II-B), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

32. The compound of any one of claims 28, 29, and 31, wherein the compound is of Formula (III-B):X (III-B), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

33. The compound of any one of claims 28-32, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof,216 / 232M1237.70154WO0012225011.1wherein at least one R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C2-C6 heteroalkynyl, or two R6are joined together to form an optionally substituted carbocyclic ring.

34. The compound of any one of claims 28-33, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one R6is optionally substituted Ci-Ce alkyl.

35. The compound of any one of claims 28-34, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one R6is unsubstituted C1-C3 alkyl.

36. The compound of any one of claims 28-35, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one R6is methyl or isopropyl.

37. The compound of any one of claims 28-36, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one R6is optionally substituted C2-C6 alkenyl.

38. The compound of any one of claims 28-37, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one R6is unsubstituted C2-C3 alkenyl.

39. The compound of any one of claims 28-38, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof,wherein at least oneR6is40. The compound of any one of claims 28-32, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each R6is independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C2-C6 heteroalkynyl, or two R6are joined together to form an optionally substituted carbocyclic ring.217 / 232M1237.70154WO0012225011.

141. The compound of any one of claims 28-40, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein two R6are joined together to form an optionally substituted carbocyclic ring.

42. The compound of any one of claims 28-41, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein two R6are joined together to form an optionally substituted C3-C4 carbocyclic ring.

43. The compound of any one of claims 28-42, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each q is independently 0, 1, 2, 3, or 4.

44. The compound of any one of claims 28-43, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each q is 1; each q is 2; or each q is 4.

45. The compound of any one of claims 28-40, 43, and 44, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one of R2and R3is of the formula:

46. The compound of any one of claims 28-40 and 43-45, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one of R2and R3is of the formula:218 / 232M1237.70154WO0012225011.

147. The compound of any one of claims 28-44, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one of R2and R3is of the formula:

48. The compound of any one of claims 28-47, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each m is independently 0, 1, 2, or 3.

49. The compound of any one of claims 28-48, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each m is 0; or each m is 1.

50. The compound of any one of claims 28-40, 43-45, 48, and 49, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one of R2and R3is of the formula:

51. The compound of any one of claims 28-40, 43-46, and 48-50, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one of R2and R3is of the formula:219 / 232M1237.70154WO0012225011.

152. The compound of any one of claims 28-44 and 47-49, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein at least one of R2and R3is of the formula:

53. The compound of any one of claims 2-8, 28-40, 43-46, and 48-50, wherein the compound is of Formulae (II-B-i) or (II-B-ii):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

54. The compound of any one of claims 1-9, 28-40, 43-46, 48-50, and 53, wherein the compound is of Formulae (III-B-i) or (III-B-ii):220 / 232M1237.70154WO0012225011.1or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

55. The compound of any one of claims 1-9, 28-40, 43-46, 48-51, 53, and 54, wherein the compound is of Formulae (III-B-i-a) or (III-B-ii-a):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

56. The compound of any one of claims 1-9, 28-44, 47-49, or 52, wherein the compound is of Formulaeor (III-C-vi):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.221 / 232M1237.70154WO0012225011.

157. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R is optionally substituted aliphatic.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R is optionally substituted alkyl.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R is optionally substituted Ci-Ce alkyl.

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R is unsubstituted C2-C4 alkyl.

61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R is n-butyl or t-butyl.

62. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R is optionally substituted alkenyl.

63. The compound of any one of claims 1-57 and 62, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R is optionally substituted C10-C20 alkenyl.

64. The compound of any one of claims 1-57, 62, and 63, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R is unsubstituted linear C10-C20 alkenyl.

65. The compound of any one of claims 1-57 and 62-64, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivativethereof, wherein R is of the formula:222 / 232M1237.70154WO0012225011.

166. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R is optionally substituted carbocyclyl.

67. The compound of any one of claims 1-57 and 66, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R is optionally substituted C3-C10 carbocyclyl.

68. The compound of any one of claims 1-57, 66, and 67, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivativethereof, wherein R is of the formula:

69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R1is optionally substituted aliphatic.

70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R1is optionally substituted alkyl.

71. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R1is optionally substituted Ci-Ce alkyl.

72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R1is substituted C2-C4 alkyl.

73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R1is of the formula:Rw%wherein:223 / 232M1237.70154WO0012225011.1each of Rlaand Rlbis independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or Rlaand Rlbare joined together to form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring.

74. The compound of claim 73, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each of Rlaand Rlbis hydrogen or independently optionally substituted Ci-Ce alkyl.

75. The compound of any one of claims 73 and 74, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each of Rlaand Rlbis hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, or optionally substituted n-butyl.

76. The compound of any one of claims 1-75, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof,H N N N77. The compound of claim 73, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein Rlaand Rlbare joined together to form an optionally substituted heterocyclic ring.

78. The compound of any one of claims 73 and 77, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein:R1is of the formula:each Rais independently optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; andxl is 0, 1, 2, 3, or 4.224 / 232M1237.70154WO0012225011.

179. The compound of any one of claims 73, 77, and 78, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivativethereof, wherein R1is of the formula:

80. The compound of any one of claims 1-73 and 77-79, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivativethereof, wherein R1is of the formula:N81. The compound of claim 73, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein Rlaand Rlbare joined together to form an optionally substituted heteroaryl ring.

82. The compound of any one of claims 73 and 81, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein:NR1is of the formula:each Rais independently optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; andx2 is 0, 1, 2, or 3.

83. The compound of any one of claims 1-73, 81, and 82, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivativethereof, wherein R1is of the formula:

84. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein R1is of the formula:225 / 232M1237.70154WO0012225011.1wherein:each of Rlcand Rldis independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or R1cand R1dare joined together to form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring.

85. The compound of claim 84, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each of Rlcand Rldis independently optionally substituted Ci-Ce alkyl.

86. The compound of any one of claims 84 and 85, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein each of Rlcand Rldis optionally substituted methyl or optionally substituted ethyl.

87. The compound of any one of claims 1-72 and 84-86, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivativethereof, wherein R1is of the formula:

88. The compound of any one of claims 1-87, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is optionally substituted aliphatic.

89. The compound of any one of claims 1-88, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is optionally substituted Ci-Ce aliphatic.

90. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is methyl.

91. The compound of any one of claims 1-88, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is optionally substituted C10-C25 aliphatic.226 / 232M1237.70154WO0012225011.

192. The compound of any one of claims 1-88 and 91, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is unsubstituted C10-C25 aliphatic.

93. The compound of any one of claims 1-88, 91, and 92, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is unsubstituted linear C10-C25 aliphatic.

94. The compound of any one of claims 1-88 and 91-93, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivativethereof, wherein X is of the formula:

95. The compound of any one of claims 1-87, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is optionally substituted C8-C30 heteroaliphatic.

96. The compound of any one of claims 1-87 and 95, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is optionally substituted branched C8-C30 heteroalkyl or optionally substituted linear C8-C30 heteroalkynyl.

97. The compound of any one of claims 1-87, 95, and 96, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is of the formula:227 / 232M1237.70154WO0012225011.

198. The compound of any one of claims 1-87, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is optionally substituted carbocyclyl.

99. The compound of any one of claims 1-87 and 98, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, wherein X is optionally substituted C3-C10 carbocyclyl.

100. The compound of any one of claims 1-87, 98, and 99, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivativethereof, wherein X is of the formula:

101. The compound of any one of claims 1-100, wherein the compound is a compound in Table A, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof.

102. A composition comprising the compound, pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, of any one of claims 1-101; a helper lipid, a PEG-lipid, a sterol, and a polynucleotide.

103. The composition of claim 102, wherein the helper lipid is DOPE, the PEG-lipid is DMG-PEG2000, the sterol is cholesterol, and the polynucleotide is mRNA.

104. The composition of any one of claims 102 and 103, further comprising a cationic lipid.228 / 232M1237.70154WO0012225011.1105. The composition of claim 104, wherein the cationic lipid is DOTAP.

106. A composition comprising the compound, pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or isotopically enriched derivative thereof, of any one of claims 1-101; an agent; and optionally an excipient.

107. The composition of any one of claims 102-106, wherein the composition is useful for delivering the agent to a subject or cell.

108. The composition of any one of claims 102-107, wherein the composition is a pharmaceutical composition, a cosmetic composition, a nutraceutical composition, or a composition with non-medical application.

109. The composition of claim 108, wherein the composition is a pharmaceutical composition.

110. The composition of any one of claims 106-109, wherein the composition further comprises cholesterol.

111. The composition of any one of claims 106-110, wherein the composition further comprises a PEGylated lipid.

112. The composition of any one of claims 106-111, wherein the composition further comprises a phospholipid.

113. The composition of any one of claims 106-112, wherein the composition further comprises an apolipoprotein.

114. The composition of any one of claims 106-113, wherein the agent is an organic molecule, inorganic molecule, nucleic acid, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, an immunological agent, or an agent useful in bioprocessing.

115. The composition of any one of claims 106-114, wherein the agent is a polynucleotide.

116. The composition of claim any one of claims 102, 104, 105, and 115, wherein the polynucleotide is an RNA.229 / 232M1237.70154WO0012225011.1117. The composition of claim 116, wherein the RNA is messenger RNA (mRNA), singlestranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, or viral satellite RNA.

118. The composition of any one of claims 116 and 117, wherein the RNA is mRNA.

119. The composition of any one of claims 102, 104, 105, and 115, wherein the polynucleotide encodes a protein or a peptide.

120. The composition of claim 119, wherein the protein or peptide is an antigen.

121. The composition of any one of claims 102, 104, 105, and 115, wherein the polynucleotide is a DNA.

122. The composition of claim 121, wherein the DNA is a plasmid DNA (pDNA).

123. The composition of any one of claims 102-122, wherein the composition is a vaccine.

124. The composition of any one of claims 106-123, wherein the agent and the compound are not covalently attached.

125. The composition of any one of claims 102-124, wherein the composition is in the form of a particle.

126. The composition of claim 125, wherein the particle is a nanoparticle or microparticle.

127. The composition of claim 125, wherein the particle is a micelle, liposome, or lipoplex.

128. The composition of claim 125, wherein the particle encapsulates the agent.230 / 232M1237.70154WO0012225011.1129. The composition of any one of claims 102-128, wherein the composition is a lyophilized solid.

130. The composition of any one of claims 102-129, wherein the composition is useful for treating or preventing a disease in a subject in need thereof.

131. The composition of any one of claims 106-130, wherein the composition comprises an effective amount of the agent.

132. A method of delivering an agent to a subject or a cell, the method comprising administering to the subject or contacting the cell with a composition of any one of claims 102-131.

133. The method of claim 132, wherein the cell is a liver cell, kidney cell, spleen cell, lung cell, skin cell, brain cell, epithelial cell, or a cell of the gastrointestinal tract.

134. A method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a composition of any one of claims 102-131.

135. The method of claim 132 or 134, wherein the subject is a human.

136. The method of claim 134 or 135, wherein the disease is a genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, kidney disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease.

137. A kit comprising a composition of any one of claims 102-131; and instructions for using the kit.231 / 232M1237.70154WO0012225011.1

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