PRMT5 synthetic lethal inhibitors targeting mtap deleted cancers

Abstract

The present disclosure provides compounds of the formulae herein (e.g., Formula (I), Formula (I')), and pharmaceutically acceptable salts thereof, which inhibit a protein arginine methyltransferase (PRMT). The present disclosure also provides pharmaceutical compositions and kits comprising the compounds, or pharmaceutically acceptable salts thereof, and methods of treating or preventing diseases by administering to a subject in need thereof the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

Description

PRMT5 SYNTHETIC LETHAL INHIBITORS TARGETING MTAP DELETED CANCERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63 / 506,032, filed June 2, 2023, titled PRMT5 SYNTHETIC LETHAL INHIBITORS TARGETING MTAP DELETED CANCERS, the contents of which are incorporated herewith by reference in their entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (U119770224WO00-SEQ-JDH.xml; Size: 11,944 bytes; and Date of Creation: May 30, 2024) is herein incorporated by reference in its entirety. GOVERNMENT SUPPORT

[0003] This invention was made with government support under R01 CA212403 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION

[0004] Breast cancer (BC) is the second most common cancer and leading cause of death in women[1,2], and triple-negative breast cancer (TNBC) is one of the highest-risk subtypes of BC[3]. Local recurrence rate after standard therapy on the early TNBC setting can be up to 72% in 5 years, but in the metastatic setting, the 5-year overall survival is only 12%[4]. The harsh reputation of TNBC comes from its therapeutic limitations[5]: TNBC tumors do not express estrogen receptor (ER), progesterone receptor (PR), or HER-2, indicating a paucity of therapeutic targets available, with chemotherapy being the primary option for the systemic treatment[6]. Unfortunately, it is common for patients to develop drug resistance after chemotherapy[7, 8]. Thus, there is an urgent need to provide new therapeutic options for these patients.

[0005] As epigenetic dysregulation has long been recognized as a key factor contributing to tumorigenesis and maintenance[9], protein arginine methyltransferases (PRMTs) are emerging as attractive epigenetic targets in cancer treatments

[0010] . PRMT family proteins, which regulate transcription, splicing, and DNA damage response, are frequently altered in many cancers, including TNBC

[0011] . PRMT5, which can symmetrically di-methylate arginine residues of its substrate proteins, is found to be overexpressed in many types of tumors and negatively correlated with patients’ survival

[0012] . PRMT5 inhibitors have been examined as a potential therapeutic treatment for TNBC

[0013] .

[0006] PRMT5 inhibition has shown significant efficacy in cancers lacking 5’-methylthioadenosine phosphorylases (MTAP)

[0014] . About 15% of all human cancers lose MTAP, due to its proximity to the CDKN2A tumor suppressor locus, with which MTAP is frequently co-deleted

[0015] . Loss of MTAP causes 5’-methylthioadenosine (MTA) accumulation, a metabolic derivative of S-adenosyl-L-methionine (SAM), by 5-20 fold

[0016] . MTA can act as the selective endogenous inhibitor for PRMT5, but not other PRMT family proteins, due to the specificity in the PRMT5-SAM binding pocket

[0016] . A high concentration of MTA sensitizes MTAP- / - cells by partial PRMT5 inhibition compared to MTAP+ / + cells, so PRMT5 inhibitors may specifically suppress MTAP- / - cells while sparing MTAP+ cells, which may be of great clinical significance. SUMMARY OF THE INVENTION

[0007] Traditional PRMT5 inhibition strategies have manifested limited cooperativity with MTA. MTA-cooperative PRMT5 inhibitors may better take advantage of MTAP deletion. Two such molecules[17, 18], including 11-2F discovered by Applicant, have shown good activity and selectivity for MTAP-deleted cancer cells. The present disclosure describes a second-generation PRMT5⋅MTA complex inhibitor, 16-19F, together with its Cryo-EM structure with PRMT5⋅MTA complex. One subtype of TNBC cells with MTAP- / - was more sensitive to 16-19F compared to PRMT5 inhibitors in clinical trials. A new potential inhibition mechanism in TNBC by 16-19F treatment is also disclosed. Specifically, a novel PRMT5 substrate MCM7 was identified, and interactions between MCM7 methylation and liquid-liquid phase separation (LLPS)[19-21]in TNBC were examined.

[0008] Accordingly, in one aspect, the present disclosure provides compounds of Formula (I):, or pharmaceutically acceptable salts thereof, wherein: A1is CR1or N; each of A2, A3, and A4is independently CH or N; R1is hydrogen or halogen; each of R2aand R2bis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;; R3ais hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, – OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, – OS(=O)2ORA, –OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, –NRAS(=O)ORA, – NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, –NRAS(=O)2SRA, – NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, –OSi(RA)3, –OSi(RA)2ORA, – OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; each of A5, A6, A7, and A8is independently CH or N; and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

[0009] In another aspect, the present disclosure provides compounds of Formula (Iʹ):or a pharmaceutically acceptable salt, wherein: A1is CR1or N; each of A2, A3, and A4is independently CH or N; R1is hydrogen or halogen; each of R2aand R2bis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;R3ais hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, – OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, – OS(=O)2ORA, –OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, –NRAS(=O)ORA, – NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, –NRAS(=O)2SRA, – NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, –OSi(RA)3, –OSi(RA)2ORA, – OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; each of A5, A6, A7, and A8is independently CH or N; and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; provided that the compound of Formula (Iʹ) is not of formula:,or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein. In some embodiments, the pharmaceutical composition comprises an excipient.

[0011] In another aspect, the present disclosure provides methods of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a provided compound or pharmaceutical composition. In certain embodiments, the disease is a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))).

[0012] In another aspect, the present disclosure provides methods of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition. In certain embodiments, the cell, tissue, or biological sample is in vivo. In certain embodiments, the cell, tissue, or biological sample is in vitro. In certain embodiments, the method comprises inhibiting a protein arginine methyltransferase (PRMT) (e.g., PRMT5).

[0013] In another aspect, the present disclosure provides kits comprising a provided compound or pharmaceutical composition disclosed herein and instructions for its use.

[0014] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIGs.1A-1F show characterization of 16-19F binding mode using cryo-EM and surface plasmon resonance. FIG.1A shows chemical structures of 11-2F, 11-9F, and 16-19F. FIGs.1B-1C show the cryo-EM structure of 16-19F binds to PRMT5: SAH complex. FIGs.1D-1F show surface plasmon resonance studies of 16-19F binding to apo-PRMT5:MEP50 (FIG.1D) and SAM- (FIG. 1E), and MTA-bound PRMT5:MEP50 (FIG.1F).

[0016] FIGs.2A-2D show identification of 16-19F cellular properties of MTA-cooperative PRMT5 inhibitors. FIG.2A shows MTAP expression level in multiple cell lines detected by Western Blot. FIG.2B shows cell viability comparison of 11-9F, 16-19F and GSK3326595 under 72 h treatment of MDA-MB-231 cells. FIG.2C shows MDA-MB-231 cells treated for 18 h with 20 µM 16-19F showed stabilization of PRMT5 in cellular thermal shift analysis in whole-cell lysates. The meltingtemperature for PRMT5 was shifted by 3.5°C. FIG 2D shows concentration-dependent inhibition of cellular SDMA substrates after 4 days treatment with 16-19F or DMSO.

[0017] FIGs.3A-3E show that PRMT5 inhibition leads to deregulation of cell cycle and alternative splicing. FIG.3A shows schematics of RNA-seq. FIG.3B shows a volcano plot comparing fold change (x-axis) and p value obtained from DESeq2 analysis (y-axis) of the expressed genes between MDA-MB-231 cell line treated with DMSO and 16-19F (n=3). Dots to the right of the rightmost dotted line indicate significantly upregulated genes, whereas dots to the left of the leftmost dotted line indicate downregulated genes. FIG.3C shows a selection of top canonical pathways found using IPA analysis. Darker and lighter shading represent negative and positive z-score and impact on the pathway, respectively. Threshold indicates pathways with a -log(p-value) > 1.301 were considered significantly regulated. FIG.3D shows gene-set enrichment analysis (GSEA) shows relative levels of expression changes in genes involved in indicated cellular processes. FIG.3E shows rMATS inclusion level differences between 16-19F-treated (6.25 µM, DAY2, DAY4, and DAY8) and DMSO control conditions. ATTS, alternative splicing at transcription factor termination sites; MES, mutually exon skipping; ES, exon skipping; A3, alternative 3’ splicing site; ATSS, alternative splicing at transcription factor starting sites; IR, intron retentions; A5, alternative 5’ splicing site. Statistically significant changes are shown by the top and bottom dots in the DAY8 experiment.

[0018] FIGs.4A-4C show MCM7 is a novel substrate of PRMT5. FIG.4A shows co-IP analysis of the interaction between PRMT5 and di-methylated MCM7 in HEK293T cells with MYC-PRMT5 and HA-MCM7 overexpressed after 48 h PRMT5 inhibition. FIG.4B shows site mutant R219K appeared to be the methylation sites in MCM7. FIG.4C shows a top view of the complex obtained from the third run (after 100 ns simulation). MCM7 N214-T224 is shown at the bottom. The inset shows the interaction between MCM7 residue R219 and PRMT5 residue E435, E444, and S578 at active site.

[0019] FIGs.5A-5C show interactions identified between PRMT5:MEP50 complex and 16-19F by surface plasmon resonance (SPR). Dissociation constant (Kd) of 16-19F under apo- (FIG.5A), SAM (FIG.5B), and MTA (FIG.5C) binding conditions.

[0020] FIGs.6A-6E show cellular activities induced by PRMT5 inhibition ligands. FIGs.6A-6C show cell viability comparison of multiple ligands under 72 h treatment of MDA-MB-231 (FIG.6A), MIA PaCa-2 (FIG.6B), and MDA-MB-435s (FIG.6C) cells. FIG.6D shows MIA PaCa-2 cells treated for 18 h with 20 µM 16-19F showed stabilization of PRMT5 in cellular thermal shift analysis in whole-cell lysates. The melting temperature for PRMT5 was shifted by 1.7°C; FIG.6E shows concentration-dependent inhibition of MIA-PACa-2 after 4 days treatment with 16-19F.

[0021] FIGs.7A-7E show RNA-seq data quality and gene ontology (GO) analysis. FIG.7A shows principal component analysis (PCA). FIG.7B shows Venn diagram of the overlap of differentially expressed genes between different treatment times. FIGs.7C-7E show GO analysis data of the topenrichment pathways in day 2 (FIG.7C), day 4 (FIG.7D), and day 8 (FIG.7E) treatments. Larger boxes indicate more genes within the pathway are involved.

[0022] FIGs.8A-8D show that PRMT5 directly interacts with MCM7. FIG.8A shows Co-IP analysis of the interaction between PRMT5 and MCM7 in HEK293T cells transiently transfected with full-length MYC-PRMT5 and / or HA-MCM7 vector with an anti-MYC or anti-HA antibody. FIG.8B shows the sequence of the evolutionarily conserved residue R219 in MCM7. FIGs.8C-8D show MCM7 peptide (209-228) and PRMT5 substrate pocket docking.

[0023] FIGs.9A-9E show the binding mode refinement process and validation of PRMT5 catalytic domain and MCM7 N214-T224. FIG.9A shows the overall model refinement process. FIG.9B shows the backbone atom RMSDs of PRMT5 P292-L637 from their starting positions was 2.01±0.187 Å among three times running. FIGs.9C-9E show the distances of MCM7 R219-Cƶ towards methyl group of SAM (FIG.9C), PRMT5 E435-Cƛ (FIG.9D), and PRMT5 E444-Cƛ (FIG. 9E) were 5.154±0.951 Å, 8.540±1.596 Å, and 4.953±1.141 Å among three times running measured by cpptraj

[0056] .

[0024] FIG.10 shows the enzymatic activity at 2.5, 0.5, and 0.1 µM for compounds 16-17F, 16-18F, and 16-19F.

[0025] FIGs.11A-11B show1H (FIG.11A) and13C (FIG.11B) NMR spectra for 16-19F.

[0026] FIGs.12A-12B show MCM7 arginine methylation is important for its stress granule localization. FIG.12A shows MDA-MB-231 cells cultured with 20 µM 16-19F 48 h treatments, followed by 0.5 mM NaAsO21h incubation. DAPI was used to stain the nuclear DNA. Anti-G3BP1 and anti-MCM7 were used to detect protein localization. Scale bar = 20 µM. FIG.12B shows 100 of cells in each treatment group were imaged and analyzed for comparison. The number and size of stress granules were analyzed with ImageJ software.

[0027] FIG.13 shows stress granule localization after PRMT5 inhibition. MDA-MB-231 cells cultured with 20 µM GSK3326595 for 48 h treatments, followed by 0.5 mM NaAsO21h incubation. DAPI was used to stain the nuclear DNA. Anti-G3BP1 and anti-MCM7 were used to detect protein localization. Scale bar = 20 µM. DEFINITIONS

[0028] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed.1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0029] 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.

[0030] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. The term “isomers” is intended to include diastereoisomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like. All such isomers of such compounds herein are expressly included in the present invention.

[0031] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C1-6alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0032] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0033] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbonatoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1–6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n- heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1–12alkyl (such as unsubstituted C1–6 alkyl, e.g., −CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, – CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).

[0034] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1–20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1–10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1–9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1–8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1–7 haloalkyl”).In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1–6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1–4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1–3haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1–2haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0035] 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 theparent 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 (“heteroC1–20alkyl”). 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 (“heteroC1–12alkyl”). 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 (“heteroC1–11alkyl”). 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 (“heteroC1–10alkyl”). 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 (“heteroC1–9 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 (“heteroC1–8 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 (“heteroC1–7 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 (“heteroC1–6 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 (“heteroC1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 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 (“heteroC2-6 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 heteroC1–12alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12alkyl.

[0036] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 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 2 to 20 carbon atoms (“C2-20alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2–12alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C2–11alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5alkenyl”). In some embodiments, an alkenyl grouphas 2 to 4 carbon atoms (“C2–4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). 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 C2–4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2–6 alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-20 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3 ormay be in the (E)- or (Z)-configuration.

[0037] 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 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–20alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–12alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–11alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–10alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–9alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–8alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–7alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–6alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2–5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2–4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2–3 alkenyl”). In someembodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2–6alkenyl”). 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 heteroC2–20alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2–20alkenyl.

[0038] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 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 C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 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 C2-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-20 alkynyl.

[0039] 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 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2–20alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2–10alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2–9alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2–8alkynyl”). In some embodiments, a heteroalkynylgroup has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2–7alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2–6alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2–5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2–4alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2–3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2–6 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 heteroC2–20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2–20 alkynyl.

[0040] 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 (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-6carbocyclyl 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 C3-10carbocyclyl groups include the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10),spiro[4.5]decanyl (C10), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-10carbocyclyl 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.

[0041] 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 (C5). 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 C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0042] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). 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 cancontain 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.

[0043] 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 1–4 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.

[0044] 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, pyrrolidinyl, 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-memberedheterocyclyl 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, 1H-benzo[e][1,4]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-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo- [2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0045] 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 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 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.

[0046] “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.

[0047] 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 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). 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 ringmembers 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.

[0048] 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.

[0049] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, 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 andtetrazinyl, 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.

[0050] “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.

[0051] The term “unsaturated bond” refers to a double or triple bond.

[0052] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0053] 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.

[0054] 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.

[0055] 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 “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.

[0056] 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), C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; wherein: each instance of Raais, independently, selected from C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 memberedheterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3- 14 membered heterocyclyl, C6-14aryl, 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, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 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 =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1– 10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3- 10 membered heterocyclyl, and 3-10 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; each instance of Rffis, independently, selected from hydrogen, C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, 3- 10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6alkyl, −ON(C1–6alkyl)2, −N(C1–6alkyl)2, −N(C1–6alkyl)3+X−, −NH(C1–6alkyl)2+X−, −NH2(C1–6alkyl)+X−, −NH3+X−, −N(OC1–6alkyl)(C1–6alkyl), −N(OH)(C1–6alkyl), −NH(OH), −SH, −SC1–6alkyl, −SS(C1–6alkyl), −C(=O)(C1–6alkyl), −CO2H, −CO2(C1–6alkyl), −OC(=O)(C1–6alkyl), −OCO2(C1–6alkyl), −C(=O)NH2, −C(=O)N(C1–6alkyl)2, −OC(=O)NH(C1–6alkyl), −NHC(=O)( C1–6alkyl), −N(C1–6alkyl)C(=O)( C1–6alkyl), −NHCO2(C1–6alkyl), −NHC(=O)N(C1–6alkyl)2, −NHC(=O)NH(C1–6alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6alkyl), −OC(=NH)(C1–6alkyl), −OC(=NH)OC1–6alkyl, −C(=NH)N(C1–6alkyl)2, −C(=NH)NH(C1–6alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6alkyl)2, −OC(NH)NH(C1–6 alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6 alkyl), −SO2N(C1–6alkyl)2, −SO2NH(C1–6alkyl), −SO2NH2, −SO2C1–6alkyl, −SO2OC1–6alkyl, −OSO2C1–6alkyl, −SOC1–6alkyl, −Si(C1–6alkyl)3, −OSi(C1–6alkyl)3−C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6 alkyl), C(=S)NH2, −C(=O)S(C1–6 alkyl), −C(=S)SC1–6 alkyl, −SC(=S)SC1–6 alkyl, −P(=O)(OC1–6 alkyl)2, −P(=O)(C1–6 alkyl)2, −OP(=O)(C1–6 alkyl)2, −OP(=O)(OC1–6 alkyl)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; and each X−is a counterion.

[0057] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 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. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 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 C1–10 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 C1–10 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 C1-6alkyl, −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 C1–10alkyl, −ORaa, −SRaa, −N(Rbb)2, – CN, –SCN, or –NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, 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 C1–10alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0058] In certain embodiments, the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0059] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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, and −NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0064] 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.

[0065] 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.

[0066] The term “sulfonyl” refers to a group selected from –SO2N(Rbb)2, –SO2Raa, and –SO2ORaa, wherein Raaand Rbbare as defined herein.

[0067] The term “sulfinyl” refers to the group –S(=O)Raa, wherein Raais as defined herein.

[0068] The term “acyl” refers to a group having the general formula −C(=O)RX1, −C(=O)ORX1, −C(=O)−O−C(=O)RX1, −C(=O)SRX1, −C(=O)N(RX1)2, −C(=S)RX1, −C(=S)N(RX1)2, and −C(=S)S(RX1), −C(=NRX1)RX1, −C(=NRX1)ORX1, −C(=NRX1)SRX1, and −C(=NRX1)N(RX1)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0069] 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.

[0070] The term “silyl” refers to the group –Si(Raa)3, wherein Raais as defined herein.

[0071] The term “phosphino” refers to the group –P(Rcc)2, wherein Rccis as defined herein.

[0072] The term “phosphono” refers to the group – (P=O)(ORcc)2, wherein Raaand Rccare as defined herein.

[0073] The term “phosphoramido” refers to the group –O(P=O)(N(Rbb)2)2, wherein each Rbbis as defined herein.

[0074] The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S.

[0075] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRbb)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, hetero C1–20 alkyl, hetero C1–20 alkenyl, hetero C1– 20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0076] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 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 C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 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 C1-10 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 C1-6alkyl or a nitrogen protecting group.

[0077] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1–10alkyl (e.g., aralkyl, heteroaralkyl), C1–20alkenyl, C1–20alkynyl, hetero C1–20alkyl, hetero C1–20alkenyl, hetero C1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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.

[0078] 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, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0079] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that includes 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 carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl 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-(1,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, 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, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N- 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-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1- phenylethyl carbamate, 1-methyl-1-(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.

[0080] 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- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0081] 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, N’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo- 3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9- fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’-oxide, N-1,1- dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N- diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’,N’- dimethylaminomethylene)amine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N- diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-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 N,N’-isopropylidenediamine.

[0082] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0083] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 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 C1-10 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 C1-6alkyl or an oxygen protecting group.

[0084] 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.

[0085] 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 methyl, methoxymethyl (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-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(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-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1- methoxyethyl, 1-methyl-1-benzyloxyethyl, 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 N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-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 (IETr-OR), 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9- anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl 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, methoxyacetate, triphenylmethoxyacetate, 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-1-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-(1,1,3,3- tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0086] 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.

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

[0088] 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, −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.

[0089] 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, asubstituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0090] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−,HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5– sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−, B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0091] A “leaving group” (LG) is an art-understood term referring to an atomic or molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6th ed. (501–502). Exemplary leaving groups include, but are not limited to, halo (e.g., fluoro, chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., –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, – OP(Rcc)2, –OP(Rcc)3, –OP(=O)2Raa, –OP(=O)(Raa)2, –OP(=O)(ORcc)2, –OP(=O)2N(Rbb)2, and – OP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein). Additional examples of suitable leaving groups include, but are not limited to, halogen alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some embodiments, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, –OTs), methanesulfonate (mesylate, –OMs), p-bromobenzenesulfonyloxy (brosylate, –OBs), –OS(=O)2(CF2)3CF3(nonaflate, –ONf), or trifluoromethanesulfonate (triflate, –OTf). In some embodiments, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some embodiments, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia,alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0092] 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.

[0093] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0094] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not limited in any manner by the above exemplary listing of substituents.

[0095] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. The term “salt” refers to 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 disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

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

[0097] 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.

[0098] 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)).

[0099] 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.

[0100] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound 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 and an acid is different from a salt formed from a compound and the acid. In the salt, a compound is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound easily occurs at room temperature. In the co-crystal, however, a compound is complexed with the acid in a way that proton transfer from the acid to a herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is substantially no proton transfer from the acid to a compound. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound.

[0101] 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.

[0102] 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.”

[0103] 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.”

[0104] The term “isotopically labeled compound” refers to a derivative of a compound that only structurally differs from the compound in that at least one atom of the derivative includes at least one isotope enriched above (e.g., enriched 3-, 10-, 30-, 100-, 300-, 1,000-, 3,000- or 10,000-fold above) its natural abundance, whereas each atom of the compound includes isotopes at their natural abundances. In certain embodiments, the isotope enriched above its natural abundance is2H. In certain embodiments, the isotope enriched above its natural abundance is13C,15N, or18O.

[0105] 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 choline ester derivatives 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, Bundgaard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include, 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.

[0106] The terms “pharmaceutical composition,” “composition,” and “formulation” are used interchangeably.

[0107] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non- human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0108] 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.

[0109] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, in or on a subject.

[0110] 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.

[0111] 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. In some embodiments, the subject is at risk of developing a disease or condition due to environmental factors (e.g., exposure to the sun).

[0112] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, 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).

[0113] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0114] 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.

[0115] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease or disorder associated with a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, a therapeutically effective amount is an amount effective for treating a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting a protein arginine methyltransferase (PRMT) (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%). In certain embodiments, the PRMT is PRMT5.

[0116] A “prophylactically effective amount” of a compound is an amount sufficient to prevent a condition, or one or more signs and / or symptoms associated with the condition or prevent its recurrence. In certain embodiments, the prophylactically effective amount is an amount that improves overall prophylaxis and / or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount effective for preventing a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer,melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, a prophylactically effective amount is an amount effective for reducing the risk of developing a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, a prophylactically effective amount is an amount effective for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, a prophylactically effective amount is an amount effective for inhibiting a protein arginine methyltransferase (PRMT) (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%). In certain embodiments, the PRMT is PRMT5.

[0117] As used herein the term “inhibit” or “inhibition” in the context of enzymes, for example, in the context of PRMT5, refers to a reduction in the activity of the enzyme. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., PRMT5 activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., PRMT5 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.

[0118] 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., uterinecancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non- Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T- cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors);penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0119] 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.

[0120] 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.

[0121] 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 oforigin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these 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.

[0122] The term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in 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, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0123] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, 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 polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardiomyopathy. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0124] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting. Compounds

[0125] In one aspect, the present disclosure provides a compound of Formula (I):or pharmaceutically acceptable salts thereof, wherein: A1is CR1or N; each of A2, A3, and A4is independently CH or N; R1is hydrogen or halogen; each of R2aand R2bis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;R3ais hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, – OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, –OS(=O)2ORA, –OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, –NRAS(=O)ORA, – NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, –NRAS(=O)2SRA, – NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, –OSi(RA)3, –OSi(RA)2ORA, – OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; each of A5, A6, A7, and A8is independently CH or N; and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

[0126] In another aspect, the present disclosure provides a compound of Formula (Iʹ):, or a pharmaceutically acceptable salt thereof, wherein: A1is CR1or N; each of A2, A3, and A4is independently CH or N; R1is hydrogen or halogen; each of R2aand R2bis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;R3ais hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, – OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, – OS(=O)2ORA, –OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, –NRAS(=O)ORA, – NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, –NRAS(=O)2SRA, – NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, –OSi(RA)3, –OSi(RA)2ORA, – OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; each of A5, A6, A7, and A8is independently CH or N; and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; provided that the compound of Formula (Iʹ) is not of formula:. A1, A2, A3, A4, and R1

[0127] In certain embodiments, A1is CR1or N, each of A2, A3, and A4is independently CH or N, and R1is hydrogen or halogen.

[0128] In certain embodiments, A1is CR1and R1is hydrogen. In certain embodiments, A1is CR1and R1is halogen. In certain embodiments, A1is CR1and R1is –F, –Cl, –Br, or –I. In certain embodiments, A1is CR1and R1is –F. In certain embodiments, A1is CR1and R1is –Cl. In certain embodiments, A1is CR1and R1is –Br. In certain embodiments, A1is CR1and R1is –I. In certain embodiments, A1is N. In certain embodiments, A2is CH. In certain embodiments, A2is N. In certain embodiments, A3is CH. In certain embodiments, A3is N. In certain embodiments, A4is CH. In certain embodiments, A4is N. In certain embodiments, at least one of A2, A3, and A4is CH. In certain embodiments, each of A2and A3is CH. In certain embodiments, each of A3and A4is CH. In certain embodiments, at least one of A2, A3, and A4is N. In certain embodiments, each of A2, A3, and A4is CH.

[0129] In certain embodiments, A1is CR1, R1is hydrogen, and at least one of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is halogen, and at least one of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is –F, –Cl, –Br, or –I, and at least one of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is –F, and at least one of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is –Cl, and at least one of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is –Br, and at least one of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is –I, and at least one of A2, A3, and A4is CH. In certain embodiments, A1is N, and at least one of A2, A3, and A4is CH.

[0130] In certain embodiments, A1is CR1, R1is hydrogen, and each of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is halogen, and each of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is –F, –Cl, –Br, or –I, and each of A2, A3, and A4is CH. In certainembodiments, A1is CR1and R1is –F, and each of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is –Cl, and each of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is –Br, and each of A2, A3, and A4is CH. In certain embodiments, A1is CR1and R1is –I, and each of A2, A3, and A4is CH. In certain embodiments, A1is N, and each of A2, A3, and A4is CH.

[0131] In certain embodiments, A1is CR1, R1is hydrogen, and at least one of A2, A3, and A4is N. In certain embodiments, A1is CR1and R1is halogen, and at least one of A2, A3, and A4is N. In certain embodiments, A1is CR1and R1is –F, –Cl, –Br, or –I, and at least one of A2, A3, and A4is N. In certain embodiments, A1is CR1and R1is –F, and at least one of A2, A3, and A4is N. In certain embodiments, A1is CR1and R1is –Cl, and at least one of A2, A3, and A4is N. In certain embodiments, A1is CR1and R1is –Br, and at least one of A2, A3, and A4is N. In certain embodiments, A1is CR1and R1is –I, and at least one of A2, A3, and A4is N. In certain embodiments, A1is N, and at least one of A2, A3, and A4is N.

[0132] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formula (I-a):, or a pharmaceutically acceptable salt thereof.

[0133] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formula (I-b) or Formula (I-c):, or a pharmaceutically acceptable salt thereof.

[0134] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formula (I-b-i) or Formula (I-c-i):, or a pharmaceutically acceptable salt thereof. R2aand R2b

[0135] In certain embodiments, each of R2aand R2bis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

[0136] In certain embodiments, at least one of R2aand R2bis hydrogen. In certain embodiments, at least one of R2aand R2bis optionally substituted acyl. In certain embodiments, at least one of R2aand R2bis optionally substituted alkyl. In certain embodiments, at least one of R2aand R2bis optionally substituted alkenyl. In certain embodiments, at least one of R2aand R2bis optionally substituted alkynyl. In certain embodiments, at least one of R2aand R2bis optionally substituted heteroalkyl. In certain embodiments, at least one of R2aand R2bis optionally substituted heteroalkenyl. In certain embodiments, at least one of R2aand R2bis optionally substituted heteroalkynyl. In certain embodiments, at least one of R2aand R2bis optionally substituted carbocyclyl. In certain embodiments, at least one of R2aand R2bis optionally substituted heterocyclyl. In certain embodiments, at least one of R2aand R2bis optionally substituted aryl. In certain embodiments, at least one of R2aand R2bis optionally substituted heteroaryl. In certain embodiments, at least one of R2aand R2bis a nitrogen protecting group. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

[0137] In certain embodiments, each of R2aand R2bis independently hydrogen or optionally substituted alkyl, or R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring. In certain embodiments, each of R2aand R2bis independently hydrogen or optionally substituted alkyl, or R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring. In certain embodiments, each of R2aand R2bis independently hydrogen or optionally substituted alkyl. In certain embodiments, at least one of R2aand R2bis hydrogen. In certain embodiments, each of R2aand R2bis hydrogen. In certain embodiments, neither of R2aand R2bis hydrogen.

[0138] In certain embodiments, at least one of R2aand R2bis optionally substituted alkyl. In certain embodiments, at least one of R2aand R2bis optionally substituted C1-12alkyl. In certain embodiments, at least one of R2aand R2bis optionally substituted C1-6alkyl. In certain embodiments, at least one of R2aand R2bis unsubstituted C1-6alkyl. In certain embodiments, at least one of R2aand R2bis substituted C1-6alkyl. In certain embodiments, at least one of R2aand R2bis optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2-butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In certain embodiments, at least one of R2aand R2bis optionally substituted methyl. In certain embodiments, at least one of R2aand R2bis substituted methyl. In certain embodiments, at least one of R2aand R2bis unsubstituted methyl. In certain embodiments, at least one of R2aand R2bis optionally substituted ethyl. In certain embodiments, at least one of R2aand R2bis optionally substituted isopropyl. In certain embodiments, at least one of R2aand R2bis optionally substituted tert-butyl. In certain embodiments, at least one of R2aand R2bis methyl, ethyl, isopropyl, or tert-butyl. In certain embodiments, at least one of R2aand R2bis methyl.

[0139] In certain embodiments, each of R2aand R2bis optionally substituted alkyl. In certain embodiments, each of R2aand R2bis optionally substituted C1-12 alkyl. In certain embodiments, each of R2aand R2bis optionally substituted C1-6 alkyl. In certain embodiments, each of R2aand R2bis unsubstituted C1-6 alkyl. In certain embodiments, each of R2aand R2bis substituted C1-6 alkyl. In certain embodiments, each of R2aand R2bis optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2-butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In certain embodiments, each of R2aand R2bis optionally substituted methyl. In certain embodiments, each of R2aand R2bis substituted methyl. In certain embodiments, each of R2aand R2bis unsubstituted methyl. In certain embodiments, each of R2aand R2bis methyl, ethyl, isopropyl, or tert-butyl. In certain embodiments, each of R2aand R2bis methyl.

[0140] In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis optionally substituted alkyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis optionally substituted C1-12 alkyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis optionally substituted C1-6 alkyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis unsubstituted C1-6 alkyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis substituted C1-6 alkyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2-butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis optionally substituted methyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis substituted methyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis unsubstituted methyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis optionally substituted ethyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis optionally substituted isopropyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis optionally substituted tert- butyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis methyl, ethyl, isopropyl, or tert-butyl. In certain embodiments, one of R2aand R2bis hydrogen, and one of R2aand R2bis methyl.

[0141] In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted, monocyclic heterocyclyl (e.g., optionally substituted, monocyclic, 3- to 10-membered heterocyclyl). In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted, polycyclic heterocyclyl (e.g., optionally substituted, bicyclic or tricyclic, 3- to 14-membered heterocyclyl). In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted saturated heterocyclyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form a substituted saturated heterocyclyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an unsubstituted saturated heterocyclyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted azirdinyl, optionally substituted azetidinyl, optionally substituted oxazetidinyl, optionally substituted pyrrolidinyl, optionally substituted dihydropyrrolyl, optionally substituted pyrrolyl-2,5-dione, optionally substituted imidazolidin-2-onyl, optionally substituted piperidinyl, optionally substituted dihydropyridinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted azepanyl, optionally substituted azocanyl, optionally substituted indolinyl, optionally substituted isoindolinyl, optionally substituted tetrahydroindolyl, optionally substituted tetrahydroquinolinyl, optionally substituted tetrahydroisoquinolinyl, optionally substituted decahydroquinolinyl, optionally substituted decahydroisoquinolinyl, optionally substituted decahydronaphthyridinyl, or optionally substituted decahydro-1,8-naphthyridinyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted aziridinyl, optionally substituted azetidinyl, optionally substituted oxazetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, or optionally substituted morpholinyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted aziridinyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted azetidinyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted oxazetidinyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted pyrrolidinyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substitutedpiperidinyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted morpholinyl.

[0142] In certain embodiments,In certain embodiments,. In certain embodiments,. certain embodiments,. certain embodiments,. certain embodiments,. In certain embodiments,s .

[0143] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formulae (I-b-ii) to (I-b- iv):or a pharmaceutically acceptable salt thereof.

[0144] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formulae (I-c-ii) to (I-c-or a pharmaceutically acceptable salt thereof.

[0145] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formulae (I-b-v) to (I-b- x):or a pharmaceutically acceptable salt thereof.

[0146] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formulae (I-c-v) to (I-c-x):),, or a pharmaceutically acceptable salt thereof. R3, A5, A6, A7, A8, and R3a

[0147] In certain embodiments, the compound is of any of the formulae herein, wherein R3iswherein R3ais hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, – OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, – OS(=O)2ORA, –OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, –NRAS(=O)ORA, – NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, –NRAS(=O)2SRA, – NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, –OSi(RA)3, –OSi(RA)2ORA, – OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; and each of A5, A6, A7, and A8is independently CH or N.

[0148] In certain embodiments, the compound is of any of the formulae herein, wherein R3iscertain embodiments, the compound is of any of the formulae herein, wherein. In certain embodiments, the compound is of any of the formulae herein, wherein R3isIn certain embodiments, the compound is of any of the formulae herein, wherein R3. In certain embodiments, the compound is of any of the formulae herein, whereinR3is . In certain embodiments, the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is orO . In certain embodiments, the compound is of any of the formulae herein, wherein R3is . In certain embodiments, the compound is of any of the formulae herein,wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is

[0149] In certain embodiments, A5is CH. In certain embodiments, A5is N. In certain embodiments, A6is CH. In certain embodiments, A6is N. In certain embodiments, A7is CH. In certain embodiments, A7is N. In certain embodiments, A8is CH. In certain embodiments, A8is N.

[0150] In certain embodiments, at least one of A5, A6, and A7is CH. In certain embodiments, each of A5and A6is CH. In certain embodiments, each of A6and A7is CH. In certain embodiments, each of A5, A6, and A7is CH. In certain embodiments, at least one of A5, A6, and A7is N. In certain embodiments, at least one of A5, A6, and A7is CH, and at least one of A5, A6, and A7is N. In certain embodiments, at least one of A5, A6, and A8is CH. In certain embodiments, each of A5and A6is CH. In certain embodiments, each of A6and A8is CH. In certain embodiments, each of A5, A6, and A8is CH. In certain embodiments, at least one of A5, A6, and A8is N. In certain embodiments, at least one of A5, A6, and A8is CH, and at least one of A5, A6, and A8is N.

[0151] In certain embodiments, the compound is of any of the formulae herein, wherein R3is, and at least one of A5, A6, and A7is CH. In certain embodiments, the compound is of any of the formulae herein, wherein R3is , or, and each of A5, A6, and A7is CH. In certain embodiments, the compound is of any of the formulae herein, wherein R3is , , , , and at least one of A5, A6, and A8is CH. In certainembodiments, the compound is of any of the formulae herein, wherein R3is, , , o , and each of A5, A6, and A8is CH.

[0152] In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , or . In certain embodiments, the compound is of any of the formulae herein, wherein R3is, . In certain embodiments,the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is not.In certain embodiments, the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is , or. In certain embodiments, the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3is. In certain embodiments, the compound is of any of the formulae herein, wherein R3. In certain embodiments, the compound is of any of the formulae herein, wherein R3is

[0153] In certain embodiments, R3ais hydrogen. In certain embodiments, R3ais halogen. In certain embodiments, R3ais optionally substituted alkyl. In certain embodiments, R3ais optionally substituted alkenyl. In certain embodiments, R3ais optionally substituted alkynyl. In certain embodiments, R3ais optionally substituted heteroalkyl. In certain embodiments, R3ais optionally substituted heteroalkenyl.In certain embodiments, R3ais optionally substituted heteroalkynyl. In certain embodiments, R3ais optionally substituted carbocyclyl. In certain embodiments, R3ais optionally substituted heterocyclyl. In certain embodiments, R3ais optionally substituted aryl. In certain embodiments, R3ais optionally substituted heteroaryl. In certain embodiments, R3ais –CN. In certain embodiments, R3ais –ORA. In certain embodiments, R3ais –SCN. In certain embodiments, R3ais –SRA. In certain embodiments, R3ais –SSRA. In certain embodiments, R3ais –N3. In certain embodiments, R3ais –NO. In certain embodiments, R3ais –N(RA)2. In certain embodiments, R3ais –NO2. In certain embodiments, R3ais – C(=O)RA. In certain embodiments, R3ais –C(=O)ORA. In certain embodiments, R3ais –C(=O)SRA. In certain embodiments, R3ais –C(=O)N(RA)2. In certain embodiments, R3ais –C(=NRA)RA. In certain embodiments, R3ais –C(=NRA)ORA. In certain embodiments, R3ais –C(=NRA)SRA. In certain embodiments, R3ais –C(=NRA)N(RA)2. In certain embodiments, R3ais –S(=O)RA. In certain embodiments, R3ais –S(=O)ORA. In certain embodiments, R3ais –S(=O)SRA. In certain embodiments, R3ais –S(=O)N(RA)2. In certain embodiments, R3ais –S(=O)2RA. In certain embodiments, R3ais – S(=O)2ORA. In certain embodiments, R3ais –S(=O)2SRA. In certain embodiments, R3ais – S(=O)2N(RA)2. In certain embodiments, R3ais –OC(=O)RA. In certain embodiments, R3ais – OC(=O)ORA. In certain embodiments, R3ais –OC(=O)SRA. In certain embodiments, R3ais – OC(=O)N(RA)2. In certain embodiments, R3ais –OC(=NRA)RA. In certain embodiments, R3ais – OC(=NRA)ORA. In certain embodiments, R3ais –OC(=NRA)SRA. In certain embodiments, R3ais – OC(=NRA)N(RA)2. In certain embodiments, R3ais –OS(=O)RA. In certain embodiments, R3ais – OS(=O)ORA. In certain embodiments, R3ais –OS(=O)SRA. In certain embodiments, R3ais – OS(=O)N(RA)2. In certain embodiments, R3ais –OS(=O)2RA. In certain embodiments, R3ais – OS(=O)2ORA. In certain embodiments, R3ais –OS(=O)2SRA. In certain embodiments, R3ais – OS(=O)2N(RA)2. In certain embodiments, R3ais –ON(RA)2. In certain embodiments, R3ais – SC(=O)RA. In certain embodiments, R3ais –SC(=O)ORA. In certain embodiments, R3ais – SC(=O)SRA. In certain embodiments, R3ais –SC(=O)N(RA)2. In certain embodiments, R3ais – SC(=NRA)RA. In certain embodiments, R3ais –SC(=NRA)ORA. In certain embodiments, R3ais – SC(=NRA)SRA. In certain embodiments, R3ais –SC(=NRA)N(RA)2. In certain embodiments, R3ais – NRAC(=O)RA. In certain embodiments, R3ais –NRAC(=O)ORA. In certain embodiments, R3ais – NRAC(=O)SRA. In certain embodiments, R3ais –NRAC(=O)N(RA)2. In certain embodiments, R3ais – NRAC(=NRA)RA. In certain embodiments, R3ais –NRAC(=NRA)ORA. In certain embodiments, R3ais – NRAC(=NRA)SRA. In certain embodiments, R3ais –NRAC(=NRA)N(RA)2. In certain embodiments, R3ais –NRAS(=O)RA. In certain embodiments, R3ais –NRAS(=O)ORA. In certain embodiments, R3ais – NRAS(=O)SRA. In certain embodiments, R3ais –NRAS(=O)N(RA)2. In certain embodiments, R3ais – NRAS(=O)2RA. In certain embodiments, R3ais –NRAS(=O)2ORA. In certain embodiments, R3ais – NRAS(=O)2SRA. In certain embodiments, R3ais –NRAS(=O)2N(RA)2. In certain embodiments, R3ais – Si(RA)3. In certain embodiments, R3ais –Si(RA)2ORA. In certain embodiments, R3ais –Si(RA)(ORA)2. In certain embodiments, R3ais –Si(ORA)3. In certain embodiments, R3ais –OSi(RA)3. In certainembodiments, R3ais –OSi(RA)2ORA. In certain embodiments, R3ais –OSi(RA)(ORA)2. In certain embodiments, R3ais –OSi(ORA)3. In certain embodiments, R3ais –B(ORA)2.

[0154] In certain embodiments, R3ais halogen, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA,–N(RA)2, –C(=O)N(RA)2,–S(=O)2N(RA)2, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, or –NRAS(=O)2N(RA)2. In certain embodiments, R3ais optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA,–N(RA)2, –C(=O)N(RA)2,–S(=O)2N(RA)2, – NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, or –NRAS(=O)2N(RA)2. In certain embodiments, R3ais optionally substituted aryl, optionally substituted heteroaryl, –C(=O)N(RA)2,–S(=O)2N(RA)2, – NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, or –NRAS(=O)2N(RA)2. In certain embodiments, R3ais – C(=O)NH2,–S(=O)2NH2, –NHC(=O)NH2, –NHC(=NH)NH2, or –NHS(=O)2NH2.

[0155] In certain embodiments, R3ais halogen, –CN, –ORA, or –N(RA)2. In certain embodiments, R3ais –F, –Cl, –Br, –I, –CN, –ORA, or –N(RA)2. In certain embodiments, R3ais –F, –Cl, –Br, –I, –CN, – OH, or –NH2. In certain embodiments, R3ais –F, –Br, –I, –CN, –OH, or –NH2.In certain embodiments, R3ais –F, –Br, –I, –CN, –ORA, or –N(RA)2. In certain embodiments, R3ais –CN, –ORA, or –N(RA)2.

[0156] In certain embodiments, R3ais halogen. In certain embodiments, R3ais not halogen. In certain embodiments, R3ais –F, –Cl, –Br, or –I. In certain embodiments, R3ais –F, –Br, or –I. In certain embodiments, R3ais not –Cl. In certain embodiments, R3ais –CN. In certain embodiments, R3ais – ORA. In certain embodiments, R3ais –ORA, and RAis hydrogen, optionally substituted acyl, optionally substituted alkyl, or an oxygen protecting group. In certain embodiments, R3ais –ORA, and RAis hydrogen. In certain embodiments, R3ais –ORA, and RAis optionally substituted acyl. In certain embodiments, R3ais –ORA, and RAis optionally substituted alkyl. In certain embodiments, R3ais – ORA, and RAis an oxygen protecting group. In certain embodiments, R3ais –OH. In certain embodiments, R3ais –N(RA)2. In certain embodiments, R3ais –N(RA)2, and at least one occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais –N(RA)2, and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais –N(RA)2, and at least one occurrence of RAis hydrogen. In certain embodiments, R3ais –N(RA)2, and at least one occurrence of RAis optionally substituted acyl. In certain embodiments, R3ais –N(RA)2, and at least one occurrence of RAis optionally substituted alkyl. In certain embodiments, R3ais –N(RA)2, and at least one occurrence of RAis a nitrogen protecting group. In certain embodiments, R3ais –NH2.

[0157] In certain embodiments, R3ais optionally substituted aryl. In certain embodiments, R3ais optionally substituted phenyl. In certain embodiments, R3ais optionally substituted heteroaryl. In certain embodiments, R3ais optionally substituted 5-6 membered heteroaryl.

[0158] In certain embodiments, R3ais –C(=O)N(RA)2. In certain embodiments, R3ais –C(=O)N(RA)2, and at least one occurrence of RAis independently hydrogen, optionally substituted acyl, optionallysubstituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais –C(=O)N(RA)2, and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais –C(=O)N(RA)2, and at least one occurrence of RAis hydrogen. In certain embodiments, R3ais –C(=O)NH2.

[0159] In certain embodiments, R3ais –S(=O)2N(RA)2. In certain embodiments, R3ais – S(=O)2N(RA)2, and at least one occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais – S(=O)2N(RA)2, and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais – S(=O)2N(RA)2, and at least one occurrence of RAis hydrogen. In certain embodiments, R3ais – S(=O)2NH2.

[0160] In certain embodiments, R3ais –NRAC(=O)N(RA)2. In certain embodiments, R3ais – NRAC(=O)N(RA)2, and at least one occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais –NRAC(=O)N(RA)2, and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais –NRAC(=O)N(RA)2, and at least one occurrence of RAis hydrogen. In certain embodiments, R3ais –NHC(=O)NH2.

[0161] In certain embodiments, R3ais –NRAC(=NRA)N(RA)2. In certain embodiments, R3ais – NRAC(=NRA)N(RA)2, and at least one occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais –NRAC(=NRA)N(RA)2, and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais –NRAC(=NRA)N(RA)2, and at least one occurrence of RAis hydrogen. In certain embodiments, R3ais –NHC(=NH)NH2.

[0162] In certain embodiments, R3ais –NRAS(=O)2N(RA)2. In certain embodiments, R3ais – NRAS(=O)2N(RA)2, and at least one occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais –NRAS(=O)2N(RA)2, and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R3ais –NRAS(=O)2N(RA)2, and at least one occurrence of RAis hydrogen. In certain embodiments, R3ais –NHS(=O)2NH2.

[0163] In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , ,, , , , , and R3ais halogen, –CN, –ORA, or –N(RA)2. In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , ,, and R3ais –CN, –ORA, or –N(RA)2. In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , ,, and R3ais –F, –Cl, –Br, –I, –CN, –ORA, or –N(RA)2. In certain embodiments, the compound is of any of the formulae herein, wherein R3is, ,, , , , ,, , or , and R3ais –F, –Cl, –Br, –I, –CN, –OH, or –NH2. In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , o , and R3ais –F, –Br, – I, –CN, –ORA, or –N(RA)2. In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , ,, , , , , and R3ais –F, –Br, –I, –CN, –OH, or –NH2.

[0164] In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , or , and R3ais halogen, –CN, –ORA, or –N(RA)2. In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , or, and R3ais –CN, –ORA, or –N(RA)2. In certain embodiments, the compound is ofany of the formulae herein, wherein,certain embodiments, the compound is of any of the formulae herein, wherein,, –CN, –OH, or –NH2. In certain embodiments, the compound is of any of the formulae herein, whereinR3ais –F, –Br, –I, –CN, –ORA, or –N(RA)2. In certain embodiments, the compound is of any of the formulae herein, wherein,

[0165] In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , o , and R3ais halogen, –CN, –ORA, or –N(RA)2. In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , or, and R3ais –CN, –ORA, or –N(RA)2. In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , and R3ais –F, –Cl, –Br, –I, –CN, –ORA, or –N(RA)2. Incertain embodiments, the compound is of any of the formulae herein, wherein R3is, , , or , and R3ais –F, –Cl, –Br, –I, –CN, –OH, or –NH2. In certain embodiments, the compound is of any of the formulae herein, wherein R3is, , , , or and R3ais –F, –Br, –I, –CN, –ORA, or –N(RA)2. In certain embodiments, thecompound is of any of the formulae herein, wherein R3is, a3and R is –F, –Br, –I, –CN, –OH, or – NH2. RA

[0166] In certain embodiments, each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring. In certain embodiments, at least one occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring. In certain embodiments, at least one occurrence of RAis hydrogen. In certain embodiments, at least one occurrence of RAis optionally substituted acyl. In certain embodiments, at least one occurrence of RAis optionally substituted C1-12 alkyl. In certain embodiments, at least one occurrence of RAis optionally substituted C1-6 alkyl. In certain embodiments, at least one occurrence of RAis unsubstituted C1-6 alkyl. In certain embodiments, at least one occurrence of RAis substituted C1-6 alkyl. In certain embodiments, at least one occurrence of RAis optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2- butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In certain embodiments, at least one occurrence of RAis optionally substituted C2-12 alkenyl. In certain embodiments, at least one occurrence of RAis optionally substituted C2-6 alkenyl. In certain embodiments, at least one occurrence of RAis optionally substituted ethenyl, optionally substituted 1–propenyl, optionally substituted 2–propenyl, optionally substituted 1–butenyl, optionally substituted 2–butenyl, optionally substituted butadienyl, optionally substituted pentenyl, optionally substituted pentadienyl, or optionally substituted hexenyl. In certain embodiments, at least one occurrence of RAis optionally substituted C2-12alkynyl. In certain embodiments, at least one occurrence of RAis optionally substituted C2-6alkynyl. In certain embodiments, at least one occurrence of RAis optionally substituted ethynyl, optionally substituted 1–propynyl, optionally substituted 2–propynyl, optionally substituted 1–butynyl, optionally substituted 2–butynyl, optionally substituted pentynyl, or optionally substituted hexynyl. In certain embodiments, at least one occurrence of RAis optionally substituted heteroC1–12alkyl. In certain embodiments, at least one occurrence of RAis optionally substituted heteroC1–6alkyl. In certain embodiments, at least one occurrence of RAis optionally substituted heteroC1–12alkenyl. In certain embodiments, at least one occurrence of RAis optionally substitutedheteroC1–6alkenyl. In certain embodiments, at least one occurrence of RAis optionally substituted heteroC1–12alkynyl. In certain embodiments, at least one occurrence of RAis optionally substituted heteroC1–6alkynyl. In certain embodiments, at least one occurrence of RAis optionally substituted C3–14cycloalkyl. In certain embodiments, at least one occurrence of RAis optionally substituted 5–10 membered heterocyclyl. In certain embodiments, at least one occurrence of RAis optionally substituted 6–14 membered aryl. In certain embodiments, at least one occurrence of RAis optionally substituted 5–14 membered heteroaryl. In certain embodiments, at least one occurrence of RAis a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one occurrence of RAis an oxygen protecting group when attached to an oxygen atom. In certain embodiments, at least one occurrence of RAis a sulfur protecting group when attached to a sulfur atom. In certain embodiments, at least two occurrences of RAare joined together with their intervening atom to form an optionally substituted 5–10 membered heterocyclic ring. In certain embodiments, at least two occurrences of RAare joined together with their intervening atom to form an optionally substituted 5–14 membered heteroaryl ring. Additional Embodiments

[0167] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formulae (I-a-i) to (I-a-x):or a pharmaceutically acceptable salt thereof.

[0168] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formulae (I-d-i) to (I-d-x):or a pharmaceutically acceptable salt thereof.

[0169] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formulae (I-e-i) to (I-e-x):or a pharmaceutically acceptable salt thereof.

[0170] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of Formulae (I-e-ii) to (I-e- x):or a pharmaceutically acceptable salt thereof.

[0171] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:,, , or a pharmaceutically acceptable salt thereof.

[0172] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula: ,, , or a pharmaceutically acceptable salt thereof.

[0173] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:, , or a pharmaceutically acceptable salt thereof.

[0174] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:, , or a pharmaceutically acceptable salt thereof.

[0175] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:,, , or a pharmaceutically acceptable salt thereof.

[0176] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:or a pharmaceutically acceptable salt thereof.

[0177] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:,or a pharmaceutically acceptable salt thereof.

[0178] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:, , or a pharmaceutically acceptable salt thereof.

[0179] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:, , or a pharmaceutically acceptable salt thereof.

[0180] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:, , or a pharmaceutically acceptable salt thereof.

[0181] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:or a pharmaceutically acceptable salt thereof.

[0182] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:, , or a pharmaceutically acceptable salt thereof.

[0183] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:, , or a pharmaceutically acceptable salt thereof.

[0184] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:,or a pharmaceutically acceptable salt thereof.

[0185] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:, , or a pharmaceutically acceptable salt thereof.

[0186] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:, , or a pharmaceutically acceptable salt thereof.

[0187] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:,, , or a pharmaceutically acceptable salt thereof.

[0188] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:,, , or a pharmaceutically acceptable salt thereof.

[0189] In certain embodiments, the compound of Formulae (I) or (Iʹ) is not of Formula (I-e-i):or a pharmaceutically acceptable salt thereof.

[0190] In certain embodiments, the compound of Formulae (I) or (Iʹ) is not of formula:, or a pharmaceutically acceptable salt thereof.

[0191] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:or a pharmaceutically acceptable salt thereof.

[0192] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula: ,, or a pharmaceutically acceptable salt thereof.

[0193] In certain embodiments, the compound of Formulae (I) or (Iʹ) is of formula:, or a pharmaceutically acceptable salt thereof.

[0194] In certain embodiments, a provided compound (a compound described herein, a compound of the present disclosure) is a compound of any of the formulae herein (e.g., Formula (I), Formula (Iʹ)) or pharmaceutically acceptable salt thereof. In certain embodiments, a provided compound is a compound of any of the formulae herein (e.g., Formula (I), Formula (Iʹ)), or a pharmaceutically acceptable salt or tautomer thereof. In certain embodiments, a provided compound is a compound of any of the formulae herein (e.g., Formula (I), Formula (Iʹ)), or a pharmaceutically acceptable salt thereof. In certain embodiments, a provided compound is a compound of any of the formulae herein (e.g., Formula (I), Formula (Iʹ)), or a salt thereof. Pharmaceutical Compositions and Kits

[0195] In one aspect, the present disclosure provides pharmaceutical compositions comprising a provided compound. In some embodiments, the pharmaceutical composition comprises one or more excipients. In certain embodiments, the pharmaceutical compositions described herein comprise a provided compound and an excipient.

[0196] In certain embodiments, the pharmaceutical composition comprises an effective amount of the provided compound. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0197] In certain embodiments, the effective amount is an amount effective for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the effective amount is an amount effective for inhibiting a proteinarginine methyltransferase (PRMT) in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the PRMT is PRMT5. In certain embodiments, the effective amount is an amount effective for treating a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof.

[0198] In certain embodiments, the subject is an animal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human aged 18 years or older. In certain embodiments, the subject is a human aged 12-18 years, exclusive. In certain embodiments, the subject is a human aged 2-12 years, inclusive. In certain embodiments, the subject is a human younger than 2 years. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0199] In certain embodiments, the effective amount is an amount effective for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample.

[0200] In certain embodiments, the effective amount is an amount effective for inhibiting a protein arginine methyltransferase (PRMT) (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%). In certain embodiments, the effective amount is an amount effective for inhibiting a protein arginine methyltransferase (PRMT) by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive. In certain embodiments, the PRMT is PRMT5.

[0201] In certain embodiments, the pharmaceutical composition is for use in treating a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, the pharmaceutical composition is for use in preventing a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, the pharmaceutical composition is for use in inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the pharmaceutical composition is for use in inhibiting a protein arginine methyltransferase (PRMT) in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the PRMT is PRMT5.

[0202] A provided compound or pharmaceutical composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The provided compounds or pharmaceutical compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof, in preventing a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof, and / or in reducing the risk of developing a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer,prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the additional pharmaceutical agents employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a provided compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the provided compounds and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0203] The provided compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound or pharmaceutical composition and may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides, synthetic proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))).

[0204] Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or pharmaceutical composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually.In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0205] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol- lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti–pyretics, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

[0206] In certain embodiments, the provided compound or pharmaceutical composition is a solid. In certain embodiments, the provided compound or pharmaceutical composition is a powder. In certain embodiments, the provided compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In certain embodiments, the provided compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parental injection. In certain embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for subcutaneous injection.

[0207] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the composition comprising a provided compound (i.e., the “active ingredient”) into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0208] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would beadministered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0209] Relative amounts of the provided compound, pharmaceutically acceptable excipient, agent, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the pharmaceutical composition is to be administered. The pharmaceutical composition may comprise between 0.1% and 100% (w / w) agent, inclusive.

[0210] Pharmaceutically acceptable excipients used in manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients and accessory ingredients, such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents, may also be present in the pharmaceutical composition.

[0211] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0212] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0213] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween®20), polyoxyethylene sorbitan monostearate (Tween®60), polyoxyethylene sorbitan monooleate (Tween®80), sorbitan monopalmitate (Span®40), sorbitan monostearate (Span®60), sorbitan tristearate (Span®65), glyceryl monooleate, sorbitan monooleate (Span®80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj®45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij®30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic®F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0214] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0215] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0216] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0217] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0218] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0219] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0220] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0221] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall®115, Germaben®II, Neolone®, Kathon®, and Euxyl®.

[0222] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0223] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0224] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0225] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0226] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0227] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0228] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0229] Pharmaceutical compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0230] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0231] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes.

[0232] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0233] Dosage forms for topical and / or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0234] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0235] Suitable devices for use in delivering injectable pharmaceutical compositions described herein include short needle devices. Injectable pharmaceutical compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of administration. Jet injection devices which deliver liquid formulations via a liquid jet injector and / or via a needle. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form are suitable.

[0236] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such pharmaceutical compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder pharmaceutical compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0237] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w / w) of the pharmaceutical composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the pharmaceutical composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0238] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutionsand / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0239] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0240] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0241] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically- administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0242] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such pharmaceutical compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the pharmaceutical compositions suitable foradministration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0243] Provided compounds are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0244] The provided compounds and pharmaceutical compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarticular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically, contemplated routes are intraarticular administration, oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0245] The exact amount of a provided compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound of the disclosure, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses of the multiple doses include different or substantially the same amounts of an agent described herein.

[0246] In certain embodiments, a pharmaceutical composition comprising a provided compound is administered, orally or parenterally, at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably fromabout 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, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and / or prophylactic effect. In certain embodiments, the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg, from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 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 and / or prophylactic effect. The desired dosage may be 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 may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). In certain embodiments, the pharmaceutical composition described herein is administered at a dose that is below the dose at which the agent causes non- specific effects.

[0247] In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.

[0248] Dose ranges as described herein provide guidance for the administration of provided compounds or 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. In certain embodiments, a dose described herein is a dose to an adult human whose body weight is 70 kg.

[0249] In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell may be, in non-limiting examples, three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks, or even slow dose controlled delivery over a selected period of time using a drug delivery device. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, oneweek, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.

[0250] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). In certain embodiments, the kit comprises a provided compound or pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition. In certain embodiments, the kit comprises a first container, wherein the first container includes the compound or pharmaceutical composition. In some embodiments, the kit further comprises a second container. In certain embodiments, the second container includes an excipient (e.g., an excipient for dilution or suspension of the compound or pharmaceutical composition). In certain embodiments, the second container includes an additional pharmaceutical agent. In some embodiments, the kit further comprises a third container. In certain embodiments, the third container includes an additional pharmaceutical agent. In some embodiments, the provided compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form one unit dosage form. In some embodiments, the provided compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are combined to form one unit dosage form. In certain embodiments, each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.

[0251] In certain embodiments, the instructions are for administering the provided compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease described herein). In certain embodiments, the instructions are for contacting a biological sample or cell with the provided compound or pharmaceutical composition. In certain embodiments, the instructions comprise information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Agency for the Evaluation of Medicinal Products (EMA). In certain embodiments, the instructions comprise prescribing information.

[0252] In certain embodiments, the kits and instructions provide for treating a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granularlymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease or disorder (e.g., a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the kits and instructions provide for inhibiting a protein arginine methyltransferase (PRMT) in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the PRMT is PRMT5.

[0253] A kit described herein may include one or more additional pharmaceutical agents described herein as a separate pharmaceutical composition.

[0254] Another object of the present disclosure is the use of a compound as described herein in the manufacture of a medicament for use in the treatment of a disorder or disease described herein. Another object of the present disclosure is the use of a compound as described herein for use in the treatment of a disorder or disease described herein. Methods of Treatment and Prevention

[0255] In another aspect, the present disclosure provides methods of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a provided compound or pharmaceutical composition. In certain embodiments, the present disclosure provides methods of treating a disease in a subject in need thereof, comprising administering to the subject in need thereof a provided compound or pharmaceutical composition. In certain embodiments, the present disclosure provides methods of preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a provided compound or pharmaceutical composition. In certain embodiments, the disease is a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))).

[0256] In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in treating or preventing a disease in a subject in need thereof. In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in treating a disease in a subject in need thereof. In another aspect, the present disclosure provides aprovided compound or pharmaceutical composition for use in preventing a disease in a subject in need thereof. In certain embodiments, the disease is a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))).

[0257] In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in the manufacture of a medicament for treatment or prevention of a disease in a subject in need thereof. In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in the manufacture of a medicament for treatment of a disease in a subject in need thereof. In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in the manufacture of a medicament for prevention of a disease in a subject in need thereof. In certain embodiments, the disease is a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))).

[0258] In certain embodiments, the disease is a proliferative disease (e.g., cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer))). In certain embodiments, the proliferative disease is cancer (e.g., multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, head and neck cancer).

[0259] In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is chronic lymphocytic leukemia (CLL). In certain embodiments, the cancer is acute myelogenous leukemia (AML). In certain embodiments, the cancer is large granular lymphocyte leukemia (LGL). In certain embodiments, the cancer is sarcoma. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is renal cancer. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is colon carcinoma. In certain embodiments, the cancer is gastric carcinoma. In certain embodiments, the cancer is cervical cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is liver cancer. In certain embodiments, the cancer is head and neck cancer.

[0260] In another aspect, the disease, disorder, or symptom includes proliferative diseases and disorders, cancer, tumor growth, cancer of the colon, breast, bone, brain and others (e.g., osteosarcoma, neuroblastoma, colon adenocarcinoma), cardiac cancer (e.g., sarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma); lung cancer (e.g., bronchogenic carcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma); various gastrointestinal cancer (e.g., cancers of esophagus, stomach, pancreas, small bowel, and large bowel); genitourinary tract cancer (e.g., kidney, bladder and urethra, prostate, testis; liver cancer (e.g., hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma); bone cancer (e.g., osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, cutaneous T-cell lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors); cancers of the nervous system (e.g., of the skull, meninges, brain, and spinal cord); gynecological cancers (e.g., uterus, cervix, ovaries, vulva, vagina); hematologic cancer (e.g., cancers relating to blood, Hodgkin's disease, non-Hodgkin's lymphoma); skin cancer (e.g., malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis); and cancers of the adrenal glands (e.g., neuroblastoma). Methods of Inhibiting Cell Proliferation or Promoting Apoptosis and Inhibiting a Protein Arginine Methyltransferase (PRMT)

[0261] In another aspect, the present disclosure provides methods of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or composition. In certain embodiments, the present disclosure provides methods of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a provided compound or composition. In certain embodiments, the present disclosure provides methods of inhibiting cell proliferation or promoting apoptosis in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or composition. In certain embodiments, the present disclosure provides a provided compound or composition for use in inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides a provided compound or composition for use in the manufacture of a medicament for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample.

[0262] In another aspect, the present disclosure provides methods of inhibiting a protein arginine methyltransferase (PRMT) in a subject in need thereof or in a cell, tissue, or biological sample,comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or composition. In certain embodiments, the present disclosure provides methods of inhibiting a protein arginine methyltransferase (PRMT) in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a provided compound or composition. In certain embodiments, the present disclosure provides methods of inhibiting a protein arginine methyltransferase (PRMT) in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or composition. In certain embodiments, the present disclosure provides a provided compound or composition for use in inhibiting a protein arginine methyltransferase (PRMT) in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides a provided compound or composition for use in the manufacture of a medicament for inhibiting a protein arginine methyltransferase (PRMT) in a subject in need thereof or in a cell, tissue, or biological sample.

[0263] In certain embodiments, the method comprises inhibiting the protein arginine methyltransferase (PRMT) (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In certain embodiments, the method comprises inhibiting a protein arginine methyltransferase (PRMT) by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive. In certain embodiments, the PRMT is PRMT5.

[0264] In certain embodiments, the cell, tissue, or biological sample is in vivo. In certain embodiments, the cell, tissue, or biological sample is in vitro. EXAMPLES

[0265] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope. Example 1: Identification and characterization of MTA-cooperative PRMT5 inhibitors.

[0266] Inspired by the pharmacophore which was screened against PRMT5 in Cambridge database

[0027] , first-generation MTA-cooperative PRMT5 inhibitors, 11-2F and 11-9F, were designed and synthesized

[0018] (FIG.1A). The cryo-EM structure of 11-2F bound to PRMT5 in the presence of MTA showed that the amino group on the quinoline ring is involved in two hydrogen interactions with the residues of Glu435 and Glu444

[0018] . Additionally, there is no interaction between cofactor-site binder and substrate-site inhibitor, indicating 11-2F and its analogues do not rely on SAM’s binding. 11-2F showed a binding preference to MTA bound PRMT5 (KD =0.109±0.023 µM) than SAM boundPRMT5 (KD = 1.26±0.213 µM) (Table 1), while GSK3326595 did not show this binding preference

[0028] . The 1,2,3,4-tetrahydrocarbazole fragment in 11-2F or 11-9F may extend into the solvent, which is not beneficial for ligand binding. Based on the GSK3235025 co-crystal structure, the pyrimidine ring is involved into two vertical π-π stackings with Phe327, Tyr304 and a parallel π-π stacking with Phe580

[0028] . To achieve these interactions, a complete redesign of the carbazole moiety was required.

[0267] Guided by the 11-2F cryo-EM structure, the amide amine was cyclized with the nearby phenyl group, not only to fix the position of amide but also to force the phenyl group to insert into “Leu327, Phe580 and Trp579” aromatic cluster so that the phenyl was not easily to expose into water. Also, introducing the halogen atom on 16-18F and 16-19F aimed to form halogen bond interaction with the backbone amide carbonyl group on Ser578. Based on those optimizations, 16-19F (0.022±0.004 µM) (Table 3) showed much lower IC50 compared to 11-9F. The cryo-EM structure was solved with 16-19F bound in the substrate pocket of PRMT5: SAH complex, and the structure confirmed hydrogen bond interactions with Glu435, Glu444, and Leu312 (FIG.1B). Moreover, the amide bond cyclization efficiently forced the phenyl group to insert into the “Leu312, Phe580 and Trp579” aromatic cluster (FIG.1C).

[0268] To further test the binding affinity, a surface plasmon resonance (SPR) assay was used to characterize the binding of 16-19F against apo- PRMT5:MEP50, SAM- and MTA- bound PRMT5:MEP50 surfaces. Examination of SPR sensorgrams revealed an effect on 16-19F binding based on the identity of the bound nucleoside analog (FIGs.1D-1F). apo-bound PRMT5 showed a modest affinity of 16-19F (KD = 2.54±0.679 µM), whereas SAM- and MTA-bound PRMT5:MEP50 bound 16-19F with much higher affinity. Similarly, 16-19F showed a binding preference to MTA bound PRMT5 (KD =0.147±0.025 µM) rather than SAM bound PRMT5 (KD = 0.360±0.071 µM) (Table 1 and FIGs.5A-5C). Therefore, it was hypothesized that 16-19F, which preferentially binds to and stabilizes the catalytically inactive PRMT5: MTA complex, would inhibit PRMT5 activity in MTAP- / - cells while preserving PRMT5 activity in MTAP+ cells, creating a potential precision oncology medicine for the treatment of MTAP- / - cancers. Table 1. PRMT5 Enzymatic Binding Assays.Table 2. PRMT5 Cellular Binding Assays.Table 3: The inhibitory activity of selected compounds against hPRMT5:MEP50 based on MTase-Glo assay.p Example 2: Biochemical and biological properties of MTA-cooperative PRMT5 inhibitors.

[0269] To test this hypothesis, two MTAP- / - cell lines (MIA PaCa-2 and MDA-MB-231) and one MTAP+ / + cell line (MDA-MB-435s) (FIG.2A) were used to assess changes in cell viability, proliferation, and methylation levels upon treatment with MTA-cooperative PRMT5 inhibitors

[0029] . The data in Tables 1&2 show that, although 11-9F showed great enzymatic and cellular inhibition efficacy, it cannot inhibit SDMA dose-dependently (FIGs.6A-6E), which may indicate off-target effects. In addition, selectivity may be another issue for 11-9F, due to the similar killing effect in both MTAP+ / + and MTAP- / - cell lines (FIGs.6A-6E).16-19F demonstrated potent selectivity for MTAP- / - cancer cell lines with IC50 values of 17.84 µM and 15.73 µM in MDA-MB-231 and MIA PaCa-2, compared to IC50 >100 µM in MDA-MB-435s cells. Additionally, the SAM-cooperative and SAM- competitive inhibitor, GSK3326595 and JNJ-64619178, showed no obvious cell viability inhibition over those cell lines tested under four-day treatment (FIG.2B). The effects of 16-19F treatment on cellular symmetric arginine di-methylation in multiple cell lines were tested by immunoblot usingSDMA (FIGs.2D & 6E). The 16-19F treatment led to a concentration-dependent decrease in the intensity of multiple bands. Further confirmation of target engagement in vitro was achieved with cellular thermal shift assay (CETSA)

[0030] . Assays with pretreated MDA-MB-231 and MIA PaCa-2 cells resulted in 3.5°C and 1.7°C shift in the melting curve of PRMT5 in the presence of 16-19F, indicating specific binding of the active compound to PRMT5 in cells (FIGs.2C & 6D). Based on the in vitro enzyme level binding affinity and in vivo cellular assay, MDA-MB-231 cells, one type of TNBC which is MTAP- / -, were determined to be more sensitive to 16-19F compared to GSK3325595

[0028] and JNJ-64619178

[0031] . Considering that PRMT5 inhibitors have already been identified as a potential treatment for TNBC

[0013] , 16-19F may be suitable for testing the underlying mechanisms. Example 3: Functional enrichment analysis by RNA-seq study.

[0270] To better understand the cellular mechanisms that may account for the attenuation of growth observed after PRMT5 inhibition, RNA-seq was performed using the MDA-MB-231 cell line after 2, 4, and 8-day treatments with 16-19F or DMSO, and the differential effects on gene expression were analyzed (FIG.3A). PCA analysis was performed to identify the variance between data sets in different treatment days

[0032] (FIG.7A).3347 genes were identified that were significantly differentially expressed in different-day treatments compared to the control (≥2-fold change, false discovery rate (FDR) < 0.05), with an overlap of 100 genes between these different days (FIG.7B). Gene ontology (GO) analysis identified the sterol biosynthesis process was significantly enriched after 2-day treatment, which was consistent with previous findings

[0033] and indicated the importance of PRMT5 in autoimmune system (FIG.7C). Compared to the DMSO control, macrophage migration, a key element of chronic inflammation responses, was found most associated with 4-day 16-19F treatment (FIGs.7D-7E). PRMT5 is recognized to play a critical role in modulating inflammation responses[34-36]. Vasculature development was found enriched in both 4 and 8-day treatments compared to DMSO control[35, 37], indicating a potential mechanism of solid cancer recurrence after PRMT5 inhibition. Overall, the enriched pathways were changed over time as the treatment duration increased. Ingenuity pathway analysis (IPA) of the differentially expressed genes (DEGs) after 8-day treatment revealed the enrichment of genes involved in kinetochore metaphase signaling and cell cycle control of the chromosomal replication pathway (FIG.3C), corroborating previous reports that PRMT5 inhibition has a profound effect on the regulators of cell cycle

[0038] . Gene set enrichment analysis (GSEA) of the DEGs confirmed those enrichments (FIG.3D). Genes in pathways associated with BRCA1 in DNA damage response were also enriched, and genes involved in cell cycle checkpoint proteins were upregulated.

[0271] The cell cycle regulation pathway was further investigated. Based on the gene set within this pathway, all subunits of minichromosome maintenance (MCM) protein complex were downregulated after PRMT5 inhibition (FIG.3B). Since this complex is a component of the prereplication complex that involves the initiation of DNA or chromosome replications

[0039] , 16-19F may induce decreased cellviability by affecting essential DNA replication biomarkers, MCMs. The MCM protein complex, a hexametric helicase that contains six distinct subunits MCM2-7, is evolutionally conserved in all eukaryotes

[0039] . Although six different subunits should work together to unwind DNA, it has been reported that each subunit expresses differently in different tissues. Because MCM7 is found overexpressed in breast cancer

[0040] , it was selected for further study. Previous studies have shown that PRMT5 methylation can activate E2F

[0041] , a transcription factor located in MCM7 promoter region

[0042] . It was hypothesized that PRMT5 inhibition induced by 16-19F may further suppress E2F to affect MCM7 transcription in TNBC.

[0272] Additionally, PRMT5 is a component of RNA splicing events[43-46]due the methylation of multiple components of the splicing complex[47, 48]. To access the role of PRMT5 inhibition in RNA- splicing, RNA-seq data was analyzed to identify disruptive alternative splicing events (ASEs) using replicate multivariate analysis of transcript splicing (rMATS). A total of 319 genes were identified as being statistically significantly differentially spliced upon PRMT5 inhibition. While multiple forms of splicing were perturbed upon inhibition treatment, alternative 5’ donor sites (A5) particularly increased, and AS at transcription factor (TF) at terminal sties (ATSS) particularly decreased (FIG. 3E). These data further indicated a role of PRMT5 in the regulation of the splicing machinery, and suggest a link between the pharmacological inhibition and the antiproliferative phenotype associated with changes in alternative splicing events. Example 4: PRMT5 is the arginine methyltransferase of MCM7.

[0273] Both Li et al.

[0049] , and data of the present disclosure (FIG.8A) indicated that MCM7 can directly conjugate with PRMT5 at cellular level. In an earlier study to identify the global substrates methylated by the PRMT family, a high-resolution mass spectrometry method was used, and MCM family proteins were detected containing several mono-methylated arginine (MMA) sites

[0050] , including MCM7. Additionally, the basic pattern of PRMT5 substrates, the “GR” motif, has been well characterized

[0051] . The methylation sites in MCM7 also consisted of these substrate pattens, as inspected using a PRMT5-methylation sites prediction tool, PRmePred

[0052] . Those peptides were successfully docked with arginine MMA sites from MCM7 into PRMT5 substrate pocket using AutoDockCrankPep

[0053] , and it was found that those peptides align well with original substrate Histone 4 peptide in PRMT5 X-ray crystal structure

[0022] (FIGs.8C-8D). These findings support that MCM7 is likely a substrate of PRMT5. Next, it was investigated whether MCM7 sDMA formation could be diminished by PRMT5 inhibition.16-19F strongly inhibited PRMT5 co-immunoprecipitated MCM7 sDMA compared to GSK3326595 (FIG.4A). To identify the arginine residues that are methylated by PRMT5, the result from PRmePred was analyzed, and arginine residues were mutated to lysine for further analyses. The substitution of R219 to K (R219K) blocked over 80% MCM7 sDMA formation in cells (FIG.4B). MCM7-R219 is evolutionarily conserved from Bursaphelenchus xylophilus toHomo sapiens, indicating a potential significant role of this methylation event in various species (FIG. 8B).

[0274] To further explore the interaction mechanism that facilitates MCM7 methylation by PRMT5 from a structural and dynamical point of view, a total of 100 ns of full atomic MD stimulation models were performed in explicit solvent. All MD simulations were performed with Amber20[54, 55]. However, the experimentally identified interaction residue R219 is in the N-terminal of MCM7, which is missing in all available MCM7 crystal or cryo-EM structures, presumably due to the high conformational variability of this region. Therefore interactions within a short stretch loop of MCM7 N214-T224 and P292-L637 of PRMT5 (PDB ID: 4GQB) were focused on. After 100 ns simulation without constrains, the complex obtained from the third run showed that R219 in MCM7 formed four hydrogen bonds with E435, E444, and S578 (FIGs.4C-4D). The backbone atom RMSDs

[0056] of PRMT5 P292-L637 from their starting positions was 2.01±0.187 Å among three times running (FIG. 9B). The distances between atoms that support methyl transfer and hydrogen bond formation were also measured

[0056] and showed great stability (FIGs.9C-9E). Altogether, these results indicate that PRMT5 is the physiological arginine methyltransferase responsible for the symmetric methylation of MCM7-R219. Example 5: Potential role of MCM7 methylation in stress granules formation.

[0275] Nevertheless, the final purpose of generating dimethylated-MCM7 by PRMT5 enzyme remains unelucidated. Arginine methylation[64, 67]regulated the formation of membrane-less organelles via liquid-liquid phase separation (LLPS) mechanisms, including stress granules, which are ribonucleoprotein assemblies formed in the cytoplasm to prevent mRNA degradation under different types of stress[19, 57, 58]. Studies have shown that PRMT family proteins play important roles in stress granules (SGs) formation, especially PRMT1 and PRMT5[65-67]. The associations of SGs with cancer

[0059] , neurodegeneration

[0060] , and cardiac diseases

[0061] have been discovered, and recent evidence suggests that various post-translational modifications (PTMs)[62, 63], including methylation

[0064] , can modulate SG dynamics. Facilitated by “GR” motif methylation

[0065] , the increased hydrophobicity can block the interactions of the substrate enzymes and SG components, thereby preventing SG assembly. Based on the well-defined modulation pattern of PRMT1 to SGs[66, 67], MCM7 demethylated by PRMT5 inhibitors may exhibit a similar SG assembly ablation effect, and PRMT5 inhibition may affect MCM7 localization by modulating the LLPS.

[0276] To test this, MDA-MB-231 was treated with sodium arsenite (NaAsO2), a potent inducer of SGs via oxidative stress. As expected, this led to the appearance of G3BP1 aggregates in the cytoplasm, a well-known SG marker

[0069] . GSK3326595 or 16-19F alone, however, did not promote the formation of stress granules, which is consistent with the previous studies[70, 71]. The addition of GSK3326595 or 16-19F to NaAsO2-stressed cells significantly increased the number of SG (FIGs. 12A-12B). This may be caused by the arginine residue de-methylation of PRMT5 inhibitors

[0065] . WithPRMT5 inhibition, the arginine guanidinium group will form multiple interactions with surrounding residues, DNA, or RNA, which support SGs formation. The role of arginine methylation on MCM7 localization function was then determined. Different from G3BP1, endogenous MCM7 mainly located in the nucleus to initiate DNA replication, co-localizing with DNA[49, 72]. No obvious subcellular localization change of MCM7 was observed with GSK3326595 or 16-19F treatment alone. In the meanwhile, when the cells were treated with NaAsO2, MCM7 partially transported out of nucleus and formed cytoplasmic foci that co-localized with G3BP1, indicating the foci were SGs. Compared to the NaAsO2 treatment, the combination treatments significantly induced more foci, which confirmed by quantitative analysis by ImageJ. Example 6: Discussion.

[0277] In this study, based on 11-2F optimization

[0018] , a second-generation PRMT5⋅MTA complex inhibitor, 16-19F, was discovered. SPR study and MTase-Glo™ methyltransferase assay confirmed the binding affinity (KD = 0.147±0.025 µM) and inhibition efficacy (IC50 = 0.022±0.004 µM) of PRMT5. The cryo-EM structure showed that the 2,4-di-NH2-quinazoline of 16-19F formed H bonds with E444, E435, and L312, and its aromatic ring is sandwiched between the sidechains of F327 and W579. For the in vitro cellular detection, MTT assay indicated the selectivity of 16-19F to MTAP- / - over MTAP+ / + cancer cells. PRMT5-dependent symmetric di-methylarginine (SDMA) protein modification was dose-dependently inhibited after 16-19F treatment. Specific binding of 16-19F to PRMT5 inside the cells was confirmed by CETSA, resulted in a 3.5°C shift in the melting curve of PRMT5. In addition, one type of TNBC, MDA-MB-231 cells, was more sensitive to 16-19F than GSK3326595

[0028] and JNJ-64619178

[0031] , implying that 16-19F could be a drug candidate for TNBC treatment. To study the mechanism, RNA-seq analysis was performed and cell cycle control of the chromosomal replication pathway was shown to be enriched in 16-19F-treated MDA-MB-231 cells compared to control. MCM family proteins, a key component of prereplication complex, were found highly related to 16-19F inhibition. Moreover, based on the known pattern of PRMT5 substrates, the “GR” motif[50, 51], it was confirmed that PRMT5 is responsible for the symmetric methylation of MCM7-R219 by site-directed mutagenesis and MD simulation. In the meanwhile, the phenotype changes, SGs formation, caused by 16-19F inhibition was identified. Imaging data showed that the addition of 16-19F to NaAsO2-stressed cells significantly increased the number of SG. Based on the well-characterized role of arginine methylation in liquid-liquid phase separation mechanism[64, 68], the increased hydrophobicity may block the interactions between the methylated substrates enzymes and SG scaffold components, thereby preventing larger SGs assembly.

[0278] PRMT5 regulated methylations of both histone[73-75]or non-histone proteins[76-80], and it also involved in modulating cell proliferation[81-83]and differentiation pathway

[0084] . However, no studies have pointed out which PRMT5 inhibition mechanisms are more dominant than others within thecancer cells, implying that all the identified mechanisms can only partially interpret the effect of PRMT5 methylation. Based on the role of PRMT5, with its substrates ubiquitously distribution, a general mechanism may be able to connect to all the involved branched mechanisms. It was hypothesized that PRMT5 regulated downstream protein expressions or gene transcriptions by affecting LLPS. As one subtype of LLPS, the components of stress granules have been identified

[0057] and found largely overlap with PRMT5 substrates proteins

[0085] . This finding provided a new insight into the relationship between PRMT5 and stress granules formation

[0065] . Then, a newly discovered PRMT5 substrate, MCM7, was used as an example to study the localization changes by PRMT5 inhibition treatment. A larger amount of MCM7 transported out of the nucleus and co-localized with G3BP1 to form cytoplasmic foci by NaAsO2 addition with 16-19F treatment compared to NaAsO2 only. Therefore, this phenomenon may confirm that PRMT5 inhibition together with additional stress induction could facilitate its substrate proteins forming SGs. In addition, due to a paucity of therapeutic target available, chemotherapy is still the primary option of TNBC treatment

[0086] . Since chemotherapeutic agents widely induced stress granules formation in variety type of cancers[87-90], it was assumed that PRMT5 inhibitors could also modulate its substrates to form SGs under chemo- treatments. Under the high concentration of separated phase, proteins in SGs will temporally lose their functions

[0091] . This may explain most companies prefer to combine PRMT5 inhibitors with chemo- drugs in their clinical trials

[0092] .

[0279] However, the main question whether this combination treatment induced SGs have a positively effect on the survival of cancer cell is still unknown. Since the formation of SGs is reversible

[0093] , whether the proteins inside SGs will get their physiological functions back after treatment remains unknown. Also, as the condensate will finally form amyloid state and aggregate to become irreversible under long time treatment

[0019] , further studies are needed to establish what is the treatment time scale that could induce permanent aggregation. In the meanwhile, SGs dynamics performed differently under PRMT5 inhibition in multiple cell types. PRMT5 inhibition significantly induced SGs formation, while other studies showed opposite results in mESCs cells

[0071] . Future studies could focus on studying the components of SGs in each cell type which may help elucidate the phenotype differences. Example 7: Materials and Methods.

[0280] Cell culture and transfection. MDA-MB-231, HEK293T, and MIA PaCa-2 cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM) (Corning, #10-013-CV). Ten percent fetal bovine serum (Corning, #35-010-CV), antibiotic antimycotic solution 100× (Corning, #30-004- Cl) were supplemented in the medium. Plasmid transfection was performed using PEI MAX, MW 40000 (Polysciences, #24765) and siRNA transfection was performed using Lipofectamine 3000 reagents following the manufacturer’s instructions. The siRNA targeting PRMT5, MCM7, and negative control were purchased from SCBT (sc-41073, sc-35887, and sc-37007).

[0281] Antibodies. All primary antibodies were used in PBST buffer with 5% BSA. Anti-SDMA (1:1000, Cell Signaling #13222S), and anti β-actin (1:1000, Cell Signaling #4970S), anti-PRMT5 (1:1000, Cell Signaling #79998), anti-HA (1:1000, Cell Signaling #3724), anti-MYC (1:1000, Cell Signaling #2278), anti-G3BP1 (1:500, proteintech #66486-1-lg), anti-MCM7 (1:500, proteintech #11225-1-AP), goat anti-rabbit secondary antibody (HRP-conjugated, 1:10000, Invitrogen #31460), goat anti-mouse IgG H&L (Alexa Fluor 647) (1:500, abcam #ab150115), goat anti-rabbit IgG H&L (Alexa Fluor 488) (1:1000, Invitrogen #A-11008).

[0282] Plasmid construction and mutagenesis. Myc-PRMT5 and Myc-MEP50 were obtained from Dr Wenjian Gan at Medical University of South Carolina. HA-MCM7 was constructed by cloning the corresponding cDNA from pET32-MCM2 / 7 (Addgene, #116949) into the FLAG-HA-pcDNA3.1 vector (Addgene, #52535). MCM7 point-mutations were introduced to plasmids using primers in a PCR protocol, and the parent template was removed by Dpn1 (ThermoFisher Scientific, #ER1701). Sequence of primers are listed below: R215K-Fw: 5’-aaaccaacaagtcaggagggaagctgtatc-3’ (SEQ ID NO: 1) R215K-Rv: 5’-ctcctgacttgttggtttggcactcctg-3’ (SEQ ID NO: 2) R219K-Fw: 5’-caggagggaagctgtatctgcagaca-3’ (SEQ ID NO: 3) R219K-Rv: 5’-agatacagcttccctcctgagcggt-3’ (SEQ ID NO: 4) R225K-Fw: 5’-tgcagacaaagggctccagattcatcaaat-3’ (SEQ ID NO: 5) R225K-Rv: 5’-tggagccctttgtctgcagatacagcttc-3’ (SEQ ID NO: 6)

[0283] PRMT5:MEP50 protein expression, purification, and characterization. Preparation of purified PRMT5:MEP50 complex was described in literature

[0022] . Full-length human PRMT5 (residues 1–637, NP_006100) and human MEP50 (residues 2–342, NP_077007) were co-expressed in Sf9 cells using a Bac-to-Bac expression system (Invitrogen). The cells were harvested and lysed. After removal of cell debris, supernatants were collected for FLAG-affinity chromatography (Sigma; A2220) and fractionated by size exclusion chromatography in a 10 / 300 Superose 6 column (GE Life Sciences). The purified PRMT5:MEP50 complex was characterized by SDS-PAGE and sedimentation velocity analytical ultracentrifugation (SV-AUC) using ProteomeLab™XL-I (Beckman Coulter). Protein samples were concentrated to 12 mg / mL in a buffer containing 10 mM HEPES at pH 7.5, 150 mM NaCl, 10% (vol / vol) glycerol and 2.0 mM DTT and were stored at -80 °C until the time of use.

[0284] Surface plasmon resonance (SPR) binding study. Binding affinity measurements were conducted on a Reichert2SPR instrument (Ametek) at room temperature.20 µg PRMT5:MEP50 proteins were directly immobilized onto the 500,000 Da carboxymethyl dextran sensor chip at pH 5.5 using the standard amine coupling approach. Small molecule ligands were injected at a flow rate of 30 µL / min at different concentrations in the running buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.005% v / v Tween-20, and 5% DMSO). The association and dissociation time were 2min and 5 min, respectively. Sensorgram data was processed using Excel and dissociation constant (KD) was calculated by GraphPad Prism9.

[0285] MTase-Glo™ methyltransferase assay. Enzymatic inhibition activity was determined by MTase-Glo™ methyltransferase assay (Promega Corporation, V7602). Compounds were serially diluted in DMSO and then added into reaction buffer (30 mM Tris-HCl at pH 7.4, 500 mM NaCl, 2 mM MgCl2, 2 mM TCEP, 0.1% (wt / vol) BSA and 0.01% (vol / vol) Tween-20) with final DMSO concentration at 5% (vol / vol).100 nM PRMT5:MEP50 enzymes, 10 μM SAM (Sigma-Aldrich, A4377), 2 μM substrate histone H4 (1-21) (ANASPEC, #AS-62499) and test compounds were added into the reactions following the manufacturers’ instructions. The luminescence was measured using the microplate reader.

[0286] In vitro cell viability and proliferation assay. Cells were seeded into 96-well plates at a density of 3000 cells / well. Test compounds were then added into the cells at different concentrations and incubated for 72 h.10 µL of CCK8 cell counting reagent (MedChemExpress #HY-K0301) was added to each well and then incubated at 37 °C for another 4 h. The absorbance was determined at 562 nm using a microplate reader. For cell proliferation assay, the initial density of cell was 2000 cells / well, and absorbance was measured in day3, 6, and 9.

[0287] Immunoblot and immunoprecipitation analyses. Cells were rinsed with ice-cold phosphate-buffered saline (PBS) and lysed with IP lysis buffer (Pierce #87787) supplemented with protease and phosphatase inhibitor cocktail (Pierce #78441). The cell lysates were centrifuged at 13,000 rpm for 30 min at 4 °C. The protein concentrations were measured using BCA Protein Assay kit (Pierce #23227). Equal amounts of whole cell lysates were resolved by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) (Bio-Rad #4561086), transferred to PVDF membrane (Bio-Rad #1620174), and then immunoblotted with the indicated antibodies. For immunoprecipitation, the lysates (3000 μg) were incubated with 30 µL Protein A / G PLUS-Agarose (SCBT #sc-2003) and corresponding primary antibodies at 4 °C overnight. The immunoprecipitates were then washed five times with IP lysis buffer before being resolved by SDS-PAGE. The membranes were analyzed by using ECL Western blotting detection reagents (Pierce #34096) and imaged with ChemiDoc MP imaging system (Bio-Rad).

[0288] Immunofluorescence. MDA-MB-231 cells, treated with either 20 μM GSK3326595 or 16- 19F for 48 h, were grown on Lab-Tek Chambered (Thermo Fisher Scientific #155411) to the 75% confluence before fixation. The cells were then left untreated or treated with 0.5 mM sodium arsenite for 1 h. The cells were rinsed with PBS and fixed with 4% paraformaldehyde (PFA) in PBS for 10 min. After incubating with 1% SDS and blocking buffer (2.5% bovine serum albumin, 0.1% TritonX- 100 in PBS), the cells were incubated with indicated antibodies at 4 °C overnight. The cells were incubated with secondary antibodies for 50 min and DAPI for 10 min at 25 °C.

[0289] Image Acquisition Conditions. Imaging was performed using a Nikon Eclipse Ti2-E and X- Cite XLED1 Multi-Triggering LED Illumination System. The microscope is equipped with ASI piezo stage to achieve fast automated imaging acquisition in three dimensions. Automated image acquisition was controlled by Micro-Manager

[0094] . Imaging was performed in the GFP, Cy5 and DAPI channels. (GFP and Cy5 channels were both at 20% full illumination intensity at exposure times of 5 ms. DAPI channel was at 80% full intensity at exposure time of 10 ms.)

[0290] Image Segmentation and Analysis. Image segmentation with custom scripts was carried out entirely in the open-source image analysis software, FIJI (1.5.3q)

[0095] . Cy5 images were first preprocessed using a Gaussian filter, morphological top-hat filter, and a median filter in succession to reduce background and noise. Automatic thresholding and segmentation were then performed on the preprocessed image to identify condensates. Average number of condensates per cell was obtained by dividing the total number of identified condensates by the number of total cells.

[0291] Cellular thermal shift assay. Cells were treated with 20 μM of selected compound or DMSO as negative control for 18 h. Cells were harvested and equally split into 11 PCR tubes before heating to different temperatures from 50 °C to 66 °C (2 °C increment) for 3 min followed by another 3 min incubation at 20 °C. Then cell samples were lysed by snap-freezing in liquid nitrogen followed by centrifugation at 13,000 rpm for 10 min. Supernatant was collected and boiled with 6×loading buffer at 95 °C for 10 minutes. Western blotting was performed as described above. The percentage of control was calculated based on the unheated control samples for each condition.

[0292] RNA-seq analysis. MDA-MB-231 cells with DMSO or 6.25 µM 16-19F treatments were grown for 8 days.16-19F / DMSO were replenished every 4 days. After 8-day treatment, cells were harvested. RNeasy Plus Kit (QIAGEN, #74134) was used for total RNA isolation. RNA purity and concentration were confirmed using Nanodrop. RNA-seq library was prepared by Illumina TrueSeq Stranded mRNA Library Prep Kit (Illumina, Cambridge, UK). The sequence reads were mapped to the UCSC human genome hg38 using RNA-seq aligner STAR (v2.7.9a)

[0023] . Then, the mapped sequencing reads were assigned to transcripts using FeatureCounts (v2.0.3)

[0024] based on GENECODE GRCh38 release 25 annotation gtf file. The differential expression analysis between DMSO and 16- 19F treated samples was performed by using DESeq2 (v1.38.2)

[0025] . Differentially expressed genes (DEGs) were determined if their p-values were less than 0.05 after multiple test correction with false discovery rate (FDR) adjustment. To distinguish pathway enrichment functions in DEGs, ingenuity pathway analysis (IPA) was used to perform functional enrichment analysis. Isoform analysis was performed in R using the packages IsoformSwitchAnalyzer

[0096] , the python tool CPAT (Coding Potential Assessment Tool)

[0097] , and the perl tool PfamScan

[0098] .

[0293] Molecular dynamics. The initial coordinates of PRMT5 were obtained from chain A of the crystal structure of the human PRMT5:MEP50 Complex obtained with 2.06 Å resolution (PDB ID: 4GQB)

[0022] , keeping only MEP50 and the PRMT5 substrate domain (P292-L637). The SAM ligandwas built in place by modifying the relevant atoms from the SAM-analog present. The system was prepared using Schrödinger Protein Preparation Protocol at pH 7.4±2.0, and water molecules with less than 2 hydrogen bonds to ligand atoms were deleted. The initial structure of the PRMT5:MCM7(N214-T224) complex was obtained using Schrödinger Induce Fit protocol

[0099] to place the MCM7 fragment into PRMT5, using core constraints to place MCM7 Gly5-Arg6 into the same position as MEP50 Gly2-Arg3 within a maximum RMSD of 8.0 Å. Residues within 8 Å of the ligand were allowed to move to fit MCM7. For the MD calculations, the system was placed in a truncated octahedral box with sides at least 20 Å distance from any solute atoms. The system was solvated with OPC waters

[0100] , charges were neutralized with Na+and Cl- ions, and extra ions added to reach a salt concentration of 0.15 M. The Amber ff19SB force field

[0055] was used for the protein atoms, and the SAM ligand was represented with GAFF

[0101] . The system was then submitted to 100 steps of minimization where only the waters were allowed to move, followed by 10,000 minimization steps where all atoms were allowed to move. The volume of the system was fixed, and it was then heated at a constant rate for 0.6 ns to 310 K, followed by 0.4 ns relaxation at the final temperature. This was followed by a 2 ns relaxation at the final temperature and constant 1 atm pressure, and a final 100 ns simulation with the same conditions. In all stages, the distance between the centers-of-mass of MCM7 and PRMT5 ^^s was kept fixed at 20 Å with harmonic restraints.

[0294] The binding mode was refined by a five step MD simulation protocol: (1) MCM7 N214-T224 was steered away from the catalytic pocket by increasing the restraint distance from 20 Å to 35 Å, with extra dihedral constrains to prevent the peptide from flipping; (2) keeping the 35 Å distance, run a 100 ns simulation to stabilize the whole system; (3) steer MCM7 N214-T224 all the way back to the PRMT5 catalytic pocket by pulling MCM7 R219-Cƶ towards methyl group of SAM, PRMT5 E435- Cƛ, and PRMT5 E444-Cƛ; (4) equilibrate with constrains (the final distance from the previous step) for 100 ns; (5) finally remove all constrains and fully relax for 100 ns. For steered MD (sMD) simulations a force constant of 7.2 kcal / mol / Å2was applied for distances and 3.0 kcal / mol / rad2for dihedral angles. Computations were repeated twice to verify the close reproducibility of the resulting refined structure for the trimmed MCM7-PRMT5 complex.

[0295] Statistical analysis. All experiments were performed in triplicate. As indicated in the figure legends, all quantitative data are presented as the mean ± SD or mean ± SEM of three biologically independent experiments or samples. Statistical significance was determined by two-tailed Student’s t-test or ANOVA test of variance. P < 0.05 was considered statistically significant. Example 8: Synthetic Procedures.

[0296] The synthesis of the compounds can be accomplished by procedures known to one of skill in the art. For example, the compounds can be prepared in a manner analogous to the processes illustrated in the schemes presented herein. Compounds can be prepared from commercially available starting materials, reagents, and intermediates.

[0297] Synthesis of 16-19FReagents and conditions: (a) guanidinium carbonate / DMF, 79%; (b) di-tert-butyl dicarbonate / K2CO3 / DMAP / DMF, 69%; (c) 1,3-dibromo-5,5-dimethylhydantoin / benzoyl Peroxide / CH3CN, 55%; (d) NaH / DMF, 53%; (e) HCl / EtOAc, 83%.

[0298] 7-Methylquinazoline-2,4-diamine.2-Fluoro-4-methylbenzonitrile (3.6 g, 26.63 mmol) and guanidinium carbonate (10.8 g, 119.89 mmol) were added into 80 mL DMF and stirred for 24 h at 150 ºC. After that, the solution was poured into 300 mL iced water and stayed still overnight. The white solids were precipitated and collected by filtration. The solids were washed by water and ether for three times and could be used in the next step directly. (3.66 g, 78.8% yield). ESI-MS: m / z = 175.1 (M+H)+.

[0299] di-tert-Butyl (7-methylquinazoline-2,4-diyl) bis((tert-butoxycarbonyl)carbamate).2,4- Diamino-7-methylquinazoline (2.2 g, 12.6 mmol), di-tert-butyl dicarbonate (17.8 g, 63.2 mmol), K2CO3(8.8 g, 63.2 mmol), and DMAP (0.15 g, 1.2 mmol) were added into 15 mL DMF and stirred at 25 ºC overnight. After that, the solution was poured into iced water. The white solids were precipitated and collected by filtration. The solids were then recrystallized by the mixture of ethanol and water (4.99 g, 69% yield).1H NMR (600 MHz, CDCl3): δ 7.87 – 7.83 (m, 2H), 7.51 (dd, J = 8.6, 1.6 Hz, 1H), 2.61 (s, 3H), 1.45 (s, 18H), 1.35 (s, 18H). ESI-MS: m / z = 575.3 (M+H)+.

[0300] di-tert-Butyl (7-(bromomethyl)quinazoline-2,4-diyl)bis((tert- butoxycarbonyl)carbamate).2-(N,N-di-(tert-Butoxycarbonyl)amino)-4-(N,N-di-(tert- butoxycarbonyl)amino)-7-methyl-quinazoline (3 g, 5.2 mmol), 1,3-dibromo-5,5-dimethylhydantoin (1.77 g, 6.2 mmol), and benzoyl Peroxide (0.12 g, 0.5 mmol) were added into CH3CN 15 mL and refluxed for 5 h. After that, the solvent was evaporated and the residue was purified by column chromatography with hexane / ethyl acetate (10: 1) to get the product (1.87 g, 55% yield).1H NMR (600 MHz, CDCl3): δ 8.05 (d, J = 1.6Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 8.5, 1.6 Hz, 1H), 4.66 (s, 2H), 1.47 (s, 18H), 1.37 (s, 18H). ESI-MS: m / z = 653.2 (M+H)+.

[0301] di-tert-butyl (7-((8-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)quinazoline-2,4- diyl)bis((tert-butoxycarbonyl)carbamate). A solution of 8-chloro-3,4-dihydroquinolin-2(1H)-one (0.09 g, 0.5 mmol) in anhydrous DMF (10 mL) was cooled to 0 °C under N2. After 10 minutes, NaH (60% dispersion in mineral oil, 0.05 g, 0.75 mmol) was added, and the resultant slurry was stirred for 1 h. di-tert-Butyl (7-(bromomethyl)quinazoline-2,4-diyl)bis((tert butoxycarbonyl) carbamate) (0.39 g,0.6 mmol) was added, and the solution was stirred at 25 °C overnight. The solution was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried by Na2SO4, and evaporated to give a crude product. This was purified by SiO2chromatography (hexane / EtOAc) to give product as white solid (0.20 g, 53% yield).1H NMR (600 MHz, CDCl3) δ 7.85 – 7.81 (m, 2H), 7.51 (dd, J = 8.7, 1.5 Hz, 1H), 7.19 (dd, J = 8.1, 1.3 Hz, 1H), 7.10 (d, J = 6.5 Hz, 1H), 6.96 (t, J = 7.7 Hz, 1H), 5.61 (s, 1H), 2.96 – 2.90 (m, 2H), 2.75 – 2.69 (m, 2H), 1.43 (s, 18H), 1.31 (s, 18H). ESI-MS: m / z = 754.3 (M+H)+.

[0302] 8-chloro-1-((2,4-diaminoquinazolin-7-yl)methyl)-3,4-dihydroquinolin-2(1H)-one. di-tert- butyl (7-((8-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl) methyl) quinazoline-2,4-diyl) bis ((tert- butoxycarbonyl) carbamate) (46 mg, 0.06 mmol) was added into 2 mL 1M HCl solution in ethyl acetate and stirred for 10 hours at 25 ºC. After that, the precipitation was filtered and washed by a mixture of ethyl acetate and ethanol. Then the solid was dried under the vacuum to give the product (18 mg, 83%).1H NMR (600 MHz, DMSO) δ 12.80 – 12.74 (m, 1H), 8.99 (s, 1H), 8.76 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.31 – 7.26 (m, 2H), 7.23 – 7.20 (m, 2H), 7.07 (t, J = 7.7 Hz, 1H), 5.32 (s, 2H), 3.02 – 2.96 (m, 2H), 2.67 – 2.61 (m, 2H).13C NMR (151 MHz, DMSO) δ 172.72, 163.25, 155.20, 146.93, 139.52, 138.12, 134.65, 130.27, 127.20, 125.97, 125.29, 123.35, 123.26, 114.46, 108.42, 48.98, 32.60, 26.07. ESI-MS: m / z=354.1 (M+H)+. References 1. Song, K. and M. 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[0303] The present application refers to various issued patent, published patent applications, scientific journal articles, and other publications, all of which are incorporated herein by reference. The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Figures, the Examples, and the Claims. EQUIVALENTS AND SCOPE

[0304] In the articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Embodiments or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0305] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim ...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):, or a pharmaceutically acceptable salt thereof, wherein: A1is CR1or N; each of A2, A3, and A4is independently CH or N; R1is hydrogen or halogen; each of R2aand R2bis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;R3ais hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, – OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, – OS(=O)2ORA, –OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, –NRAS(=O)ORA, – NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, –NRAS(=O)2SRA, – NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, –OSi(RA)3, –OSi(RA)2ORA, – OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; each of A5, A6, A7, and A8is independently CH or N; and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

2. A compound of Formula (Iʹ):, or a pharmaceutically acceptable salt thereof, wherein: A1is CR1or N; each of A2, A3, and A4is independently CH or N; R1is hydrogen or halogen;each of R2aand R2bis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;R3ais hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, – OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, – OS(=O)2ORA, –OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, –NRAS(=O)ORA, –NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, –NRAS(=O)2SRA, – NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, –OSi(RA)3, –OSi(RA)2ORA, – OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; each of A5, A6, A7, and A8is independently CH or N; and each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; provided that the compound of Formula (Iʹ) is not of formula:, or a pharmaceutically acceptable salt thereof.

3. The compound of any one of claims 1 or 2, wherein the compound is of Formula (I-a):, or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein A1is CR1and R1is hydrogen.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein A1is N.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein A1is CR1and R1is –F, –Cl, –Br, or –I.

7. The compound of any one of claims 1, 2, 4, or 5, wherein the compound is of Formula (I-b) or, or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1, 2, or 4-7, or a pharmaceutically acceptable salt thereof, wherein each of A2, A3, and A4is CH.

9. The compound of any one of claims 1-5, 7, or 8, wherein the compound is of Formula (I-b-i) or Formula (I-c-i):, or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each of R2aand R2bis independently hydrogen or optionally substituted alkyl, or R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein each of R2aand R2bis independently hydrogen or optionally substituted alkyl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein at least one of R2aand R2bis hydrogen.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein each of R2aand R2bis hydrogen.

14. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein neither of R2aand R2bis hydrogen.

15. The compound of any one of claims 1-12 or 14, or a pharmaceutically acceptable salt thereof, wherein at least one of R2aand R2bis optionally substituted alkyl.

16. The compound of any one of claims 1-11, 14, or 15, or a pharmaceutically acceptable salt thereof, wherein each of R2aand R2bis optionally substituted alkyl.

17. The compound of any one of claims 1-12 or 14-16, or a pharmaceutically acceptable salt thereof, wherein at least one of R2aand R2bis methyl.

18. The compound of any one of claims 1-11 or 14-17, or a pharmaceutically acceptable salt thereof, wherein each of R2aand R2bis methyl.

19. The compound of any one of claims 1-4 or 7-18, wherein the compound is of Formulae (I-b- ii) to (I-b-iv):or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1-3, 5, or 7-18, wherein the compound is of Formulae (I- c-ii) to (I-c-iv):or a pharmaceutically acceptable salt thereof.

21. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

22. The compound of any one of claims 1-10 or 21, or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare joined together with their intervening nitrogen atom to form an optionally substituted aziridinyl, optionally substituted azetidinyl, optionally substituted oxazetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, or optionally substituted morpholinyl.

23. The compound of any one of claims 1-10, 21, or 22, or a pharmaceutically acceptable salt thereof, wherein24. The compound of any one of claims 1-4, 7-10, or 21-23, wherein the compound is of Formulae (I-b-v) to (I-b-x):or a pharmaceutically acceptable salt thereof.

25. The compound of any one of claims 1-3, 5, 7-10, or 21-23, wherein the compound is of Formulae (I-c-v) to (I-c-x):(I c ix), (I c x), or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein each of A5, A6, and A7is CH.

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein each of A5, A6, and A8is CH.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof,, , ,29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R3is not30. The compound of any one of claims 1-3, 8, or 26-28, wherein the compound is of Formulae (I-a-i) to (I-a-x):or a pharmaceutically acceptable salt thereof.

31. The compound of any one of claims 1-4, 7-9, 26-28, or 30, wherein the compound is of Formulae (I-d-i) to (I-d-x):or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 1-3, 5, 7-9, 26-28, or 30, wherein the compound is of Formulae (I-e-i) to (I-e-x):,or a pharmaceutically acceptable salt thereof.

33. The compound of any one of claims 1-3, 5, 7-9, 26-28, or 30, wherein the compound is not of Formula (I-e-i):or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R3ais halogen, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA,– N(RA)2, –C(=O)N(RA)2,–S(=O)2N(RA)2, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, or – NRAS(=O)2N(RA)2.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R3ais optionally substituted aryl, optionally substituted heteroaryl, –C(=O)N(RA)2,– S(=O)2N(RA)2, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, or –NRAS(=O)2N(RA)2.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R3ais –C(=O)NH2,–S(=O)2NH2, –NHC(=O)NH2, –NHC(=NH)NH2, or –NHS(=O)2NH2.

37. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R3ais halogen, –CN, –ORA, or –N(RA)2.

38. The compound of any one of claims 1-34 or 37, or a pharmaceutically acceptable salt thereof, wherein R3ais –F, –Br, –I, –CN, –ORA, or –N(RA)2.

39. The compound of any one of claims 1-34, 37, or 38, or a pharmaceutically acceptable salt thereof, wherein R3ais –F, –Cl, –Br, or –I.

40. The compound of any one of claims 1-34 or 37-39, or a pharmaceutically acceptable salt thereof, wherein R3ais –F, –Br, or –I.

41. The compound of any one of claims 1-34, 37, or 38, or a pharmaceutically acceptable salt thereof, wherein R3ais –CN.

42. The compound of any one of claims 1-34, 37, or 38, or a pharmaceutically acceptable salt thereof, wherein R3ais –ORA.

43. The compound of any one of claims 1-34, 37, 38, or 42, or a pharmaceutically acceptable salt thereof, wherein R3ais –OH.

44. The compound of any one of claims 1-34, 37, or 38, or a pharmaceutically acceptable salt thereof, wherein R3ais –N(RA)2.

45. The compound of any one of claims 1-34, 37, 38, or 44, or a pharmaceutically acceptable salt thereof, wherein R3ais –NH2.

46. The compound of any one of claims 1-45, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

47. The compound of any one of claims 1-46, wherein the compound is not of formula:, or a pharmaceutically acceptable salt thereof.

48. A composition comprising the compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, and an excipient.

49. A method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of: the compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof; or the composition of claim 48.

50. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or the composition of claim 48, for use in treating a disease in a subject in need thereof.

51. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or the composition of claim 48, for use in the manufacture of a medicament for treatment of a disease in a subject in need thereof.

52. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of clams 49-51, wherein the disease is a proliferative disease.

53. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of claim 52, wherein the proliferative disease is cancer.

54. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of claim 53, wherein the cancer is multiple myeloma, lymphoma, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), large granular lymphocyte leukemia (LGL), sarcoma, lung cancer, breast cancer, renal cancer, prostate cancer, pancreatic cancer, melanoma, colon carcinoma, gastric carcinoma, cervical cancer, ovarian cancer, liver cancer, or head and neck cancer.

55. A method of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of: a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof; or the composition of claim 48; wherein the cell, tissue, or biological sample is in vivo.

56. A method of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of: a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof; or the composition of claim 48; wherein the cell, tissue, or biological sample is in vitro.

57. The method of any one of claims 55 or 56, comprising inhibiting a protein arginine methyltransferase (PRMT).

58. The method of claim 57, wherein the PRMT is PRMT5.

59. A kit comprising: the compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or the composition of claim 48; and instructions for its use.

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