HDAC8 degraders and uses thereof

Abstract

The present disclosure is related to certain compounds, and pharmaceutically acceptable salts thereof, that function as degraders of HD AC (e.g., HD ACS). The present invention also relates to the preparation of these compounds, to pharmaceutical compositions comprising them, and to methods of using these compounds in the treatment of diseases or conditions in which HD AC (e.g., HD ACS) activity is implicated.

Description

HDAC8 DEGRADERS AND USES THEREOFCROSS-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 / 561,385, filed March 5, 2024, titled HDAC8 DEGRADERS AND USES THEREOF, the contents of which are incorporated herewith by reference in their entirety.BACKGROUND

[0002] Histone deacetylases (HDACs) are key enzymes in epigenetic regulation, influencing gene expression by cleaving acetyl groups from histone (Chen et al., 2022). Although termed as histone deacetylases, HDACs have non-histone substrate proteins and can also remove acyl groups other than acetyl group form the 8-amino group of lysines in their substrate proteins (Shang et al., 2022). Dysregulation of HDACs is implicated in the pathogenesis of various human diseases including cancer; metabolic disorders such as type 2 diabetes, adipose tissue inflammation, excessive hepatic lipid accumulation, lipodystrophy, and insulin resistance; neurodegenerative and neurological diseases; inflammatory disorders such as rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, cystic fibroses, acute respiratory distress syndrome, and interstitial fibrosis; kidney diseases; infectious diseases including influenza and pneumonia; and cardiovascular diseases and their complications including heart disease, and stroke (Ho et al., 2020; He et al., 2022).

[0003] Human cells contain eleven isoforms of zinc-dependent HDACs, which can be divided into four phylogenetic groups: class I (HDACs 1-3, and 8), class Ila (HDACs 4, 5, 7, and 9), class lib (HDACs 6 and 10), and class IV (HD AC 11), and seven isoforms of nicotinamide adenine dinucleotide (NAD+)-dependent mammalian sirtuins (SIRT1-7). During the past three decades, HDAC inhibitors (HDACi) with different chemical scaffolds have been developed, and many of them have been evaluated in preclinical and clinical studies for their anticancer activities (Ho et al., 2020; He et al., 2022). Four HDACi have been approved by the FDA for treating lymphomas, leukemias, and multiple myelomas. However, these drugs are either pan or class I selective HDACi, which could limit their use in the clinic due to safety and tolerability concerns.

[0004] HDAC8 is distinguished from other class I HDACs by its unique structural conformation and its capacity to function enzymatically without relying on co-factors. HDAC8 has been reported to interact with various non-histone proteins, such as structural maintenance of chromosomes protein 3 (SMC3), estrogen-related receptor alpha (ERRa), and p53, either as substrates or as partners in interaction (Kim et al., 2022). Beyond its role as a deacetylase, HDAC8 engages in signaling and acts as a scaffold. For example, it plays a dual role as both a deacetylase and a scaffold within the inv(16) fusion protein / HDAC8 / p53 complex (Qi et al., 2015). It also stabilizes the human ever-shorter telomeres IB (EST1B) independently of its deacetylase activity (Lee et al., 2006) and interacts with transcription factors such as signal transducer and activator of transcription 3 (STAT3) (Kang et al.,2014), cAMP response element-binding protein (CREB) (Gao et al., 2009), and deleted in esophageal cancer 1 (DECI) (Qian et al., 2014) to regulate gene expression. Dysregulation of HDAC8 has been linked to diseases including various cancers, immune dysfunctions, fibrotic diseases, and various neurodegenerative diseases, highlighting its potential as a therapeutic target (Fontana et al., 2022).SUMMARY OF THE INVENTION

[0005] The present disclosure provides proteolysis targeting chimeras (PROTACs) capable of binding to HDAC (e.g., HDAC8) and a E3 ligase (e.g., Cereblon and VHL E3 ubiquitin ligase).

[0006] In one aspect, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or C 1-3 alkyl;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; andB is a moiety capable of binding to an E3 ubiquitin ligase.

[0007] In another aspect, the present disclosure provides a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or Cm alkyl;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; and

[0008] In another aspect, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or C 1-3 alkyl;X’ and Y’ are each independently CH, CR1, or N;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; andB is a moiety capable of binding to an E3 ubiquitin ligase.

[0009] In another aspect, the present disclosure provides a compound of Formula (II’):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or C 1-3 alkyl;X’ and Y’ are each independently CH, CR1, or N;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; and

[0010] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.[Oil] In another aspect, the present disclosure provides a method of degrading a HD AC protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0012] In another aspect, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

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

[0014] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims. It should be understood that the aspects described herein are not limited to specific embodiments, methods, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, provide non-limiting examples of the invention.

[0016] FIG 1. shows Western blot of HD AC degradation in MDA-MB-231 cells.

[0017] FIG 2. shows additional Western blot of HD AC degradation in MDA-MB-231 cells.DEFINITIONS

[0018] 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.

[0019] 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, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are 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.

[0020] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0021] 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 “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, Ce, Ci-6, C1-5, Ci^t, C1-3, C1-2, C2-6, C2-5, C2 4, C2-3, C3-6, C3-5, C s 4, C4-6, C4-5, and C5-6 alkyl.

[0022] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0023] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci^t alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of Ci-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) e.g., n-butyl,tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., zz- entyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (Ce) (e.g., zi-hexyl). Additional examples of alkyl groups include n- heptyl (C7), n-octyl (Cs), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted Ci-12 alkyl (such as unsubstituted Ci-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z'-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted / / -butyl (zr-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z'-Bu)). In certain embodiments, the alkyl group is a substituted Ci-12 alkyl (such as substituted Ci-6 alkyl, e.g., -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0024] 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 (“Ci-2o haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“Ci-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 (“Ci-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 (“Ci^ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). 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, -CCI3, -CFCI2, -CF2C1, and the like.

[0025] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-2o alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-i2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-n alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-io alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-s alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“hctcroCi 4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC26 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-12 alkyl.

[0026] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“Ci-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“Ci-12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“Ci-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“Ci-10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1-9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1-8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“Ci-6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“Ci^t alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“Ci alkenyl”). In some embodiments, the one or more carbon-carbon double bonds are internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of Ci 4 alkenyl groups include methylidenyl (Ci), ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.Examples of Ci-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), 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 Ci-20 alkenyl. In certain embodiments, the alkenyl group is a substituted Ci-20 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g.,-CH=CHCH3 or) may be in the (E)- or (Z)-configuration.

[0027] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-s alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkenyl”). In some embodiments, a heteroalkenyl group has Ito 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or2 heteroatoms within the parent chain (“heteroCi-5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“hctcroCi 4 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substitutedheteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroCi-20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroCi-20 alkenyl.

[0028] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“Ci -20 alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“Ci-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“Ci-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“Ci-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“CM alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“Ci alkynyl”). In some embodiments, the one or more carbon-carbon triple bonds are internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of CM alkynyl groups include, without limitation, methylidynyl (Ci), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1- butynyl (C4), 2-butynyl (C4), and the like. Examples of Ci-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), 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 Ci-20 alkynyl. In certain embodiments, the alkynyl group is a substituted Ci-20 alkynyl.

[0029] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi- 20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi- 10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-s alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkynyl”). Insome embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“hctcroCi 4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroCi-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroCi-20 alkynyl.

[0030] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3 -14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3 -13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3 -11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3 -10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3 -7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5 -10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3 -s carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (Cn), spiro[5.5]undecanyl (Cn), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoingexamples 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, in some embodiments, are saturated or 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.

[0031] 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 (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0032] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“bicyclic heterocyclyl”)), and, in some embodiments, is saturated or contains one or more carbon-carbon double or triple bonds. In some embodiments, heterocyclyl polycyclic ring systems include one or more heteroatoms in one or bothrings. “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.

[0033] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 - ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0034] 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-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8- membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl.Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1,4,5 ,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H- furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo- [2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0035] 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 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ctu aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce-i4 aryl. In certain embodiments, the aryl group is a substituted Ce u aryl.

[0036] “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.

[0037] 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 n 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, in some embodiments the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, heteroaryl polycyclic ring systems include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is eitheron 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 is 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. “Heterobiaryl” refers to an instance of two aryl rings being fused together, wherein at least one of the aryl rings is heteroaryl.

[0038] 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.

[0039] 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 and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom includeazepinyl, 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.

[0040] “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.

[0041] The term “unsaturated bond” refers to a double or triple bond.

[0042] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0043] 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.

[0044] 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.

[0045] 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 organiccompounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

[0046] 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), Ci20alkyl, Ci20perhaloalkyl, Ci20alkenyl, Ci-20 alkynyl, heteroCi-2o alkyl, heteroCi-2o alkenyl, heteroCi-2o alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, Ce i4aryl, 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; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; wherein: each instance of Raais, independently, selected from Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-2o alkenyl, Ci-20 alkynyl, heteroCi-2o alkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce i4aryl, 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, CI 20 alkyl, Ci20perhaloalkyl, Ci-2o alkenyl, Ci-20 alkynyl, heteroCi-2oalkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce -14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X’, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-ioalkyl, heteroCi-ioalkenyl, heteroCi- loalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce 10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =0 or =S; each instance of Reeis, independently, selected from Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, Ce 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, Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce 10 aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCi_6 alkyl, — ON(CI-6alkyl)2, -N(CI-6 alkyl)2, -N(CI-6 alkyl)3+X“, -NH(Ci- _6alkyl)2+X“, -NH2(CI_6 alkyl)+X“, -NH3+X“, -NlOCiGalkyl)(Ci^ alkyl), -N(OH)(Ci^ alkyl), -NH(OH), -SH, -SCi^ alkyl, -SSlCiGalkyl), -C(=O)(Ci^ alkyl), -CO2H, -CCMCiGalkyl), -OC(=O)(Ci_6 alkyl), -OCO2(CiGalkyl), -C(=O)NH2, -C(=O)N(Ci-6 alkyl)2, -OC(=O)NH(Ci-6 alkyl), -NHC(=O)( CM, alkyl), -N(Ci^ alkyl)C(=O)( Cwalkyl), -NHCO2(CI_6 alkyl), -NHC(=O)N(CI_6alkyl)2, -NHC(=0)NH(CM alkyl), -NHC(=O)NH2, -C(=NH)0(CM alkyl), -0C(=NH)(CM alkyl), — C)C(=NH)C)Ci <, alkyl, -C(=NH)N(CI_6alkyl)2, -C(=NH)NH(CI_6 alkyl), -C(=NH)NH2, -0C(=NH)N(CM alkyl)2, -OC(NH)NH(C,_ 6 alkyl), -OC(NH)NH2, -NHC(NH)N(CM alkyl)2, -NHC(=NH)NH2, -NHSO2(CI _6alkyl), -SO2N(CI -6 alkyl)2, -S02NH(CM alkyl), -SO2NH2, -S02CM alkyl, -S020CM alkyl, -0S02CM alkyl, -SOCiGalkyl, -Si(Ci-6 alkyl)3, -OSilCiGalkyl)3-C(=S)N(CWalkyl)2, C(=S)NH(CI-6alkyl), C(=S)NH2, -C(=O)S(Ci-6 alkyl), -C(=S)SCM alkyl, -SC(=S)SCi. _6alkyl, -P(=O)(OCi-6 alkyl)2, -P(=O)(Ci-6 alkyl)2, -0P(=0)(CM alkyl)2, -0P(=0)(0CM alkyl)2, Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents are joined to form =0 or =S; and each X" is a counterion.

[0047] In some embodiments, nln certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -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 Ci-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 Ci-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2- pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6alkyl, -0Raa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted Ci-10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0048] 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.

[0049] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0050] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxy,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -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.

[0051] The term “alkoxy” as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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)3and -N(Rbb)3+X“, wherein Rbband X“ are as defined herein.

[0057] The term “sulfonyl” refers to a group selected from -SO2N(Rbb)2, -SO2Raa, and -SO2ORaa, wherein Raaand Rbbare as defined herein.

[0058] The term “sulfinyl” refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0059] The term “acyl” refers to a group having the general formula -C(=O)RX1, -C(=O)ORX1,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 substituentsdescribed 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).

[0060] 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.

[0061] The term “silyl” refers to the group -Si(Raa)3, wherein Raais as defined herein.

[0062] The term “boronyl” refers to boranes, boronic acids, boronic esters, borinic acids, and borinic esters, e.g., boronyl groups of the formula -B(Raa)2, -B(ORCC)2, and -BRaa(ORcc), wherein Raaand Rccare as defined herein.

[0063] The term “phosphino” refers to the group -P(RCC)2, wherein Rccis as defined herein.

[0064] The term “phosphono” refers to the group - (P=O)(ORCC)2, wherein Raaand Rccare as defined herein.

[0065] The term “phosphoramido” refers to the group -O(P=O)(N(Rbb)2)2, wherein each Rbbis as defined herein.

[0066] The term “stannyl” refers to the group -Sn(Rcc)3, wherein Rccis as defined herein.

[0067] The term “germyl” refers to the group -Ge(Rcc)3, wherein Rccis as defined herein.

[0068] The term “arsenyl” refers to the group -As(Rcc)2, wherein Rccis as defined herein.

[0069] The term “oxo” refers to the group =0, and the term “thiooxo” refers to the group =S.

[0070] In some embodiments, nitrogen atoms are 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, Ci-2operhaloalkyl, C 1-20 alkenyl, C 1-20 alkynyl, hetero C 1-20 alkyl, hetero C 1-20 alkenyl, hetero Ci-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce -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.

[0071] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CC R^, -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CChR”, -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a nitrogen protecting group.

[0072] 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, Ci-io alkyl (e.g., aralkyl, heteroaralkyl), Ci-20 alkenyl, Ci-20 alkynyl, hetero C1-20 alkyl, hetero Ci-20 alkenyl, hetero Ci-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce 14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0073] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3- methyl-3-nitrobutanamide, o-nitrocinnamide, -acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0074] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with thenitrogen 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), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-py ridy l)cthy 1 carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1 -dime thyl-2-cy anoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m- nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6- nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(A7V-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-(2V,.A- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1- (3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1- phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0075] 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 thenitrogen 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), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4 / ,8 / -dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0076] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, A-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, A-phthalimidc, A-dithiasuccinimide (Dts), A-2,3-diphcnylmalcimidc, A-2,5-dimethylpyrrole, A-l , 1 ,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1, 3 -dibenzyl- 1,3,5 - triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, A-methylamine, A-allylamine, A-[2- (trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, A-(l-isopropyl-4-nitro-2-oxo- 3-pyroolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, A-di(4- methoxyphenyl)methylamine, A-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), A-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenylfluorenylamine (PhF), A-2,7-dichloro-9- fluorenylmethyleneamine, A-ferrocenylmethylamino (Fem), A-2-picolylamino A’-oxide, A- 1,1- dimethylthiomethyleneamine, A-benzylideneamine, A-p-methoxybenzylideneamine, A- diphenylmethyleneamine, A-[(2-pyridyl)mesityl]methyleneamine, A-(A’,A’- dime thylaminome thy lene) amine, A-p-nitrobenzylideneamine, A-salicylideneamine, A-5- chlorosalicylideneamine, A-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, A- cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, A-borane derivatives, A- diphenylborinic acid derivatives, A-[phenyl(pentaacylchromium- or tungsten)acyl]amine, A-copper chelate, A-zinc chelate, A-nitroamine, A-nitrosoamine, amine A-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o- nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2- nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are A,A’-isopropylidenediamine.

[0077] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0078] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CChR”, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CC R”, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or an oxygen protecting group.

[0079] 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.

[0080] 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 -methoxy cyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl .S'..S'-dioxidc, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1 ,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8- trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1- methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p- nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3- methyl-2-picolyl A-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4'-dimethoxytrityl (4,4'-dimethoxytriphenylmethyl or DMT), a- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’ -bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4, 4', 4"- tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4’-Dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), 1 ,l-bis(4- methoxyphenyl)-l'-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, methoxy acetate, triphenylmethoxy acetate, phenoxy acetate, p-chlorophenoxy acetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p- phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o- nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6- dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(l , 1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(l,l-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (£)-2- methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl iV-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl2.4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0081] 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.

[0082] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogenprotecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a sulfur protecting group.

[0083] 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.

[0084] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0085] 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", CP, Br , I"), NO3, CIO4 , 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~, PEp, PFe", AsFe", SbFe", B[3,5-(CF3)2CeH3]4] , B(C6F5)4~, BPh4 , A1(OC(CF3)3)4", and carborane anions (e.g., CBHHI2- or (HCBi iMesBre) ). 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.

[0086] A “leaving group” (EG) 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. In some embodiments, a leaving group is an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6thed. (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,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, A,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.

[0087] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.

[0088] The term “proteolysis-targeting chimera,” “PROTAC,” “PROTAC degrader,” or “degrader” refer to a heterobifunctional molecule capable of inducing intracellular proteolysis. In some embodiments, a PROTAC comprises an E3 -ubiquitin ligase binding molecule covalently linked to a component that binds the protein targeted for degradation.

[0089] As used herein, the term “degrade” or “degradation” in the context of proteins, for example, in the context of degrading a HD AC protein (e.g., HDAC8), refers to a reduction in the amount of the protein. In some embodiments, the term refers to a reduction of the amount of protein, e.g., a HD AC protein (e.g., HDAC8), to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of amount of the protein. In some embodiments, the term refers to a reduction of the amount of protein, e.g., a HD AC protein (e.g., HDAC8), 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 the amount of protein.

[0090] 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.

[0091] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0092] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present disclosure is not limited in any manner by the above exemplary listing of substituents.

[0093] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and NACi 4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0094] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an aminogroup formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci-4 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.

[0095] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0096] 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 (z.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”.

[0097] The term “crystalline” or “crystalline form” refers to a solid form substantially exhibiting three-dimensional order. In certain embodiments, a crystalline form of a solid is a solid form that is substantially not amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks.

[0098] The term “amorphous” or “amorphous form” refers to a form of a solid (“solid form”), the form substantially lacking three-dimensional order. In certain embodiments, an amorphous form of a solid is a solid form that is substantially not crystalline. In certain embodiments, the X-ray powderdiffraction (XRPD) pattern of an amorphous form includes a wide scattering band with a peak at 20 of, e.g., between 20 and 70°, inclusive, using Cu rz radiation. In certain embodiments, the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures. In certain embodiments, the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 20 of between 20 and 70°, inclusive, is not more than 300-fold, not more than 100-fold, not more than 30-fold, not more than 10-fold, or not more than 3-fold of the maximum intensity of the wide scattering band. In certain embodiments, the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures.

[0099] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid. In the salt, a compound disclosed herein is complexed with the acid in a way that proton transfer e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature. In the co-crystal, however, a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.

[0100] 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.

[0101] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester 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 acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of theparent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Ci-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred.

[0102] The terms “composition” and “formulation” are used interchangeably.

[0103] A “subject” to which administration is contemplated refers to a human (z.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the nonhuman animal is a mammal (e.g., primate e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0104] 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.

[0105] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0106] 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.

[0107] The terms “condition,” “disease,” and “disorder,” are used interchangeably.

[0108] 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).

[0109] 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.

[0110] In certain embodiments, the compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0111] 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.

[0112] 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 certainembodiments, a therapeutically effective amount is an amount sufficient for HD AC (e.g., HDAC8) degradation. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a proliferative disease, metabolic disorder, inflammatory disorder, neurological disease, pulmonary disease, cardiovascular disease, immune disorder, fibrotic disease, hepatic disease, infectious disease, or myopathy.

[0113] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for HD AC (e.g., HDAC8) degradation. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating a proliferative disease, metabolic disorder, inflammatory disorder, neurological disease, pulmonary disease, cardiovascular disease, immune disorder, fibrotic disease, hepatic disease, infectious disease, or myopathy.

[0114] 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.

[0115] 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.

[0116] 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 malignantone, 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.

[0117] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these 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.

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

[0119] The term “metabolic disorder” refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

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

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

[0122] The term “neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease. Examples of neurological diseases include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia;Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; bbrain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt- Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes- dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg- Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox- Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis;Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig- Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0123] The term “lung disease” or “pulmonary disease” refers to a disease of the lung. Examples of lung diseases include, but are not limited to, bronchiectasis, bronchitis, bronchopulmonary dysplasia, interstitial lung disease, occupational lung disease, emphysema, cystic fibrosis, acute respiratorydistress syndrome (ARDS), severe acute respiratory syndrome (SARS), asthma (e.g., intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma), chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, interstitial lung disease, sarcoidosis, asbestosis, aspergilloma, aspergillosis, pneumonia (e.g., lobar pneumonia, multilobar pneumonia, bronchial pneumonia, interstitial pneumonia), pulmonary fibrosis, pulmonary tuberculosis, rheumatoid lung disease, pulmonary embolism, and lung cancer (e.g., non-small-cell lung carcinoma (e.g., adenocarcinoma, squamous-cell lung carcinoma, large-cell lung carcinoma), small-cell lung carcinoma).

[0124] “Cardiovascular disease” refers to a class of diseases that involve the heart and / or blood vessels. While the term technically refers to diseases that affects the the heart and / or blood vessels, other organs such as, for example, the lungs, and joints might be affected or involved in the disease. Examples of cardio vasular diseases include, but are not limited to athersclerosis, arteriosclerosis, aneurysms, angina, chronic stable angina pectoris, unstable angina pectoris, myocardial ischemia (MI), acute coronary syndrome, coronary artery disease, stroke, coronary re-stenosis, coronary stent re-stenosis, coronary stent re-thrombosis, revascularization, post myocardial infarction (MI) remodeling (e.g., post MI remodeling of the left ventricle), post MI left ventricular hypertrophy, angioplasty, transient ischemic attack, pulmonary embolism, vascular occlusion, venous thrombosis, arrhythmias, cardiomyopathies, congestive heart failure, congenital heart disease, myocarditis, valve disease, dialated cardiomyopathy, diastolic dysfunction, endocarditis, rheumatic fever, hypertension (high blood pressure), hypertrophic cardiomyopathy, anneurysms, and mitral valve prolapse.

[0125] Immune disorders, such as auto-immune disorders, include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren’s syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet’s disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), and disorders ameliorated by a gastroprokinetic agent (e.g., ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and food allergies and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costo-chondritis)).

[0126] Infectious diseases, as described herein, are selected from viral, bacterial, protozoological, prion and other infectious diseases. Non-limiting examples of infectious diseases include: Acinetobacter infections, African sleeping sickness (African trypanosomiasis), AIDS (Acquired immunodeficiency syndrome), Amoebiasis, Anaplasmosis, Anthrax, Appendicitis, Arcanobacterium haemolyticum infections, Argentine hemorrhagic fever, Ascariasis, Aspergillosis, Astrovirus infections, Athlete's foot, Babesiosis, Bacillus cereus infections, Bacterial meningitis, Bacterial pneumonia, Bacterial vaginosis (BV), Bacteroides infections, Balantidiasis, Baylisascaris infections, Bilharziosis, BK virus infections, Black piedra, Blastocystis hominis infections, Blastomycosis, Bolivian hemorrhagic fever, Borrelia infections (Borreliosis), Botulism (and Infant botulism), Bovine tapeworm, Brazilian hemorrhagic fever, Brucellosis, Burkholderia infections, Buruli ulcer, Calicivirus infections (Norovirus and Sapovirus), Campylobacteriosis, Candidiasis (Candidosis), Canine tapeworm infections, Cat-scratch disease, Chagas Disease (American trypanosomiasis), Chancroid, Chickenpox, Chlamydia infections, Chlamydia trachomatis infections, Chlamydophila pneumoniae infections, Cholera, Chromoblastomycosis, Climatic bubo, Clonorchiasis, Clostridium difficile infections, Coccidioidomycosis, Cold, Colorado tick fever (CTF), Common cold (Acute viral rhinopharyngitis; Acute coryza), Condyloma acuminata, Conjunctivitis, Creutzfeldt- Jakob disease (CJD), Crimean-Congo hemorrhagic fever (CCHF), Cryptococcosis, Cryptosporidiosis, Cutaneous larva migrans (CLM), Cutaneous Leishmaniosis, Cyclosporiasis, Cysticercosis, Cytomegalovirus infections, Dengue fever, Dermatophytosis, Dientamoebiasis, Diphtheria, Diphy llobothriasis, Donavanosis, Dracunculiasis, Early summer meningoencephalitis (FSME), Ebola hemorrhagic fever, Echinococcosis, Ehrlichiosis, Enterobiasis (Pinworm infections), Enterococcus infections, Enterovirus infections, Epidemic typhus, Epiglottitis, Epstein-Barr Virus Infectious Mononucleosis, Erythema infectiosum (Fifth disease), Exanthem subitum, Fasciolopsiasis, Fasciolosis, Fatal familial insomnia (FFI), Fifth disease, Filariasis, Fish poisoning (Ciguatera), Fish tapeworm, Flu, Food poisoning by Clostridium perfringens, Fox tapeworm, Free-living amebic infections, Fusobacterium infections, Gas gangrene, Geotrichosis, Gerstmann-Strussler-Scheinker syndrome (GSS), Giardiasis, Glanders, Gnathostomiasis, Gonorrhea, Granuloma inguinale (Donovanosis), Group A streptococcal infections, Group B streptococcal infections, Haemophilus influenzae infections, Hand foot and mouth disease (HFMD), Hantavirus Pulmonary Syndrome (HPS), Helicobacter pylori infections, Hemolytic -uremic syndrome (HUS), Hemorrhagic fever with renal syndrome (HFRS), Henipavirus infections, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, Herpes simplex, Herpes simplex type I, Herpes simplex type II, Herpes zoster, Histoplasmosis, Hollow warts, Hookworm infections, Human bocavirus infections, Human ewingii ehrlichiosis, Human granulocytic anaplasmosis (HGA), Human metapneumo virus infections, Human monocytic ehrlichiosis, Human papillomavirus (HPV) infections, Human parainfluenza virus infections, Hymenolepiasis, Influenza, Isosporiasis, Japanese encephalitis, Kawasaki disease, Keratitis, Kingella kingae infections, Kuru, Lambliasis (Giardiasis), Lassa fever, Legionellosis (Legionnaires' disease, Pontiac fever), Leishmaniasis, Leprosy,Leptospirosis, Lice, Listeriosis, Lyme borreliosis, Lyme disease, Lymphatic filariasis (Elephantiasis), Lymphocytic choriomeningitis, Malaria, Marburg hemorrhagic fever (MHF), Marburg virus, Measles, Melioidosis (Whitmore's disease), Meningitis, Meningococcal disease, Metagonimiasis, Microsporidiosis, Miniature tapeworm, Miscarriage (prostate inflammation), Molluscum contagiosum (MC), Mononucleosis, Mumps, Murine typhus (Endemic typhus), Mycetoma, Mycoplasma hominis, Mycoplasma pneumonia, Myiasis, Nappy / diaper dermatitis, Neonatal conjunctivitis (Ophthalmia neonatorum), Neonatal sepsis (Chorioamnionitis), Nocardiosis, Noma, Norwalk virus infections, Onchocerciasis (River blindness), Osteomyelitis, Otitis media, Paracoccidioidomycosis (South American blastomycosis), Paragonimiasis, Paratyphus, Pasteurellosis, Pediculosis capitis (Head lice), Pediculosis corporis (Body lice), Pediculosis pubis (Pubic lice, Crab lice), Pelvic inflammatory disease (PID), Pertussis (Whooping cough), Pfeiffer's glandular fever, Plague, Pneumococcal infections, Pneumocystis pneumonia (PCP), Pneumonia, Polio (childhood lameness), Poliomyelitis, Porcine tapeworm, Prevotella infections, Primary amoebic meningoencephalitis (PAM), Progressive multifocal leukoencephalopathy, Pseudo-croup, Psittacosis, Q fever, Rabbit fever, Rabies, Rat-bite fever, Reiter's syndrome, Respiratory syncytial virus infections (RSV), Rhinosporidiosis, Rhinovirus infections, Rickettsial infections, Rickettsialpox, Rift Valley fever (RVF), Rocky mountain spotted fever (RMSF), Rotavirus infections, Rubella, Salmonella paratyphus, Salmonella typhus, Salmonellosis, SARS (Severe Acute Respiratory Syndrome), Scabies, Scarlet fever, Schistosomiasis (Bilharziosis), Scrub typhusc, Sepsis, Shigellosis (Bacillary dysentery), Shingles, Smallpox (Variola), Soft chancre, Sporotrichosis, Staphylococcal food poisoning, Staphylococcal infections, Strongyloidiasis, Syphilis, Taeniasis, Tetanus, Three-day fever, Tick-borne encephalitis, Tinea barbae (Barber's itch), Tinea capitis (Ringworm of the Scalp), Tinea corporis (Ringworm of the Body), Tinea cruris (Jock itch), Tinea manuum (Ringworm of the Hand), Tinea nigra, Tinea pedis (Athlete's foot), Tinea unguium (Onychomycosis), Tinea versicolor (Pityriasis versicolor), Toxocariasis (Ocular Larva Migrans (OLM) and Visceral Larva Migrans (VLM)), Toxoplasmosis, Trichinellosis, Trichomoniasis, Trichuriasis (Whipworm infections), Tripper, Trypanosomiasis (sleeping sickness), Tsutsugamushi disease, Tuberculosis, Tularemia, Typhus, Typhus fever, Ureaplasma urealyticum infections, Vaginitis (Colpitis), Variant Creutzfeldt- Jakob disease (vCJD, nvCJD), Venezuelan equine encephalitis, Venezuelan hemorrhagic fever, Viral pneumonia, Visceral Leishmaniosis, Warts, West Nile Fever, Western equine encephalitis, White piedra (Tinea blanca), Whooping cough, Yeast fungus spots, Yellow fever, Yersinia pseudotuberculosis infections, Yersiniosis, and Zygomycosis.In some embodiments, the present disclosure provides methods for treating an infectious disease, comprising administering to a subject suffering therefrom an effective amount of a provided solid oral dosage form. In some embodiments, a provided method comprises administering an effective amount of a provided solid oral dosage form and another therapeutic agent known for treatment of an infectious disease.

[0127] In some embodiments, a provided method for treating an infectious disease includes administering to a patient in need thereof a provided solid oral dosage form and another therapeutic agent that is an anti-infectious disease agent. Exemplary anti-infectious disease agents are widely known in the art, including but not limited to P-Lactam Antibiotics such as Penicillin G, Penicillin V, Cloxacilliin, Dicloxacillin, Methicillin, Nafcillin, Oxacillin, Ampicillin, moxicillin, Bacampicillin, Azlocillin, Carbenicillin, Mezlocillin, Piperacillin and Ticarcillin; Aminoglycosides: Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Streptomycin and Tobramycin; Macrolides such as Azithromycin, Clarithromycin, Erythromycin, Lincomycinand Clindamycin; Tetracyclines such as Demeclocycline, Doxycycline, Minocycline, Oxytetracycline and Tetracycline; Quinolones such as Cinoxacin and Nalidixic Acid; Fluoroquinolones such as Ciprofloxacin, Enoxacin, Grepafloxacin, Levofloxacin, Lomefloxacin, Norfloxacin, Ofloxacin, Sparfloxacin and Trovafloxicin; Polypeptides such as Bacitracin, Colistin and Polymyxin B; Sulfonamides such as Sulfisoxazole, Sulfamethoxazole, Sulfadiazine, Sulfamethizole and Sulfacetamide; Miscellaneous Antibacterial Agents such as Trimethoprim, Sulfamethazole, Chloramphenicol, Vancomycin, Metronidazole, Quinupristin, Dalfopristin, Rifampin, Spectinomycin, Nitrofurantoin; General Antiviral Agents such as Idoxuradine, Vidarabine, Trifluridine, Acyclovir, Famcicyclovir, Pencicyclovir, Valacyclovir, Gancicyclovir, Foscarnet, Ribavirin, Amantadine, Rimantadine, Cidofovir, Antisense Oligonucleotides, Immunoglobulins and Inteferons; Drugs for HIV infection such as Tenofovir, Emtricitabine, Zidovudine, Didanosine, Zalcitabine, Stavudine, Lamivudine, Nevirapine, Delavirdine, Saquinavir, Ritonavir and Indinavir, Nelfinavir.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTSCompounds

[0128] In one aspect, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or C 1-3 alkyl;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionallysubstituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; andB is a moiety capable of binding to an E3 ubiquitin ligase.

[0129] In another aspect, the present disclosure provides a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or Cm alkyl;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; and

[0130] In some embodiments, the compound of Formula (I) is of Formula (II).

[0131] In another aspect, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or C 1-3 alkyl;X’ and Y’ are each independently CH, CR1, or N;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene;each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; andB is a moiety capable of binding to an E3 ubiquitin ligase.

[0132] In another aspect, the present disclosure provides a compound of Formula (II’):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or Cm alkyl;X’ and Y’ are each independently CH, CR1, or N;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; and

[0133] In some embodiments, the compound of Formula (I’) is of Formula (II’).R1and m

[0134] As generally described herein, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 3. In some embodiments, m is 4.

[0135] As generally described herein, each instance of R1is independently halogen or Cm alkyl.

[0136] In certain embodiments, at least one instance of R1is halogen. In certain embodiments, at least two instances of R1are halogen. In certain embodiments, at least three instances of R1are halogen. In certain embodiments, at least four instances of R1are halogen. In some embodiments, at least one instance of R1is fluorine. In some embodiments, at least one instance of R1is iodine. In some embodiments, at least one instance of R1is bromine. In some embodiments, at least one instance of R1is chlorine.

[0137] In certain embodiments, at least one instance of R1is Cm alkyl. In certain embodiments, at least two instances of R1are Cm alkyl. In certain embodiments, at least three instances of R1are Cm alkyl. In certain embodiments, at least four instances of R1are Cm alkyl. In some embodiments, at least one instance of R1is methyl. In some embodiments, at least one instance of R1is ethyl. In some embodiments, at least one instance of R1is n-propyl. In some embodiments, at least one instance of R1is ethyl. In some embodiments, at least one instance of R1is isopropyl.

[0138] In some embodiments, the moietyf formula:

[0139] In some embodiments, the moietyembodiments, the moietysome embodiments, the moiety, embodiments, the moietyL1

[0140] As generally described herein, L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, - S(=O)-, -S(=O)2- or -C(=O)-.

[0141] In some embodiments, L1is optionally substituted C3-10 carbocyclylene, optionally substituted C3 10 heterocyclylene, optionally substituted Ce 10 arylene, optionally substituted C3-10 heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C3 10 carbocyclylene, optionally substituted C3 10 heterocyclylene, optionally substituted Ce 10 arylene, or optionally substituted C3 10 heteroarylene are independently replaced with -O-, -NR3-, or -C(=O)-.

[0142] In some embodiments, L1comprises optionally substituted carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. In some embodiments, L1comprises optionally substituted C3 10 carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C3 10 carbocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L1comprises optionally substituted C46 carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C4-6 carbocyclylene are independently replaced with -O-, - NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-.

[0143] In some embodiments, L1comprises optionally substituted carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, are independently replaced with -O-, -NR3-, or -C(=O)-. In some embodiments, L1comprises optionally substituted C3 10 carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C3 10 carbocyclylene, are independently replaced with -O-, -NR3-, or - C(=O)-. In some embodiments, L1is optionally substituted C46 carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C4-6 carbocyclylene, are independently replaced with -O-, -NR3-, or -C(=O)-.

[0144] In some embodiments, L1comprises optionally substituted carbocyclylene. In some embodiments, L1comprises optionally substituted C3-10 carbocyclylene. In some embodiments, L1comprises optionally substituted C4-6 carbocyclylene. In some embodiments, L1comprises unsubstituted carbocyclylene. In some embodiments, L1comprises unsubstituted C3-10 carbocyclylene. In some embodiments, L1comprises unsubstituted C4-6 carbocyclylene. In some embodiments, L1comprises cyclohexylene. In some embodiments, L1comprises. In some embodiments, a structure which comprises two attachment points using this indicator, , may be attached left to right or right to left.

[0145] In some embodiments, L1comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. In some embodiments, L1comprises optionally substituted 3-10 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted 3-10 membered heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, or — C(— O)— . In some embodiments, L1comprises optionally substituted 4-6 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted 4-6 membered heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-.

[0146] In some embodiments, L1comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, or -C(=O)-. In some embodiments, L1comprises optionally substituted 3-10 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted 3-10 membered heterocyclylene are independently replaced with -O-, -NR3-, or -C(=O)-. In some embodiments, L1comprises optionally substituted 4-6 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted 4-6 membered heterocyclylene are independently replaced with -O-, -NR3-, or -C(=O)-.

[0147] In some embodiments, L1comprises unsubstituted heterocyclylene. In some embodiments, L1comprises optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted 3-10 membered heterocyclylene. In some embodiments, L1comprises optionally substituted 4-6 membered heterocyclylene. In some embodiments, L1comprises optionally substituted 4-6 membered heterocyclylene containing 1 or 2 ring heteroatoms selected from N and O. In some embodiments, L1comprises optionally substituted 4-6 membered heterocyclylene containing 1 ring N atom. In some embodiments, L1comprises optionally substituted 4-6 membered heterocyclylene containing 2 ring N atoms. In some embodiments, L1comprises optionally substituted 4-6 membered heterocyclylene containing 1 ring N atom and 1 ring O atom. In some embodiments, L1comprisessome embodiments, L1comprises. In some embodiments, L1comprises. In some embodiments,L1comprises. In some embodiments, L1comprises

[0148] In some embodiments, L1comprises

[0149] In some embodiments, L1comprises optionally substituted arylene, optionally wherein one or more backbone carbon atoms in the optionally substituted arylene are independently replaced with — O— , -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L1is optionally substituted Ce-io arylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ce-io arylene, are independently replaced with -O-, -NR3-, =N-, -N=, -S-, - S(=O)-, -S(=O)2- or — C(— O)— . In some embodiments, L1is optionally substituted Ce arylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ce arylene, are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. In some embodiments, L1is optionally substituted Ce-io arylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ce 10 arylene, are independently replaced with - O— , -NR3-, or — C(— O)— . In some embodiments, L1is optionally substituted Ce arylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ce arylene are independently replaced with -O-, -NR3-, or -C(=O)-. In some embodiments, L1comprises optionally substituted arylene. In some embodiments, L1comprises optionally substituted Ce 10 arylene. In some embodiments, L1comprises optionally substituted Ce arylene. In some embodiments, L1comprises unsubstituted arylene. In some embodiments, L1comprises unsubstituted Ce 10 arylene. In some embodiments, L1comprises unsubstituted Ce arylene. In some embodiments, L1comprises phenylene. In some embodiments, L1comprises

[0150] In some embodiments, L1comprises optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L1comprises optionally substituted Ce io heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ce io heteroarylene, are independently replaced with -O-, - NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. In some embodiments, L1comprises optionally substituted Ce heteroarylene, optionally wherein one or more backbone carbon atoms in theoptionally substituted Ce heteroarylene, are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, or — C(— O)— . In some embodiments, L1comprises optionally substituted Ce 10 heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ce 10 heteroarylene, are independently replaced with -O-, -NR3-, or -C(=O)-. In some embodiments, L1comprises optionally substituted Ce heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ce heteroarylene are independently replaced with -O-, - NR3-, or -C(=O). In some embodiments, L1comprises optionally substituted heteroarylene. In some embodiments, L1comprises optionally substituted Ce 10 heteroarylene. In some embodiments, L1comprises optionally substituted Ce heteroarylene. In some embodiments, L1comprises unsubstituted heteroarylene. In some embodiments, L1comprises unsubstituted Ce 10 heteroarylene. In some embodiments, L1comprises unsubstituted Ce heteroarylene. In some embodiments, L1comprises benzene. In some embodiments, L1comprises pyridylene. In some embodiments, L1comprises,

[0151] In some embodiments, L1is does not comprise optionally substituted arylene or optionally substituted heteroarylene. In some embodiments, L1is does not comprise phenylene or pyridylene. In some embodiments, L1is does not compriseL2

[0153] As generally described herein, L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene. In some embodiments, L2is a bond.

[0154] In some embodiments, L2comprises a bond. In certain embodiments, L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, - S(=O)2- — C(=O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene. In certain embodiments, L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with - O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene.

[0155] In certain embodiments, L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-. In certain embodiments, L2comprisesoptionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -0-, -NR3-, or -C(=0)-.

[0156] In certain embodiments, L2comprises optionally substituted Ci-20 alkylene. In certain embodiments, L2comprises optionally substituted Cm alkylene. In certain embodiments, L2comprises substituted Ci-20 alkylene. In certain embodiments, L2comprises substituted Cm alkylene. In certain embodiments, L2comprises unsubstituted Ci-20 alkylene. In certain embodiments, L2comprises unsubstituted Ci-12 alkylene.combination thereof, wherein p is 0, 1, 3, or 5.

[0160] In some embodiments, L2comprises O , wherein p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or10. In some embodiments, L2comprises O , wherein p is 0. In some embodiments, L2comprises O , wherein p is 1 or 2. In some embodiments, L2comprises O , wherein pis 3 or 4. In some embodiments, L2comprises O , wherein p is 5 or 6. In some embodiments,L2comprises O , wherein p is 7 or 8. In some embodiments, L2comprises O wherein p is 9 or 10.

[0161] In some embodiments, L2comprises, wherein p is 0. In some embodiments, L2comprises, wherein p is 1 or 2. In some embodiments, L2comprises, wherein p is 3 or 4. In some embodiments, L2comprises, wherein p is 5 or 6. In some embodiments,L2comprises, wherein p is 7 or 8. In some embodiments, L2compriseswherein p is 9 or 10.

[0162] In some embodiments, L2comprises, wherein p is 0. In some embodiments, L2comprises, wherein p is 1 or 2. In some embodiments, L22 comprises, wherein p is 3 or 4. In some embodiments, L2compriseswherein p is 5 or 6. In some embodiments, L2compriseswherein p is 7 or 8. In some embodiments, L2comprises

[0163] In some embodiments, L2comprises O , wherein p is 0. In some embodiments, L2comprises, wherein p is 1 or 2. In some embodiments, L2comprises, wherein p is 3 or 4. In some embodiments, L2comprises, wherein p is 5 or 6. In someembodiments, L2comprises O , wherein p is 7 or 8. In some embodiments, L2comprises, wherein p is 9 or 10.

[0164] In some embodiments, L2comprises, wherein p is 0. In some embodiments, L2comprises, wherein p is 1 or 2. In some embodiments, L2, p . , p wherein p is 7 or 8. In some embodiments, L2comprises, wherein p is 9 or 10.

[0165] In some embodiments, L2comprises, wherein each occurrence of p is independently 0, 1, 2, 3, 4, or 5. In some embodiments, L2comprises, wherein each p is independently 0. In some embodiments, L2comprises, wherein each p is independently 0, 1, or 2. In some embodiments, L2comprises, wherein each p is independently 1. In some embodiments, L2comprises, wherein each p is independently 0 or 1.

[0166] In some embodiments, L2comprises, wherein p is 0. In some embodiments,L2comprises, wherein p is 1 or 2. In some embodiments, L2compriseswherein p is 3 or 4. In some embodiments, L2comprises, wherein p is 5 or 6. In some embodiments, L2comprises, wherein p is 7 or 8. In some embodiments, L2comprises, wherein p is 9 or 10.

[0167] In some embodiments, L2comprises, wherein p is 0. In some embodiments,, p . , p , wherein p is 5 or 6. In some embodiments, L2comprises, wherein p is 7 or 8. In some embodiments, L2comprises, wherein p is 9 or 10.

[0168] In some embodiments, L2comprises, wherein p is 0. In some embodiments,, p . , p , wherein p is 5 or 6. In some embodiments, L2comprises, wherein p is 7 or 8. In some embodiments, L2comprises, wherein p is 9 or 10.

[0169] In some embodiments, L2comprises, wherein p is 0. In some embodiments, L2comprises, wherein p is 1 or 2. In some embodiments, L2, p . , p, wherein p is 7 or 8. In some embodiments, L2comprises[, p , wherein p is 0. In some embodiments, L2comprises, wherein p is 1 or 2. In some embodiments, L2comprises, wherein p is 3 or 4. In some embodiments, L2comprises wherein p is 5 or 6. In some embodiments, L2comprises wherein p is 7 or 8. In some embodiments, L2compriseswherein p is 9 or 10.

[0171] In some embodiments, L2comprises, wherein p is 0. In some embodiments, L2comprises, wherein p is 1 or 2. In some embodiments,L2comprises, wherein p is 3 or 4. In some embodiments, L2comprises, p .

[0172] In some embodiments, L2comprises optionally substituted C2-20 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkynylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted C2-12 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-12 alkynylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, - S(=O)2- — C(=O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkylene, or optionally substituted heteroarylene

[0173] In some embodiments, L2comprises optionally substituted C2-20 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkynylene are independently replaced with -O-, -NR3-, or -C(=O)-. In some embodiments, L2comprises optionally substituted C2-12 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-12 alkynylene are independently replaced with -O-, -NR3-, or -C(=O)-.

[0174] In certain embodiments, L2comprises optionally substituted C2-20 alkynylene. In certain embodiments, L2comprises optionally substituted C2 12 alkynylene. In certain embodiments, L2comprises substituted alkynylene. In certain embodiments, L2comprises substituted C2-20 alkynylene. In certain embodiments, L2comprises substituted C2-12 alkynylene. In certain embodiments, L2comprises unsubstituted alkynylene. In certain embodiments, L2comprises unsubstituted C2-20 alkynylene. In certain embodiments, L2comprises unsubstituted C2-12 alkynylene.

[0175] . In some embodiments, L2comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted alkylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted 3- 10 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the 3-10 membered heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, - S(=O)2- — C(=O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted 4-6 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the 4-6 membered heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkylene, or optionally substituted heteroarylene.

[0176] In some embodiments, L2comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, or -C(=O)-. In some embodiments, L2comprises optionallysubstituted 3-10 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted 3-10 membered heterocyclylene are independently replaced with -O-, - NR3-, or — C(=O)— . In some embodiments, L2comprises optionally substituted 4-6 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted 4-6 membered heterocyclylene are independently replaced with -O-, -NR3-, or -C(=O)-.

[0177] In certain embodiments, L2comprises optionally substituted heterocylylene. In certain embodiments, L2comprises optionally substituted 3-10 membered heterocyclylene. In certain embodiments, L2comprises optionally substituted 4-6 membered heterocyclylene. In certain embodiments, L2comprises substituted heterocylylene. In certain embodiments, L2comprises substituted 3-10 membered heterocyclylene. In certain embodiments, L2comprises substituted 4-6 membered heterocyclylene. In certain embodiments, L2comprises unsubstituted heterocylylene. In certain embodiments, L2comprises unsubstituted 3-10 membered heterocyclylene. In certain embodiments, L2comprises substituted 4-6 unmembered heterocyclylene. In some embodiments, L2comprises optionally substituted 4-6 membered heterocyclylene containing 1 or 2 ring heteroatoms selected from N and O. In some embodiments, L2comprises optionally substituted 4-6 membered heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises optionally substituted 4-6 membered heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises optionally substituted 4-6 membered heterocyclylene containing 1 ring N atom and 1 ring O atom.

[0178] In certain embodiments, L2is Cm alkylene, wherein at least one backbone carbon atom in the Ci -12 alkylene is replaced with -NH-. In certain embodiments, L2is Cm alkylene, wherein at least two backbone carbon atoms in the Cm alkylene are replaced with -NH-. In certain embodiments, L2is Cm alkylene, wherein at least three backbone carbon atoms in the Cm alkylene are replaced with - NH-. In certain embodiments, L2is Ci-6 alkylene, wherein at least one backbone carbon atom in the Ci- 12 alkylene is replaced with -NH-. In certain embodiments, L2is Ci-6 alkylene, wherein at least two backbone carbon atoms in the Ci-6 alkylene are replaced with -NH-. In certain embodiments, L2is Ci-6 alkylene, wherein at least three backbone carbon atoms in the Ci-6 alkylene are replaced with -NH-. In certain embodiments, L2is Cm alkylene, wherein at least one backbone carbon atom in the Cm alkylene is replaced with -NH-. In certain embodiments, L2is Cm alkylene, wherein at least two backbone carbon atoms in the Cm alkylene are replaced with -NH-. In certain embodiments, L2is Cm alkylene, wherein at least three backbone carbon atoms in the Cm alkylene are replaced with -NH-. In certain embodiments, L2is Ce 12 alkylene, wherein at least one backbone carbon atom in the Ce 12 alkylene is replaced with -NH-. In certain embodiments, L2is Ce 12 alkylene, wherein at least two backbone carbon atoms in the Ce 12 alkylene are replaced with -NH-. In certain embodiments, L2is Ce 12 alkylene, wherein at least three backbone carbon atoms in the Ce 12 alkylene are replaced with -NH-.

[0179] In some embodiments, L2is Cm alkylene and wherein one or more backbone carbon atoms in the Cm alkylene is replaced with -C(=O)-. In some embodiments, L2is Ci-ie alkylene and wherein one or more backbone carbon atoms in the Ci-6 alkylene is replaced with -C(=O)-. In someembodiments, L2is C7-12 alkylene and wherein one or more backbone carbon atoms in the C7-12 alkylene is replaced with -C(=O)-.

[0180] In some embodiments, L2is Ci-12 alkylene, wherein one or more backbone carbon atoms in the Ci -12 alkylene is replaced with heterocyclylene. L2is Ci-6 alkylene, wherein one or more backbone carbon atoms in the Ci-6 alkylene is replaced with heterocyclylene. L2is C7-12 alkylene, wherein one or more backbone carbon atoms in the C7-12 alkylene is replaced with heterocyclylene.

[0001] In certain embodiments, L2is Ci-12 alkylene and one or more backbone carbon atoms in the C 1-12 alkylene is replaced with a C3-6 heterocyclylene. In certain embodiments, L2is Ci-6 alkylene and one or more backbone carbon atoms in the Ci-6 alkylene is replaced with a C3 6 heterocyclylene. In certain embodiments, L2is C7-12 alkylene and one or more backbone carbon atoms in the C7-12 alkylene is replaced with a C36 heterocyclylene. In certain embodiments, L2is Cm alkylene and one or more backbone carbon atoms in the Ci-12 alkylene is replaced with a heterocyclylene.

[0181] In some embodiments, L2is Cm alkylene and one or more backbone carbon atoms in the Ci- 12 alkylene is replaced with C2-C11 alkynylene. In some embodiments, L2is Ci-6 alkylene and one or more backbone carbon atoms in the Ci-6 alkylene is replaced with C2-C11 alkynylene. In some embodiments, L2is C7-12 alkylene and one or more backbone carbon atoms in the C7-12 alkylene is replaced with C2-C11 alkynylene. In certain embodiments, L2is Cm alkylene, wherein one or more backbone carbon atoms is replaced with alkynylene.

[0182] In some embodiments, L2is Cm alkylene, wherein one or more backbone carbon atoms in the Ci -12 alkylene is replaced with carbocyclylene. In some embodiments, L2is Ci-6 alkylene and one or more backbone carbon atoms in the Ci-6 alkylene is replaced with carbocyclylene. In some embodiments, L2is C7-12 alkylene and one or more backbone carbon atoms in the C7-12 alkylene is replaced with carbocyclylene. In certain embodiments, L2is Cm alkylene, wherein one or more backbone carbon atoms is replaced with carbocyclylene.R3

[0183] As generally described herein, each instance of R3is independently hydrogen or optionally substituted alkyl. In certain embodiment, each instance of R3is independently hydrogen or optionally substituted alkyl. In certain embodiment, at least one instance of R3is hydrogen. In certain embodiment, each instance of R3is independently hydrogen. In certain embodiment, each instance of R3optionally substituted alkyl. In certain embodiment, each instance of R3optionally substituted Ci-10 alkyl.B1In certain embodiments,some embodiments, B1isembodiments,certain embodiments, B1isIn some embodiments, B1isIn certain embodiments, B1is

[0186] As generally described herein, B is a moiety capable of binding to an E3 ubiquitin ligase. In

[0187] In certain embodiments,some embodiments, B isembodiments,certain embodiments,certain embodiments,Additional Embodiments

[0188] In some embodiments, the compound of Formulae (I) or (II) is of Formulae (I-a), (I-b), (I-or a pharmaceutically acceptable salt thereof, wherein: L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with alkynylene, -0-, -NR3-,-C(=0)-, or heterocyclylene; R2is hydrogen, optionally substituted Ci-Cs alkyl, or optionally substituted C3-8 cycloalkyl; and each of X and Y is independently N or CH.

[0189] In some embodiments, the compound of Formula (I) or (II) is of Formula (I-a). In some embodiments, the compound of Formula (I) or (II) is of Formula (I-b). In some embodiments, the compound of Formula (I) or (II) is of Formula (I-c). In some embodiments, the compound of Formula(I) or (II) is of Formula (I-d). In some embodiments, the compound of Formula (I) or (II) is of Formula (I-e). In some embodiments, the compound of Formula (I) or (II) is of Formula (I-f). In some embodiments, the compound of Formula (I) or (II) is of Formula (I-g).

[0190] In some embodiments, the compound of Formula (I) or (II) is Formula (I-a), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-a), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-a), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; andexactly one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I- a), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with - O- , -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0191] In some embodiments, the compound of Formula (I) or (II) is Formula (I-b), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-b), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-b), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I- b), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with - O— , -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0192] In some embodiments, the compound of Formula (I) or (II) is Formula (I-c), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-c), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-c), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I- c), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with - O— , -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0193] In some embodiments, the compound of Formula (I) or (II) is Formula (I-d), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=0)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-d), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-d), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I- d), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with - O— , -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0194] In some embodiments, the compound of Formula (I) or (II) is Formula (I-e), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-e), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-e), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I- e), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with - O— , -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0195] In some embodiments, the compound of Formula (I) or (II) is Formula (I-f), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-f), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-f), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene areindependently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I- f), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with - O— , -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0196] In some embodiments, the compound of Formula (I) or (II) is Formula (I-g), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-g), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-g), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I- g), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with - O— , -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0197] In some embodiments, the compound of Formulae (I’) or (II’) is of Formulae(I-a’), (I-b’), (I-c’), (I-d’), (I-e’), (I-f ’), d-g’), d-h’), (I-i*):or a pharmaceutically acceptable salt thereof, wherein: each of X and Y is independently N or CH.

[0198] In some embodiments, the compound of Formula (I’) or (II’) is of Formula (I-a’). In some embodiments, the compound of Formula (I’) or (II’) is of Formula (I-b’). In some embodiments, the compound of Formula (I’) or (II’) is of Formula (I-c’). In some embodiments, the compound of Formula (I’) or (II’) is of Formula (I-d’). In some embodiments, the compound of Formula (I’) or (II’) is of Formula (I-e’). In some embodiments, the compound of Formula (I’) or (II’) is of Formula (I-f ’). In some embodiments, the compound of Formula (I’) or (II’) is of Formula (I-g’).

[0199] In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-a’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-a’), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, thecompound of Formula (I’) or (II’) is Formula (I-a’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-a’), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0200] In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-b’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-b’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-b’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-b’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0201] In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-c’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-c’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-c’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-c’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one ormore backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0202] In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-d’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-d’), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-d’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-d’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0203] In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-e’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-e’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-e’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-e’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0204] In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-f ’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbonatoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-f’), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-f’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-f’), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0205] In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-g’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-g’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-g’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-g’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0206] In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-h’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-h’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2isoptionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-h’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-h’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.

[0207] In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-i’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-i’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-i’), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N. In some embodiments, the compound of Formula (I’) or (II’) is Formula (I-i’), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is optionally substituted Ci-Cs alkyl; and exactly one of X or Y is N.X and Y

[0208] As generally described herein, each of X and Y is independently N or CH. In some embodiments, X is C and Y is N. In some embodiments, X is C and Y is C. In some embodiments X is N and Y is C. In certain embodiments, at least one of X or Y is N. In some embodiments, X and Y are both N.X’ and Y’

[0209] As generally described herein, each of X’ and Y’ is independently CH, CR1, or N, wherein each instance of R1is independently halogen or C1-3 alkyl;. In some embodiments, X’ is CH or CR1and Y’ is N. In some embodiments, X’ is CH or CR1. In some embodiments, Y’ is N. In some embodiments, Y’ is CH or CR1. In some embodiments, X’ is CH or CR1and Y’ is CH or CR1. Insome embodiments, X’ is CH and Y’ is CR1. In some embodiments, X’ is CR1and Y’ is CH. In some embodiments, X’ is CH and Y’ is CH. In some embodiments, X’ is CH and Y’ is N. In some embodiments, X’ is N and Y’ is CH.R2

[0210] As generally described herein, R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl.

[0211] In certain embodiments, R2is hydrogen. In certain embodiments, R2is optionally substituted Ci-C8alkyl. In certain embodiments, R2is optionally substituted alkyl. In certain embodiments, R2is optionally substituted C1-C3 alkyl. In certain embodiments, R2is optionally substituted cycloalkyl. In certain embodiments, R2is optionally substituted C48 cycloalkyl. In certain embodiments, R2is Ci-C8alkyl substituted with one or more halo. In certain embodiments, R2is Ci-C8alkyl substituted with one or more fluorines. In certain embodiments, R2is Ci-C8alkyl substituted with one fluorine. In certain embodiments, R2is Ci-C8alkyl substituted with two fluorines. In certain embodiments, R2is Ci-C8alkyl substituted with three fluorines.

[0212] In certain embodiments,wherein q is 1, 2, 3, 4, 5, or 6. In some embodiments, R2is, wherein q is 1, 2, 3, 4, 5, or 6. In certain embodiments, R2is, wherein q is 1, 2, 3, 4, 5, or 6. In certain embodiments, R2is, wherein q is 1, 2, 3, 4, 5, or 6. In some embodiments, R2is, wherein q is 1 or 2.In some embodiments, R2iswherein q is 1.

[0213] In some embodiments, R2is, wherein q is 1. In some embodiments, R2iswherein q is 2. In some embodiments, R2is, wherein q is 3. In some embodiments, R2is, wherein q is 4. In some embodiments, R2is, wherein q is 5, In some embodiments,wherein q is 6.

[0214] In some embodiments, R2is, wherein q is 1. In some embodiments, R2is, wherein q is 2. In some embodiments, R2is '3', wherein q is 3. In some embodiments, R2is '3', wherein q is 4. In some embodiments, R2isl’3l, wherein q is 5,In some embodiments, R2is '3', wherein q is 6.

[0215] In some embodiments, R2is, wherein q is 1, 2, 3, 4, 5, or 6. In some embodiments, R2is, wherein q is 1. In some embodiments, R2is, wherein q is 2.In some embodiments, R2is, wherein q is 3. In some embodiments, R2iswherein q is 4. In some embodiments, R2is, wherein q is 5, In some embodiments, R2is, wherein q is 6.

[0216] In some embodiments, R2is, wherein q is 1, 2, 3, 4, 5, or 6. In some embodiments, R2is, wherein q is 1. In some embodiments, R2is, wherein q is 2.In some embodiments, R2is, wherein q is 3. In some embodiments, R2iswherein q is 4. In some embodiments, R2is, wherein q is 5, In some embodiments, R2is '* , wherein q is 6.

[0217] In some embodiments, R2is, wherein q is 1, 2, 3, 4, 5, or 6. In some embodiments, R2is, wherein q is 1. In some embodiments, R2is, wherein q is2. In some embodiments, R2is, wherein q is 3. In some embodiments, R2iswherein q is 4. In some embodiments, R:is, wherein q is 5, In some embodiments, R2is, wherein q is 6.

[0218] In some embodiments, the compound of Formula (I) or (II) is Formula (I-a), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n-propyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-a), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n-propyl; and at least one of X or Y is N.

[0219] In some embodiments, the compound of Formula (I) or (II) is Formula (I-b), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n-propyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-b), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n-propyl; and at least one of X or Y is N.

[0220] In some embodiments, the compound of Formula (I) or (II) is Formula (I-c), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n-propyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-c), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n-propyl; and at least one of X or Y is N.

[0221] In some embodiments, the compound of Formula (I) or (II) is Formula (I-d), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n-propyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-d), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n-propyl; and at least one of X or Y is N.

[0222] In some embodiments, the compound of Formula (I) or (II) is Formula (I-e), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n-propyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-e), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n-propyl; and at least one of X or Y is N.

[0223] In some embodiments, the compound of Formula (I) or (II) is Formula (I-f), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n-propyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-f), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n-propyl; and at least one of X or Y is N.

[0224] In some embodiments, the compound of Formula (I) or (II) is Formula (I-g), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbonatoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n-propyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-g), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n-propyl; and at least one of X or Y is N.

[0225] In some embodiments, the compound of Formula (I) or (II) is Formula (I-a), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n- hexyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-a), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n- hexyl; and at least one of X or Y is N.

[0226] In some embodiments, the compound of Formula (I) or (II) is Formula (I-b), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n- hexyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-b), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n- hexyl; and at least one of X or Y is N.

[0227] In some embodiments, the compound of Formula (I) or (II) is Formula (I-c), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n- hexyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-c), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n- hexyl; and at least one of X or Y is N.

[0228] In some embodiments, the compound of Formula (I) or (II) is Formula (I-d), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n- hexyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-d), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n- hexyl; and at least one of X or Y is N.

[0229] In some embodiments, the compound of Formula (I) or (II) is Formula (I-e), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n- hexyl; and at least one of X or Y is N. In some embodiments, the compound ofFormula (I) or (II) is Formula (I-e), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n- hexyl; and at least one of X or Y is N.

[0230] In some embodiments, the compound of Formula (I) or (II) is Formula (I-f), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n- hexyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-f), wherein L2comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n- hexyl; and at least one of X or Y is N.

[0231] In some embodiments, the compound of Formula (I) or (II) is Formula (I-g), wherein L2comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR3-, or - C(=O)-; R2is n- hexyl; and at least one of X or Y is N. In some embodiments, the compound of Formula (I) or (II) is Formula (I-g), wherein L2comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NR3-, or -C(=O)-; R2is n-hexyl; and at least one of X or Y is N.

[0232] In some embodiments, the compound of Formula (I) or (II) is selected from any one of the compounds of Tables 1-2, and pharmaceutically acceptable salts thereof. In some embodiments, the compound of Formula (I) or (II) is selected from a pharmaceutically acceptable salt of any one of the compounds of Tables 1-2. In some embodiments, the compound of Formula (I) or (II) is selected from any one of the compounds of Tables 1-2.

[0233] In certain embodiments, the present disclosure provides a compound selected from any one of the compounds of Tables 1-2, and pharmaceutically acceptable salts thereof:

[0234] In some embodiments, a provided compound is any compound of the present disclosure (e.g., Formula (I), Formula (II)), or a pharmaceutically acceptable salt thereof. In some embodiments, a provided compound is any compound of the present disclosure (e.g., Formula (I), Formula (II)), or a salt thereof. In some embodiments, a provided compound is any compound of the present disclosure (e.g., Formula (I), Formula (II)).Pharmaceutical Compositions, Kits, and Administration

[0235] The present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described hereincomprises a compound of disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0236] In one aspect, provided herein a pharmaceutical composition comprising the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, pharmaceutical composition of the present disclosure further comprises an additional pharmaceutical agent. In certain embodiments, the additional pharmaceutical agent is an anticancer agent. In certain embodiments, the additional pharmaceutical agent is a chemotherapeutic agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof.

[0237] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophy tactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a in a painful condition subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a painful condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for degrading a HD AC protein (e.g., HDAC8) in a subject or cell.

[0238] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. 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, thesubject 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.

[0239] In certain embodiments, the cell is present in vitro. In certain embodiments, the cell is present in vivo.

[0240] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0241] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0242] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0243] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents or fillers, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0244] Exemplary diluents or fillers include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, starches (such as dry starch, cornstarch), sugars (such as powdered sugar), calcium trisulfate, carboxymethylcellulose calcium, dextrate, dextrin, dextrose, fructose, lactitol, lactose, magnesiumcarbonate, magnesium, maltitol, maltodextrin, maltose, sucrose, glucose, mannitol, silicic acid, xylitol, and mixtures thereof.

[0245] 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.

[0246] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene 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.

[0247] Exemplary disintegrating agents or disintegrants include agar, algin, alginic acid, sodium alginate, silicates, sodium carbonate, calcium carbonate, carboxymethylcellulose, cellulose, clay, colloidal silicon dioxide, croscarmellose sodium, crospovidone, rubber, magnesium silicate, methylcellulose, potassium krillin, hydroxypropylcellulose (e.g., low substituted Hydroxypropylcellulose), crosslinked polyvinylpyrrolidone, hydroxypropylcellulose, and starch (e.g., sodium glycolate starch, potato or tapioca starch).

[0248] Exemplary binding agents include starch (e.g., glycolate starch, cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxy ethylcellulose, 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.

[0249] 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.

[0250] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxy toluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0255] 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.

[0256] 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, NeoIone®, Kathon®, and Euxyl®.

[0257] 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.

[0258] Exemplary lubricating agents include agar, ethyl oleate, ethyl laurate, glycerin, blyceryl palmitostearate, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycol, sodium stearyl, sorbitol, zinc stearate, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0259] 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.

[0260] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein aremixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0261] 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.

[0262] In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a ready-to-use (“RTU”) preparation that can be directly administered to a subject. In some embodiments, the RTU preparation is a suspension. In some embodiments, the RTU preparation is a solution. In some embodiments, the RTU preparation is an emulsion. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a solid that is reconstituted prior to administration. In some embodiments, the solid is a lyophilized solid. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a liquid or suspension that is diluted prior to administration.

[0263] In some embodiments, the pharmaceutical compositions disclosed herein comprise a bulking agent. Bulking agents can be used, e.g., to improve the appearance of a solid composition, to provide visible “bulk” to demonstrate product quality or to facilitate preparation, e.g., of a solid composition prepared for reconstitution prior to administration. Bulking agents can be used for low dose (high potency) drugs that do not have the necessary bulk to support their own structure or provide a visible composition in a unit dosage form. Bulking agents are used in lyophilized formulations. Bulking agents provide a desirable structure for a lyophilized cake comprising pores that provide the means for vapor to escape from the product during lyophilization cycles, and facilitate dissolution on reconstitution. In some embodiments, the bulking agent is mannitol, lactose, sucrose, dextran, trehalose, povidone, dextran, glycine, isoleucine, methionine, or a cyclodextrin (e.g., (2-hydroxypropyl)- P-cyclodextrin) .

[0264] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0265] 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 andcrystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0266] 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.

[0267] 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.

[0268] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0269] 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 mayoptionally 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.

[0270] 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.

[0271] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0272] 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.

[0273] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry 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 nanometersand at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0274] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0275] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface-active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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 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 compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0280] Compounds provided herein 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 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.

[0281] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, 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 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). In certain embodiments, the compound orpharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0282] The exact amount of a 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, 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 tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. 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 is 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. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, 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. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0283] 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.

[0284] A compound or 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 compounds or 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 in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and / or in degrading a HDAC protein (e.g., HDAC8) in a subject or cell), 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 therapy 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 compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound 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.

[0285] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which 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 or 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 e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder). 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 composition described herein in a single dose or composition or administered separately in different doses or compositions. 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.

[0286] 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, antipyretics, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anticancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase. 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 (HD AC 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.Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

[0287] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound describedherein provided in the first container and the second container are combined to form one unit dosage form.

[0288] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for degrading an HD AC protein (e.g., HDAC8) in a subject or cell.

[0289] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for degrading an HD AC protein (e.g., HDAC8) in a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0290] In one aspect, the present disclosure provides a kit comprising: a compound provided herein, or a pharmaceutical composition described herein; and instructions for its use.Methods of Degrading a HDAC Protein, Treatment and Prevention, and Treating Disease

[0291] In one aspect, provided herein is a method of degrading a HDAC protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition. In another aspect, provided herein is a method of degrading a HDAC protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In anotheraspect, provided herein is a method of degrading a HDAC protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0292] In some embodiments, the HDAC protein is a class 1 HDAC protein. In certain embodiments, the HDAC protein is HDAC8. In some embodiments, the cell, tissue, or biological sample is in vitro. In certain embodiments, the cell, tissue, or biological sample is in vivo. In some embodiments, the cell is a cancer cell.

[0293] In another aspect, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition disclosed herein. In another aspect, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0294] In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a provided compound or pharmaceutical composition. In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0295] In another aspect, the present disclosure provides a method of preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a provided compound or pharmaceutical composition. In another aspect, the present disclosure provides a method of preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the present disclosure provides a method of preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compoundof Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0296] In some embodiments, the disease is a proliferative disease, metabolic disorder, inflammatory disorder, neurological disease, pulmonary disease, cardiovascular disease, immune disorder, fibrotic disease, hepatic disease, infectious disease, or myopathy. In certain embodiments, the disease is proliferative disease. In certain embodiments, the disease is metabolic disorder. In certain embodiments, the disease is inflammatory disorder. In certain embodiments, the disease is neurological disease. In certain embodiments, the disease is pulmonary disease. In certain embodiments, the disease is cardiovascular disease. In certain embodiments, the disease is an immune disorder. In certain embodiments, the disease is fibrotic disease. In certain embodiments, the disease is systemic disease. In certain embodiments, the disease is infectious disease. . In certain embodiments, the disease is hepatic disease. . In certain embodiments, the disease is myopathy.

[0297] In certain embodiments, the proliferative disease is cancer. In some embodiments, the cancer is breast cancer, lung cancer, prostate cancer, neuroblastoma, melanoma, colon cancer, brain tumor, liver cancer, or hematological malignancies. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is neuroblastoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is brain tumor. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is hematological malignancies.

[0298] In certain embodiments, the metabolic disorder is type 2 diabetes, adipose tissue inflammation, excessive hepatic lipid accumulation, lipodystrophy, or insulin resistance. In certain embodiments, the metabolic disorder is type 2 diabetes. In certain embodiments, the metabolic disorder is adipose tissue inflammation. In certain embodiments, the metabolic disorder is excessive hepatic lipid accumulation. In certain embodiments, the metabolic disorder is lipodystrophy. In certain embodiments, the metabolic disorder is insulin resistance. In certain embodiments, the metabolic disorder is obesity.

[0299] In certain embodiments, the neurological disease is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Parkinsons disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In certain embodiments, the neurodegenerative disease is Huntington’s disease. In certain embodiments, the neurodegenerative disease is prion disease. In certain embodiments, the neurodegenerative disease is Amyotrophic lateral sclerosis disease. In certain embodiments, the neurodegenerative disease is motor neuron disease. In certain embodiments, the neurodegenerative disease is spinal muscular atrophy disease. In some In some embodiments the neurodegenerative disease is Lewy body dementia disease. In some embodiments the neurodegenerative disease is Batten disease. In some embodiments the neurodegenerative disease is Frontotemporal dementia.

[0300] In some embodiments, the inflammatory disorder is rheumatoid arthritis or asthma. In some embodiments, the inflammatory disorder is rheumatoid arthritis. In some embodiments, the inflammatory disorder is asthma. In certain embodiments, the pulmonary disorder is cystic fibrosis, acute respiratory distress syndrome, or interstitial fibrosis. In certain embodiments, the pulmonary disorder is cystic fibrosis. In certain embodiments, the pulmonary disorder is acute respiratory distress syndrome. In certain embodiments, the pulmonary disorder is interstitial fibrosis. In some embodiments, the infectious disease is influenza or pneumonia. In some embodiments, the infectious disease is influenza. In some embodiments, the infectious disease is pneumonia. In some embodiments, the infectious disease is coronavirus. In certain embodiments, the disease is associated with HD AC 8.EXAMPLES

[0301] 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.

[0302] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.Example 1: Synthesis and characterization.

[0303] General Methods.- THF, DCM, and toluene were obtained via a solvent purification system by filtering through two columns packed with activated alumina and 4 A molecular sieves, respectively. All other chemicals obtained from commercial sources were used without further purification. Flash chromatography was performed using silica gel (230-400 mesh) as the stationary phase. Reaction progress was monitored by thin-layer chromatography (silica- coated glass plates) and visualized by UV light, and / or by LC-MS. 1H NMR spectra were recorded in CDC13, DMSO-d6, or CD3OD at 600 MHz. Chemical shifts 5 are given in ppm using tetramethylsilane as an internal standard. Multiplicities of NMR signals are designated as singlet (s), broad singlet (br s), doublet (d), doublet of doublets (dd), triplet (t), quartet (q), and multiplet (m). All final compounds for biological testing were of >95.0% purity as analyzed by LC-MS, performed on an Advion AVANT LC system with the expression CMS using a Thermo Accucore™ Vanquish™ Cl 8+ UHPLC Column (1.5 pm, 50 x 2.1 mm) at 40 °C. Gradient elution was used for UHPLC with a mobile phase of acetonitrile and water containing 0.1% formic acid.

[0304] Synthesis of A1-A9:Synthetic route for A1-A9: (i) CbzCl, DCM, EtsN. (ii) Hydrazine hydrate, EtOH, reflux, (iii) a) Aldehyde, MeOH, THF; b) NaBH4, MeOH, THE (iv) BOC2O, EtsN, DCM. (v) H2, Pd / C, MeOH. (vi) K2CO3, DIPEA, MeCN, 55 °C. (vii) TFA, DCM.

[0305] Intermediate 2: Benzyl 4-(4-(ethoxycarbonyl)phenyl)piperazine-l-carboxylate. A mixture of 1 (2.0 g, 8.55 mmol), CbzCl (1.67g, 9.83 mmol), and EpN (3.5 mL) in DCM (30 mL) was stirred at room temperature for 12 h. The mixture was poured into water and extracted with EA. The combined organic layers were washed with NaHCO3(aq.) x 1, brine x 1, dried over anhydrous Na^SO-i. filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography to afford the title compound (2.74 g, yield 87%). ’H NMR (600 MHz, Chloroform-cZ) 5 7.97 - 7.92 (m, 2H), 7.40 - 7.31 (m, 5H), 6.89 - 6.84 (m, 2H), 5.17 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.71 - 3.62 (m, 4H), 3.31 (s, 4H), 1.37 (t, J = 7.1 Hz, 3H). LC-MS (ESI): m / z 369.2 [M+H]+.

[0306] Intermediate 5a: Benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-ethylhydrazine-l- carbonyl)phenyl)piperazine-l-carboxylate. A mixture of 2 (2.0 g, 5.4 mmol), Hydrazine monohydrate (2.7 g, 54 mmol) in ethanol (30 mL) was refluxed for 24 h. The mixture was cooled to room temperature and concentrated under vacuum, the resulting crude 3 was used without further purification. A mixture of 3, acetaldehyde (753 mg, 17.1 mmol) in MeOH-THF (1:1, v / v, 30 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in MeOH-THF (1:1, v / v, 30 mL). The solution was treated with NaBH4 (965 mg, 25.5 mmol) and stirred for 30 min. Then it was diluted with water and extracted with ethyl acetate. The organic phase was washed with water x 1, brine xl, dried over Na^SOr. filtered, and evaporated to dryness. The crude product was purified by flash column chromatography to afford the compound 4a (1.5 g, yield 72%). LC-MS (ESI): m / z 383.2 [M+H]+. A mixture of 4a (1.5 g, 4.04 mmol), BOC2O (969 mg, 4.45 mmol), and EpN (1.3 mL) in DCM (30 mL) was stirred at room temperature for 12 h. The mixture was poured into water and extracted with EA. The combined organic layers were washed with brine x 1, dried over anhydrous Na^SOr. filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography to afford the title compound (1.64 g, yield 83 %). ’H NMR (600 MHz, Chloroform-d) 57.74 - 7.69 (m, 2H), 7.39 - 7.31 (m, 5H), 6.90 - 6.71 (br, 2H), 5.17 (s, 2H), 3.69 - 3.59 (m, 6H), 3.36 - 3.16 (m, 4H), 1.46 (s, 9H), 1.17 (t, 7= 7.2 Hz, 3H). LC-MS (ESI): m / z 483.3 [M+H]+.

[0307] Intermediate 5b: benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-propylhydrazine-l- carbonyl)phenyl)piperazine-l-carboxylate. Following similar procedure, 5b was obtained from 3 and propionaldehyde (540 mg, 51%). ’H NMR (600 MHz, Chloroform-c / ) 57.76 - 7.68 (m, 2H), 7.41 - 7.31 (m, 5H), 6.93 - 6.77 (m, 2H), 5.17 (s, 2H), 3.73 - 3.62 (m, 4H), 3.54 (t, 7= 7.3 Hz, 2H), 3.27 (s, 4H), 1.65 - 1.34 (m, 11H), 0.92 (t, 7 = 7.4 Hz, 3H). LC-MS (ESI): m / z 497.2 [M+H]+.

[0308] Intermediate 5c: Benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-butylhydrazine-l- carbonyl)phenyl)piperazine-l-carboxylate. Following similar procedure, 5c was obtained from 3 and butyraldehyde (200 mg, 60%). ’H NMR (600 MHz, Chloroform-<7) 57.73 (d, 7 = 8.5 Hz, 2H), 7.41 - 7.34 (m, 5H), 6.94 - 6.83 (m, 2H), 5.19 (s, 2H), 3.69 (t, 7= 5.3 Hz, 4H), 3.60 (t, 7= 7.3 Hz, 2H), 3.35 - 3.25 (m, 4H), 1.64 - 1.27 (m, 13H), 0.96 - 0.94 (m, 3H). LC-MS (ESI): m / z 511.2 [M+H]+.

[0309] Intermediate 5d: Benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-pentylhydrazine-l- carbonyl)phenyl)piperazine-l-carboxylate. Following similar procedure, 5d was obtained from 3 and pentanal (183 mg, 53%). ’H NMR (600 MHz, Chloroform-<7) 5 7.73 - 7.68 (m, 2H), 7.39 - 7.31 (m, 5H), 6.93 - 6.75 (m, 2H), 5.17 (s, 2H), 3.66 (t, 7= 5.3 Hz, 4H), 3.56 (t, 7= 7.4 Hz, 2H), 3.34 - 3.19 (m, 4H), 1.62 - 1.25 (m, 15H), 0.89 (t, 7 = 7.0 Hz, 3H). LC-MS (ESI): m / z 525.4 [M+H]+.

[0310] Intermediate 5e: Benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-hexylhydrazine-l- carbonyl)phenyl)piperazine-l-carboxylate. Following similar procedure, 5e was obtained from 3 and hexanal (430 mg, 65%). ’H NMR (600 MHz, Chloroform-<7) 57.70 (d, 7= 8.2 Hz, 2H), 7.40 -7.27 (m, 6H), 6.94 - 6.69 (m, 2H), 5.17 (s, 2H), 3.65 (t, J = 5.2 Hz, 4H), 3.59 - 3.50 (m, 2H), 3.32 -3.15 (m, 4H), 1.60 - 1.25 (m, 17H), 0.91 - 0.84 (m, 3H). LC-MS (ESI): m / z 539.4 [M+H]+.

[0311] Intermediate 5f: Benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-heptylhydrazine-l- carbonyl)phenyl)piperazine-l-carboxylate. Following similar procedure, 5f was obtained from 3 and heptanal (180 mg, 54%). ’H NMR (600 MHz, Chloroform-<7) 57.72 - 7.69 (m, 2H), 7.41 - 7.31 (m, 5H), 6.95 - 6.71 (m, 2H), 5.17 (s, 2H), 3.66 (t, 7= 5.1 Hz, 4H), 3.56 (t, J= 7.4 Hz, 2H), 3.35 -3.16 (m, 4H), 1.61 - 1.26 (m, 19H), 0.87 (t, J= 6.8 Hz, 3H). LC-MS (ESI): m / z 553.2 [M+H]+.

[0312] Intermediate 5g: Benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-isobutylhydrazine-l- carbonyl)phenyl)piperazine-l-carboxylate. Following similar procedure, 5g was obtained from 3 and isobutyraldehyde (80 mg, 59%). ’H NMR (600 MHz, Chloroform-<7) 57.69 (d, J = 8.4 Hz, 2H), 7.40 - 7.31 (m, 5H), 6.94 - 6.68 (br, 2H), 5.17 (s, 2H), 3.69 - 3.60 (m, 4H), 3.40 (d, J = 7.2 Hz, 2H), 3.32 - 3.20 (m, 4H), 1.92 (dt, J= 13.7, 6.8 Hz, 1H), 1.56 - 1.38 (m, 9H), 0.93 (d, J= 6.7 Hz, 6H). LC-MS (ESI): m / z 511.2 [M+H]+.

[0313] Intermediate 5h: Benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-isopentylhydrazine-l- carbonyl)phenyl)piperazine-l-carboxylate. Following similar procedure, 5h was obtained from 3 and 3 -methylbutanal (95 mg, 53%). ’H NMR (600 MHz, Chloroform-c / ) 57.70 (d, J = 8.5 Hz, 2H), 7.40 - 7.31 (m, 5H), 6.93 - 6.71 (br, 2H), 5.17 (s, 2H), 3.66 (t, 7= 5.2 Hz, 4H), 3.59 (t, 7= 7.6 Hz, 2H), 3.33 - 3.18 (m, 4H), 1.64 - 1.38 (m, 12H), 0.91 (d, 7= 6.6 Hz, 6H).LC-MS (ESI): m / z 525.4 [M+H]+.

[0314] Intermediate 5i: Benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-(cyclopropylmethyl)hydrazine- l-carbonyl)phenyl)piperazine-l-carboxylate. Following similar procedure, 5i was obtained from 3 and cyclopropanecarbaldehyde (83 mg, 55%). ’H NMR (600 MHz, Chloroform-<7) 57.75 - 7.68 (m, 2H), 7.38 - 7.30 (m, 6H), 6.92 - 6.77 (m, 2H), 5.17 (s, 2H), 3.69 - 3.62 (m, 4H), 3.53 - 3.49 (m, 1H), 3.48 - 3.42 (m, 2H), 3.32 - 3.21 (m, 4H), 1.57 - 1.34 (m, 9H), 0.52 - 0.46 (m, 2H), 0.21 (dt, 7= 6.0, 4.5 Hz, 2H). LC-MS (ESI): m / z 509.3 [M+H]+.

[0315] Intermediate 5j: Benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-(cyclobutylmethyl)hydrazine- l-carbonyl)phenyl)piperazine-l-carboxylate. Following similar procedure, 5j was obtained from 3 and cyclobutanecarbaldehyde (69 mg, 52%). ’H NMR (600 MHz, Chloroform-<7) 57.71 (d, 7= 8.4 Hz, 2H), 7.41 - 7.34 (m, 6H), 6.94 - 6.81 (m, 2H), 5.19 (s, 2H), 3.71 - 3.62 (m, 6H), 3.37 - 3.23 (m, 4H), 2.67 - 2.58 (m, 1H), 2.10 - 2.04 (m, 2H), 1.95 - 1.88 (m, 2H), 1.81 - 1.73 (m, 2H), 1.59 - 1.36 (m, 9H). LC-MS (ESI): m / z 523.3 [M+H]+.

[0316] Al-9 were synthesized according to method A. A mixture of 5a-j (1 equiv.), Pd / C (0.05 equiv.) in MeOH was purged by nitrogen then hydrogen and stirred at room temperature for 4 h. The mixture was filtered and concentrated under vacuum. The crude product 6a-i was used without further purification. A mixture of 6a-j (1 equivalent), 7 (1.0 equiv.), KI (0.1 equiv.), DIPEA (3.0 equiv.) and K2CO3 (3.0 equiv.) in CH3CN was stirred at 55 °C for 24 h. The mixture was poured into water and extracted with EA. The combined organic layers were washed with brine x 1 , dried over anhydrousNa2SO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography. The product was dissolved in DCM and treated with TFA (20 equiv.). The mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. EA was added. The combined organic layers were washed with NaHCCh (aq.) XI, brine x 1, and dried over anhydrous Na^SO-i. filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography to afford the title compound.

[0317] Compound Al: (2S,4R)-l-((S)-2-(8-(4-(4-(2-ethylhydrazine-l- carbonyl)phenyl)piperazin-l-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. Al was synthesized according to method A (8 mg, 43%). ’H NMR (600 MHz, Chloroform-7) 5 8.68 (s, 1H), 7.71 - 7.56 (m, 3H), 7.45- 7.35 (m, 5H), 6.93 - 6.84 (m, 2H), 6.16 (d, J= 8.8 Hz, 1H), 5.13 - 5.05 (m, 1H), 4.73 (t, J= 7.9 Hz, 1H), 4.58 (d, J= 8.8 Hz, 1H), 4.50 (dt, 7 = 4.2, 2.0 Hz, 1H), 4.11 (dt, J= 11.5, 1.9 Hz, 1H), 3.58 (dd, J = 11.4, 3.6 Hz, 1H), 3.32 (t, 7= 5.1 Hz, 4H), 2.96 (q, 7= 7.2 Hz, 2H), 2.68 - 2.59 (m, 4H), 2.53 (s, 4H), 2.44 - 2.38 (m, 2H), 2.25 - 2.17 (m, 2H), 2.10 - 2.05 (m, 1H), 1.67 - 1.58 (m, 2H), 1.56 - 1.46 (m, 5H), 1.34 - 1.27 (m, 6H), 1.14 (t, 7= 7.1 Hz, 3H), 1.04 (s, 9H). LC-MS (ESI): m / z 817.5 [M+H]+.

[0318] Compound A2: (2S,4R)-l-((S)-2-(8-(4-(4-(2-butylhydrazine-l- carbonyl)phenyl)piperazin-l-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. A2 was synthesized according to method A (7 mg, 51%). ’H NMR (600 MHz, Chloroform-<7) 5 8.68 (s, 1H), 7.68 - 7.63 (m, 2H), 7.55 (s, 1H), 7.44 - 7.39 (m, 3H), 7.39 - 7.35 (m, 2H), 6.90 - 6.86 (m, 2H), 6.13 (d, 7= 8.8 Hz, 1H), 5.13- 5.05 (m, 1H), 4.73 (t, 7 = 7.9 Hz, 1H), 4.57 (d, 7 = 8.8 Hz, 1H), 4.53 - 4.49 (m, 1H), 4.12 (dt, 7 = 11.5, 1.9 Hz, 1H), 3.62 - 3.55 (m, 1H), 3.34 - 3.26 (m, 4H), 2.92 (t, 7 = 7.3 Hz, 2H), 2.63 - 2.52 (m, 8H), 2.39 - 2.34 (m, 2H), 2.25 - 2.18 (m, 2H), 2.09 - 2.04 (m, 1H), 1.64 - 1.31 (m, 17H), 1.04 (s, 9H), 0.94 (t, 7 = 7.4 Hz, 3H). LC-MS (ESI): m / z 845.5 [M+H]+.

[0319] Compound A3: (2S,4R)-l-((S)-3,3-dimethyl-2-(4-(4-(4-(2-pentylhydrazine-l- carbonyl)phenyl)piperazin-l-yl)butanamido)butanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol- 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. A3 was synthesized according to method A (9 mg, 45%). 'H NMR (600 MHz, Chloroform-7) 5 8.67 (s, 1H), 7.70 - 7.55 (m, 3H), 7.44 - 7.34 (m, 5H), 6.92 - 6.84 (m, 2H), 6.16 (d, 7= 8.7 Hz, 1H), 5.12 - 5.05 (m, 1H), 4.73 (t, 7 = 7.9 Hz, 1H), 4.58 (d, 7 = 8.8 Hz, 1H), 4.53 - 4.48 (m, 1H), 4.12 (dt, 7= 11.5, 1.9 Hz, 1H), 3.58 (dd, 7= 11.4, 3.6 Hz, 1H), 3.36 (t, 7= 5.2 Hz, 4H), 2.91 (t, 7 = 7.3 Hz, 2H), 2.72 (s, 4H), 2.58 - 2.47 (m, 6H), 2.24 - 2.19 (m, 2H), 2.10 - 2.05 (m, 1H), 1.64 - 1.54 (m, 6H), 1.47 (d, 7= 6.9 Hz, 3H), 1.39 - 1.27 (m, 10H), 1.04 (s, 9H), 0.93 - 0.89 (m, 3H). LC-MS (ESI): m / z 859.4 [M+H]+.

[0320] Compound A4: (2S,4R)-l-((S)-2-(8-(4-(4-(2-hexylhydrazine-l- carbonyl)phenyl)piperazin-l-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. A4 was synthesized according to method A (lOmg, 53%). ’H NMR (600 MHz, Chloroform-<7) 58.68 (s, 1H), 7.67 - 7.64 (m, 2H), 7.54(s, 1H), 7.44 - 7.36 (m, 5H), 6.90 - 6.86 (m, 2H), 6.14 (d, J= 8.7 Hz, 1H), 5.12 - 5.05 (m, 1H), 4.73 (t, 7= 7.9 Hz, 1H), 4.58 (d, J= 8.8 Hz, 1H), 4.51 (dt, 7= 4.2, 2.1 Hz, 1H), 4.11 (dt, 7 = 11.6, 1.9 Hz, 1H), 3.58 (dd, 7= 11.4, 3.6 Hz, 1H), 3.30 (t, 7= 5.2 Hz, 4H), 2.91 (t, 7= 7.3 Hz, 2H), 2.63 - 2.50 (m, 8H), 2.42 - 2.34 (m, 2H), 2.26 - 2.18 (m, 2H), 2.08 - 2.04 (m, 1H), 1.65 - 1.60 (m, 2H), 1.57 - 1.46 (m, 7H), 1.41 - 1.26 (m, 12H), 1.04 (s, 9H), 0.89 (t, 7 = 6.8 Hz, 3H). LC-MS (ESI): m / z 873.4 [M+H]+.

[0321] Compound A5: (2S,4R)-l-((S)-2-(8-(4-(4-(2-heptylhydrazine-l- carbonyl)phenyl)piperazin-l-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. A5 was synthesized according to method A (8 mg, 49%). 'H NMR (599 MHz, Chloroform-tf) 58.68 (s, 1H), 7.70 - 7.58 (m, 3H), 7.44 - 7.35 (m, 5H), 6.90 - 6.86 (m, 2H), 6.14 (d, 7 = 8.8 Hz, 1H), 5.12 - 5.05 (m, 1H), 4.73 (t, 7= 7.9 Hz, 1H), 4.57 (d, 7 = 8.7 Hz, 1H), 4.54 - 4.48 (m, 1H), 4.12 (dt, 7= 11.5, 1.9 Hz, 1H), 3.58 (dd, 7 = 11.3,3.6 Hz, 1H), 3.31 (t, 7= 5.2 Hz, 4H), 2.91 (t, 7= 7.3 Hz, 2H), 2.66 - 2.51 (m, 8H), 2.44 - 2.36 (m, 2H), 2.25 - 2.19 (m, 2H), 2.09 - 2.03 (m, 1H), 1.65 - 1.46 (m, 10H), 1.37 - 1.28 (m, 13H), 1.05 (s, 9H), 0.88 (t, 7= 6.9 Hz, 3H). LC-MS (ESI): m / z 887.3 [M+H]+.

[0322] Compound A6: (2S,4R)-4-hydroxy-l-((S)-2-(8-(4-(4-(2-isobutylhydrazine-l- carbonyl)phenyl)piperazin-l-yl)octanamido)-3,3-dimethylbutanoyl)-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. A6 was synthesized according to method A (7 mg, 45%). 'H NMR (600 MHz, Chloroform-d) 58.68 (s, 1H), 7.68 - 7.64 (m, 2H), 7.58 (s, 1H), 7.45 - 7.34 (m, 5H), 6.90 - 6.86 (m, 2H), 6.16 (d, 7 = 8.8 Hz, 1H), 5.12 - 5.05 (m, 1H), 4.72 (t, 7= 7.9 Hz, 1H), 4.58 (d, 7= 8.8 Hz, 1H), 4.50 (dt, 7= 4.2, 2.1 Hz, 1H), 4.09 (dt, 7= 11.5, 1.9 Hz, 1H), 3.58 (dd, 7= 11.4, 3.6 Hz, 1H), 3.31 (t, 7= 5.1 Hz, 4H), 2.74 (d, 7= 6.8 Hz, 2H), 2.60 (t, 7= 5.1 Hz, 4H), 2.58 - 2.51 (m, 4H), 2.43 - 2.35 (m, 2H), 2.24 - 2.18 (m, 2H), 2.09 - 2.03 (m, 1H), 1.85 - 1.78 (m, 1H), 1.65 - 1.58 (m, 2H), 1.54 - 1.46 (m, 5H), 1.34 - 1.28 (m, 6H), 1.04 (s, 9H), 0.98 (d, 7 =6.6 Hz, 6H). LC-MS (ESI): m / z 845.5 [M+H]+.

[0323] Compound A7: (2S,4R)-4-hydroxy-l-((S)-2-(8-(4-(4-(2-isopentylhydrazine-l- carbonyl)phenyl)piperazin-l-yl)octanamido)-3,3-dimethylbutanoyl)-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. A7 was synthesized according to method A (9 mg, 54%). ’H NMR (600 MHz, Chloroform-7) 5 8.68 (s, 1H), 7.77 - 7.63 (m, 3H), 7.46 - 7.35 (m, 5H), 6.90 - 6.85 (m, 2H), 6.21 (d, 7= 8.8 Hz, 1H), 5.12 - 5.05 (m, 1H), 4.72 (t, 7= 7.9 Hz, 1H), 4.58 (d, 7= 8.8 Hz, 1H), 4.50 (dt, 7 = 4.3, 2.2 Hz, 1H), 4.08 (dt, 7= 11.5, 1.9 Hz, 1H), 3.59 (dd, 7= 11.3, 3.7 Hz, 1H), 3.30 (t, 7= 5.2 Hz, 4H), 2.97 - 2.90 (m, 2H), 2.65 - 2.58 (m, 4H), 2.57 - 2.50 (m, 4H), 2.42 - 2.35 (m, 2H), 2.25 - 2.16 (m, 2H), 2.08 - 2.03 (m, 1H), 1.71 - 1.64 (m, 1H), 1.64 - 1.58 (m, 2H), 1.53 - 1.45 (m, 5H), 1.45 - 1.41 (m, 2H), 1.35 - 1.27 (m, 6H), 1.04 (s, 9H), 0.91 (d, 7 =6.6 Hz, 6H). LC-MS (ESI): m / z 859.4 [M+H]+.

[0324] Compound A8: (2S,4R)-l-((S)-2-(8-(4-(4-(2-(cyclopropylmethyl)hydrazine-l- carbonyl)phenyl)piperazin-l-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. A8 was synthesized according to method A (10 mg, 56%). ’H NMR (600 MHz, Chloroform-tf) 58.70 (s, 1H), 7.69 - 7.65 (m, 2H), 7.63 (s, 1H), 7.46 - 7.37 (m, 5H), 6.92 - 6.88 (m, 2H), 6.17 (d, J= 8.8 Hz, 1H), 5.14 - 5.07 (m, 1H), 4.75 (t, 7= 7.9 Hz, 1H), 4.60 (d, 7= 8.8 Hz, 1H), 4.53 (dt, 7= 4.2, 2.0 Hz, 1H), 4.13 (dt, 7= 11.6, 1.9 Hz, 1H), 3.60 (dd, 7= 11.4, 3.6 Hz, 1H), 3.33 (t, 7= 5.1 Hz, 4H), 2.80 (d, 7= 7.0 Hz, 2H), 2.65 - 2.53 (m, 8H), 2.43 - 2.36 (m, 2H), 2.28 - 2.20 (m, 2H), 2.13 - 2.06 (m, 1H), 1.68 - 1.61 (m, 2H), 1.57 - 1.48 (m, 5H), 1.37 - 1.30 (m, 6H), 1.06 (s, 9H), 1.03 - 0.97 (m, 1H), 0.58 - 0.52 (m, 2H), 0.30 - 0.23 (m, 2H). LC-MS (ESI): m / z 843.4 [M+H]+.

[0325] Compound A9: (2S,4R)-l-((S)-2-(4-(4-(4-(2-(cyclobutylmethyl)hydrazine-l- carbonyl)phenyl)piperazin-l-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. A9 was synthesized according to method A (7 mg, 50%). ’H NMR (600 MHz, Chloroform-<7) 5 8.68 (s, 1H), 7.67 - 7.62 (m, 2H), 7.49 (s, 1H), 7.44 - 7.35 (m, 5H), 6.90 - 6.86 (m, 2H), 6.14 (d, 7= 8.7 Hz, 1H), 5.12 - 5.05 (m, 1H), 4.73 (t, 7= 7.9 Hz, 1H), 4.57 (d, 7= 8.7 Hz, 1H), 4.53 - 4.49 (m, 1H), 4.11 (dt, 7= 11.5, 1.9 Hz, 1H), 3.58 (dd, 7 = 11.4, 3.6 Hz, 1H), 3.31 (t, 7= 5.2 Hz, 4H), 2.96 (d, 7= 7.3 Hz, 2H), 2.64 - 2.50 (m, 9H), 2.40 - 2.36 (m, 2H), 2.24 - 2.18 (m, 2H), 2.13 - 2.05 (m, 3H), 1.96 - 1.85 (m, 3H), 1.80 - 1.74 (m, 2H), 1.65 - 1.58 (m, 2H), 1.54 - 1.45 (m, 5H), 1.34 - 1.28 (m, 6H), 1.04 (s, 9H). LC-MS (ESI): m / z 857.5 [M+H]+.

[0326] Synthesis of A10:Synthetic route for A10: (i) CbzCl, DCM, Et3N. (ii) Hydrazine hydrate, EtOH, reflux, (iii) a) Aldehyde, MeOH, THF; b) NaBH4, MeOH, THE (iv) Boc2O, Et3N, DCM. (v) H2, Pd / C, MeOH. (vi) K2CO3, DIPEA, MeCN, 55 °C. (vii) TFA, DCM.

[0327] Intermediate 9: Benzyl 4-(4-(methoxycarbonyl)phenyl)piperazine-l-carboxylate. A mixture of 8 (0.3 g, 1.17 mmol), CbzCl (0.3g, 1.76 mmol), and Et3N (0.35mg, 3.51 mmol) in DCM (5 mL) was stirred at room temperature for 12 h. The mixture was poured into water and extracted with EA. The combined organic layers were washed with NaHCO3(aq.) x 1 , brine x 1 , dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography to afford the title compound (0.35 g, yield 84%). ’H NMR (600 MHz, CDC13) 57.97 (d, J= 8.4 Hz, 2H), 7.40 - 7.27 (m, 5H), 7.24 (d, J= 8.4 Hz, 2H), 5.15 (s, 2H), 4.41 - 4.23 (m, 2H), 3.87 (s, 3H), 2.93 - 2.80 (m, 2H), 2.73 - 2.61 (m, 1H), 1.86 - 1.76 (m, 2H), 1.68 - 1.56 (m, 2H). LC-MS (ESI): m / z 354.1 [M+H]+.

[0328] Intermediate 12a: Benzyl 4-(4-(2-(tert-butoxycarbonyl)-2-propylhydrazine-l- carbonyl)phenyl)piperidine-l-carboxylate. A mixture of 9 (0.35 g, 0.99 mmol), Hydrazine monohydrate (0.49 g, 9.9 mmol) in ethanol (3 mL) was refluxed for 24 h. The mixture was cooled to room temperature and concentrated under vacuum, the resulting crude 10 was used without further purification. A mixture of 10, Propionaldehyde (115 mg, 1.98 mmol) in MeOH-THF (1:1, v / v, 3 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOH (3 mL). The solution was treated with NaBH4 (110 mg, 2.97 mmol) and stirred for 2 h. Then it was diluted with water and extracted with ethyl acetate. The organic phase was washed with water x 1, brine xl, dried over Na^SOr. filtered, and evaporated to dryness. The crude product was purified by flash column chromatography to afford the compound Ila (269 mg, yield 69%). LC-MS (ESI): m / z 396.2 [M+H]+. Amixture of Ila (269 mg, 0.68 mmol), BOC2O (224 mg, 1.02 mmol), and EpN (207 mg, 2.06 mmol) in DCM (3 mL) was stirred at room temperature for 12 h. The mixture was poured into water and extracted with EA. The combined organic layers were washed with brine x 1, dried over anhydrous Na^SOr. filtered, and concentrated...

Claims

CLAIMS1. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or C 1-3 alkyl;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; andB is a moiety capable of binding to an E3 ubiquitin ligase.

2. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or C 1-3 alkyl;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; and3. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 or 2, wherein m is 0.

4. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-3, wherein L1is optionally substituted C3 10 carbocyclylene, optionally substituted C3 10 heterocyclylene, optionally substituted Ce 10 arylene, optionally substituted Ce 10 heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C3-10 carbocyclylene, optionally substituted C3 10 heterocyclylene, optionally substituted Ce 10 arylene, or optionally substituted Ce 10 heteroarylene are independently replaced with -O-, -NR3-, or -C(=O)-.

5. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-4,6. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-5,7. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-5, wherein8. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 or 2, wherein the compound is of Formulae (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), or (I-g):or a pharmaceutically acceptable salt thereof, wherein:L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with alkynylene, - O- , -NR3-,-C(=O)-, or heterocyclylene;R2is hydrogen, optionally substituted Ci-Cs alkyl, or optionally substituted C3-8 cycloalkyl; and each of X and Y is independently N or CH.

9. The compound, or a pharmaceutically acceptable salt thereof, of claim 8, wherein at least one of X or Y is N.

10. The compound, or a pharmaceutically acceptable salt thereof, of claim 9, wherein X and Y are both N.

11. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-10, wherein L2is Cm alkylene and at least one backbone carbon atom in the Ci-12 alkylene is replaced with -NH-.

12. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-11, wherein L2is Cm alkylene and wherein one or more backbone carbon atoms in the Ci-12 alkylene is replaced with -C(=O)-.

13. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-12, wherein L2is Ci-12 alkylene, wherein one or more backbone carbon atoms in the Ci-12 alkylene is replaced with heterocyclylene.

14. The compound, or a pharmaceutically acceptable salt thereof, of claim 13, wherein L2is Ci-12 alkylene and one or more backbone carbon atoms in the Ci-12 alkylene is replaced with a C3-6 heterocyclylene.

15. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-12, wherein L2is Cm alkylene and one or more backbone carbon atoms in the Ci-12 alkylene is replaced with C2-Cn alkynylene.

16. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-15,8, 9, or 10.

17. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-16 whereinwherein q is 1, 2, 3, 4, 5, or 6.

18. A compound of Formula (I’):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or C 1-3 alkyl;X’ and Y’ are each independently CH, CR1, or N;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , — S(— O)— , -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; andB is a moiety capable of binding to an E3 ubiquitin ligase.

19. A compound of Formula (II ’ ) :or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently halogen or Cm alkyl;X’ and Y’ are each independently CH, CR1, or N;R2is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;L1is optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR3-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;L2is a bond, optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR3-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, alkynylene, or optionally substituted heteroarylene; each instance of R3is independently hydrogen or optionally substituted alkyl; m is 0, 1, 2, 3, or 4; and20. The compound, or a pharmaceutically acceptable salt thereof, of claim 18 or 19, wherein m is 0 or 1.

21. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 18-20, wherein X’ is CH or CR1.

22. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 18-21, wherein Y’ is N.

23. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 18-21, wherein Y’ is CH or CR1.

24. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 18-23, wherein L1is optionally substituted C3 10 carbocyclylene, optionally substituted C3 loheterocyclylene, optionally substituted Ce 10 arylene, optionally substituted Ce 10 heteroarylene, or combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C3-10 carbocyclylene, optionally substituted C3 loheterocyclylene, optionally substituted Ce 10 arylene, or optionally substituted Ce 10 heteroarylene are independently replaced with -O-, -NR3-, or -C(=O)-.

25. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 18-24,26. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 18-25, wherein27. The compound, or a pharmaceutically acceptable salt thereof, of claim 18 or 19, wherein the compound ior a pharmaceutically acceptable salt thereof, wherein: each of X and Y is independently N or CH.

28. The compound, or a pharmaceutically acceptable salt thereof, of claim 27, wherein at least one of X or Y is N.

29. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 18-28, wherein L2is Cm alkylene, wherein one or more backbone carbon atoms in the Cm alkylene is replaced with heterocyclylene.

30. The compound, or a pharmaceutically acceptable salt thereof, of claim 29, wherein L2is Cm alkylene and one or more backbone carbon atoms in the Cm alkylene is replaced with a C3-6 heterocyclylene.

31. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 18-28, wherein L2is Cm alkylene, wherein one or more backbone carbon atoms in the Cm alkylene is replaced with carbocyclylene.

32. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 18-28,33. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 18-32, whereinwherein q is 1, 2, 3, 4, 5, or 6.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds of Tables 1-2, and pharmaceutically acceptable salts thereof.

35. A pharmaceutical composition comprising the compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

36. The pharmaceutical composition of claim 35, further comprising an additional pharmaceutical agent.

37. The pharmaceutical composition of claim 36, wherein the additional pharmaceutical agent is an anticancer agent.

38. A method of degrading a HDAC protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of the compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 35-37.

39. The method of claim 38, wherein the HDAC protein is a class 1 HDAC protein.

40. The method of claim 38 or 39, wherein the HDAC protein is HDAC8.

41. The method of any one of claims 38-40, wherein the cell, tissue, or biological sample is in vitro.

42. The method of any one of claims 38-40, wherein the cell, tissue, or biological sample is in vivo.

43. The method of claim 41 or 42, wherein the cell is a cancer cell.

44. A method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 35-37.

45. The method of claim 44, wherein the disease is proliferative disease, metabolic disorder, inflammatory disorder, neurological disease, pulmonary disease, cardiovascular disease, immune disorder, fibrotic disease, hepatic disease, infectious disease, or myopathy.

46. The method of claim 45, wherein the proliferative disease is cancer.

47. The method of claim 46, wherein the cancer is breast cancer, lung cancer, prostate cancer, neuroblastoma, melanoma, colon cancer, brain tumor, liver cancer, or hematological malignancies.

48. The method of claim 45, wherein the metabolic disorder is type 2 diabetes, adipose tissue inflammation, excessive hepatic lipid accumulation, lipodystrophy, or insulin resistance.

49. The method of claim 45, wherein the neurological disease is neurodegenerative disease.

50. The method of claim 45, wherein the inflammatory disorder is rheumatoid arthritis or asthma.

51. The method of claim 45, wherein the pulmonary disorder is cystic fibrosis, acute respiratory distress syndrome, or interstitial fibrosis.

52. The method of claim 45, wherein the infectious disease is influenza or pneumonia.

53. The method of any one of claims 45-52, wherein the disease is associated with HDAC8.

54. A kit comprising: the compound of any one of the preceding claims, or the pharmaceutical composition of any one of the preceding claims; and instructions for its use.

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