Compounds for inducing biostasis

Abstract

Provided herein are compounds useful for inducing biostasis. Also provided are pharmaceutical compositions comprising the compounds, kits comprising the compounds, methods of inducing biostasis in subjects, biological samples and cells, and methods of preserving biological samples (e.g., mammalian tissue) by a compound or composition described herein.

Description

COMPOUNDS FOR INDUCING BIOSTASISRELATED APPLICATION

[0001] This patent application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application U.S.S.N. 63 / 591,821, filed October 20, 2023, which is incorporated herein by reference in its entirety.GOVERNMENT SUPPORT

[0002] This invention was made with government support under W91 INF-19-2-0027 awarded by U.S. Army Research Office. The government has certain rights in this invention.BACKGROUND

[0003] Tissue and organ loss to trauma, disease, and physical injury account for a large proportion of human ailments and approximately $400 billion in annual medical burden. The rapid and reversible slowing of metabolic and other physiological processes, here referred to as 'biostasis', can improve the survival of cells and organs for transplantation. This is currently accomplished clinically by lowering temperature and static cold storage is the standard of care for organ and tissue preservation; however, its long-term use can cause damage to the integrity of the graft. Hypothermia also has been used to induce a state of biostasis clinically using ex-vivo machine perfusion technologies, for example, during cardiac transplant surgery. Combination of protective agents with perfusion and / or partial freezing approaches have extended preservation times in rat livers and whole pigs, and neural modulation approaches have been successful at demonstrating central control of body temperature and general metabolic state. However, both mechanical cooling and neural stimulation approaches are challenging to implement in a trauma triage or resource-limited situations, which would be better addressed by pharmaceutical interventions.

[0004] Several molecular strategies have been proposed to achieve metabolic suppression for organ preservation, including modulating H2S, AMPK, opioid receptors, microRNAs, HO-1, and Nrf2. H2S exposure has been reported to induce a hypometabolic state (reduced metabolism and body temperature) in a rodent model, although this was later found to be mediated in part by a low baseline laboratory temperature. The synthetic opioid peptide DADLE also can induce hypometabolism and improve organ preservation via a delta opioid receptor (DOR) mechanism, but with varied results. Compounds that directly impact glycolysis and mitochondrial respiration also have been considered for modulating organmetabolism, but many are acutely toxic and not reversible, fail to protect tissues from ischemic injury, or lack drug-like properties. Specifically, reduced functionality of the mitochondrial electron transport chain system without the endogenous antioxidant and antiinflammatory molecules released by hibernators can result in the release of reactive oxygen species and cause tissue damage.

[0005] Despite these efforts, there remains a large unmet need for improved tissue and organ preservation approaches across multiple application areas.SUMMARY

[0006] The present disclosure stems from the recognition that drugs that induce reversible slowing of metabolic and other physiological processes would have great benefit in tissue preservation, especially for organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. As such, pharmacological induction of physiological slowing in combination with organ perfusion transport systems offer a new therapeutic approach for tissue and organ preservation for transplantation, trauma management, and enhancing patient survival in remote and low-resource locations.

[0007] Using whole-organism screening of metabolism, mobility, and development in Xenopus, an existing drug, SNC80 (also referred to as WB1 herein), was identified that rapidly and reversibly slows biochemical and metabolic activities while preserving cell and tissue viability. However, SNC80 is a potent delta opioid receptor agonist.

[0008] A medicinal chemistry campaign led to novel compounds that effectively induce biostasis while minimizing or eliminating DOR activity. Accordingly, disclosed herein are novel compounds that slow metabolism and mimic states normally induced by hypothermia, hibernation, or torpor, and are useful for preservation of living cells, tissues, and organs in vivo and ex vivo. In embodiments, the compounds induce biostasis rapidly (< 1 hour) and are safely reversible, with major tissue functions returning to control levels within 24 hours.

[0009] In one aspect, disclosed are compounds of Formula (I)and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein:Ring A is a substituted or unsubstituted monocyclic 5-7-membered heterocyclic ring;R is -OR1or -N(Ra)2;R1is substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, or hydrogen; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl;L is -C(=O)- or a bond;R5is -N(R7)(R8), -OR6, or substituted or unsubstituted heteroaryl;R6is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl; each instance of R7and R8are independently substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or hydrogen, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic ring; x is 0, 1, 2, 3, or 4; and y is 0, 1, 2, 3, or 4; provided that the compound is not of the formula:

[0010] In another aspect, disclosed are pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In another aspect, disclosed are methods of inducing biostasis in a subject, biological sample, or cell, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I), to the subject, biological sample, or cell.

[0012] In another aspect, disclosed are methods of inducing physiological slowing in a subject, biological sample, or cell, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I), to the subject, biological sample, or cell.

[0013] In another aspect, disclosed are methods comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I), to a subject, biological sample, or cell.

[0014] In another aspect, disclosed are methods of preserving a biological sample, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I).

[0015] In another aspect, disclosed are kits comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I); and instructions for administering the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject, biological sample, or cell.

[0016] 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIGs 1A-1C show SNC80 treatment in Xenopus tadpoles. FIG. 1A shows swimming activity of Xenopus during 100 pM SNC80 or vehicle treatment. Data represent the mean ± SD of n=3 replicates, with 10 tadpoles per replicate. FIG. IB shows oxygen consumption rate for Xenopus treated with SNC80 or vehicle controls. N=5 medium only, n=7 vehicle and n=9 SNC80, with each data point representing the cumulative oxygen consumption for 5 tadpoles. FIG. 1C shows heart rate in SNC80 and vehicle-treated Xenopus (n=10 tadpoles / group). Statistical comparisons were performed using a Brown-Forsythe and Welch ANOVA test with a Dunnett correction for multiple comparisons (FIG. IB) and a 2- way ANOVA (treatment x timepoint) with Tukey correction for multiple comparisons (FIG. 1C). Bar plots show the mean ± SD of each group.

[0018] FIGs. 2A-2D show SNC80 uptake and activity at the delta opioid receptor. FIG. 2A shows distribution of SNC80 in Xenopus tadpoles after 1 and 2 hours of compound exposure. FIG. 2B shows uptake of SNC80 in the tadpole skeletal muscle, GI tract, and gills at 1 and 2 hours of exposure. FIG. 2C shows levels of acylcamitine and cholesterol ester in the skeletal muscle and brain after 1 hour of SNC80 treatment. In vivo distributions of SNC80 and lipid levels measured from N=5 tadpoles per condition; N=3 sections / slide. FIG. 2D shows oxygen consumption in Xenopus tadpoles treated with SNC80, the delta opioid antagonist naltrindole, or a combination of SNC80 and naltrindole. N=3 replicates / group with each data point representing the cumulative oxygen consumption from 5 tadpoles. Statistical comparisons were performed using a two-way ANOVA (time x tissue region) with Sidak’s correction for multiple comparisons (FIG. 2B), multiple unpaired t-tests for each tissue region with FDR correction (FIG. 2C), and a Welch ANOVA test with Dunnett correction for multiple comparisons between vehicle and each treatment group (FIG. 2D). Bar plots show the mean ± SD of each group.

[0019] FIGs. 3A-3D show design and in vivo screening of novel compound WB3.

[0020] FIGs. 4A-B are response curves showing that novel compounds WB3 and WB4 were at least about 1000-fold less potent against the delta opioid receptor than WB1 and DADLE, both of which are known delta opioid receptor agonists.

[0021] FIG. 5 shows the activity of novel non-opioid biostasis inducers on swimming behavior of Xenopus. Experiments were performed by treating tadpoles with 36 non-opioid biostasis inducers. Swimming behavior was quantified in the course of treatment and recovery from stasis. Lead compounds (e.g., WB3) were identified with most effective effect in reversible suppression of movement.

[0022] FIG. 6 is a series of graphs showing that removing delta opioid receptor activity improves biostasis induction and recovery.

[0023] FIG. 7 shows quantification of induction slope across WB1 (referred to as WC1 in figure) and 36 non-opioid analogs. Compounds show a range of induction speeds: 19 compounds show >25% reduction in the first 30 min. More negative values indicate faster induction rates. Slopes closer to zero indicate no change in movement. The shaded area indicates compounds that show more than 25% reduction in movement in the first 30 min (Slope = -0.25).

[0024] FIG. 8 shows quantification of recovery slope across WB1 (referred to as WC1 in figure) and 36 non-opioid analogs. Not all 19 compounds induce reversible stasis (i.e. >25% recovery in the first 30 min after wash). More positive values indicate faster recovery rates. Slopes closer to zero indicate no change in movement (i.e. no recovery or no change for those that had no effect to begin with). The shaded area indicates compounds that show more than 25% recovery in movement in the first 30 min (Slope = +0.25)

[0025] FIGs. 9A-9B show quantification of minimim and maximum movement after treatment and recovery, respectively. The no effect threshold in FIG. 20A was less than 25% amplitude reduction. The no recovery threshold in FIG. 20B was less than 75% amplitude recovery.

[0026] FIG. 10 shows induction and recovery parameter space across all novel compounds of the present disclosure.

[0027] FIGs. 11A-11B show compounds identified as most (reversible) and least effective on suppressing movement in a swimming test.

[0028] FIGs. 12A-12B show the impact of compounds on startle response and its habituation (learning).

[0029] FIG. 13 shows WB3 and not WB4 induces full stasis (lack of sensory response), with full recovery achieved 3h post wash.

[0030] FIGs. 14A-14B show that an effect on swimming is not always predictive on effect on sensory responsiveness. Although both WB4 and WB3 were very effective at suppressing swimming, their effect on sensory response was different.

[0031] FIGs. 15A-15B show that treatment with WB3 effectively suppressed movement as well as oxygen consumption and responsiveness to sensory stimuli.

[0032] FIGs. 16A-16B show an effect of WB3 or WB1 100 uM on heart rate in X. laevis. Results shown as mean + SD. (n= 10). Statistics: 1-way ANOVA. For WB3, remarkable suppression of cardiac beats (yet not 100 %), increased time-dependency, and lower recoveryafter 8 h was observed. For WB1, 100 % suppression of cardiac beats was observed for up to 8h with 90% recovery after 24h.DEFINITIONSChemical definitions

[0033] 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 Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’ s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0034] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0035] In a formula, is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, - is absent or a single bond, and = or= is a single or double bond.

[0036] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Forexample, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0037] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, C6, C1-6, Ci-5, C1-4, C1-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5.6alkyl.

[0038] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0039] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 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 (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (Cs), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec -butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., -CF3, Bn).

[0040] 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. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“Ci-s 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 4 carbon atoms (“Ci-4 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”). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFC12, -CF2C1, and the like.

[0041] 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 (i.e., 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 some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-18 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-16 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-14 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 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 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 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 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 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi-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-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, theheteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. 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-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl.

[0042] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 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 C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 or) may be an (E)- or (Z)- double bond.

[0043] 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 (z.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-io alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.

[0044] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2- 7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In someembodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carboncarbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (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 C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.

[0045] 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 (z.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-io alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2- 8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynylgroup is an unsubstituted heteroC2-io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-io alkynyl.

[0046] 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 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, without limitation, 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, without limitation, 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, without limitation, 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] dec any 1 (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0047] 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.

[0048] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carboncarbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is anunsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0049] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the5-6 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.

[0050] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydro thiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, 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, l,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.

[0051] 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 147t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 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-14 aryl. In certain embodiments, the aryl group is a substituted Ce-14 aryl.

[0052] “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.

[0053] 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 7t electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroarylring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0054] 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.

[0055] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation,tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, 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, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, pheno thiazinyl, phenoxazinyl, and phenazinyl.

[0056] “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.

[0057] The term “unsaturated bond” refers to a double or triple bond.

[0058] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0059] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0060] 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.

[0061] 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 may be substituted or unsubstituted e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present 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 intended to be limited in any manner by the exemplary substituents described herein.

[0062] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR33, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X“, -N(ORcc)Rbb, -SH, -SR33, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)3, -CO2R33, -0C(=0)R33, -OCO2R33, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=0)R33, -NRbbC02R33, -NRbbC(=O)N(Rbb)2, -C(=NRbb)R33, -C(=NRbb)0R33, -0C(=NRbb)R33, -0C(=NRbb)0R33, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02R33, -NRbbS02R33, -SO2N(Rbb)2, -SO2R33, -SO2OR33, -OSO2R33, -S(=0)R33, -0S(=0)R33, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=0)SR33, -C(=S)SR33, -SC(=S)SR33, -SC(=0)SR33, -0C(=0)SR33, -SC(=0)0R33, -SC(=0)R33, -P(=0)(R33)2, -P(=O)(ORCC)2, -0P(=0)(R33)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=0)(R33)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(R33)2, -B(ORCC)2, -BR33(0RCC), Ci-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X- is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; each instance of Raais, independently, selected from Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-i oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X- is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io 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,-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, Ci-6alkyl, Ci-6perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 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 can be joined to form =0 or =S; wherein X- is a counterion; each instance of Reeis, independently, selected from Ci-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io 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-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(CI-6alkyl)2, -N(CI-6alkyl)2, -N(CI-6alkyl)3+X-, -NH(CI-6alkyl)2+X-, -NH2(CI-6alkyl)+X“, -NH3+X“, -N(OCI-6alkyl)(Ci-6alkyl), -N(OH)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6alkyl), -C(=O)(Ci-6alkyl), -CO2H, -CO2(Ci-6alkyl), -OC(=O)(Ci-6alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI-6alkyl)2, -OC(=O)NH(CI-6alkyl), -NHC(=O)(CI-6alkyl), -N(CI-6alkyl)C(=O)( Ci-6 alkyl), -NHCO2(CI-6alkyl), -NHC(=O)N(CI-6alkyl)2, -NHC(=O)NH(CI-6alkyl), -NHC(=O)NH2, -C(=NH)O(CI-6alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCI-6alkyl, -C(=NH)N(CI-6alkyl)2, -C(=NH)NH(CI-6alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6alkyl)2, -OC(=NH)NH(CI-6alkyl), -OC(=NH)NH2, -NHC(=NH)N(CI-6alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6alkyl), -SO2N(CI-6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2, -SO2(Ci-6alkyl), -SO2O(Ci-6alkyl), -OSO2(Ci-6alkyl), -SO(Ci-6alkyl), -Si(Ci-6alkyl)3, -OSi(Ci-6alkyl)3-C(=S)N(CI-6alkyl)2, C(=S)NH(CI-6alkyl), C(=S)NH2, -C(=O)S(Ci-6alkyl), -C(=S)SCi-6alkyl, -SC(=S)SCi-6alkyl, -P(=O)(OCi-6alkyl)2, -P(=O)(Ci-6alkyl)2, -OP(=O)(Ci-6alkyl)2, -0P(=0)(0Ci-6 alkyl)2, Ci-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X- is a counterion.

[0063] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0064] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, -OCO^, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO^, -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)2, wherein X-, R^, Rbb, and Rccare as defined herein.

[0065] 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.

[0066] 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, -NHSChR^, -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.

[0067] 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, -NR^SO^, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein R^, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0068] 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.

[0069] The term “acyl” refers to a group having the general formula -C(=O)RX1, -C(=O)ORX1, -C(=O)-O-C(=O)RX1, -C(=O)SRX1, -C(=O)N(RX1)2, -C(=S)RX1, -C(=S)N(RX1)2, -C(=S)O(RX1), -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRX1)ORX1, -C(=NRX1)SRX1, and -C(=NRX I)N(RX I)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or un substituted, 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- hetero alkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, hetero aliphatic, 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).

[0070] The term “carbonyl” refers 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 (e.g., -C(=O)Raa), carboxylic acids (e.g., -CO2H), aldehydes (-CHO), esters (e.g., -CO2Raa, -C(=O)SRaa, -C(=S)SRaa), amides (e.g., -imines (e.g., -C(=NRbb)Raa, - C(=NRbb)ORaa), -C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0071] The term “silyl” refers to the group -Si(Raa)3, wherein Raais as defined herein.

[0072] The term “oxo” refers to the group =0, and the term “thiooxo” refers to the group =S.

[0073] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR33, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -S02R33, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOR33, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(Raa)2, -P(=O)(N(RCC)2)2, CI-IO alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-ioalkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, 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, Rcc, and Rddare as defined herein.

[0074] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -S02R33, -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-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io 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.

[0075] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N- acetylmethionine derivative, o-nitrobenzamide, and o- (benzoyloxymethyl)benzamide.

[0076] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa) include, but are not limited to, 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), l,l-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'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3- dithianyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cy anoethyl carbamate, m- chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4- dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1 , 1 -dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinylcarbamate, p-(p’ -methoxyphenylazo )benzyl carbamate, 1 -methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-l-(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.

[0077] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2Raa) include, but are not limited to, 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.

[0078] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl- (lO)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N' -phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N- acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l,l,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, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl- 4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N- 2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fem), N-2- picolylamino N’ -oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl] methyleneamine, N-(N’ ,N’-dimethylaminomethylene)amine, N,N’- isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl] amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiopho sphinamide (Mpt), diphenylthiopho sphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3 -nitropyridinesulf enamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tertbutyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[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, but are not limited to, -R^, -N(Rbb)2, -C(=O)SRaa, -C(=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] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxycyclohexyl, 4- methoxy tetrahydropyranyl (MTHP), 4-methoxy tetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1 - [(2-chloro-4-methyl)phenyl] -4- methoxypiperidin-4-yl (CTMP), l,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, 1- (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, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 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, 3-(imidazol-l-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2- iodobenzoate, 4-azidobutyrate, 4- nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1 , 1 -dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2- trichloroethoxy ethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxy trityl (MMT), dimethoxy trityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0081] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, -R^, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa,-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. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0082] 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 (z.e., including one formal negative charge). An anionic counterion may also be multivalent (z.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F , Cl", Br , I"), NO3 ", CIO4 ", OH ", H2PO4 ", HCOa", HSO4 ", sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid- 2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4-, PF4", PFe , AsFe", SbFe , B[3,5- (CFahCeHa^]", B(C6F5)4-, BPI14", A1(OC(CF3)3)4", and carborane anions (e.g., CB11H12" or(HCB nMesBre) ). 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.

[0083] The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’ s Advanced Organic Chemistry 6th ed. (501- 502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, MO-di methyl hydroxy lam i no, pixyl, and haloformates. In some cases, 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 cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. The leaving group may also be 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. Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SRaa, -OC(=O)Raa, - OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, - OS(=O)Raa, -OSO2Raa, -OP(RCC)2, -OP(RCC)3, -OP(=O)2Raa, -OP(=O)(Raa)2, - OP(=O)(ORCC)2, -OP(=O)2N(Rbb)2, and -OP(=O)(NRbb)2, wherein R^, Rbb, and Rccare as defined herein).

[0084] As used herein, 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.

[0085] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0086] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.Other definitions

[0087] The following definitions are more general terms used throughout the present disclosure.

[0088] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0089] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(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.

[0090] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association mayinclude hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0091] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R O.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).

[0092] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0093] 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”.

[0094] 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 lightand 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”.

[0095] 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.

[0096] 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, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-12 arylalkyl esters of the compounds described herein may be preferred.

[0097] The terms “composition” and “formulation” are used interchangeably.

[0098] 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 non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. Thenon-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. The subject may also be a plant. In certain embodiments, the plant is a land plant. In certain embodiments, the plant is a non- vascular land plant. In certain embodiments, the plant is a vascular land plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicot. In certain embodiments, the plant is a monocot. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant. In some embodiments, the plant is a tree or shrub.

[0099] 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.

[0100] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound, particle, and / or composition of the disclosure is delivered. A tissue may be an abnormal or unhealthy tissue, which may need to be treated. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the tissue is the central nervous system. In certain embodiments, the tissue is the brain.

[0101] 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.

[0102] 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 thedisease 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). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0103] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0104] 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, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health 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.

[0105] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inducing biostasis and / or inducing physiological slowing.

[0106] A “prophylactic ally effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or 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.

[0107] The terms “biologic,” “biologic drug,” and “biological product” refer to a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells,gene therapy, tissues, nucleic acids, and proteins. Biologies may include sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living entities, such as cells and tissues. Biologies may be isolated from a variety of natural sources (e.g., human, animal, microorganism) and may be produced by biotechnological methods and other technologies.

[0108] The term “small molecule” or “small molecule therapeutic” refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (z.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g / mol, not more than about 900 g / mol, not more than about 800 g / mol, not more than about 700 g / mol, not more than about 600 g / mol, not more than about 500 g / mol, not more than about 400 g / mol, not more than about 300 g / mol, not more than about 200 g / mol, or not more than about 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and not more than about 500 g / mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present disclosure.

[0109] The term “therapeutic agent” refers to any substance having therapeutic properties that produce a desired, usually beneficial, effect. For example, therapeutic agents may treat, ameliorate, and / or prevent disease. Therapeutic agents, as disclosed herein, may be biologies or small molecule therapeutics.

[0110] The term “biostasis” refers to a state of a biological system in which metabolism is slowed and energy demands reduced such that a cell, tissue (e.g., organ), or a whole organism remains viable but respiration, biochemical processes and metabolic demands are reduced such that the system maintains viability under conditions that, absent the induction of the biostatic state, would normally kill the cell, tissue (e.g., organ), or organism. As the term is used herein, biostasis is reversible, such that the cell, tissue (e.g., organ), or organism returns to substantially normal metabolic and physical activity upon withdrawal of an inducer or inducers of biostasis.

[0111] The term “preserving” refers to maintaining the original physiological state and functionality of a cell or tissue (e.g., organ) prior to or upon removal from a donor for transplant. In one embodiment, preserving is achieved by treatment of the donor or donor cell or tissue (e.g., organ) prior to removal from a donor.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0112] Provided herein are compounds that induce biostasis while having reduced or no delta opioid receptor activity. Accordingly, disclosed herein is a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:Ring A is a substituted or unsubstituted monocyclic 5-7-membered heterocyclic ring;R is -OR1or -N(Ra;R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2,-NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl;L is a bond or -C(=O)-;R5is -OR6, -N(R7)(R8), or heteroaryl;R6is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl; each instance of R7and R8are independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic ring; x is 0, 1, 2, 3, or 4; and y is 0, 1, 2, 3, or 4.

[0113] In certain embodiments, the compound of Formula (I) does not comprise a compound of formula:Ring A

[0114] As described herein, Ring A is a substituted or unsubstituted monocyclic 5-7- membered heterocyclic ring. In certain embodiments, Ring A is a substituted or unsubstituted monocyclic 5-6-membered heterocyclic ring. In certain embodiments, Ring A is a substituted or unsubstituted monocyclic 6-7-membered heterocyclic ring.

[0115] In certain embodiments, Ring A is a substituted or unsubstituted monocyclic 6- membered heterocyclic ring. In certain embodiments, Ring A is a substituted or unsubstituted piperidine, piperazine, or morpholine ring. In certain embodiments, Ring A is an unsubstituted piperidine, piperazine, or morpholine ring. In certain embodiments, Ring A is a substituted piperidine, piperazine, or morpholine ring. In certain embodiments, Ring A is a substituted piperidine, piperazine, or morpholine ring, wherein A is substituted with oxo, or substituted or unsubstituted Ci-6 alkyl. In certain embodiments, Ring A is a substituted piperidine, piperazine, or morpholine ring, wherein A is substituted with oxo, -CH3, or allyl.

[0116] In certain embodiments, Ring A is a substituted or unsubstituted piperidine ring. In certain embodiments, Ring A is a substituted piperidine ring. In certain embodiments, Ring A is an unsubstituted piperidine ring. In certain embodiments, Ring A is a substituted piperidine ring, wherein A is substituted with oxo, or substituted or unsubstituted C1-6 alkyl. In certain embodiments, Ring A is a substituted piperidine ring, wherein A is substituted with oxo, - CH3, or allyl. In certain embodiments, Ring A is a substituted piperidine ring, wherein A is substituted with oxo or -CH3.

[0117] In certain embodiments, Ring A is a substituted or unsubstituted piperazine ring. In certain embodiments, Ring A is a substituted piperazine ring. In certain embodiments, Ring A is an unsubstituted piperazine ring. In certain embodiments, Ring A is a substituted piperazine ring, wherein A is substituted with oxo, or substituted or unsubstituted C1-6 alkyl. In certain embodiments, Ring A is a substituted piperazine ring, wherein A is substituted with oxo, -CH3, or allyl.

[0118] In certain embodiments, Ring A is a substituted or unsubstituted morpholine ring. In certain embodiments, Ring A is a substituted morpholine ring. In certain embodiments, Ring A is an unsubstituted morpholine ring. In certain embodiments, Ring A is a substituted morpholine ring, wherein A is substituted with oxo, or substituted or unsubstituted C1-6 alkyl. In certain embodiments, Ring A is a substituted morpholine ring, wherein A is substituted with oxo, -CH3, or allyl. In certain embodiments, Ring A is a substituted morpholine ring, wherein A is substituted with substituted or unsubstituted C1-6 alkyl. In certain embodiments, Ring A is a substituted morpholine ring, wherein A is substituted with -CH3.

[0119] In certain embodiments, Ring A is of the formula:each instance of Rlais independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, z is 0, 1, 2, 3, or 4. In certain embodiments, z is 0, 1, or 2. In certain embodiments, z is 0 or 1. In certain embodiments, z is 1 or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2.

[0120] In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0, 1, 2, 3, or 4. In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0,1, or 2. In certain embodiments, each instance of Rlais independently halogen, or substituted or unsubstituted alkyl; and z is 0, 1, or 2. In certain embodiments, each instance of Rlais independently substituted or unsubstituted alkyl; and z is 0, 1, or 2. In certain embodiments, each instance of Rlais independently substituted or unsubstituted Ci-6 alkyl; and z is 0, 1, or2. In certain embodiments, each instance of Rlais independently methyl or allyl; and z is 0, 1, or 2. In certain embodiments, at least one instance of Rlais substituted or unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of Rlais substituted or unsubstituted methyl. In certain embodiments, at least one instance of Rlais unsubstituted methyl. In certain embodiments, at least one instance of Rlais of the formula:. In certain embodiments, at least two instances of Rlais substituted or unsubstituted Ci-6 alkyl. In certain embodiments, at least two instances of Rlais substituted or unsubstituted methyl. In certain embodiments, at least two instances of Rlais unsubstituted methyl.

[0121] In certain embodiments, Ring A is of the formula:, wherein: each instance of Rlais independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and z is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, z is 0, 1, 2, 3, or 4. In certain embodiments, z is 0, 1, or 2. In certain embodiments, z is 0 or 1. In certain embodiments, z is 1 or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2.

[0122] In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0, 1, 2, 3, or 4. In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0,1, or 2. In certain embodiments, each instance of Rlais independently halogen, or substituted or unsubstituted alkyl; and z is 0, 1, or 2. In certain embodiments, each instance of Rlais independently substituted or unsubstituted alkyl; and z is 0, 1, or 2. In certain embodiments, each instance of Rlais independently substituted or unsubstituted Ci-6 alkyl; and z is 0, 1, or2. In certain embodiments, each instance of Rlais independently methyl or allyl; and z is 0, 1, or 2. In certain embodiments, at least one instance of Rlais substituted or unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of Rlais substituted or unsubstituted methyl. In certain embodiments, at least one instance of Rlais unsubstituted methyl. In certain embodiments, at least one instance of Rlais of the formula:. In certain embodiments, at least two instances of Rlais substituted or unsubstituted Ci-6 alkyl. In certain embodiments, at least two instances of Rlais substituted or unsubstituted methyl. In certain embodiments, at least two instances of Rlais unsubstituted methyl.

[0123] In certain embodiments, Ring A is of the formula:?wherein: each instance of Rlais independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and z is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, z is 0, 1, 2, 3, or 4. In certain embodiments, z is 0, 1, or 2. In certain embodiments, z is 0 or 1. In certain embodiments, z is 1 or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2.

[0124] In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0, 1, 2, 3, or 4. In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0,1, or 2. In certain embodiments, each instance of Rlais independently halogen, or substituted or unsubstituted alkyl; and z is 0, 1, or 2. In certain embodiments, each instance of Rlais independently substituted or unsubstituted alkyl; and z is 0, 1, or 2. In certain embodiments, each instance of Rlais independently substituted or unsubstituted Ci-6 alkyl; and z is 0, 1, or2. In certain embodiments, each instance of Rlais independently methyl or allyl; and z is 0, 1, or 2. In certain embodiments, at least one instance of Rlais substituted or unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of Rlais substituted or unsubstituted methyl. In certain embodiments, at least one instance of Rlais unsubstituted methyl. In certain embodiments, at least one instance of Rlais of the formula:. In certain embodiments, at least two instances of Rlais substituted or unsubstituted Ci-6 alkyl. In certain embodiments, at least two instances of Rlais substituted or unsubstituted methyl. In certain embodiments, at least two instances of Rlais unsubstituted methyl.

[0125] In certain embodiments, Ring A is of the formula:, wherein: each instance of Rlais independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and z is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, z is 0, 1, 2, 3, or 4. In certain embodiments, z is 0, 1, or 2. In certain embodiments, z is 0 or 1. In certain embodiments, z is 1 or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2.

[0126] In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0, 1, 2, 3, or 4. In certain embodiments, each instance of Rlais independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and z is 0,1, or 2. In certain embodiments, each instance of Rlais independently halogen, or substituted or unsubstituted alkyl; and z is 0, 1, or 2. In certain embodiments, each instance of Rlais independently substituted or unsubstituted alkyl; and z is 0, 1, or 2. In certain embodiments, each instance of Rlais independently substituted or unsubstituted Ci-6 alkyl; and z is 0, 1, or2. In certain embodiments, each instance of Rlais independently methyl or allyl; and z is 0, 1, or 2. In certain embodiments, at least one instance of Rlais substituted or unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of Rlais substituted or unsubstituted methyl. In certain embodiments, at least one instance of Rlais unsubstituted methyl. In certain embodiments, at least one instance of Rlais of the formula:. In certain embodiments, at least two instances of Rlais substituted or unsubstituted Ci-6 alkyl. In certain embodiments, at least two instances of Rlais substituted or unsubstituted methyl. In certain embodiments, at least two instances of Rlais unsubstituted methyl.

[0127] In certain embodiments, Ringembodiments, Ringcertain embodiments, Ringcertain embodiments, Ringcertain embodiments, Ringcertain embodiments, Ringcertain embodiments, Ringcertain embodiments, Ringcertain embodiments, RingIn certain embodiments, Ring

[0128] In certain embodiments, Ringcertain embodiments, Ring A is,

[0129] In certain embodiments, Ringcertain embodiments,Ringcertain embodiments, Ringcertain embodiments,Ringcertain embodiments, Ringcertain embodiments, Ringcertain embodiments, Ringcertain embodiments, Ring

[0130] In certain embodiments, RingR

[0131] As described herein, R is -OR1or -N(Ra)2. In certain embodiments, R is -OR1. In certain embodiments, R is -N(Ra)2. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring. In certain embodiments, R is -N(Ra, wherein each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring. In certain embodiments, R is -N(Ra, wherein each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently substituted or unsubstituted alkyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently hydrogen or substituted or unsubstituted Ci-6 alkyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently substituted or unsubstituted Ci-6 alkyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently hydrogen or unsubstituted Ci-6 alkyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently unsubstituted Ci-6 alkyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently hydrogen or unsubstituted C1-4 alkyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently unsubstituted C1-4 alkyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently hydrogen or unsubstituted C1-2 alkyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently unsubstituted C1-2 alkyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais independently hydrogen or unsubstituted ethyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais unsubstituted ethyl. In certain embodiments, R is - N(Ra)2, wherein each instance of Rais independently hydrogen or unsubstituted methyl. In certain embodiments, R is -N(Ra)2, wherein each instance of Rais unsubstituted methyl.R1

[0132] As described herein, R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl.

[0133] In certain embodiments, R1is substituted or unsubstituted Ci-6 alkyl. In certain embodiments, R1is unsubstituted Ci-6 alkyl. In certain embodiments, R1is substituted Ci-6 alkyl. In certain embodiments, R1is substituted or unsubstituted C1-4 alkyl. In certain embodiments, R1is unsubstituted C1-4 alkyl. In certain embodiments, R1is substituted C1-4 alkyl. In certain embodiments, R1is substituted or unsubstituted C1-2 alkyl. In certain embodiments, R1is unsubstituted C1-2 alkyl. In certain embodiments, R1is substituted C1-2 alkyl. In certain embodiments, R1is substituted or unsubstituted methyl. In certain embodiments, R1is unsubstituted methyl. In certain embodiments, R1is substituted or unsubstituted ethyl. In certain embodiments, R1is substituted ethyl. In certain embodiments,R1is substituted ethyl. In certain embodiments, R1is of the formula: \ .

[0134] In certain embodiments, R1is hydrogen.

[0135] In certain embodiments, R1is substituted or unsubstituted C1-6 heteroalkyl. In certain embodiments, R1is substituted or unsubstituted C1-4 heteroalkyl. In certainembodiments, R1is of the formula: \ .R2and R4

[0136] As described herein, each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, - C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, - OC(=O)ORa, or -OC(=O)N(Ra)2.

[0137] In certain embodiments, each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -N(Ra)2, -ORa, -SRa, -CN, or -C(=O)N(Ra)2.

[0138] In certain embodiments, each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or -C(=O)N(Ra)2. In certain embodiments, each instance of R2and R4are independently -C(=O)N(Ra)2. In certain embodiments, each instance of R2and R4are independently -C(=O)N(Ra)2; and each Rais independently substituted or unsubstituted alkyl. In certain embodiments, each instance of R2and R4are independently -C(=O)N(Ra)2; and each Rais independently unsubstituted alkyl.

[0139] In certain embodiments, each instance of R2is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or -C(=O)N(Ra)2. In certain embodiments, each instance of R2is independently -C(=O)N(Ra)2. In certain embodiments, each instance of R2is independently -C(=O)N(Ra)2; and each Rais independently substituted or unsubstituted alkyl. In certain embodiments, each instance of R2is independently - C(=O)N(Ra)2; and each Rais independently unsubstituted alkyl.

[0140] In certain embodiments, each instance of R4is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or -C(=O)N(Ra)2. In certain embodiments, each instance of R4is independently -C(=O)N(Ra)2. In certain embodiments, each instance of R4is independently -C(=O)N(Ra)2; and each Rais independently substituted or unsubstituted alkyl. In certain embodiments, each instance of R4is independently - C(=O)N(Ra)2; and each Rais independently unsubstituted alkyl.

[0141] In certain embodiments, x is 0, 1, or 2; and y is 0, 1, or 2. In certain embodiments, x is 0 or 1; and y is 0 or 1. In certain embodiments, x is 1; and y is 0. In certain embodiments, x is 0; and y is 0.R3

[0142] As described herein, R3is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl. In certain embodiments, R3is hydrogen or substituted or unsubstituted Ci-6 alkyl. In certain embodiments, R3is hydrogen or substituted or unsubstituted Ci-4 alkyl. In certain embodiments, R3is hydrogen or substituted or unsubstituted C1-2 alkyl. In certain embodiments, R3is hydrogen or unsubstituted C1-6 alkyl. In certain embodiments, R3is hydrogen or unsubstituted C1-4 alkyl. In certain embodiments, R3is hydrogen or unsubstituted C1-2 alkyl. In certain embodiments, R3is unsubstituted C1-2 alkyl. In certain embodiments, R3is hydrogen.L

[0143] As described herein, L is a bond or -C(=O)-. In certain embodiments, L is a bond. In certain embodiments, L is -C(=O)-.R5

[0144] As described herein, R5is -OR6, -N(R7)(R8), or substituted or unsubstituted heteroaryl.

[0145] In certain embodiments, R5is substituted or unsubstituted heteroaryl. In certain embodiments, R5is substituted or unsubstituted heteroaryl, wherein the heteroaryl is any bioisostere of an amide group. In certain embodiments, L is a bond; and R5is substituted or unsubstituted heteroaryl. In certain embodiments, L is a bond; and R5is 5-membered substituted or unsubstituted heteroaryl. In certain embodiments, L is a bond; and R5is substituted or unsubstituted oxazole, thiazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazole, triazole, tetrazole, imidazole, or pyrrole.

[0146] In certain embodiments, R5is -OR6or -N(R7)(R8). In certain embodiments, L is - C(=O)- and R5is -OR6or -N(R7)(R8). In certain embodiments, R5is -OR6. In certain embodiments, R5is -OR6; and R6is hydrogen or substituted or unsubstituted Ci-6 alkyl. In certain embodiments, R5is -OR6; and R6is hydrogen or unsubstituted Ci-6 alkyl. In certain embodiments, R5is -OR6; and R6is hydrogen or unsubstituted Ci-4 alkyl. In certain embodiments, R5is -OR6; and R6is hydrogen or unsubstituted C1-2 alkyl. In certain embodiments, R5is -OH.

[0147] In certain embodiments, R5is -N(R7)(R8). In certain embodiments, R5is - N(R7)(R8); and each instance of R7and R8are independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic ring. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 6- membered heterocyclic ring.

[0148] In certain embodiments, R7is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R7is substituted or unsubstituted C1-4 alkyl. In certain embodiments, R7is substituted or unsubstituted C1-2 alkyl. In certain embodiments, R7is substituted or unsubstituted methyl. In certain embodiments, R7is substituted or unsubstituted ethyl.

[0149] In certain embodiments, R7is unsubstituted C1-6 alkyl. In certain embodiments, R7is unsubstituted C1-4 alkyl. In certain embodiments, R7is unsubstituted C1-2 alkyl. In certain embodiments, R7is unsubstituted methyl. In certain embodiments, R7is unsubstituted ethyl. In certain embodiments, R7is hydrogen.

[0150] In certain embodiments, R7is substituted or unsubstituted aryl. In certain embodiments, R7is substituted or unsubstituted phenyl. In certain embodiments, R7is unsubstituted phenyl.

[0151] In certain embodiments, R7is substituted or unsubstituted heteroaryl. In certain embodiments, R7is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, R7is substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, R7is substituted or unsubstituted 6-membered heteroaryl. In certain embodiments, R7is unsubstituted substituted or unsubstituted pyridine, pyrimidine, thiazole, or pyrazole. In certain embodiments, R7iscertain embodiments, R7is. In certain embodiments, R7is. In certain embodiments, R7is. In certain embodiments, R7is,

[0152] In certain embodiments, R8is substituted or unsubstituted Ci-6 alkyl. In certain embodiments, R8is substituted or unsubstituted C1-4 alkyl. In certain embodiments, R8is substituted or unsubstituted C1-2 alkyl. In certain embodiments, R8is substituted or unsubstituted methyl. In certain embodiments, R8is substituted or unsubstituted ethyl.

[0153] In certain embodiments, R8is unsubstituted C1-6 alkyl. In certain embodiments, R8is unsubstituted C1-4 alkyl. In certain embodiments, R8is unsubstituted C1-2 alkyl. In certainembodiments, R8is unsubstituted methyl. In certain embodiments, R8is unsubstituted ethyl. In certain embodiments, R8is hydrogen.

[0154] In certain embodiments, R8is substituted or unsubstituted aryl. In certain embodiments, R8is substituted or unsubstituted phenyl. In certain embodiments, R8is unsubstituted phenyl.

[0155] In certain embodiments, R8is substituted or unsubstituted heteroaryl. In certain embodiments, R8is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, R8is substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, R8is substituted or unsubstituted 6-membered heteroaryl. In certain embodiments, R8is unsubstituted substituted or unsubstituted pyridine, pyrimidine, thiazole,certain embodiments, R8is. In certain embodiments, R8isIn certain embodiments, R8isIn certain embodiments, R8isIn certain embodiments, R8isIn certain embodiments, R8is?In certain embodiments, R8is

[0156] In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted Ci-6 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted C1-4 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted C1-4 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted C1-2 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted methyl. Incertain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted ethyl.

[0157] In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or unsubstituted Ci-6 alkyl. In certain embodiments, R5is - N(R7)(R8); and each instance of R7and R8are independently hydrogen or unsubstituted C1-4 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or unsubstituted C1-2 alkyl. In certain embodiments, R5is - N(R7)(R8); and each instance of R7and R8are independently hydrogen or unsubstituted methyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or unsubstituted ethyl.

[0158] In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, R5is - N(R7)(R8); and each instance of R7and R8are independently substituted or unsubstituted C1-4 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently substituted or unsubstituted C1-4 alkyl. In certain embodiments, R5is - N(R7)(R8); and each instance of R7and R8are independently substituted or unsubstituted C1-2 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently substituted or unsubstituted methyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently substituted or unsubstituted ethyl.

[0159] In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently unsubstituted C1-6 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently unsubstituted C1-4 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently unsubstituted C1-4 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently unsubstituted C1-2 alkyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently unsubstituted methyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently unsubstituted ethyl.

[0160] In certain embodiments, R5is -NH2.

[0161] In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted aryl. In certain embodiments, R5is - N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted phenyl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or unsubstituted phenyl.

[0162] In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted heteroaryl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or substituted or unsubstituted pyridine, pyrimidine, thiazole, or pyrazole. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or

[0163] In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen,N(R7)(R8); and each instance of R7and R8are independently hydrogen,. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen oris -N(R7)(R8); and each instance of R7and R8are independently hydrogen or. In certain embodiments, R5is -N(R7)(R8); and each instance of R7and R8are independently hydrogen or. In certain embodiments, R5is -N(R7)(R8); and each instance of R7andJQR8are independently hydrogen or . In certain embodiments, R5is -N(R7)(R8); andA? each instance of R7and R8are independently hydrogen or^

[0164] In certain embodiments, R5is -N(R7)(R8); and R7and R8are joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted 5-6 membered heterocyclic ring. In certain embodiments, R5is -N(R7)(R8); and R7and R8are joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted piperazine or substituted or unsubstituted morpholine ring. In certain embodiments, R5is -N(R7)(R8); and R7and R8are joined together with the nitrogen atom to which they are attached to form a heterocyclic ring of the formula:In certain embodiments, R5is -N(R7)(R8); and R7and R8are joined together with the nitrogen atom to which they are attached to form a heterocyclic ring of the formula:certain embodiments, R5is -N(R7)(R8); and R7and R8are joined together with the nitrogen atom to which they are attached to form a heterocyclic ring of the formula:Embodiments of Formula (I)

[0165] In certain embodiments, the compound of Formula (I) is of Formula (I-a):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein A, R1, R2, R3, R4, R5, x, and y are as defined herein.

[0166] In certain embodiments, of Formula (I-a):Ring A is a substituted or unsubstituted monocyclic 5-7-membered heterocyclic ring;R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2,-NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl;R5is -OR6or -N(R7)(R8);R6is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl; each instance of R7and R8are independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic ring; x is 0, 1, 2, 3, or 4; and y is 0, 1, 2, 3, or 4.

[0167] In certain embodiments, the compound of Formula (I) is of Formula (I-b):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein A, R1, R2, R3, R4, R7, R8, x, and y are as defined herein.

[0168] In certain embodiments of Formula (I-b):Ring A is a substituted or unsubstituted 6-membered monocyclic heterocyclic ring;R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl; each instance of R7and R8are independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5 or 6 membered heterocyclic ring; x is 0, 1, 2, 3, or 4; and y is 0, 1, 2, 3, or 4.

[0169] In certain embodiments, the compound of Formula (I) is of Formula (I-c):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein A, R1, R2, R3, R4, R6, x, and y are as defined herein.

[0170] In certain embodiments of Formula (I-c):Ring A is a substituted or unsubstituted 6-membered monocyclic heterocyclic ring;R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl;R6is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl; x is 0, 1, 2, 3, or 4; and y is 0, 1, 2, 3, or 4

[0171] In certain embodiments, the compound of Formula (I) is of Formula (II):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R1, R2, R3, R4, R7, R8, x, y, and z are as defined herein.

[0172] In certain embodiments of Formula (II):R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl; each instance of R7and R8are independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5 or 6 membered heterocyclic ring; each instance of Rlais independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, 4, 5, or 6

[0173] In certain embodiments, the compound of Formula (II) is of Formula (II- a):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R1, R3, R7, R8, and z are as defined herein.

[0174] In certain embodiments, the compound of Formula (II) is of Formula (Il-b):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R1, R7, R8, and z are as defined herein.

[0175] In certain embodiments, the compound of Formula (II) is of Formula (II-c):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R7, R8, and z are as defined herein.

[0176] In certain embodiments, the compound of Formula (II) is of Formula (Il-d):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R7, R8, and z are as defined herein.

[0177] In certain embodiments, the compound of Formula (II) is of Formula (Il-e):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R7, R8, and z are as defined herein.

[0178] In certain embodiments, the compound of Formula (I) is of Formula (III):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R1, R2, R3, R4, R7, R8, x, y, and z are as defined herein.

[0179] In certain embodiments of Formula (III):R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2;each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R7and R8are independently hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5 or 6 membered heterocyclic ring; each instance of Rlais independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, 4, 5, or 6

[0180] In certain embodiments, the compound of Formula (III) is of Formula (Ill-a):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R1, R3, R7, R8, and z are as defined herein.

[0181] In certain embodiments, the compound of Formula (III) is of Formula (Ill-b):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R1, R7, R8, and z are as defined herein.

[0182] In certain embodiments, the compound of Formula (III) is of Formula (III-c):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R7, R8, and z are as defined herein.

[0183] In certain embodiments, the compound of Formula (III) is of Formula (Ill-d):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R7, R8, and z are as defined herein.

[0184] In certain embodiments, the compound of Formula (III) is of Formula (Ill-e):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R7, R8, and z are as defined herein.

[0185] In certain embodiments, the compound of Formula (I) is of Formula (IV):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein A, R1, R2, R3, R4, R5, x, and y are as defined herein.

[0186] In certain embodiments of Formula (IV):R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group whenattached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R7and R8are independently hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5 or 6 membered heterocyclic ring; each instance of Rlais independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, 4, 5, or 6

[0187] In certain embodiments, the compound of Formula (IV) is of Formula (IV-a):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R1, R3, R7, R8, and z are as defined herein.

[0188] In certain embodiments, the compound of Formula (IV) is of Formula (IV-b):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R1, R7, R8, and z are as defined herein.

[0189] In certain embodiments, the compound of Formula (IV) is of Formula (IV-c):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R7, R8, and z are as defined herein.

[0190] In certain embodiments, the compound of Formula (IV) is of Formula (IV-d):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R7, R8, and z are as defined herein.

[0191] In certain embodiments, the compound of Formula (IV) is of Formula (IV-e):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rla, R7, R8, and z are as defined herein.

[0192] In certain embodiments, the compound of Formula (I) is of formula:or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof

[0193] In certain embodiments, the compound of Formula (I) is not a delta opioid receptor agonist. In certain embodiments, the compound of Formula (I) inhibits the delta opioid receptor with an IC50 of greater than 10 nM, greater than 50 nM, greater than 100 nM, greater than 500 nM, greater than 1,000 nM, or greater than 10,000 nM.Pharmaceutical Compositions, Kits, and Administration

[0194] The present disclosure provides pharmaceutical compositions comprising a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0195] In certain embodiments, a compound of the disclosure (e.g., a compound of Formula (I)) 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 prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for inducing biostasis in a subject, biological sample, or cell. In certain embodiments, the effective amount is an amount effective for inducing physiological slowing in a subject, biological sample, or cell.

[0196] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the composition comprising a compound of the disclosure (e.g., a compound of Formula (I)) into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0197] 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. As used herein, 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, for example, one-half or one-third of such a dosage.

[0198] The compound 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, mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol.

[0199] 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, and / or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve their ability to cross the bloodbrain barrier, 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 appreciatedthat 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 exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

[0200] 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. 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 administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0201] 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 is a mammal. 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 non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In anotherembodiment, 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.

[0202] 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 described herein provided in the first container and the second container are combined to form one unit dosage form.

[0203] 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 inducing biostasis in a subject, biological sample, or cell. In certain embodiments, the kits are useful for inducing physiological slowing in a subject, biological sample, or cell.

[0204] 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, a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. In certain embodiments, the instructions comprise administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), to mammalian tissue (e.g., human tissue).Methods of Use

[0205] The present disclosure provides methods for inducing biostasis. The methods may comprise inducing biostasis in a subject, biological sample, and / or cell. In certain embodiments, the present disclosure provides a method for inducing physiological slowing. In certain embodiments, the physiological slowing comprises slowing of metabolic processes. In certain embodiments, the physiological slowing is reversible.

[0206] In certain embodiments, the methods of the disclosure comprise administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0207] In certain embodiments, the methods comprise administering a compound of the disclosure, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, or a pharmaceutical composition comprising a compound of the disclosure, to a subject. In certain embodiments, the methods comprise administering a compound of the disclosure, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, or a pharmaceutical composition comprising a compound of the disclosure, to a cell. In certain embodiments, the methods comprise administering a compound of the disclosure, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, or a pharmaceutical composition comprising a compound of the disclosure, to a biological sample. In certain embodiments, the biological sample comprises tissue. In certain embodiments, the biological sample comprises mammalian tissue. In certain embodiments, the biological sample comprises human tissue. In certain embodiments, the biological sample comprises a whole organ. In certain embodiments, the biological sample comprises a whole organ for transplant. In certain embodiments, the biological sample comprises liver, heart, lung, kidney, pancreas, or intestinal tissue. In certain embodiments, the biological sample comprises heart tissue. In certain embodiments, the biological sample comprises a limb for reimplantation.

[0208] In certain embodiments, the present disclosure provides a compound for use in inducing biostasis. In certain embodiments, the present disclosure provides a compound for use in inducing physiological slowing. In certain embodiments, the physiological slowing comprises slowing of metabolic processes. In certain embodiments, the physiological slowing is reversible.

[0209] In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for inducing biostasis. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for inducingphysiological slowing. In certain embodiments, the physiological slowing comprises slowing of metabolic processes. In certain embodiments, the physiological slowing is reversible.

[0210] The present disclosure also provides methods for preserving a biological sample. In certain embodiments, the biological sample comprises mammalian tissue. In certain embodiments, the biological sample comprises human tissue. In certain embodiments, the biological sample comprises a whole organ. In certain embodiments, the biological sample comprises a whole organ for transplant. In certain embodiments, the biological sample comprises liver, heart, lung, kidney, pancreas, or intestinal tissue. In certain embodiments, the biological sample comprises heart tissue. In certain embodiments, the biological sample comprises a limb (e.g., human limb) for reimplantation.

[0211] In certain embodiments, the compounds of the disclosure induce biostasis (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% slowing of a tissue function as compared to a baseline level of that tissue function) in less than 2 hours, less than 1 hour, less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes. In certain embodiments, the induction of biostasis by compounds of the disclosure is reversible, with major tissue functions returning to normal or baseline levels. In certain embodiments, tissue function returns to normal or baseline levels less than 48 hours, less than 36 hours, less than 24 hours, less than 18 hours, less than 12 hours, less than 6 hours, less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, or less than 1 hour after induing biostasis.

[0212] In certain embodiments, the subject being treated is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0213] Certain methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein. Theadditional pharmaceutical agent(s) may be administered at the same time as a compound of the disclosure (e.g., a compound of Formula (I)), or at different times than a compound of the disclosure (e.g., a compound of Formula (I)). For example, a compound of the disclosure (e.g., a compound of Formula (I)) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules. All or some doses of a compound of the disclosure (e.g., a compound of Formula (I)) may be administered before all or some doses of an additional pharmaceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof. The timing of administration of a compound of the disclosure (e.g., a compound of Formula (I)) and additional pharmaceutical agents may be different for different additional pharmaceutical agents. In certain embodiments, the additional pharmaceutical agent comprises an agent useful for inducing biostasis. In certain embodiments, the additional pharmaceutical agent is useful for inducing physiological slowing.EXAMPLESIdentification of pharmacological inducers of a reversible hypometabolic state for whole organ preservation

[0214] Through survey of the literature, drugs with unintended side effects, such as lowering body temperature, were identified, which suggested they might have broad effects on metabolism. Among these drugs was SNC80 (also referred to as WB1 herein), a small molecule drug originally developed as a nonaddictive pain reliever that acts independently of the mu-opioid pathway. This drug has been shown to induce hypothermia and protect against the effects of spinal cord ischemia in rodents. To explore whether SNC80 had potential to broadly slow tissue metabolism and physiology, the drug was administered to Xenopus laevis embryos and tadpoles, which have been previously shown to be useful models for drug screening due to their small size, extrauterine development, and skin permeability to small molecules. The Xenopus tadpoles were dosed at higher levels than dictated by SNC80’s defined IC50 value, with the goal of exploring the effects of SNC80 outside its known pain relief properties and accentuating the drug’s “off-target” effects, including hypometabolism.Demonstration of physiological slowing in Xenopus

[0215] SNC80’s impacts on mobility, metabolism, and heart activity were first assessed in Xenopus. Behavioral assessment in mobile tadpoles showed that 100 pM SNC80 slows movement relative to vehicle-treated counterparts, reducing activity by approximately 50%within 1 hour, which is rapidly reversible when the drug is removed (FIG. 1A). SNC80 also suppressed the rate of oxygen consumption to one-third of baseline within 3 hours of treatment (FIG. IB) and had extreme suppressive, but fully reversible, effects on heart rate after only 1 hour of exposure (FIG. 1C). Oxygen consumption was reduced in immobile Xenopus embryos treated with SNC80 as well (FIG. 9), suggesting that its metabolismsuppressing effects are independent of the slowed movement observed in mobile tadpoles.

[0216] Using in situ Matrix- As sisted-Laser Desorption / Ionization-Time of Flight Mass Spectrometry Imaging (MALDI-ToF MSI), the biodistribution of SNC80 was assessed and visualized in the Xenopus tadpole. SNC80 was detected within 1 hour of treatment and it appeared in a punctate distribution in the gastrointestinal (GI) tract, gill region and skeletal muscle (FIGs. 2A-2B), suggesting full-body delivery of the drug. Past lipidomic studies of hibernating mammals demonstrated the importance of lipid molecules for thermal adaptation during hibernation with significant alterations of lipidomic profiles being observed in liver, plasma, brain, skeletal muscle and cardiac muscle during torpor as compared to the animal’s active state. Similarly, MALDI-ToF MSI analysis revealed significantly higher levels of acylcarnitine and cholesterol ester in SNC80-treated groups in both skeletal muscle and brain (FIG. 2C). Increased levels of long chain acylcamitine associated with enhanced mitochondrial fatty acid oxidation are observed during fasting as well as in hibernating brown bears, and cholesterol ester levels increase in hibernating ground squirrels. While the increased acylcarnitine and cholesterol ester levels in brain suggest a shift towards beta oxidation of fatty acids, they also have been implicated in other pathways including antioxidant activity and neurotransmission.

[0217] Having confirmed that SNC80 induces slowing of multiple physiological parameters in the whole Xenopus organism, the molecular basis for these effects was then explored. As SNC80 is a known DOR agonist, whether its effects could be mediated by delta opioids was then evaluated. However, when the DOR antagonist, naltrindole (NTI), was tested at double the concentration (200 pM), it did not block the hypometabolic effects of SNC80 (FIG. 2D), suggesting that SNC80 modulates metabolism independent of DOR activation.Attenuating the delta opioid activity ofSNC80

[0218] A medicinal chemistry campaign was initiated to discover compounds that induce biostasis while minimizing or eliminating DOR activity. Toward this end, molecular entities were designed void of the distal basic nitrogen (N-allyl group within SNC80), which wasbelieved to be a DOR pharmacophore. As part of this effort, novel morpholino compound, WB3 (FIG. 3A) was synthesized and subsequently tested for DOR activity using a radioligand binding assay and non-linear fitting for specific binding to calculate the Hill Slope and IC50 value. A specific binding curve could not be fit for SNC80 and therefore its IC50 is <4.6 nM, whereas WB3 exhibited an IC50 of 3,470 nM (FIG. 3B), suggesting at least 1,000 times less DOR activity for WB3 compared to SNC80. An additional compound, WB4, was also evaluated for delta opioid activity demonstrating similar potency to WB3 (FIG. 4A- B). Subsequently, WB3 was screened in the Xenopus swimming and heart rate assays described previously and it was found that the analog retains physiological slowing properties in vivo despite 1,000 times less delta opioid activity (FIGs. 3C-3D). In fact, more potent and rapid effects were observed on swimming with exposure to WB3 compared to SNC80.Discussion

[0219] Described herein are experiments demonstrating that SNC80 is capable of slowing multiple physiological processes, and thereby inducing a hypometabolic state without external cooling. Also described herein are compounds (e.g., compounds of Formula (I)), such as WB3, designed to remove delta opioid receptor activity (>1000 fold less activity than SNC80). The data described throughout herein demonstrate that removing delta opioid receptor activity improves biostasis induction and recovery (e.g., Table 1 below). These novel compounds have similar or improved biological activities over SNC80 such that they would also be useful in applications of slowing of multiple physiological processes, thus making compounds of the disclosure (e.g., compounds of Formula (I)) attractive compounds for use in inducing biostasis.Table 1.Fast = more than 25% decline / increase in normalized movement indexSlow= less than 25% decline / increase in normalized movement indexXenopus model

[0220] Xenopus embryos were fertilized at Tufts University using procedures reviewed and approved by the Tufts University Institutional Animal Care and Use Committeeregulations and transferred to the Wyss Institute. Xenopus embryos and tadpoles were housed at 18°C with a 12 / 12 h light / dark cycle in 0.1X Marc’s Modified Ringer’s (MMR) medium. All animal experiments and procedures were reviewed and approved by the Harvard Medical School (HMS) Institutional Animal Care and Use Committee regulations.

[0221] Drugs used in the Xenopus studies were dissolved in DMSO to a stock concentration of 10 mM and diluted to their final concentrations with a 1% DMSO concentration or less. Media with dosed compound were made fresh and screening was performed in tadpoles at Stages 46-50. The activity of free-swimming tadpoles during and after exposure to drugs were recorded in 60 mm dishes using a SONY Alpha a6100 camera with 16 mm objective (Sony Corporation, Tokyo, Japan) against an illuminated background. Mobility was quantified in Matlab (Mathworks, Natick, MA) by mapping differences between frames to a movement index (0 - 1), with 0 indicating no movement and 1 indicating maximal movement. Oxygen consumption was measured during Xenopus exposure to drugs as a proxy for whole-organism metabolism using the Firesting Optical Oxygen Meter and the Pyro Oxygen Logger software (version 3.317) (Pyroscience GmbH, Aachen, Germany). Oxygen consumption for Xenopus embryos was measured using the OxoPlate (PreSens Precision Sensing GmbH, Regensburg, Germany). Oxygen consumption rate for each sample was measured using a linear fit to the oxygen consumption curves in Prism (GraphPad, San Diego, CA). Heart rate was measured by microscopy imaging in Xenopus following 1 hour of drug exposure. Vehicle and drug-treated groups were briefly incubated in 0.01% tricaine (Syndel, Ferndale, WA) to minimize tadpole movement during heart imaging. Videos of heart function were acquired using a ZEISS Axio Zoom.V16 microscope and ZEN BLUE Microscopy software (version 3.1) (Carl Zeiss AG, Oberkochen, Germany) at a rate of 1 frame / 100 ms. Heart beats were counted automatically in Matlab by mapping differences between video frames to a movement index and identifying local maxima in the movement index. Automated counting was previously validated by comparison of Matlab outputs with manual counting by two independent assessors. At the completion of experiments, Xenopus were euthanized by immersion in 0.2% tricaine for 30 minutes, followed by fixation or bleaching and disposal.MALDI-ToF

[0222] Tadpoles were embedded in gelatin (0.11 g / mL) and stored in -80C. Embedded tadpoles were sectioned into 16 um-thick slices using a Leica CM1850 (Leica Microsystems, Wetzlar, Germany) onto indium tin oxide (ITO)-coated glass slides (Bruker Daltonics,Billerica, MA) and immediately placed in a vacuum desiccator before matrix application (N=5 tadpoles per condition; N=3 sections / slide). Experiments were duplicated to confirm the reproducibility. The matrix solution was composed of 2,4 Dihydroxybenzoic acid (40mg / mL) in 0.1% formic acid, methanol / water (1:1 v / v) and was made fresh for each application. The HTX-sprayer nebulizer (HTX Technologies, Carrboro, NC, USA) was used to apply the matrix at 80°C at 24 passes over the sample, at a flow rate of 50pL / min, 10 psi pressure and a track speed at 1,250 mm / min. Before imaging, SNC80 spotting with matrix and Xenopus lysate was performed to determine the optimal matrix for the best S / N ratio and the least ion suppression from Xenopus tissue and to identify which adducts were detectable for each compound for imaging. In situ MALDI-ToF imaging was acquired using the rapifleX (Bruker Daltonics, Billerica, MA), in positive ion mode at 1000 Hz in the mass range of 300-990 m / z. The laser raster step spacing was set to 45 pm step size at 500 shots per pixel. External calibration was performed using a red phosphorus slurry drop casted on a region of the ITO slide without tissue. Preliminary processing of the data was performed using FlexAnalysis (Bruker Daltonics, Billerica, MA). Images were normalized by the total ion count and baseline-corrected using Top Hat algorithm with a baseline width. After MALDI-ToF MSI acquisition, ITO slides were then stained for H&E and imaged using the Cytation 5 (Agilent, Santa Clara, CA) and Epsilon scanner at 3000 dpi to select regions of interest using the open-source program, Qupath. Mass selection windows and signal intensity analysis was conducted with SCiLS Lab (Bruker Daltonics, Billerica, MA), where ions of interest, including SNC80, acylcarnitine and cholesterol ester Cl 8, were chosen with a width of ± 0.25 Da. Reference peaks of target analytes were based on previous MALDI-ToF work in Xenopus tissues from previous findings, and during spotting of target analytes with MALDI-ToF MS / MS. The mean signal intensity of the defined regions of interest were obtained with each ion of interest.Statistical analysis

[0223] All graphing and statistical analyses were performed with Prism 9 (GraphPad Software Inc., La Jolla, CA, USA) with a (two-sided) significance level of 0.05. Statistical tests and corrections for multiple comparisons are described in each figure panel.Compound synthesis

[0224] As used herein the following terms have the meanings given: “DMF” refers to N,N -dimethylformamide; “EtOAc” refers to ethyl acetate; “DCM” refers to dichloromethane;“DMSO” refers to dimethylsulfoxide; “THF” refers to tetrahydrofuran; “MeOH” refers to methanol; “MeCN” refers to acetonitrile; “DIPEA” or “DIEA” refers to N,N- diisopropylethylamine; “TEA” refers to trimethylamine; “t-BuOK” refers to potassium tert- butoxide; “n-BuLi” refers to n-butyllithium; “TFA” refers to trifluoro acetic acid, “FA” refers to formic acid; “PPI13” refers to triphenylphosphine; “DIAD” refers to diisopropyl azodicarboxylate; “EhSiH” refers to triethylsilane; “NH v H2O” refers to ammonium hydroxide; “NaH” refers to sodium hydride; “NH4CI” refers to ammonium chloride; “CbzQ” refers to benzyl chloroformate; “Mel” refers to methyl iodide; “NaBHaCN” refers to sodium cyanoborohydride; “HOAc” refers to acetic acid; “BOC2O” refers to di-tert-butyl dicarbonate; “LiOH.HoO” refers to lithium hydroxide monohydrate; “HQ” refers to hydrochloric acid; “SOCI2” refers to thionyl chloride; “HBr” refers to hydrobromic; “BCE” refers to boron trichloride; “BBr,” refers to boron tribromide; “TiCh” refers to titanium trichloride; “NaOH” refers to sodium hydroxide; “t-BuOH” refers to tert-butanol; “NMP” refers to N- methyl pyrrolidone; “HCHO” refers to formaldehyde; “HNO3” refers to nitric acid; “AC2O” refers to acetic anhydride; “CHCI3” refers to trichloromethane; “T4P” refers to 1, 3, 5, 2,4,6- trioxatriphosphorinane, 2,4,6-tributyl-2,4,6-trioxide; “HATU” refers to 1- [bis(dimethylamino)methylene]- 1H- 1 ,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate; “Pd(PPh3)4” refers to Tetrakis(triphenylphosphine)palladium; “HPLC” refers to high performance liquid chromatography; “LCMS” or “LC-MS” refers to liquid chromatography / mass spectrometry; “min” refers to minute; “Pet. Ether” refers to Pet. Ether; “TLC” refers to thin layer chromatography; “SFC” refers to supercritical fluid chromatography ;

[0225] ‘ ‘Rf refers to Retention factor; “RT” refers to retention time; “r.t.” refers to room temperature; “Na2CO3” refers to sodium carbonate; “K2CO3” refers to potassium carbonate.

[0226] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at r.t. unless otherwise stated. Compound identity and purity confirmations were performed by LCMS UV using a SHIMADZU LCMS-2020. The PDA wavelength was 220&254 nM and the MS was in positive electrospray mode (m / z: 100-1000). The aliquot was injected onto a HPLC column (Kinetex® EVO C18 2.1x30 mm, 2.6 um) in sequence maintained at 50 °C. The samples were eluted at a flow rate of 1.5 mL / min with a mobile phase system composed of A (0.0375% (v / v) TFA in water) and B (0.01875% (v / v) TFA in Acetonitrile) according to the gradients outlined in Table 2 below. Retention times RT are reported in min.

[0227] NMR was also used to characterize final compounds. 1H NMR spectra were obtained at r.t., unless otherwise stated, on a Bruker AVANCE III 400 with a 5 mm BBO probe with Z gradients, a Bruker AVANCE III HD 400 with a 5 mm BBO probe with Z gradients, a Bruker AVANCE NEO 400 with either a 5 mm BBO probe or 5 mm BBO prodigy cryoprobe with Z gradients, a Bruker NEO NANOBAY 400 with either a 5 mm BBO probe or 5 mm BBO iProbe with Z gradients. Chemical shifts are reported in ppm and referenced to either DMSO-d6 (2.50 ppm), CDC13 (7.26 ppm). NH or OH signals that exchange with deuterated solvent are not reported.

[0228] Compound identity and purity confirmations were performed by LCMS UV using a SHIMADZU LCMS-2020. The PDA wavelength was 220&254 nM and the MS was in positive electrospray mode (m / z: 100-1000). The aliquot was injected onto a HPLC column (XBridge C18 2.1x50 mm, 5 um) in sequence maintained at 40 °C. The samples were eluted at a flow rate of 1.5-2.0 mL / min with a mobile phase system composed of A (0.025% (v / v) NH3«H2O in water) and B (Acetonitrile) according to the gradients outlined in Table 3 below. Retention times RT are reported in min.

[0229] Compound identity and purity confirmations were performed by LCMS UV using a Agilent 1260\G6125B. The DAD wavelength was 220 & 254 nM and the MS was inpositive electrospray mode (m / z: 100-1000). The aliquot was injected onto a HPLC column (XBridge C18 2.1x50 mm, 5 um) in sequence maintained at 40 °C. The samples were eluted at a flow rate of 1.5-2.0 mL / min with a mobile phase system composed of A (0.025% (v / v) NH3«H2O in water) and B (Acetonitrile) according to the gradients outlined in Table 4 below. Retention times RT are reported in min.

[0230] Optionally, compound Rf values on silica thin layer chromatography (TLC) plates were measured. Compound purification was performed by flash column chromatography on silica or by preparative

[0231] HPLC. HPLC purification was performed using either Gilson-281 or Shimadzu LC-20AP in positive electrospray mode (m / z: 100-1000) with a Shimadzu SPD-20A.Samples were eluted at a flow rate of 25 mL / min on a Phenomenex Luna C18 150x25 mmxlO um column with a mobile phase system composed of: 1. Basic conditions: A (0.05% ammonia (v / v) in H2O) and B (Acetonitrile), 2. TFA conditions: A (0.075% TFA (v / v) in H2O and B (Acetonitrile), 3. A (0.225% FA (v / v) in H2O and B (Acetonitrile), 4. HC1 conditions: A (0.05% HC1 (v / v) in H2O and B (Acetonitrile), 5. Neutral conditions: A (H2O) and B (Acetonitrile) or A (10 mmol NH^HCCh) in H2O and B (Acetonitrile) according to the different linear gradient for samples. SFC purification was performed using SHIMADZU LC- 30ADsf in positive electrospray mode (m / z: 100-1000) with a Shimadzu SPD-20A.

[0232] General route for the synthesis of Intermediate 1:

[0233] Step 1: A,A-diethyl-4-formylbenzamide

[0234] To a solution of 4-formylbenzoic acid (10 g, 66.61 mmol) and HATU (30.39 g, 79.93 mmol) in DMF (500 mL) in one portion at 15 °C under N2. The heated to 30 °C and stirred for 1 h, then slowed add DIEA (34.43 g, 266.43 mmol, 46.41 mL) and N- ethylethanamine (7.31 g, 99.91 mmol, 10.29 mL) in one portion at 15 °C. The heated to 25 °C and stirred for 12 h. After the mixture was cooled to room temperature, the reaction mixture was diluted with H2O (2000 mL), and then extracted with ethyl acetate (5000 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 3 / 1 to 1 / 1) to give N,N- diethyl-4-formyl-benzamide (57 g, 277.71 mmol, 83.38% yield) was obtained as a yellow solid. LC-MS (ES+, Method A), 0.43 min, m / z 206.1 [M+H]+.

[0235] Step 2: A,A-diethyl-4-(hydroxy(3-methoxyphenyl)methyl)benzamide

[0236] To a solution of A,A-diethyl-4-formyl-benzamide (8 g, 38.98 mmol) in THE (320 mL) was dropwise added bromo-(3-methoxyphenyl)magnesium (I M, 46.77 mL) at 0 °C under N2. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. After the mixture was cooled to room temperature, the reaction mixture was diluted with H2O (1000 mL), and then extracted with dichloromethane (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 3 / 1 to 1 / 1). Dissolve the crude into 130ml EA and slowly add 100ml PE. Dissolve the crude into 25 mL DCM and slowly add 50 mL PE. The filter cake was dried under reduced pressure to give A,A-diethyl-4-[hydroxy-(3-methoxyphenyl)methyl]benzamide (6 g, 19.15 mmol, 6.14% yield) was obtained as a white solid. LC-MS (ES+, Method A), 0.48 min, m / z 314.1 [M+H]+.

[0237] Intermediate 1: 4-(chloro(3-methoxyphenyl)methyl)-A,A-diethylbenzamide

[0238] To a solution of A,A-diethyl-4-[hydroxy-(3-methoxyphenyl)methyl]benzamide (11.75 g, 37.49 mmol) in CHCh (110 mL) was added dropwise HC1 (12 M, 421.80 mL) and stirred at 20 °C for 12 h. After the mixture was cooled to room temperature, the reaction mixture was diluted with H2O (50 mL), and then extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-[chloro-(3- methoxyphenyl)methyl]-A,A-diethyl-benzamide (23 g, 69.31 mmol, 92.43% yield) was obtained as a yellow oil.

[0239] Intermediate 2: (4-(chloro(3-methoxyphenyl)methyl)phenyl)(4-methylpiperazin- 1 - yl)methanone

[0240] JH NMR (400 MHz, CDCh) 5 (ppm) = 7.53 - 7.46 (m, 2H), 7.44 - 7.40 (m, 2H), 7.31 - 7.27 (m, 1H),6.98 - 6.95 (m, 2H), 6.88 - 6.84 (m, 1H), 6.09 (s, 1H), 5.02 - 4.49 (m, 1H), 4.27 - 3.71 (m, 6H), 3.48 (br d, 7=1.3 Hz, 2H), 2.83 (br d, J = 4.5 Hz, 4H), 1.74 (br s, 1H).

[0241] Intermediate 3: 4-(chloro(phenyl)methyl)-A,A-diethylbenzamide

[0242] To a solution of A,A-diethyl-4-(hydroxy(phenyl)methyl)benzamide (1.8 g, 6.35 mmol) in CHCh (20 mL) was added HC1 (12 M, 71.46 mL). The mixture was stirred at 25 °C for 12 h. The solution was poured into water (30 mL), and extracted with EtOAc (30 mL x 3).The combined organic phase was washed with brine (lOmL x 3), dried over anhydrous Na2SO4, and concentrated to afford 4-(chloro(phenyl)methyl)-N,N-diethylbenzamide (2.1 g, 6.26 mmol, 98.58% yield) as a yellow oil. ’ H NMR (400 MHz, CDCh) 5 0.95 - 1.27 (m, 6 H)3.02 - 3.31 (m, 2 H) 3.31 - 3.64 (m, 2 H) 6.05 (s, 1 H) 7.17 - 7.25 (m, 2 H) 7.27 (d, J=6.8Hz, 3 H) 7.29 - 7.33 (m, 2 H) 7.36 (d, J=8.0 Hz, 2 H).

[0243] Intermediate 4: 1 -(chloro(phenyl)methyl)-3-methoxybenzene

[0244] To a solution of (3-methoxyphenyl)(phenyl)methanol (1.9 g, 8.87 mmol) in CHCh (20 mL) was added HC1 (12 M, 99.76 mL). The mixture was stirred at 25 °C for 12 h. The solution was poured into water (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated to give a crude product to afford l-(chloro(phenyl)methyl)-3- methoxybenzene (1.9 g, 7.76 mmol, 87.47% yield) as a pink oil.1H NMR (400 MHz, CDCL) 5 3.68 (s, 3 H) 6.00 (s, 1 H) 6.69 - 6.77 (m, 1 H) 6.85 - 6.93 (m, 2 H) 7.14 - 7.27 (m, 4 H) 7.29 - 7.34 (m, 2 H).

[0245] Intermediate 5: methyl 4-(chloro(3-methoxyphenyl)methyl)benzoate

[0246] 1H NMR (400 MHz, CDCL) 5 = 8.02 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.27 (s, 1H), 6.99 - 6.93 (m, 2H), 6.88 - 6.83 (m, 1H), 6.11 (s, 1H), 3.92 (s, 3H), 3.80 (s, 3H).

[0247] General route for the synthesis of Intermediate 6:

[0248] Step 1: 2-(3-bromophenoxy)-N,N-dimethylethan-l -amine

[0249] To a solution of 2-(dimethylamino)ethanol (6.18 g, 69.36 mmol, 6.96 mL) , 3- bromophenol (10 g, 57.80 mmol) and PPI13 (24.26 g, 92.48 mmol) in THF (160 mL) was dropwise added the DIAD (16.36 g, 80.92 mmol, 15.69 mL) at 0 °C. The mixture was stirred at 15 °C for 16 h. The solvent was removed under reduce pressure to give a residue. It was purified by column (SiCL, Dichloromethane / Methanol = 8:1) to give (2-(3-bromophenoxy)- N,N-dimethyl-ethanamine (16 g, crude) ) was obtained as a colorless oil. LC-MS (ES+, Method A), 0.47 min, m / z 362.2 [M+H]+.

[0250] Step 2: 4-(3-(2-(dimethylamino)ethoxy)benzoyl)-N,N-diethylbenzamide

[0251] To a solution of 2-(3-bromophenoxy)-N,N-dimethyl-ethanamine (1.26 g, 5.14 mmol) and [4-(diethylcarbamoyl)phenyl]boronic acid (1.40 g, 6.33 mmol) in dioxane (25 mL) was added K2CO3 (2.35 g, 16.98 mmol), Pd(PPh3)4 (594.52 mg, 514.48 pmol). The mixture was stirred at 80 °C for 16 h under CO atmosphere (40 Psi). The reaction mixture was filtered and washed. The combined layer was concentrated under reduce pressure to give residue. The residue was purified by column chromatography(SiO2, Dichloromethane :Methanol= 1 / 0 to 9 / 1). The residue was further purification by preparative-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:22%-52% B over 15 min) and lyophilized to give 4-[3-[2-(dimethylamino) ethoxy]benzoyl]-N,N-diethyl- benzamide (350 mg, 949.88 pmol, 18.46% yield) was obtained as a brown oil. LC-MS (ES+, Method A), 0.42 min, m / z 369.2 [M+H]+.

[0252] Step 3: 4-((3-(2-(dimethylamino)ethoxy)phenyl)(hydroxy)methyl)-N,N- diethylbenzamide

[0253] To a mixture of 4-[3-[2-(dimethylamino)ethoxy]benzoyl]-N,N-diethyl-benzamide (100 mg, 271.39 pmol) in MeOH (8 mL) was added Pd / C (100 mg, 10% purity) the mixturewas stirred at 25 °C for 16 h under H2 (40Psi). The reaction mixture was filtered and the mother solution was concentrated under reduced pressure to give 4-[[3-[2- (dimethylamino)ethoxy]phenyl]-hydroxy-methyl]-N,N-diethyl-benzamide (85 mg, crude) was obtained as a colorless solid. LC-MS (ES+, Method A), 0.40 min, m / z 371.2 [M+H]+.

[0254] Intermediate 6: 4-(chloro(3-(2-(dimethylamino)ethoxy)phenyl)methyl)-N,N- diethylbenzamide

[0255] LC-MS (ES+, Method A), 0.44 min, m / z 389.1 [M+H]+.

[0256] JH NMR (400 MHz, DMSO-tfc) 8 ppm 0.97 - 1.17 (m, 6 H) 2.29 (s, 2 H) 2.81 (d, J=4.88 Hz, 5 H) 3.26 - 3.46 (m, 2 H) 3.46 - 3.54 (m, 2 H) 4.37 (t, 7=5.00 Hz, 2 H) 5.92 (br s, 6 H) 6.54 (s, 1 H) 6.88 - 7.01 (m, 1 H) 7.06 - 7.14 (m, 2 H) 7.16 (d, 7=7.38 Hz, 2 H) 7.31 - 7.39 (m, 3 H) 7.52 (d, 7=8.13 Hz, 2 H).

[0257] General route for the synthesis of Intermediate 7 :

[0258] Step 1 : tert-butyl (2S, 5 / ?)-4-allyl-2,5-di methyl piperazine- 1 -carboxylate

[0259] To a mixture of tert-butyl (2S, 57?)-2,5-dimethylpiperazine- 1 -carboxylate (5 g, 23.33 mmol) and 3-bromoprop-l-ene (2.82 g, 23.33 mmol) in acetone (50 mL) was added K2CO3 (3.29 g, 23.80 mmol) in one portion and stirred at 55 °C for 2 h, at which time 3-bromoprop-l-ene (2.82 g, 23.33 mmol) was added and stirred at 55 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (100 mL) and stirred at 25 °C for 1 h, and then filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (25',57?)-4-allyl-2,5-dimethyl-piperazine- 1-carboxylate (12.4 g, 48.75 mmol, 52.23% yield) was obtained as a yellow oil. LC-MS (ES+, Method A), 0.49 min, m / z 255.0 [M+H]+.

[0260] Intermediate 7 : (2 / ?, 5.8% I -allyl-2,5-di methyl piperazine

[0261] To a mixture of tert-butyl (2S,57?)-4-allyl-2,5-dimethyl-piperazine- 1-carboxylate (13.9 g, 54.65 mmol) in DCM (140 mL) was added EtaSiH (15.89 g, 136.62 mmol, 21.82 mL) and TFA (62.31 g, 546.45 mmol, 40.46 mL) in one portion at 25 °C under N2. The mixture was stirred at 25 °C for 2 h. The pH of reaction mixture was adjusted to 9 by adding NH3 H2O, and then extracted with dichloromethane (300 mL x 5). The combined organic layers were washed with brine (100 mL), dried over NaaSCL, filtered and concentrated under reduced pressure to give (27?,5S)-l-allyl-2,5-dimethyl-piperazine (6 g, 38.90 mmol, 71.18% yield) was obtained as a yellow oil.

[0262] General route for the synthesis of Intermediate 8:

[0263] Step 1: tert-butyl (5')-4-allyl-2-methyl-5-oxopiperazine-l-carboxylate

[0264] To a solution of tert-butyl (5')-2-methyl-5-oxopiperazine-l-carboxylate (1.2 g, 5.60 mmol) in THF (12 mL) was added the NaH (336.01 mg, 8.40 mmol, 60% purity) in portions at 0 °C under N2. The mixture was stirred at 0 °C for 30 min, then the stirred at 25 °C for 30 min and was added the 3-bromoprop-l-ene (1.36 g, 11.20 mmol) with stirred at 25 °C for 2 h. The mixture with diluted with saturated NH4CI (100 mL) and extracted with ethyl acetate (60 mL x 3). The organic layer was washed with brine (60 mL) and dried over NaaSCU. After filtration and solvent evaporation give the residue to afford tert-butyl (5')-4-allyl-2-methyl-5- oxopiperazine- 1-carboxylate (1.41 g, 5.54 mmol, 98.99% yield) as a yellow oil. LC-MS (ES+, Method A), 0.48 min m / z 255.0 [M+H]+. ’ H NMR (400 MHz, DMSO-t / e) 8 5.72 (d, J= 6.3Hz, 1H), 5.25 - 5.14 (m, 2H), 4.08 - 3.96 (m, 2H), 3.84 (dd, J = 6.4, 15.1 Hz, 1H), 3.70 (d, J = 18.0 Hz, 1H), 3.51 (dd, 7 = 4.4, 12.8 Hz, 1H), 3.06 (dd, 7= 2.8, 12.8 Hz, 1H), 1.49 - 1.46 (m, 1H), 1.41 (s, 9H), 1.10 (d, 7= 6.8 Hz, 3H).

[0265] Intermediate 8: (S)- 1 -allyl-5-methylpiperazin-2-one

[0266] To a solution of tert-butyl 6S%4-allyl-2-mcthyl-5-oxopipcrazinc- 1 -carboxylate (1.41 g, 5.54 mmol) in DCM (14 mL) was added TFA (632.15 mg, 5.54 mmol, 411.83 pL). The mixture was stirred at 25 °C for 3.5 h. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 2). The combined organic layers were concentrated under reduced pressure to give a residue to afford 6SJ- 1 -allyl-5-mcthylpipcrazin- 2-one (850 mg, 5.51 mmol, 99.42% yield) as a yellow liquid.!H NMR (400 MHz, DMSO-rfc) 5 9.77 - 9.47 (m, 1H), 5.87 - 5.64 (m, 1H), 5.32 - 5.08 (m, 2H), 4.07 - 3.91 (m, 2H), 3.88 - 3.74 (m, 2H), 3.68 (dd, J= 4.3, 6.4, 10.5 Hz, 1H), 3.42 - 3.37 (m, 2H), 1.27 (d, J= 6.8 Hz, 3H).

[0267] General route for the synthesis of Intermediate 9:

[0268] Step 1: benzyl (5')-2-methyl-4-oxopiperidine-l -carboxylate

[0269] To a solution of (2S)-2-methylpiperidin-4-one (7 g, 46.79 mmol, HC1) in THF (70 mL) was added DIEA (18.18 g, 140.66 mmol, 24.50 mL). After stirring 0.5 h, CbzCI (11.97 g, 70.18 mmol, 10.02 mL) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 3 / 1) to give benzyl (25)-2- methyl-4-oxo-piperidine-l -carboxylate (10 g, 40.44 mmol, 90.91% yield) was obtained as a light yellow oil. ’ H NMR (400 MHz, CDCh) 5 = 7.31 - 7.21 (m, 5H), 5.08 (s, 2H), 4.70 (br s,1H), 4.29 - 4.15 (m, 1H), 3.33 - 3.24 (m, 1H), 2.59 (dd, J= 6.8, 14.5 Hz, 1H), 2.45 - 2.34 (m, 1H), 2.30 - 2.22 (m, 1H), 2.17 (td, J = 2.0, 14.5 Hz, 1H), 1.11 (d, J = 7.0 Hz, 3H).

[0270] Step 2: benzyl (2.S%2,5-dimcthyl-4-oxopipcridinc- 1 -carboxylate

[0271] To a solution of A-isopropylpropan-2-amine (4.50 g, 44.48 mmol, 6.29 mL) in THF (200 mL) was added n-BuLi (2.5 M, 16.98 mL) at -78 °C under N2. After stirring 15 min at under -78 °C, benzyl (25')-2-methyl-4-oxo-piperidine-l -carboxylate (10 g, 40.44 mmol) in THF (20 mL) was added. After stirring 2 h at under -78 °C, Mel (6.03 g, 42.46 mmol, 2.64 mL) was added. The mixture was allowed to warm gradually to 25 °C and stirred for 16 h. The reaction mixture was poured into water (500 ml), extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give benzyl (25)-2,5- dimethyl-4-oxopiperidine- 1 -carboxylate (9.9 g, 37.89 mmol, 93.69% yield) was obtained as a yellow oil.

[0272] Step 3: benzyl (9S)-6,9-dimethyl-l,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate

[0273] To a solution of benzyl (25')-2,5-dimethyl-4-oxopiperidine-l-carboxylate (9.9 g, 37.89 mmol) and ethylene glycol (4.75 g, 76.53 mmol, 4.27 mL) in toluene (200 mL) was added the 4-methylbenzenesulfonic acid;hydrate (86.48 mg, 454.62 pmol) was stirred at 130 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give benzyl (9S)-6,9-dimethyl-l,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (11 g, 36.02 mmol, 95.08% yield) was obtained as a yellow oil.

[0274] Intermediate 9: (9S)-6,9-dimethyl-l,4-dioxa-8-azaspiro[4.5]decane

[0275] To a solution of benzyl (9S)-6,9-dimethyl-l,4-dioxa-8-azaspiro[4.5]decane-8- carboxylate (11 g, 36.02 mmol) in MeOH (400 mL) was added Pd / C (5 g, 10% purity) and stirred at 25 °C for 16 hours under H2 (40 psi) in sealed tube. The reaction mixture was filtered with diatomaceous earth and the filtrate was concentrated under reduced pressure togive (9S)-6,9-dimethyl-l,4-dioxa-8-azaspiro[4.5]decane (6 g, 35.04 mmol, 97.27% yield) was obtained as a yellow oil.

[0276] General route for the synthesis of Intermediate 10:

[0277] Step 1 : tert-butyl (S)-(l-((2,4-dimethoxybenzyl)amino)propan-2-yl)carbamate

[0278] To a mixture of tert-butyl (S)-(l-oxopropan-2-yl)carbamate (6 g, 34.64 mmol) and (2,4-dimethoxyphenyl)methanamine (8.69 g, 51.96 mmol, 7.83 mL) in MeOH (60 mL) was added NaBthCN (3.27 g, 51.96 mmol) and HO Ac (5.20 g, 86.60 mmol, 4.95 mL) slowly at 25 °C under N2. The mixture was stirred at 25 °C for 1.5 h. The mixture was stirred at 25 °C for 15 h. After the mixture was cooled to room temperature, the reaction mixture was diluted with H2O (100 mL), and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate=l / O, 0 / 1) to afford tert-butyl A-[(lS)-2-[(2,4- dimethoxyphenyl)methylamino]-l-methyl-ethyl]carbamate (9.53 g, 29.38 mmol, 84.80% yield) as light yellow oil. ’ H NMR (400 MHz, DMSO-de) 8 8.52 - 8.27 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.94 - 6.82 (m, 1H), 6.64 (d, J= 2.4 Hz, 1H), 6.61 - 6.52 (m, 1H), 4.06 - 4.04 (m, 2H), 3.83 (s, 3H), 3.83-3.79 (m, 1H), 3.79 (s, 3H), 2.89 - 2.82 (m, 2H), 1.43 - 1.36 (m, 9H), 1.08 - 1.04 (m, 3H).

[0279] Step 2: tert-butyl (S)-(l-(2-chloro-N-(2,4-dimethoxybenzyl)acetamido)propan-2- yl)carbamate

[0280] To a solution of tert-butyl (S)-(l-((2,4-dimethoxybenzyl)amino)propan-2- yl)carbamate (9.53 g, 29.38 mmol) in DCM (100 mL) was added TEA (4.46 g, 44.06 mmol, 6.13 mL) in one portion at 0 °C under N2. Then 2-chloroacetyl chloride (3.65 g, 32.31 mmol, 2.57 mL) was added to the reaction mixture slowly, and the mixture was stirred at 20 °C for 13.5 h. The reaction mixture was diluted with H2O (100 mL), and then extracted with dichloromethane (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 3 / 1) to afford tert-butyl (S)-(l-(2-chloro-N-(2,4-dimethoxybenzyl)acetamido)propan-2- yl)carbamate (8.26 g, 20.60 mmol, 70.14% yield) as a light yellow oil .!H NMR (400 MHz, DMSO-t / d) 5 7.03 - 6.90 (m, 1H), 6.73 - 6.57 (m, 1H), 6.55 - 6.43 (m, 1H), 4.66 - 4.44 (m, 2H), 4.42 - 4.26 (m, 2H), 3.86 - 3.70 (m, 7H), 3.30 (s, 1H), 3.26 - 3.01 (m, 2H), 1.36 (d, J = 5.6 Hz, 9H), 1.04 - 0.92 (m, 3H).

[0281] Step 3 : tert-butyl (2S)-4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-5-oxo- piperazine- 1 -carboxylate

[0282] A solution of tert-butyl (S)-(l-(2-chloro-N-(2,4- dimethoxybenzyl)acetamido)propan-2-yl)carbamate (8.26 g, 20.60 mmol) in DME (80 mL) was stirred at 0 °C and added NaH (2.47 g, 61.81 mmol, 2.44 mL, 60% purity) in portions at 0 °C under N2. Then the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated NH4CI (100 mL) at 0 °C, and then extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue to afford tert-butyl (2S)-4- [(2,4-dimethoxyphenyl)methyl]-2-methyl-5-oxo-piperazine-l-carboxylate (7.26 g, 19.92 mmol, 96.69% yield) as a brown oil. ’ H NMR (400 MHz, DMSO-t / d) 8 7.07 (d, J= 8.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 2.0, 8.3 Hz, 1H), 4.49 (d, J = 14.8 Hz, 1H), 4.32 (d, J = 14.4 Hz, 1H), 4.15 (s, 1H), 4.07 - 4.02 (m, 1H), 3.76 (d, J = 10.0 Hz, 6H), 3.69 (s,1H), 3.46 (dd, J = 4.4, 12.8 Hz, 1H), 3.02 (dd, J= 2.8 Hz, 1H), 1.40 (s, 9H), 0.99 (d, J= 6.8 Hz, 3H).

[0283] Step 4: (S)-5-methylpiperazin-2-one

[0284] A solution of tert-butyl (2S)-4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-5-oxo- piperazine-1 -carboxylate (1 g, 2.74 mmol) in TFA (6 mL) was stirred at 60 °C for 4 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was dissolved in water (30 mL) and washed by ethyl acetate (20 mL x 3) and lyophilized to afford (S)-5-methylpiperazin-2-one (0.418 g, crude) as a yellow oil.!H NMR (400 MHz, DMSO-tfc) 8 9.35 (s, 1H), 3.85 - 3.61 (m, 2H), 3.64 - 3.49 (m, 1H), 3.21 - 3.10 (m,lH), 1.26 (d, J = 6.4 Hz, 3H).

[0285] Intermediate 10: tert-butyl (5')-2-methyl-5-oxopiperazine-l-carboxylate

[0286] To a solution of (S)-5-methylpiperazin-2-one (1.5 g, 13.14 mmol) and TEA (1.60 g, 15.77 mmol, 2.19 mL) in DCM (15 mL) was added the BOC2O (2.87 g, 13.14 mmol, 3.02 mL) with stirred at 25 °C for 12 h. The reaction mixture was diluted with saturated NaHCOa (20 mL), and then extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica get eluted with petroleum ether / ethyl acetate =1 / 1 to 0 / 1 to afford tert-butyl (S)-2- methyl-5-oxopiperazine-l -carboxylate (1.2 g, 5.60 mmol, 42.62% yield) as a light yellow solid. ’ H NMR (400 MHz, CDCh) 8 (m, 1H), 4.32 (d, J = 18.8 Hz, 1H), 3.77 (d, J= 18.8 Hz, 1H), 3.66 - 3.58 (m, 1H), 3.10 (dd, J = 5.2, 12.2 Hz, 1H), 1.48 (s, 9H), 1.27 (d, J = 6.4 Hz, 3H).

[0287] General route for the synthesis of Intermediate 11:

[0288] Intermediate 12: 4-(((9S)-6,9-dimethyl-l,4-dioxa-8-azaspiro[4.5]decan-8-yl)(3- methoxyphenyl)methyl)-N,N-diethylbenzamide

[0289] To a solution of (6 / ?,9.S%6,9-dimcthyl- 1 ,4-dioxa-8-azaspiro|4.5 |dccanc (3.2 g, 18.69 mmol) and 4-[chloro-(3-methoxyphenyl)methyl]-N,N-diethyl-benzamide (3.10 g, 9.34 mmol) in MeCN (30 mb) was added K2CO3 (10.33 g, 74.75 mmol) .The mixture was stirred at 80 °C for 60 h. The reaction mixture was filtered and the mother solution was concentrated. The residue was purified by column chromatography (S i O2, Petroleum ether / Ethyl acetate = 3 / 1 to 1 / 1). The residue was further purification by preparative-HPLC (column: Phenomenex luna C18 150*40mm* 15um;mobile phase: [water(FA)- ACN];gradient:15%-45% B over 15 min ) and lyophilized. The residue was purified by prep- TLC (Petroleum ether / Ethyl acetate = 2 / l)*3 to give 4-[[(6R,9S)-6,9-dimethyl-l,4-dioxa-8- azaspiro[4.5]decan-8-yl]-(3-methoxyphenyl)methyl]-N,N-diethyl-benzamide (79 mg, 169.31 pmol, 1.23% yield) was obtained as a colorless oil. 4-(((9S)-6,9-dimethyl-l,4-dioxa-8- azaspiro[4.5]decan-8-yl)(3-methoxyphenyl)methyl)-N,N-diethylbenzamide (60 mg, 132.57 pmol, 9.67e-l% yield) was obtained as a colorless oil. LC-MS (ES+, Method A), 0.45 min, m / z 467.2 [M+H]+.

[0290] Intermediate 13: A,A-diethyl-4-((3-methoxyphenyl)((S)-7-methyl-l,4-dioxa-8- azaspiro [4.5] decan- 8 -y l)methy l)benzamide

[0291] LC-MS (ES+, Method A), 0.44 min, m / z 453.2 [M+H]+.

[0292] General route for the synthesis of Compounds 1 and 2:

[0293] Compound 1 (WB3): 4-(((2R,5S)-2,5-dimethylmorpholino)(3- methoxyphenyl)methyl)-N,N-diethylbenzamide

[0294] To a mixture of 4-[chloro-(3-methoxyphenyl)methyl]-N,N-diethyl-benzamide (23 g, 69.31 mmol) and (2R,55')-2,5-dimethylmorpholine (15.97 g, 138.62 mmol) in ACN (230 mL) was added K2CO3 (19.16 g, 138.62 mmol) with stirred at 80 °C for 4 days. The reaction mixture was filtered and the mother solution was concentrated. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 5 / 1 to 2 / 1). The residue was further purification by preparative-HPLC (column: UniSil 10-120 C18 70x250mm;mobile phase: [water(FA)-ACN];gradient:20%-50% B over 20 min ) and lyophilizated. The residue was further purification by preparative-HPLC (column: Phenomenex luna Cl 8 (250*70mm,10 um); mobile phase: [water (FA)-ACN];gradient:10%-50% B over 35 min) and lyophilizated. N-hexane was added to the reactants by drops and stirred at 60 °C for 30 min (500mg / 8mL), cool until the crystals precipitate. The filter cake was dried under reduced pressure to give 4-((R)-((2R,5S)-2,5-dimethylmorpholino)(3-methoxyphenyl)methyl)-N,N- diethylbenzamide (3.3 g, 8.03 mmol, 11.59% yield, 99.9% purity) was obtained as a white solid. LC-MS (ES+, Method A), 0.46 min, m / z 296.1 [M+H]+.

[0295] 1H NMR (400 MHz, CDCh) 5 = 7.47 (d, J = 7.8 Hz, 2H), 7.34 - 7.27 (m, 3H), 6.88 (dd, J= 2.0, 8.3 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.72 - 6.67 (m, 1H), 5.32 (s, 1H), 3.81 (s,3H), 3.76 - 3.66 (m, 2H), 3.64 - 3.45 (m, 2H), 3.44 - 3.24 (m, 3H), 2.61 (dd, J= 2.0, 11.6 Hz, 1H), 2.57 - 2.48 (m, 1H), 1.82 (dd, J = 9.5, 11.6 Hz, 1H), 1.24 (br d, J = 0.8 Hz, 3H), 1.12 (d,J= 6.1 Hz, 6H), 1.06 (d, J= 6.3 Hz, 3H).

[0296] The compounds in the table below were prepared in a similar manner to the methods described above.

[0297] General route for the synthesis of Compounds 10 and 11:

[0298] Step 1: 4-(((27?,5S')-2,5-dimethylmorpholino)(3-methoxyphenyl)methyl)benzoic acid

[0299] To a solution of methyl 4-[[(2R,5S)-2,5-dimethylmorpholin-4-yl]-(3- methoxyphenyl)methyl]benzoate (440 mg, 1.19 mmol) in THF (2.5 mL) and H2O (2.5 mL) was added LiOH.FhO (149.93 mg, 3.57 mmol). The mixture was stirred at 50 °C for 12 h. The reaction mixture was basified to pH about 7 with 1.2 N HC1, and extracted with DCM (10 mL x 3). The organic layer was washed brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-[[(2R,5S)-2,5-dimethylmorpholin-4-yl]-(3- methoxyphenyl)methyl] benzoic acid (340 mg, 956.60 pmol, 80.32% yield) was obtained as a white solid. LC-MS (ES+, Method A), 0.43 min, m / z 356.1 [M+H]+. ’ H NMR (400 MHz, CDCh) 5 = 8.14 - 8.09 (m, 2H), 8.05 (d, J= 8.5 Hz, 2H), 7.57 (d, J= 8.0 Hz, 2H), 7.33 - 7.28 (m, 3H), 7.24 (t, J = 7.9 Hz, 1H), 7.06 (s, 1H), 6.96 - 6.87 (m, 2H), 6.81 (dd, J = 2.5, 8.1 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.71 - 6.68 (m, 1H), 5.39 (s, 1H), 5.35 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.78 - 3.73 (m, 8H), 3.46 - 3.38 (m, 2H), 2.68 (dd, J= 2.0, 11.5 Hz, 1H), 2.61 - 2.55 (m, 2H), 2.49 (tdd, J= 3.1, 6.3, 9.4 Hz, 1H), 1.87 (td, J= 3.3, 6.7 Hz, 4H), 1.13 (dd, J = 3.3, 6.1 Hz, 6H), 1.08 (d, J= 6.3 Hz, 6H).

[0300] Compound 10 (WB35): 4-((R)-((2R,5S)-2,5-dimethylmorpholino)(3- methoxyphenyl)methyl)benzoic acid

[0301] 4-[[(2R,5S)-2,5-dimethylmorpholin-4-yl]-(3-methoxyphenyl)methyl]benzoic acid (140 mg, 378.94 pmol) was purified by SFC ((column: ChiralPak IH,250*50mm, 10um;mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:25%, isocratic elution mode) to afford 4-((R)-((2R,5S)-2,5-dimethylmorpholino)(3-ethoxyphenyl)methyl)benzoic acid (10 mg,28.14 pmol, 7.42% yield) as a white solid. LC-MS (ES+, Method A), 0.43 min, m / z 356.1 [M+H]+. ’ H NMR (400 MHz, CDCh) 5 1.03 - 1.15 (m, 6 H), 1.70 - 1.79 (m, 2 H), 2.43 - 2.52 (m, 1 H), 2.62 - 2.71 (m, 1 H), 3.35 - 3.44 (m, 1 H), 3.68 - 3.81 (m, 5 H), 5.33 - 5.41 (m, 1H), 6.77 - 6.84 (m, 1 H), 6.88 - 6.96 (m, 1 H), 7.03 - 7.08 (m, 1 H), 7.17 - 7.27 (m, 3 H), 8.04 -8.14 (m, 2 H).

[0302] Compound 11 (WB35-1): 4-((S)-((2R,5S)-2,5-dimethylmorpholino)(3- methoxyphenyl)methyl)benzoic acid

[0303] LC-MS (ES+, Method A), 0.43 min, m / z 356.2 [M+H]+.JH NMR (400 MHz, CDCh) 5 1.07 (d, 7=6.25 Hz, 3 H), 1.12 (d, 7=6.13 Hz, 3 H), 1.79 - 1.87 (m, 1 H), 2.52 - 2.61 (m, 2 H), 3.37 - 3.46 (m, 1 H), 3.69 - 3.78 (m, 2 H), 3.80 - 3.84 (m, 3 H), 5.31 - 5.36 (m, 1 H), 6.67 - 6.70 (m, 1 H), 6.74 (br d, 7=7.50 Hz, 1 H), 6.86 - 6.91 (m, 1 H), 7.28 - 7.33 (m, 1 H), 7.52 - 7.60 (m, 2 H), 7.99 - 8.06 (m, 2 H).

[0304] General route for the synthesis of Compound 12:

[0305] Compound 12 (WB36): 4-((R)-((2R,5S)-2,5-dimethylmorpholino)(3- methoxyphenyl)methyl)benzoic acid

[0306] To a mixture of 4-[[(2R,5S)-2,5-dimethylmorpholin-4-yl]-(3- methoxyphenyl)methyl] benzoic acid (150 mg, 422.03 pmol) and ethanamine (28.54 mg, 633.04 pmol, 41.42 pL) in DMF (1.5 mL) was added HATU (192.56 mg, 506.43 pmol) and DIEA (218.18 mg, 1.69 mmol, 294.04 pL) in one portion at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 2). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was further purification by preparative-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v / v)-ACN];gradient:30%-60% B over 10 min) and lyophilizated. The residue was further purification by chiral SEC (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2-MeOH(0.1%NH3H2O)];B%:25%, isocratic elution mode) and lyophilizated to give 4-[(R)- [(2R,5S)-2,5-dimethylmorpholin-4-yl]-(3-methoxyphenyl)methyl]-N-ethyl-benzamide (16.5 mg, 42.71 pmol, 10.89% yield, 99% purity) was obtained as a yellow solid. LC-MS (ES+, Method C), 0.64 min, m / z 383.1 [M+H]+. ’ H NMR (400 MHz, CDCh) 5 ppm 1.03 - 1.08 (m, 3 H), 1.13 (s, 3 H), 1.27 (t, 7=7.25 Hz, 3 H), 1.73 (dd, 7=11.44, 9.57 Hz, 1 H), 2.39 - 2.50 (m, 1 H), 2.66 (dd, J=11.51, 1.88 Hz, 1 H), 3.35 - 3.43 (m, 1 H), 3.49 - 3.56 (m, 2 H), 3.69 - 3.75(m, 2 H), 3.76 - 3.80 (m, 3 H), 5.36 (s, 1 H), 6.12 (br s, 1 H), 6.80 (dd, J= 8.13, 2.38 Hz, 1H), 6.93 (d, J = 7.63 Hz, 1 H), 7.02 - 7.07 (m, 1 H), 7.20 - 7.26 (m, 3 H), 7.71 - 7.81 (m, 2H).

[0307] The compounds in the table below were prepared in a similar manner to the methods described above above.

[0308] General route for the synthesis of Compound 34:

[0309] Compound 34 (WB7): 4-(((2S)-2,5-dimethyl-4-oxopiperidin- l-yl)(3- methoxyphenyl)methyl)-A,A-diethylbenzamide

[0310] To a mixture of 4-[[(6R,9S)-6,9-dimethyl-l,4-dioxa-8-azaspiro[4.5]decan-8-yl]-(3- methoxyphenyl)methyl]-N,N-diethyl-benzamide (79 mg, 169.31 pmol) in HCl / MeOH (4 M, 6 mL). The mixture was stirred at 45 °C for 30 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was further purification by preparative- HPLC ( column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v / v)-ACN];gradient:30%-60% B over 10 min) and lyophilizated to give 4-(((2S)- 2,5-dimethyl-4-oxopiperidin-l-yl)(3-methoxyphenyl)methyl)-N,N-diethylbenzamide (3 mg, 7.00 pmol, 4.13% yield, 98.6% purity) was obtained as a white gum. LC-MS (ES+, Method A), 0.68 min, m / z 423.3 [M+H]+.JH NMR (400 MHz, CDCh) 5 7.56 - 7.49 (m, 2H), 7.34 - 7.30 (m, 2H), 7.26 - 7.20 (m, 1H), 7.11 - 7.03 (m, 2H), 6.77 (br d, J= 7.4 Hz, 1H), 4.69 (d, J= 5.6 Hz, 1H), 3.82 - 3.80 (m, 3H), 3.58 - 3.47 (m, 3H), 3.35 - 3.19 (m, 2H), 3.02 - 2.93 (m, 1H), 2.88 - 2.73 (m, 1H), 2.70 - 2.40 (m, 2H), 2.19 - 2.05 (m, 1H), 1.28 - 1.19 (m, 3H), 1.18 - 1.08 (m, 3H), 0.94 (t, J= 6.1 Hz, 3H), 0.90 - 0.80 (m, 4H).

[0311] Compound 35 (WB7-1): N,N-diethyl-4-((3-methoxyphenyl)((S)-2-methyl-4- oxopiperidin- 1 -yl)methyl)benzamide

[0312] LC-MS (ES+, Method A), 0.66 min, m / z 409.2 [M+H]+.JH NMR (400 MHz, CDCh) 5 = 7.55 - 7.47 (m, 2H), 7.32 (d, J= 8.1 Hz, 2H), 7.25 - 7.21 (m, 1H), 7.10 - 7.00 (m, 2H), 6.80 - 6.74 (m, 1H), 4.77 - 4.73 (m, 1H), 3.80 (d, J = 2.6 Hz, 3H), 3.58 - 3.40 (m, 3H), 3.33 - 3.20 (m, 2H), 2.96 - 2.74 (m, 3H), 2.62 - 2.48 (m, 1H), 2.26 - 2.05 (m, 2H), 1.25 - 1.09 (m, 6H), 1.01 (dd, J = 6.8, 9.8 Hz, 3H).

[0313] General route for the synthesis of Compound 36:

[0314] Compound 36 (WB54): N,N-diethyl-4-((3-methoxyphenyl)(4-oxopiperidin- 1 - yl)methyl)benzamide

[0315] To a mixture of 4-[l,4-dioxa-8-azaspiro[4.5]decan-8-yl-(3- methoxyphenyl)methyl]-N,N-diethyl-benzamide (100 mg, 228.02 pmol) and 4- methylbenzenesulfonic acid;pyridine (114.60 mg, 456.04 pmol) in acetone (1.5 mL) and H2O (1.5 mL) in one portion at 25 °C. The mixture was stirred at 65 °C for 42 h. The residue was lyophilizated. The residue was further purification by preparative-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v / v)- ACN];gradient:30%-60% B over 10 min) and lyophilizated to give N,N-diethyl-4-[(3- methoxyphenyl)-(4-oxo-l-piperidyl)methyl]benzamide (6 mg, 14.74 pmol, 6.46% yield, 96.9% purity) was obtained as an off-white solid. LC-MS (ES+, Method A), 0.62 min, m / z 395.2 [M+H]+. ’ H NMR (400 MHz, CDCh) 5 = 7.49 (d, J = 8.1 Hz, 2H), 7.32 (d, J= 8.1 Hz, 2H), 7.26 - 7.21 (m, 1H), 7.05 - 7.01 (m, 2H), 6.80 - 6.75 (m, 1H), 4.40 (s, 1H), 3.80 (s, 3H),3.61 - 3.45 (m, 2H), 3.26 (br s, 2H), 2.74 - 2.67 (m, 4H), 2.46 (t, J= 5.9 Hz, 4H), 1.28 - 1.19 (m, 3H), 1.12 (br s, 3H).

[0316] General route for the synthesis of Compound 37 :

[0317] Compound 37 (WB41): 4-(((2R,5S)-2,5-dimethylmorpholino)(3- methoxyphenyl)methyl)-N,N-diethylbenzamide

[0318] To a mixture of 4-[[(2R,55')-2,5-dimethylmorpholin-4-yl]-(3- methoxyphenyl)methyl] benzoic acid (50 mg, 140.68 pmol) dissolved in THF (1 mL) was added SOCh (25.10 mg, 211.01 pmol, 15.33 pL) in one portion at 25 °C . The mixture was stirred at 60 °C for 1 h. Then mixture was cooled to 25 °C, add NH3.H2O (13.33 mg, 140.68 pmol, 3.80 pL, 37% purity) stirred 5 min at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was further purification by preparative- HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v / v)-ACN];gradient:23%-53% B over 10 mi ) and lyophilizated to give 4-((R)-((2R,5S)-2,5- dimethylmorpholino)(3-methoxyphenyl)methyl)benzamide was as a white solid. LC-MS (ES+, Method A), 0.40 min, m / z 355.1 [M+H]+.JH NMR (400 MHz, CDCh) 5 = 7.75 (d, J = 8.4 Hz, 2H), 7.54 (d, J= 7.9 Hz, 2H), 7.33 - 7.28 (m, 1H), 6.88 (dd, J = 2.0, 8.3 Hz, 1H), 6.74 (d, J= 7.8 Hz, 1H), 6.70 - 6.67 (m, 1H), 6.17 - 5.90 (m, 1H), 5.75 - 5.45 (m, 1H), 5.33 (s, 1H), 3.81 (s, 3H), 3.77 - 3.69 (m, 2H), 3.44 - 3.38 (m, 1H), 2.59 - 2.50 (m, 2H), 1.83 (dd, J = 9.6, 11.7 Hz, 1H), 1.12 (d, J = 6.1 Hz, 3H), 1.06 (d, J= 6.3 Hz, 3H).

[0319] Compound 38 (WB41-1): 4-((S)-((2R,5S)-2,5-dimethylmorpholino)(3- methoxyphenyl)methyl)benzamide

[0320] LC-MS (ES+, Method A), 0.39 min, m / z 355.2 [M+H]+.JH NMR (400 MHz, CDCh) 5 7.82 (d, J= 8.3 Hz, 2H), 7.28 (s, 1H), 7.27 - 7.20 (m, 2H), 7.05 (s, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.80 (dd, J = 2.5, 8.1 Hz, 1H), 6.21 - 5.94 (m, 1H), 5.85 - 5.59 (m, 1H), 5.37 (s, 1H), 3.79 (s, 3H), 3.76 - 3.70 (m, 2H), 3.43 - 3.37 (m, 1H), 2.67 (dd, J = 2.0, 11.5 Hz, 1H), 2.46 (dqd, J= 3.3, 6.2, 9.5 Hz, 1H), 1.74 (dd, J= 9.4, 11.6 Hz, 1H), 1.13 (d, J = 6.1 Hz, 3H), 1.06 (d, J = 6.3 Hz, 3H).

[0321] Compound 1 HC1 salt (WB3-HC1): 4-(((2R,5S)-2,5-dimethylmorpholino)(3- methoxyphenyl)methyl)-N,N-diethylbenzamide

[0322] To a mixture of WB3 (300 mg, 730.73 pmol) in ACN (6 mL) was added H2O (30 mL) and HC1 (1 M, 2 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 h. The residue was further purification by preparative-HPLC (column: Phenomenex luna Cl 8 150*25mm* 10um;mobile phase: [water(HCl)-ACN];gradient:15%-45% B over 10 min ) and lyophilizated.to give 4-[[(2R,5S)-2,5-dimethylmorpholin-4-yl]-(3-methoxyphenyl)methyl]- N,N-diethyl-benzamide (214.5 mg, 476.98 pmol, 65.27% yield, 99.4% purity, HC1) was obtained as a white solid. LC-MS (ES+, Method A), 0.46 min, m / z 411.2 [M+H]+. ’ H NMR (400 MHz, CDCh) 5 = 13.11 (br d, J= 1.9 Hz, 1H), 7.98 (d, J= 8.1 Hz, 2H), 7.46 - 7.40 (m, 3H), 7.16 - 7.11 (m, 2H), 7.01 (dd, J = 2.0, 8.3 Hz, 1H), 5.72 (br s, 1H), 4.60 - 4.51 (m, 1H), 4.45 (dd, J = 11.0, 12.8 Hz, 1H), 3.87 (s, 3H), 3.72 (dd, J= 3.8, 12.9 Hz, 1H), 3.59 - 3.11 (m, 6H), 2.76 - 2.65 (m, 1H), 1.38 (d, J= 6.4 Hz, 3H), 1.28 - 1.07 (m, 9H).

[0323] General route for the synthesis of Compound 39:

[0324] Compound 39 (WB34): 4-((R)-((2R,5S)-2,5-dimethylmorpholino)(3- hydroxyphenyl)methyl)-N,N-diethylbenzamide

[0325] To a mixture of 4-[[(2R,5S)-2,5-dimethylmorpholin-4-yl]-(3- methoxyphenyl)methyl]-N,N-diethyl-benzamide (100.00 mg, 243.58 pmol) in HBr (4 mL) in one portion at 20 °C under N2.The mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was further purification by preparative-HPLC (column: YMC-Actus Triart C18 150*30mm*7um;mobile phase: [water(FA)-ACN];gradient:15%-45% B over 10 min) and lyophilizated to give 4-[(R - [ ( 2R, 5SJ-2.5 -di mcthy I morphol i n-4-y 11 -(3 -hydroxyphenyl)methyl] -N,N -diethyl-benzamide (10.6 mg, 26.55 pmol, 10.90% yield, 99.3% purity) was obained as a white solid. LC-MS (ES+, Method A), 0.41 min, m / z 397.2 [M+H]+.JH NMR (400 MHz, CDCh) 5 = 7.46 (d, J = 7.9 Hz, 2H), 7.31 (d, J= 8.3 Hz, 2H), 7.23 (t, J= 7.8 Hz, 1H), 6.79 (dd, J = 2.2, 7.9 Hz, 1H), 6.71 (d, J= 7.6 Hz, 1H), 6.60 - 6.57 (m, 1H), 5.46 - 5.32 (m, 1H), 5.25 (s, 1H), 3.76 - 3.67 (m, 2H), 3.64 - 3.48 (m, 2H), 3.44 - 3.27 (m, 3H), 2.58 (dd, J= 2.0, 11.6 Hz, 1H), 2.55 - 2.47 (m, 1H), 1.80 (dd, J= 9.6, 11.6 Hz, 1H), 1.32 - 1.22 (m, 3H), 1.18 - 1.08 (m, 6H), 1.06 (d, J = 6.3 Hz, 3H).

[0326] General route for the synthesis of Compound 40:

[0327] Step 1: 4-bromo-N,N-diethyl-2-methoxybenzamide

[0328] To a mixture of 4-bromo-2-methoxy-benzoic acid (5 g, 21.64 mmol) and N- ethylethanamine (1.32 g, 18.03 mmol, 1.86 mL) in DMF (50 mL) was added DIEA (11.65 g, 90.17 mmol, 15.71 mL) and T4P (19.49 g, 54.10 mmol) in one portion at 0 °C. The mixture was stirred at 25 °C for 1 h. After the mixture was cooled to room temperature, the reaction mixture was diluted with H2O (300 mL), and then extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 8 / 1 to 5 / 1) to give 4-bromo-N,N- diethyl-2-methoxy-benzamide (24.69 g, 86.27 mmol, 95.67% yield) was obtained as a yellow solid. LC-MS (ES+, Method A), 0.52 min, m / z 285.9 [M+H]+.

[0329] Step 2: A,A-diethyl-4-formyl-2-methoxybenzamide

[0330] Reagent solution A: a solution of 4-bromo-N,N-diethyl-2-methoxy-benzamide (16 g) in THE (20 V). Reagent solution B: a solution of n-BuLi (1.6 M). Reagent solution C: a solution of DME ( 20.4 g , 5 eq) in THE (10 V). The temperature of FLRiwas -70 °C, FLR2 was -70 °C. The solution of A was added at 5.69 mL / min, solution of B was added at 0.723 mL / min, solution of C was added at 3.084 mL / min. Following completion of the addition, the reaction was quenched by adding sat. NH4CI (100 mL), and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S 1O2, Petroleum ether / Ethyl acetate = 1 / 0 to 2 / 1). A,A-diethyl-4-formyl-2-methoxy-benzamide (4.6 g, 19.55 mmol, 28.75% yield) was obtained as a yellow solid. LC-MS (ES+, Method A), 0.44 min, m / z 236.1 [M+H]+. ’ H NMR (400 MHz, CDCE) 5 = 9.99 (s, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J= 7.5 Hz, 1H), 3.90 (s, 3H), 3.67 - 3.50 (m, 2H), 3.13 (dq, J = 3.2, 6.9 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H).

[0331] Step 3: 4,4'-(hydroxymethylene)bis(N,N-diethyl-2-methoxybenzamide)

[0332] Reagent solution A: a solution of A,A-diethyl-4-iodo-2-methoxybenzamide ( 4 g) in THF (30 V). Reagent solution B: a solution of n-BuLi (1.6 M). Reagent solution C: a solution of N,N-diethyl-4-formyl-2-methoxy-benzamide (1.1 eq) in THF (30 V). The temperature of FLRiwas -70 °C, FLR2 was -70 °C. The solution of A was added at 3.18 mL / min, solution of B was added at 0.35 mL / min, solution of C was added at 3.16 mL / min. Following completion of the addition, the reaction was quenched by adding sat. NH4CI (50 mL), the reaction mixture was diluted with H2O (10 mL), and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.LC-MS (ES+, Method C), 0.54 min, m / z 443.2 [M+H]+. ’ H NMR (400 MHz, CDCh) 5 7.13 (d, J = 7.8 Hz, 2H), 7.07 - 6.91 (m, 4H), 5.81 - 5.77 (m, 1H), 3.85 - 3.77 (m, 6H), 3.56 (br s, 4H), 3.14 (q, 7= 7.1 Hz, 4H), 1.27 - 1.21 (m, 6H), 1.03 (t, 7 = 7.1 Hz, 6H).

[0333] Step 4: 4,4'-(chloromethylene)bis(N,N-diethyl-2-methoxybenzamide)

[0334] To a solution of 4,4'-(hydroxymethylene)bis(N,N-diethyl-2-methoxybenzamide) (52 mg, 112.80 pmol) in toluene (1 mL) was added SOCh (50.32 mg, 423.00 pmol, 30.72 pL) under N2 .The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give 4-[chloro-[4-(diethylcarbamoyl)-3-methoxy- phenyl]methyl]-N,N-diethyl-2-methoxy-benzamide (50 mg, 108.46 pmol, 96.15% yield) was obtained as a brown gum.

[0335] Intermediate 14: A,A-diethyl-4-iodo-2-methoxybenzamide

[0336] LC-MS (ES+, Method A), 0.53 min, m / z 333.9 [M+H]+. >H NMR (400 MHz, CDCh) 5 = 7.37 (dd, 7= 1.3, 7.8 Hz, 1H), 7.31 (s, 1H), 6.96 (d, 7= 7.8 Hz, 1H), 3.85 (s, 3H), 3.69 - 3.49 (m, 2H), 3.17 (q, 7= 7.1 Hz, 2H), 1.27 (t, 7= 7.1 Hz, 3H), 1.07 (t, 7= 7.1 Hz, 3H).

[0337] Compound 40 (WB53): 4,4'-(morpholinomethylene)bis(N,N-diethyl-2- methoxybenzamide)

[0338] LC-MS (ES+, Method A), 0.432 min, m / z 512.2 [M+H]+.JH NMR (400 MHz, CDCh) 5 = 7.13 - 6.92 (m, 6H), 4.14 (s, 1H), 3.81 (s, 6H), 3.73 (t, J = 4.5 Hz, 4H), 3.63 - 3.47 (m, 4H), 3.14 (q, J = 6.9 Hz, 4H), 2.47 - 2.37 (m, 4H), 1.27 - 1.19 (m, 6H), 1.04 (t, J = 7.1 Hz, 6H).

[0339] Compound 41 (WB 31) was prepared in a similar manner using methods described above.EQUIVALENTS AND SCOPE

[0340] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0341] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and anyelement(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0342] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0343] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof, wherein:Ring A is a substituted or unsubstituted monocyclic 5-7-membered heterocyclic ring;R is -OR1or -N(Ra)2;R1is substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, or hydrogen; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl;L is -C(=O)- or a bond;R5is -N(R7)(R8), -OR6, or substituted or unsubstituted heteroaryl;R6is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl;each instance of R7and R8are independently substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or hydrogen, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic ring; x is 0, 1, 2, 3, or 4; and y is 0, 1, 2, 3, or 4; provided that the compound is not of the formula:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -OR1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is -C(=O)-.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R5is -N(R7)(R8) or -OR6.

5. The compound of any of claims 1-4, wherein the compound is of Formula (I-a):or a pharmaceutically acceptable salt thereof, wherein:Ring A is a substituted or unsubstituted monocyclic 5-7-membered heterocyclic ring;R1is substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, or hydrogen;each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl;R5is -N(R7)(R8) or -OR6;R6is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl; each instance of R7and R8are independently substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or hydrogen, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic ring; x is 0, 1, 2, 3, or 4; and y is 0, 1, 2, 3, or 4.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R5is -N(R7)(R8).

7. The compound of claim 5 or 6, wherein the compound is of Formula (I-b):or a pharmaceutically acceptable salt thereof, wherein:Ring A is a substituted or unsubstituted 6-membered monocyclic heterocyclic ring;R1is substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, or hydrogen; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl; each instance of R7and R8are independently substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or hydrogen, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5 or 6 membered heterocyclic ring; x is 0, 1, 2, 3, or 4; and y is 0, 1, 2, 3, or 4.

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R5is -OR6.

9. The compound of claim 1 or 4, wherein the compound is of Formula (I-c):or a pharmaceutically acceptable salt thereof, wherein:Ring A is a substituted or unsubstituted 6-membered monocyclic heterocyclic ring;R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl;R6is hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-6 heteroalkyl; x is 0, 1, 2, 3, or 4; and y is 0, 1, 2, 3, or 4.

10. The compound of any one of claims 1-6, or 8, or a pharmaceutically acceptable salt thereof, wherein Ring A is a substituted or unsubstituted, monocyclic 6-membered heterocyclic ring.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula:each instance of Rlais independently substituted or unsubstituted alkyl, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z is 2, 3, 4, 5, 6, 0, or 1.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula:, wherein: each instance of Rlais independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z is 2, 3, 4, 5, 6, 0, or 1.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula:

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula:

15. The compound of any one of claims 1-7 or 10-14, wherein the compound is of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:R1is substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, or hydrogen; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl;each instance of R7and R8are independently substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or hydrogen, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5 or 6 membered heterocyclic ring; each instance of Rlais independently substituted or unsubstituted alkyl, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 2, 3, 4, 5, 6, 0, or 1.

16. The compound of any one of claims 1-7 or 10-14, wherein the compound is of Formula (III):or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R7and R8are independently hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5 or 6 membered heterocyclic ring; each instance of Rlais independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, 4, 5, or 6.

17. The compound of any one of claims 1-7 or 10-14, wherein the compound is of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R2and R4are independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - N(Ra)2, -ORa, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -NO2,-NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, or -OC(=O)N(Ra)2; each instance of Rais independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raare joined together with the nitrogen atom to which they are attached to form a heterocyclic ring;R3is hydrogen, substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted Ci-6 heteroalkyl; each instance of R7and R8are independently hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R7and R8are joined together with the nitrogen atom to which they are attached to form a 5 or 6 membered heterocyclic ring; each instance of Rlais independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, 4, 5, or 6.

18. The compound of any one of claims 11, 12, or 15-17, or a pharmaceutically acceptable salt thereof, wherein at least one instance of Rlais substituted or unsubstituted Ci- 6 alkyl.

19. The compound of any one of claims 11, 12, or 15-18, or a pharmaceutically acceptable salt thereof, wherein at least one instance of Rlais substituted or unsubstituted methyl.

20. The compound of any one of claims 11, 12, or 15-19, or a pharmaceutically acceptable salt thereof, wherein at least one instance of Rlais unsubstituted methyl.

21. The compound of any one of claims 11, 12, or 15-19, or a pharmaceutically acceptable salt thereof, wherein at least one instance of Rlais of the formula:.

22. The compound of any one of claims 11, 12, or 15-21, or a pharmaceutically acceptable salt thereof, wherein at least two instances of Rlais substituted or unsubstituted Ci-6 alkyl.

23. The compound of any one of claims 11, 12, or 15-22, or a pharmaceutically acceptable salt thereof, wherein at least two instances of Rlais substituted or unsubstituted methyl.

24. The compound of any one of claims 11, 12, or 15-23, or a pharmaceutically acceptable salt thereof, wherein at least two instances of Rlais unsubstituted methyl.

25. The compound of any one of claims 11-17, or a pharmaceutically acceptable salt thereof, wherein z is 0.

26. The compound of any one of claims 11-21, or a pharmaceutically acceptable salt thereof, wherein z is 1.

27. The compound of any one of claims 11-24, or a pharmaceutically acceptable salt thereof, wherein z is 2.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R7is substituted or unsubstituted Ci-6 alkyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R7is substituted or unsubstituted methyl.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R7is unsubstituted methyl.

31. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R7is substituted or unsubstituted ethyl.

32. The compound of any one of claims 1-28 or 31, or a pharmaceutically acceptable salt thereof, wherein R7is unsubstituted ethyl.

33. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R8is substituted or unsubstituted Ci-6 alkyl.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R8is substituted or unsubstituted methyl.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R8is unsubstituted methyl.

37. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R8is substituted or unsubstituted ethyl.

38. The compound of any one of claims 1-34 or 37, or a pharmaceutically acceptable salt thereof, wherein R8is unsubstituted ethyl.

39. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R8is hydrogen.

40. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R8is substituted or unsubstituted aryl.

41. The compound of any one of claims 1-33 or 40, or a pharmaceutically acceptable salt thereof, wherein R8is substituted or unsubstituted phenyl.

42. The compound of any one of claims 1-33 or 40-41, or a pharmaceutically acceptable salt thereof, wherein R8is unsubstituted phenyl.

43. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R8is substituted or unsubstituted 5-6 membered heteroaryl ring.

44. The compound of any one of claims 1-33 or 43, or a pharmaceutically acceptable salt thereof, wherein R8is substituted or unsubstituted pyridine, pyrimidine, thiazole, or pyrazole.

45. The compound of any one of claims 1-33 or 43-44, or a pharmaceutically acceptable salt thereof, wherein R8is of the formula:

46. The compound of any one of claims 1-27, wherein R7and R8are joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted 5-6 membered heterocyclic ring.

47. The compound of any one of claims 1-27, or 46, or a pharmaceutically acceptable salt thereof, wherein R7and R8are joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted piperazine or substituted or unsubstituted morpholine ring.

48. The compound of any one of claims 1-37 or 46-47, or a pharmaceutically acceptable salt thereof, wherein R7and R8are joined together with the nitrogen atom to which they are attached to form a heterocyclic ring of the formula:

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, wherein R1is substituted or unsubstituted Ci-6 alkyl.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, wherein R1is substituted or unsubstituted methyl.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein R1is unsubstituted methyl.

52. The compound of any one of claims 1-49, or a pharmaceutically acceptable saltthereof, wherein R1is of the formula:

53. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein x is 0.

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein y is 0.

56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

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

58. A pharmaceutical composition comprising a compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

59. A method of inducing biostasis in a subject, biological sample, or cell, comprising administering a compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 to the subject, biological sample, or cell.

60. A method of inducing physiological slowing in a subject, biological sample, or cell, comprising administering a compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 to the subject, biological sample, or cell.

61. The method of claim 60, wherein the physiological slowing comprises slowing of metabolic processes.

62. The method of claim 60 or 61, wherein the physiological slowing is reversible.

63. A method comprising administering a compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58, to a biological sample.

64. A method of preserving a biological sample, the method comprising administering a compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 to the biological sample.

65. The method of any one of claims 59-64, wherein the biological sample comprises mammalian tissue.

66. The method of any one of claims 59-65, wherein the biological sample comprises human tissue.

67. The method of any one of claims 59-66, wherein the biological sample comprises a whole organ.

68. The method of any one of claims 59-67, wherein the biological sample comprises a whole organ for transplant.

69. The method of any one of claims 59-68, wherein the biological sample comprises liver, heart, lung, kidney, pancreas, or intestinal tissue.

70. The method of any one of claims 59-69, wherein the biological sample comprises heart tissue.

71. The method of any one of claims 59-66, wherein the biological sample comprises a limb for reimplantation.

72. A kit comprising a compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58; and instructions foradministering the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject.

73. The kit of claim 71, wherein the instructions comprise administering the compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58, to mammalian tissue.

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