TOX inhibitors and molecular glues, methods of use thereof, and kits comprising the same

Abstract

Disclosed herein are compounds (e.g, compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, isotopically labeled compounds, and prodrugs thereof), and pharmaceutical compositions, kits, methods, and uses thereof. The compounds disclosed herein are inhibitors of TOX protein and are useful for treating diseases (e.g., immune diseases, proliferative diseases, and viral infections).

Description

TOX INHIBITORS AND MOLECULAR GLUES, METHODS OF USE THEREOF, AND KITS COMPRISING THE SAME CROSS-REFERENCE TORELATEDAPPLICATIONS

[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S. Provisional Application U.S.S.N. 63 / 562,443, filed March 7, 2024, the entire contents of which are incorporated herein by reference in their entirety. BACKGROUND

[0002] Thymocyte selection-associated high mobility group box protein (TOX) is necessary for T-cell persistence but is also implicated in T-cell exhaustion. Exhausted T-cells exhibit reduced proliferative capacity, reduced production of effector cytokines, reduced cytotoxicity, and increased expression of multiple inhibitory expression. Endogenous T-cell exhaustion may contribute to the immune system failure. There remains a need for treating disease associated with T-cell exhaustion. SUMMARY OF THE DISCLOSURE

[0003] Disclosed herein are compounds (e.g., compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, isotopically labeled compounds, and prodrugs thereof), as well as pharmaceutical compositions and kits comprising the same and associated methods of use.

[0004] In one aspect, the present disclosure a of Formula (I):(I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1, R2, R3, R4, R5, R9a, and R9bare as defined herein.

[0005] In another aspect, the present disclosure provides a pharmaceutical composition comprising: a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopicallyM1237.70139WO00 1 / 111#13711954v1labeled compound, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0006] In another aspect, the present disclosure provides a kit comprising: a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein; and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition.

[0007] In another aspect, the present disclosure provides a method of inhibiting the activity of TOX protein in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with an effective amount of a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.

[0008] In another aspect, the present disclosure provides a method of treating or preventing a disease comprising administering to a subject in need thereof an effective amount of a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.

[0009] In another aspect, the present disclosure provides method of inhibiting the activity of TOX protein in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with an effective amount of a compound of the ,, ,M1237.70139WO00 2 / 111#13711954v1, , , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof.

[0010] In another aspect, the present disclosure provides method of treating or preventing a disease mediated by TOX protein comprising administering to a subject in need thereof an effective amount, ,M1237.70139WO00 3 / 111#13711954v1, , ,M1237.70139WO00 4 / 111#13711954v1or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof.

[0011] The details of certain embodiments of the disclosure are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the disclosure will be apparent from the Definitions, Examples, Figures, and Claims. It should be understood that the aspects described herein are not limited to specific embodiments, methods, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the present disclosure and together with the description, provide non- limiting examples of the disclosure. The figures are exemplary and do not limit the scope of the present disclosure.

[0013] FIGs. 1A-1B show schematics of the NFAT pathway and T-cell exhaustion.

[0014] FIG. 2A shows a schematic depicting various mechanisms implicating TOX. FIG. 2B shows a schematic depicting screening of compounds that block protein-protein interactions with TOX to achieve cytotoxicity to cancer cells or T cell recovery.

[0015] FIGs. 3A-3C show the methodology for identifying small molecule TOX inhibitors. FIG. 3A shows a schematic depicting a microarray used for compound screening. FIG. 3B shows a schematic demonstrating stages of TOX inhibitor screening and selection. FIG. 3C shows a small molecule microarray scatterplot depicting block Z score comparisons of evaluated compounds. Data shown applied a cut-off threshold of Z score = 3.

[0016] FIG. 4 shows structures of selected small molecule TOX inhibitor candidates.

[0017] FIGs. 5A-5D show ELISA and cytotoxicity screening. FIG. 5A shows a schematic of an ELISA assay. FIG. 5B shows a table of results obtained for KI-TOX-A3 in cell proliferation and ELISA assays. FIG. 5C show ELISA screening of 280 hit compounds (>70% inhibition threshold). FIG. 5D shows dose dependent TOX PPI for three compounds.

[0018] FIG. 6A-6F show target validation for candidate compounds. FIG. 6A shows Western blot analysis of compounds KI-TOX-A3, KI-TOX-D22, and KI-TOX-P14 with Ku70 / 80, BSA, and TOX. FIG. 6B shows variation in response over time for various amounts of KI- TOX-A3. FIG. 6C shows Western blot analysis of compound KI-TOX-A3 with TOX andM1237.70139WO00 5 / 111#13711954v1GAPDH. FIG. 6D shows changes in TOX mRNA levels as a function of concentration of KI-TOX-A3. FIG. 6E shows fold change in TOX mRNA levels over time in Jurkat cells treated with KI-TOX-A3. FIG. 6F shows fold change of mRNA levels of RUNX3, CDK9, Myc, MDM2, TNF-a, and PD-L1 at 12 hours of treatment with KI-TOX-A3.

[0019] FIGs. 7A-7F show activity of selected compounds against TOX on T-ALL. FIG. 7A shows Western blot analysis of 92838-E16 and KI-TOX-A3 with TOX, RUNX3, GAPDH, Caspase 3, and Clv-Caspase 3. FIGs. 7B-7D show the percent expression of TOX (FIG. 7B), RUNX3 / TOX (FIG. 7C), and Caspase 3 (FIG. 7D) activation for compounds KI-TOX-E16 and KI-TOX-A3 at various concentrations. FIG.7E shows the percentage of live cells (Jurkat, HBPALL, HH, Molt-4, Hut78, Raji) as a function of concentration of KI-TOX-A3. FIG. 7F shows the fold change ratio of mRNA levels of TOX, RUNX3, TNF, MDM2, PD- L1, IKBKB, CDK9, and MYC in Jurkat cells.

[0020] FIG. 8 shows the structures of selected compounds according to the present disclosure.

[0021] FIG. 9A shows simulations of the TOX-KAT7 interaction and of KI-TOX-A3 binding to the C-terminal of TOX. FIGs. 9B-9D show cytotoxicity data for selected compounds according to the present disclosure.

[0022] FIGs. 10A-10K show the effect of TOX inhibitors KI-TOX-A3, KI-TOX-D22, and KI-TOX-P14 on T-cells. FIG. 10A shows the percentage of live CD8+ T-cells as a function of concentration of KI-TOX-D22. FIG. 10B shows fold change of mRNA of PD1, TOX, TNF-A, NR4A1, IFN-γ, CDK-9, and Myc in T-cells after KI-TOX-D22 treatment. FIGs. 10C-10F show flow cytometry data for T cells treated with DMSO control (FIG. 10C), 2.5 µM KI-TOX-D22 (FIG. 10D), 5 µM KI-TOX-D22 (FIG. 10E), or 10 µM KI-TOX-D22 (FIG. 10F) in a cell cycle arrest experiment. FIG. 10G shows the percentage of live CD8+ T-cells as a function of concentration of KI-TOX-A3, KI-TOX-D22, or KI-TOX-P14. FIGs. 10H- 10K show qPCR data showing that compounds KI-TOX-A3, KI-TOX-D22, and KI-TOX- P14 regulated mRNA levels of T cells after 24h treatment.

[0023] FIGs. 11A-11C show flow cytometry data showing T-cell exhaustion recovery after treatment with KI-TOX-A3, KI-TOX-D22, or KI-TOX-P14. FIGs. 11A-11C show the expression percentage after 15, 17, and 21 days of treatment, respectively.

[0024] FIG. 12 shows fold change of mRNA of T-cells after treatment with KI-TOX-D22 became toxic.

[0025] FIG. 13 shows a table summarizing the effect of treatment with KI-TOX-A3, KI- TOX-D22, or KI-TOX-P14 on markers PD-1, TIM3, and LAG3 after 15 days of treatment.M1237.70139WO00 6 / 111#13711954v1

[0026] FIGs. 14A-14D show flow cytometry data upon 15 days of treatment with KI-TOX- A3 (FIG. 14B), KI-TOX-D22 (FIG. 14C), or KI-TOX-P14 (FIG. 14D), as compared to DMSO treatment (FIG. 14A).

[0027] FIG. 15 shows a table summarizing the effect of treatment with KI-TOX-A3, KI- TOX-D22, or KI-TOX-P14 on markers PD-1, TIM3, and LAG3 after 17 days of treatment.

[0028] FIGs. 16A-16F show flow cytometry data upon 17 days of treatment with KI-TOX- A03 (FIGs. 16A and 16B), KI-TOX-D22 (FIGs. 16C and 16D), or KI-TOX-P14 (FIG. 16E), as compared to DMSO treatment and naïve T cells (FIG. 16F).

[0029] FIG. 17 shows a table summarizing the effect of treatment with KI-TOX-A3, KI- TOX-D22, or KI-TOX-P14 on markers PD-1, TIM3, and LAG3 after 21 days of treatment.

[0030] FIGs. 18A-18F show flow cytometry data upon 21 days of treatment with KI-TOX- A3 (FIGs. 18A and 18B), KI-TOX-D22 (FIGs. 18C and 18D), or KI-TOX-P14 (FIGs. 18E and 18F), as compared to DMSO.

[0031] FIGs. 19A-19F show proximity ligation assay (PLA) of TOX / KAT7 on Molt-4 cells. FIG. 19A shows a native gel to visualize the HEK293-T expressed hTOX-KAT7 interaction and PPI inhibition from KI-TOX-A3. FIG.19B shows SPR-demonstrated KI-TOX-A3 binding to E. Coli expressed hTOX with KD = 0.92 µM. FIG. 19C shows a schematic depicting PLA. FIG. 19D shows fluorescence imaging of cells treated with 10 µM KI-TOX- A3, KI-TOX-D22, or KI-TOX-P14. FIG. 19E shows quantification of fluorescence of PLA TOX / KAT7 binding in cells treated with DMSO, KI-TOX-A3, KI-TOX-D22, or KI-TOX- P14. FIG. 19F shows results of a Molt-4 pulldown assay where the KI-TOX-A3 derivative could pull down TOX protein and KI-TOX-A3 as a competitor could interfere with the IP. FIG. 19G shows Western blot analysis of compound KI-TOX-A3 with TOX and GAPDH. FIG. 19H shows downregulation of TOX protein by KI-TOX-A3 in MOLT-4 cells with an additional proteosome-dependent manner to rescue TOX by MG132.

[0032] FIG. 20 shows a schematic for T cell stimulation and assessing T cell exhaustion recovery. T cells expressed high levels of TOX after the fifth cycle.

[0033] FIGs. 21A-21C show flow cytometry histograms on day 21 for T cells treated with KI-TOX-A3 (FIG. 21A), KI-TOX-D22 (FIG. 21B), or KI-TOX-P14 (FIG. 21C) in a T cell exhaustion recovery experiment (3-day bead stimulation 24 hour treatment).

[0034] FIGs. 22A-22F show flow cytometry data on day 21 for T cells treated with KI-TOX- A3 (FIGs. 22A and 22B), KI-TOX-D22 (FIGs. 22C and 22D), or KI-TOX-P14 (FIGs. 22E and 22F) in a T cell exhaustion recovery experiment (3-day bead stimulation 24 hour treatment).M1237.70139WO00 7 / 111#13711954v1

[0035] FIGs. 23A-23C show flow cytometry histograms on day 27 for T cells treated with KI-TOX-A3 (FIG. 23A), KI-TOX-D22 (FIG. 23B), or KI-TOX-P14 (FIG. 23C) in a T cell exhaustion recovery experiment (3-day bead stimulation 24 hour treatment)

[0036] FIGs. 24A-24F show flow cytometry data on day 27 for T cells treated with KI-TOX- A3 (FIGs. 24A and 24B), KI-TOX-D22 (FIGs. 24C and 24D), or KI-TOX-P14 (FIGs. 24E and 24F) in a T cell exhaustion recovery experiment (3-day bead stimulation 24 hour treatment).

[0037] FIGs. 25A-25E show flow cytometry histograms on day 30 for IFN-gamma expression following treatment with KI-TOX-A3 (FIG. 25A), KI-TOX-D22 (FIG. 25B), or KI-TOX-P14 (FIG. 25C) as compared to exhausted T cells (FIG. 25D) and activated T cells (FIG. 25E).

[0038] FIGs. 26A-26H show flow cytometry data on day 30 for T cells under 24 hour treatment and simultaneous stimulation with KI-TOX-A3 (FIGs. 26A and 26B), KI-TOX- D22 (FIGs. 26C and 26D), or KI-TOX-P14 (FIGs. 26E and 26F) as compared to naïve and exhausted T cells (FIGs. 26G-26H).

[0039] FIG. 27 shows a schematic of T cell expression of TOX and treatment with TOX inhibitors and shows imaging of TOX in non-exhausted and exhausted T cells.

[0040] FIG. 28 shows downregulation of TIM3 and LAG3 as co-expressed inhibitory receptors (T cell exhaustion biomarkers) following treatment with KI-TOX-A3, KI-TOX- D22, or KI-TOX-P14.

[0041] FIG. 29 shows a co-culture killing assay showing that the T cells after 24 h treatment with TOXi were re-activated and killed CD19-Ramos cells under the use of Bispecific CD3 / CD19 antibody. DEFINITIONS

[0042] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, JohnM1237.70139WO00 8 / 111#13711954v1Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0043] In some embodiments, compounds described herein comprise one or more asymmetric centers, and thus exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. In some embodiments, isomers are 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 are 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.

[0044] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0045] When a range of values is listed, it is intended to encompass each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C1-6 alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl.

[0046] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0047] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12 alkyl”). In some embodiments, an alkyl group has 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 carbonM1237.70139WO00 9 / 111#13711954v1atoms (“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 (“C1–4alkyl”). 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 (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1–6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n- propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n- hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1–12 alkyl (such as unsubstituted C1–6 alkyl, e.g., −CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, – CH2CF3, or benzyl (Bn)).

[0048] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1–20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1–10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1–9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1–8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1–7 haloalkyl”).In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1–6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1–4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1–3 haloalkyl”). In someM1237.70139WO00 10 / 111#13711954v1embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1–2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0049] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–11 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatomsM1237.70139WO00 11 / 111#13711954v1within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1–12alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12 alkyl.

[0050] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1–12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1–11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1–10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1–9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1–8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1–7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1–6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1–5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1–4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1–3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1–2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1 alkenyl”). In some embodiments, the one or more carbon-carbon double bonds are internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C1–4 alkenyl groups include methylidenyl (C1), ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1–6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20 alkenyl. In an alkenyldouble bond for which the stereochemistry is not specified (e.g., −CH=CHCH3 or ) may be in the (E)- or (Z)-configuration.M1237.70139WO00 12 / 111#13711954v1

[0051] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkenyl”). In some embodiments, a heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–4 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC1–20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1–20 alkenyl.M1237.70139WO00 13 / 111#13711954v1

[0052] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20 alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C1-10alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C1 alkynyl”). In some embodiments, the one or more carbon-carbon triple bonds are internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C1-4 alkynyl groups include, without limitation, methylidynyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.

[0053] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkynyl”). In some embodiments, aM1237.70139WO00 14 / 111#13711954v1heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC1–4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC1–20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1–20 alkynyl.

[0054] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclylM1237.70139WO00 15 / 111#13711954v1groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and is saturated or contains 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.

[0055] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (anM1237.70139WO00 16 / 111#13711954v1“unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0056] 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 some embodiments, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is either 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 is saturated or contains one or more carbon-carbon double or triple bonds. In some embodiments, heterocyclyl polycyclic ring systems include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0057] 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”). InM1237.70139WO00 17 / 111#13711954v1some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0058] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5- dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetra- hydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6- dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.M1237.70139WO00 18 / 111#13711954v1

[0059] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6- 14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.

[0060] “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.

[0061] 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 p 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 some embodiments, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, heteroaryl polycyclic ring systems include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is 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. In some embodiments, polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment is onM1237.70139WO00 19 / 111#13711954v1either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0062] 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.

[0063] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groupsM1237.70139WO00 20 / 111#13711954v1containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0064] “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.

[0065] 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.

[0066] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than oneM1237.70139WO00 21 / 111#13711954v1position 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. In some embodiments, heteroatoms such as nitrogen have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

[0067] Exemplary carbon atom substituents include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −C −C −OC −C 2, −C 2, 2, −P−OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; wherein: each instance of Raais, independently, selected from C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5- 14 membered heteroaryl, or two Raagroups are joined to form a 3-14 memberedM1237.70139WO00 22 / 111#13711954v1heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20alkyl, heteroC1– 20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1–20 alkyl, C1– 20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5- 14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N −N −N −C 2, −C−SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10 carbocyclyl, 3- 10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5M1237.70139WO00 23 / 111#13711954v1Rgggroups, or two geminal Rddsubstituents are joined to form =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from C1–10 alkyl, C1–10 perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3- 10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–10 alkyl, C1– 10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5- 10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6 alkyl, −ON(C1–6 alkyl)2, −N(C1–6 alkyl)2, −N(C1–6 alkyl)3+X−, −NH(C1–6 alkyl)2+X−, −NH2(C1–6 alkyl)+X−, −NH3+X−, −N(OC1–6 alkyl)(C1–6 alkyl), −N(OH)(C1–6 alkyl), −NH(OH), −SH, −SC1–6 alkyl, −SS(C1–6 alkyl), −C(=O)(C1–6 alkyl), −CO2H, −CO2(C1–6 alkyl), −OC(=O)(C1–6 alkyl), −OCO2(C1–6 alkyl), −C(=O)NH2, −C(=O)N(C1–6 alkyl)2, −OC(=O)NH(C1–6 alkyl), −NHC(=O)( C1–6 alkyl), −N(C1–6 alkyl)C(=O)( C1–6 alkyl), −NHCO2(C1–6 alkyl), −NHC(=O)N(C1–6 alkyl)2, −NHC(=O)NH(C1–6 alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6 alkyl), −OC(=NH)(C1–6 alkyl), −OC(=NH)OC1–6 alkyl, −C(=NH)N(C1–6 alkyl)2, −C(=NH)NH(C1–6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6 alkyl)2, −OC(NH)NH(C1– 6 alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6 alkyl), −SO2N(C1–6 alkyl)2, −SO2NH(C1–6 alkyl), −SO2NH2, −SO2C1–6 alkyl, −SO2OC1–6 alkyl, −OSO2C1–6 alkyl, −SOC1–6 alkyl, −Si(C1–6 alkyl)3, −OSi(C1–6 alkyl)3 −C(=S)N(C1–6 alkyl)2, C(=S)NH(C1–6 alkyl), C(=S)NH2, −C(=O)S(C1–6 alkyl), −C(=S)SC1–6 alkyl, −SC(=S)SC1–6 alkyl, −P(=O)(OC1–6 alkyl)2, −P(=O)(C1–6 alkyl)2, −OP(=O)(C1–6 alkyl)2, −OP(=O)(OC1–6 alkyl)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3- 10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; andM1237.70139WO00 24 / 111#13711954v1each X−is a counterion.

[0068] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, In(e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0069] In certain embodiments, the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine,M1237.70139WO00 25 / 111#13711954v1oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0070] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0071] The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −ORaa, −ON(Rbb)2, −OC(=O)SRaa, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −OC(=NRbb)N(Rbb)2, −OS(=O)Raa, −OSO2Raa, −OSi(Raa)3, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, and −OP(=O)(N(Rbb))2, wherein X−, Raa, Rbb, and Rccare as defined herein.

[0072] The term “thiol” or “thio” refers to the group –SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from –SRaa, –S=SRcc, –SC(=S)SRaa, –SC(=S)ORaa, –SC(=S) N(Rbb)2, – SC(=O)SRaa, –SC(=O)ORaa, –SC(=O)N(Rbb)2, and –SC(=O)Raa, wherein Raaand Rccare as defined herein.

[0073] 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.

[0074] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from −NH(Rbb), −NHC(=O)Raa, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2, and −NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0075] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, andM1237.70139WO00 26 / 111#13711954v1−NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0076] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from −N(Rbb)3 and −N(Rbb)3+X−, wherein Rbband X−are as defined herein.

[0077] The term “acyl” refers to a group having the general formula −C(=O)RX1, −C(=O)ORX1, −C(=O)−O−C(=O)RX1, −C(=O)SRX1, −C(=O)N(RX1)2, −C(=S)RX1, −C(=S)N(RX1)2, and −C(=S)S(RX1), −C(=NRX1)RX1, −C(=NRX1)ORX1, −C(=NRX1)SRX1, and −C(=NRX1)N(RX1)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like; in some embodiments, each of which is unsubstituted or further substituted).

[0078] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (–C(=O)Raa), carboxylic acids (–CO2H), aldehydes (– CHO), esters (–CO2Raa, –C(=O)SRaa, –C(=S)SRaa), amides (–C(=O)N(Rbb)2, –M1237.70139WO00 27 / 111#13711954v1C(=O)NRbbSO2Raa, −C(=S)N(Rbb)2), and imines (–C(=NRbb)Raa, –C(=NRbb)ORaa), – C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0079] In some embodiments, nitrogen atoms are substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRbb)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, hetero C1–20 alkyl, hetero C1–20 alkenyl, hetero C1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0080] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group.

[0081] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1–10 alkyl (e.g., aralkyl, heteroaralkyl), C1–20 alkenyl, C1–20 alkynyl, hetero C1–20 alkyl, hetero C1–20 alkenyl, hetero C1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independentlyM1237.70139WO00 28 / 111#13711954v1substituted 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.

[0082] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3- phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4- chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0083] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2- phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1- dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2¢- and 4¢-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-M1237.70139WO00 29 / 111#13711954v1nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p- nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4- dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1- dimethyl-2-cyanoethyl 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, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1- cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl- 1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4- pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t- butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0084] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-M1237.70139WO00 30 / 111#13711954v1methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9- anthracenesulfonamide, 4-(4¢,8¢-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0085] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N- acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N- dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5- triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1- substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4- nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’- oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N-p- nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1- cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N- [phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N- nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine.M1237.70139WO00 31 / 111#13711954v1

[0086] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

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

[0088] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C −Si2, and −P(=O)(N(Rbb) 2)2, wherein X−, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0089] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,M1237.70139WO00 32 / 111#13711954v12,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 4,4'-Dimethoxy-3"'-[N-(imidazolylmethyl) ]trityl Ether (IDTr- OR), 4,4'-Dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 1,1-bis(4- methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4- nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate,M1237.70139WO00 33 / 111#13711954v1chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0090] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0091] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group.

[0092] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur −N −C 2,−S 3, 2, 2, −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.

[0093] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon,M1237.70139WO00 34 / 111#13711954v1hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0094] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. In some embodiments, an anionic counterion is monovalent (e.g., including one formal negative charge). In some embodiments, an anionic counterion is multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−, HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10– camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). In some embodiments, multivalent counterions 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.

[0095] 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.

[0096] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The disclosure is not limited in any manner by the above exemplary listing of substituents.

[0097] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by usingM1237.70139WO00 35 / 111#13711954v1other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0098] 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,M1237.70139WO00 36 / 111#13711954v1persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4−salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0099] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. In some embodiments, this physical association includes hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. In some embodiments, the compounds described herein are solvated. In some embodiments, the compounds described here are in crystalline form and 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.

[0100] 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, in some embodiments, a hydrate of a compound is represented, for example, by the general formula R×x H2O, wherein R is the compound, and x is a number greater than 0. In some embodiments, a given compound forms more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R×0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R×2 H2O) and hexahydrates (R×6 H2O)).

[0101] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. In some embodiments, tautomerization (i.e., the reaction providing aM1237.70139WO00 37 / 111#13711954v1tautomeric pair) is catalyzed by acid or base. Exemplary tautomerizations include keto-to- enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0102] 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”.

[0103] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. In some embodiment, an enantiomer is characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). In some embodiments, a chiral compound exists as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0104] The term “crystalline” or “crystalline form” refers to a solid form substantially exhibiting three-dimensional order. In certain embodiments, a crystalline form of a solid is a solid form that is substantially not amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks.

[0105] The term “amorphous” or “amorphous form” refers to a form of a solid (“solid form”), the form substantially lacking three-dimensional order. In certain embodiments, an amorphous form of a solid is a solid form that is substantially not crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a wide scattering band with a peak at 2θ of, e.g., between 20 and 70°, inclusive, using CuKα radiation. In certain embodiments, the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures. In certain embodiments, the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 2θ of between 20 and 70°, inclusive, is not more than 300-fold, not more than 100-fold, not more than 30-fold, not more than 10-fold, or not more than 3-fold of the maximum intensity of the wide scattering band. In certain embodiments, the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures.M1237.70139WO00 38 / 111#13711954v1

[0106] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid. In the salt, a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature. In the co-crystal, however, a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein. In some embodiments, co-crystals are useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.

[0107] 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. In some embodiments, recrystallization solvent, rate of crystallization, storage temperature, or other factors cause one crystal form to dominate. In some embodiments, various polymorphs of a compound are prepared by crystallization under different conditions.

[0108] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of 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 compoundsM1237.70139WO00 39 / 111#13711954v1described herein are particular prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein.

[0109] The term “molecular glue” refers to a compound that binds at least two different molecules at a time by cooperative binding. In some embodiments, a molecular glue has no binding affinity to at least one of the at least two different molecules separately. In some embodiments, a molecular glue refers to a compound that simultaneously binds to a target protein and to a second protein.

[0110] The terms “composition” and “formulation” are used interchangeably.

[0111] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. In some embodiments, the non-human animal is a male or female at any stage of development. In some embodiments, the non-human animal is a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0112] 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.

[0113] 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.M1237.70139WO00 40 / 111#13711954v1

[0114] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0115] 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 is administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment is administered in the absence of signs or symptoms of the disease. For example, in some embodiments, treatment is administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). In some embodiments, treatment is continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0116] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0117] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. In some embodiments, an effective amount of a compound described herein varies depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0118] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mgM1237.70139WO00 41 / 111#13711954v1to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0119] In certain embodiments, the compounds are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0120] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. In some embodiments, the amount to be administered to, for example, a child or an adolescent is determined by a medical practitioner or person skilled in the art. In some embodiments, the amount to be administered to, for example, a child or an adolescent is lower or the same as that administered to an adult.

[0121] 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. In some embodiments, the term “therapeutically effective amount” encompasses 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 inhibiting TOX. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease (e.g., an immune disease, a proliferative disease, or a viral infection). In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting TOX and treating a disease (e.g., an immune disease, a proliferative disease, or a viral infection).

[0122] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. In some embodiments, the termM1237.70139WO00 42 / 111#13711954v1“prophylactically effective amount” encompasses an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting TOX. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease (e.g., an immune disease, a proliferative disease, or a viral infection). In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting TOX and preventing a disease (e.g., an immune disease, a proliferative disease, or a viral infection).

[0123] As used herein the term “inhibit” or “inhibition,” for example, in the context of TOX, refers to a reduction in the activity. In some embodiments, the term refers to a reduction of the level of activity, e.g., TOX activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of activity. In some embodiments, the term refers to a reduction of the level of activity, e.g., TOX activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of activity.

[0124] Immune diseases and disorders, such as auto-immune disorders, include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), and disorders ameliorated by a gastroprokinetic agent (e.g., ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); eosinophilicM1237.70139WO00 43 / 111#13711954v1esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and food allergies and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD) and non- cardiac chest pain (NCCP, including costo-chondritis)).

[0125] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). In some embodiments, a proliferative disease is associated with: 1) the pathological proliferation of normally quiescenT-cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0126] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. In some embodiments, angiogenesis is chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0127] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. In some embodiments, a neoplasm or tumor is “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas,M1237.70139WO00 44 / 111#13711954v1acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors later give rise to malignant neoplasms. In some embodiments, certain “benign” tumors later give rise to malignant neoplasms which result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0128] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oralM1237.70139WO00 45 / 111#13711954v1cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B- cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarianM1237.70139WO00 46 / 111#13711954v1adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), IsleT-cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0129] The term “viral infection” refers to viruses actively or passively penetrating into, remaining in, and subsequently propagating in an organism, such as, for example, a human, an animal or a plant. Exemplary viral infections include, but are not limited to, respiratory infections (e.g., rhinovirus, influenza, COVID-19, respiratory syncytial virus, human metapneumovirus, parainfluenza), digestive system infections (e.g., norovirus, rotavirus, astrovirus, hepatitis viruses), viral hemorrhagic fevers (e.g., ebola, hantavirus pulmonary syndrome, dengue, yellow fever), sexually transmitted infections (STIs) (e.g., human immunodeficiency virus, human papilloma virus, genital herpes, hepatitis B), exanthematous (rash-causing) infections (e.g., chickenpox, measles, rubella, roesola, fifth disease, Mpox), neurological infections (e.g., West Nile virus, polio, rabies), and congenital infections (e.g., cytomegalovirus, rubella).

[0130] The term “T-cell exhaustion” refers to a state of T cell dysfunction characterized by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. See e.g., Wherry, E. J. Nat. Immunol. 2011, 12, 492-499. In some embodiments, T-cell exhaustion prevents optimal control of infection and tumors.

[0131] Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of theM1237.70139WO00 47 / 111#13711954v1measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, or more typically, within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0132] Unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0133] Disclosed herein are compounds (e.g., compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, isotopically labeled compounds, and prodrugs thereof), as well as pharmaceutical compositions and kits comprising the same and associated methods of use. In some embodiments, the compounds provided herein inhibit TOX. The inventors unexpectedly discovered that TOX inhibitors recover exhausted T-cells. Additionally, without wishing to be bound by theory, the inventors posit that TOX inhibitors prevent T-cell exhaustion in immunotherapies, such as immune checkpoint inhibitors and adoptive cell therapy, preserving their potency. Compounds

[0134] In one aspect, the present disclosure provides a compound of Formula (I):, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: R1and R2are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or R1and R2are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring;M1237.70139WO00 48 / 111#13711954v1R3i R4i eac ly halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –SCN, –SRB, –SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, – C(=O)SRB, –C(=O)N(RB)2, –C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, –C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, –S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, –OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, – OC(=NRB)RB, –OC(=NRB)ORB, –OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, – OS(=O)ORB, –OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, – OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, – NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC(=NRB)ORB, –NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, – NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, – NRBS(=O)2SRB, –NRBS(=O)2N(RB)2; R6is hydrogen, halogen,–OH, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, –CN, –SRB, –NH2, –NO2, –C(=O)ORB, –S(=O)2RB, – S(=O)2ORB, or –S(=O)2N(RB)2; each instance of R7is independently unsubstituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally – C – S S RB, OSOS 2, 2, 2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, –M1237.70139WO00 49 / 111#13711954v1NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC –NRBC –NRBC N –NRBS – –substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORB, –SCN, –SRB, –SSRB, –N3, –NO, –N(RB)2, – NO2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, –C(=NRB)RB, –C(=NRB)ORB, – C S OC OC 2RB, –OS – SC SC 2, –R9aand R9bare each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl,–ORB, –SRB, –N(RB)2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, or –C(=O)N(RB)2; X1is –NRA–, –S–, or –O–; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and each instance of RAand RBis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfurM1237.70139WO00 50 / 111#13711954v1protecting group when attached to a sulfur atom, or two instances of RAor RBattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; provided that the compound is not: , or atautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0135] In some embodiments, the compound is of Formula (I-A), (I-B), (I-C), or (I-D): B),, D), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0136] In some embodiments, E):(I-E), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.M1237.70139WO00 51 / 111#13711954v1

[0137] In some embodiments, the compound is of Formula (I-F): , or a pharmaceutically co-crystal, tautomer,stereoisomer, isotopically or

[0138] In some embodiments, R1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group. In some embodiments, R1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group. In some embodiments, R1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R1is hydrogen or a nitrogen protecting group. In some embodiments, R1is hydrogen. In some embodiments, R1is a nitrogen protecting group.

[0139] In some embodiments, R2is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group. In some embodiments, R2is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group. In some embodiments, R2is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R2is hydrogen or a nitrogen protecting group. In some embodiments, R2is hydrogen. In some embodiments, R2is a nitrogen protecting group. In some embodiments, R2is optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl. In some embodiments, R2is C1-C6 alkyl or C1-C6 heteroalkyl, isoptionally substituted with =O. In some embodiments, R2is , ,M1237.70139WO00 52 / 111#13711954v1, or .

[0140] In some embodiments, R1and R2are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring. In some embodiments, R1and R2are joined together with the intervening atom to form an optionallyM1237.70139WO00 53 / 111#13711954v1substituted, monocyclic, heterocyclic ring. In some embodiments, R1and R2are joined together with the intervening atom to form an optionally substituted, monocyclic, heteroaryl ring.

[0141] In some embodiments, R1and R2are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group. In some embodiments, R1and R2are each hydrogen. In some embodiments, one of R1and R2is hydrogen, and the other of R1and R2is optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl. In some embodiments, one of R1and R2is hydrogen, and the other of R1and R2is C1-C6 alkyl or C1-C6 heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted with =O. In some embodiments, one of R1and R2is hydrogen, and the other of R1and R2,.M1237.70139WO00 54 / 111#13711954v1[001 is 3 is 3 is some embodiments, some embodiments, R3isis. .

[0143] In some embodiments, R3is . In some R3is . Insome embodiments, R3is . In some someembodiments, R3is . In some embodiments, R3is . In someM1237.70139WO00 55 / 111#13711954v1embodiments, R3In some embodiments, R3i me embodiments, R3In some In someembodiments, R3is . In some embodiments, R3is . In some embodiments, R3is3In some embodiments, Rembodiments, R3. In some embodiments, R3. some embodiments, R3is, or.

[0145] In some embodiments, R4is –ORA, –SRA, or –N(RA)2. In some embodiments, R4is embodiments, R4is –ORAor –N(RA)2. In some embodiments, R4is embodiments, R4is –ORA. In some embodiments, R4is –OH, –OMe, or . In some embodiments, R4is –OH or –OMe. In some embodiments,M1237.70139WO00 56 / 111#13711954v1R4is –OH. In some embodiments, R4is –SRA. In some embodiments, R4is –SH or –SMe. In some embodiments, R4is –N(RA)2. In some embodiments, R4is –N(H)2, –N(H)Me, or – N(Me)2.

[0146] In some embodiments, at least one instance of R5is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –SCN, –SRB, –SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, – C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, –C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, – C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, – S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, –OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, – OC(=O)N(RB)2, –OC(=NRB)RB, –OC(=NRB)ORB, –OC(=NRB)SRB, –OC(=NRB)N(RB)2, – OS(=O)RB, –OS(=O)ORB, –OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, – OS(=O)2SRB, –OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, – SC(=O)N(RB)2, –SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, – NRBC(=O)RB, –NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC(=NRB)ORB, –NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, – NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, – NRBS(=O)2SRB, –NRBS(=O)2N(RB)2. In some embodiments, at least one instance of R5is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R5is halogen, –CN, –SCN, –SRB, –SSRB, –N3, –NO, –N(RB)2, or –NO2. In some embodiments, at least one instance of R5is –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, or –C(=NRB)N(RB)2. In some embodiments, at least one instance of R5is –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, – S(=O)2ORB, –S(=O)2SRB, or –S(=O)2N(RB)2. In some embodiments, at least one instance of R5is –OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, – OC(=NRB)ORB, –OC(=NRB)SRB, or –OC(=NRB)N(RB)2. In some embodiments, at least one instance of R5is –OS(=O)RB, –OS(=O)ORB, –OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, – OS(=O)2ORB, –OS(=O)2SRB, –OS(=O)2N(RB)2, or –ON(RB)2. In some embodiments, at least one instance of R5is –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, or –SC(=NRB)N(RB)2. In some embodiments, at least one instance of R5is –NRBC(=O)RB, –NRBC(=O)ORB, – NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, –NRBC(=NRB)ORB, –M1237.70139WO00 57 / 111#13711954v1NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, –NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, –NRBS(=O)2SRB, or – NRBS(=O)2N(RB)2. In some embodiments, each instance of R5is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, – CN, –SRB, –N(RB)2, –NO2, –C(=O)RB,–C(=O)ORB, –C(=O)SRBor –C(=O)N(RB)2. In some embodiments, at least one instance of R5is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, –CN, –SRB, –N(RB)2, –NO2, –C(=O)RB,– C(=O)ORB, –C(=O)SRBor –C(=O)N(RB)2.

[0147] In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0148] In some embodiments, R6is hydrogen, halogen, –OH, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, –CN, –SRB, –NH2, –NO2, – C(=O)ORB, –S(=O)2RB, –S(=O)2ORB, or –S(=O)2N(RB)2. In some embodiments, R6is halogen,–OH, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, –CN, –SRB, –NH2, –NO2, –C(=O)ORB, –S(=O)2RB, –S(=O)2ORB, or – S(=O)2N(RB)2. In some embodiments, R6is hydrogen. In some embodiments, R6is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R6is halogen, –OH, –CN, –SRB, –NH2, –NO2, or –C(=O)ORB. In some embodiments, R6is –S(=O)2RB, –S(=O)2ORB, or –S(=O)2N(RB)2. In some embodiments, R6is –OH, –SRB, or –NH2. In some embodiments, R6is –OH, –SH, or –NH2. In some embodiments, R6is hydrogen, halogen, or –OH. In some embodiments, R6is hydrogen, –OH, or –F. In some embodiments, R6is halogen. In some embodiments, R6is - Br, -Cl, or -F. In some embodiments, R6is hydrogen. In some embodiments, R6is -F. In some embodiments, R6is -Cl. In some embodiments, R6is -Br. In some embodiments, R6is -OH. In some embodiments, R6is -SH. In some embodiments, R6is -NH2.

[0149] In some embodiments, at least one instance of R7is unsubstituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –SCN, –SRB, –SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, – C(=O)SRB, –C(=O)N(RB)2, –C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, –C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, –S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, –OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –M1237.70139WO00 58 / 111#13711954v1OC(=NRB)RB, –OC(=NRB)ORB, –OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, – OS(=O)ORB, –OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, – OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, – NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC(=NRB)ORB, –NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, – NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, – NRBS(=O)2SRB, –NRBS(=O)2N(RB)2. In some embodiments, at least one instance of R7is unsubstituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R7is –CN, – SCN, –SRB, –SSRB, –N3, –NO, –N(RB)2, or –NO2. . In some embodiments, at least one instance of R7is –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, –C(=NRB)RB, – C(=NRB)ORB, –C(=NRB)SRB, or –C(=NRB)N(RB)2. In some embodiments, at least one instance of R7is –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, – S instance of R7is – OCat least one instance of R7is –OS(=O)RB, –OS(=O)ORB, –OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, – OS(=O)2ORB, –OS(=O)2SRB, –OS(=O)2N(RB)2, or –ON(RB)2. In some embodiments, at least one instance of R7is –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, or –SC(=NRB)N(RB)2. In some embodiments, at least one instance of R7is –NRBC(=O)RB, –NRBC(=O)ORB, – NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, –NRBC(=NRB)ORB, – NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, –NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, –NRBS(=O)2SRB, or – NRBS(=O)2N(RB)2. In some embodiments, each instance of R7is independently unsubstituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, –CN, – SRB, –N(RB)2, –NO2, –C(=O)RB,–C(=O)ORB, –C(=O)SRBor –C(=O)N(RB)2. In some embodiments, at least one instance of R7is unsubstituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, –CN, –SRB, –N(RB)2, –NO2, –C(=O)RB,–C(=O)ORB, – C(=O)SRBor –C(=O)N(RB)2.

[0150] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 0, 1, or 2. In someM1237.70139WO00 59 / 111#13711954v1embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0151] In some embodiments, at least one instance of R8is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORB, –SCN, –SRB, –SSRB, –N3, –NO, – N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, –C(=NRB)RB, – C(=NRB)ORB, –C(=NRB)SRB, –C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, –S(=O)SRB, – S(=O)N(RB)2, –S(=O)2RB, –S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, –OC(=O)RB, – OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, –OC(=NRB)ORB, – OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, –OS(=O)SRB, – OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, –OS(=O)2N(RB)2, –ON(RB)2, – SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, –SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, –NRBC(=O)ORB, –NRBC(=O)SRB, – NRBC(=O)N(RB)2, –NRBC(=NRB)RB, –NRBC(=NRB)ORB, –NRBC(=NRB)SRB, – NRBC(=NRB)N(RB)2, –NRBS(=O)RB, –NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, –NRBS(=O)2SRB, –NRBS(=O)2N(RB)2. In some embodiments, at least one instance of R8is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R8is halogen, –CN, – ORB, –SCN, –SRB, –SSRB, –N3, –NO, –N(RB)2, or –NO2. In some embodiments, at least one instance of R8is –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, –C(=NRB)RB, – C(=NRB)ORB, –C(=NRB)SRB, or –C(=NRB)N(RB)2. In some embodiments, at least one instance of R8is –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, – S(=O)2ORB, –S(=O)2SRB, or –S(=O)2N(RB)2. In some embodiments, at least one instance of R8is –OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, – OC(=NRB)ORB, –OC(=NRB)SRB, or –OC(=NRB)N(RB)2. In some embodiments, at least one instance of R8is –OS(=O)RB, –OS(=O)ORB, –OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, – OS(=O)2ORB, –OS(=O)2SRB, –OS(=O)2N(RB)2, or –ON(RB)2. In some embodiments, at leastM1237.70139WO00 60 / 111#13711954v1one instance of R8is –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, or –SC(=NRB)N(RB)2. In some embodiments, at least one instance of R8is –NRBC(=O)RB, –NRBC(=O)ORB, – NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, –NRBC(=NRB)ORB, – NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, –NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, –NRBS(=O)2SRB, – NRBS(=O)2N(RB)2. In some embodiments, each instance of R8is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, –CN, –ORB, –SRB, – N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, or –C(=O)N(RB)2. In some embodiments, at least one instance of R8is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, –CN, –ORB, –SRB, –N(RB)2, –NO2, –C(=O)RB, – C(=O)ORB, –C(=O)SRB, or –C(=O)N(RB)2. In some embodiments, at least one instance of R8is optionally substituted C1-6 alkyl. In some embodiments, at least one instance of R8is C1-6 alkyl optionally substituted with –ORB. In some embodiments, at least one instance of R8is C1-6 alkyl optionally substituted with –OH. In some embodiments,.

[0152] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 2 or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0153] In some embodiments, R9aand R9bare each hydrogen. In some embodiments, at least one of R9aand R9bis hydrogen. In some embodiments, at least one of R9aand R9bis halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl,–ORB, –SRB, –N(RB)2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, or – C(=O)N(RB)2. In some embodiments, at least one of R9aand R9bis optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one of R9aand R9bis halogen, –ORB, –SRB, –N(RB)2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, or –C(=O)N(RB)2. In some embodiments, at least one of R9aand R9bis –ORB, –SRB, or –N(RB)2. In some embodiments, at least one of R9aand R9bis –M1237.70139WO00 61 / 111#13711954v1C(=O)RB, –C(=O)ORB, –C(=O)SRB, or –C(=O)N(RB)2. In some embodiments, at least one of R9aand R9bis halogen.

[0154] In some embodiments, X1is –NRA–, –S–, or –O–. In some embodiments, X1is – NH–, –S–, or –O–. In some embodiments, X1is –NRA– or –S–. In some embodiments, X1is –NH– or –S–. In some embodiments, X1is –NRA– or –O–. In some embodiments, X1is – NH– or –O–. In some embodiments, X1is –S– or –O–. In some embodiments, X1is –NRA–. In some embodiments, X1is –NRA–, wherein RAis hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In some embodiments, X1is –NRA–, wherein RAis hydrogen or a nitrogen protecting group. In some embodiments, X1is –NH–. In some embodiments, X1is –S–. In some embodiments, X1is –O–.

[0155] In some embodiments, each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom. In some embodiments, at least one instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl. In some embodiments, at least one instance of RAis optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of RAis 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.

[0156] In some embodiment, two instances of RAattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring. In some embodiment, two instances of RAattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiment, two instances of RAattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heteroaryl ring.

[0157] In some embodiments, each instance of RBis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionallyM1237.70139WO00 62 / 111#13711954v1substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom. In some embodiments, at least one instance of RBis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl. In some embodiments, at least one instance of RBis optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of RBis 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.

[0158] In some embodiment, two instances of RBattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring. In some embodiment, two instances of RBattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiment, two instances of RBattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heteroaryl ring.

[0159] In some embodiments, the is of the formula: ,, , ,M1237.70139WO00 63 / 111#13711954v1, , or . Pharmaceutical Compositions, Kits, and Administration

[0160] In another aspect, the present disclosure provides a pharmaceutical composition comprising: a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and a pharmaceutically acceptable excipient.M1237.70139WO00 64 / 111#13711954v1

[0161] In another aspect, the present disclosure provides a kit comprising: a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein; and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition.

[0162] In some embodiments, the pharmaceutical composition further comprises one or more additional pharmaceutical agents. In some embodiments, pharmaceutical compositions described herein are prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0163] In some embodiments, pharmaceutical compositions are prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0164] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. In some embodiments, the composition comprises between 0.1% and 100% (w / w) active ingredient.

[0165] Pharmaceutically acceptable excipients used in the manufacture of disclosed pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. In some embodiments, excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents are present in the composition.

[0166] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodiumM1237.70139WO00 65 / 111#13711954v1phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0167] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0168] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween®20), polyoxyethylene sorbitan (Tween®60), polyoxyethylene sorbitan monooleate (Tween®80), sorbitan monopalmitate (Span®40), sorbitan monostearate (Span®60), sorbitan tristearate (Span®65), glyceryl monooleate, sorbitan monooleate (Span®80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj®45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij®30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic®F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0169] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.),M1237.70139WO00 66 / 111#13711954v1natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0170] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0171] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0172] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0173] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0174] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0175] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.M1237.70139WO00 67 / 111#13711954v1

[0176] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall®115, Germaben®II, Neolone®, Kathon®, and Euxyl®.

[0177] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0178] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0179] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0180] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In someM1237.70139WO00 68 / 111#13711954v1embodiments, in addition to the active ingredients, the liquid dosage forms comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In some embodiments, besides inert diluents, the oral compositions include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0181] In some embodiments, injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions are formulated according to the known art using suitable dispersing or wetting agents and suspending agents. In some embodiments, the sterile injectable preparation is a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. In some embodiments, the acceptable vehicles and solvents include water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. In some embodiments, any bland fixed oil is suitable for this purpose, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0182] In some embodiments, the injectable formulations are sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which, in some embodiments, are dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0183] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. In some embodiments, this is accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. In some embodiments, the rate of absorption of the drug then depends upon its rate of dissolution. In some embodiments, the rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, depends upon crystal size and crystalline form. Alternatively, in some embodiments, delayed absorption of a parenterally administered drug is accomplished by dissolving or suspending the drug in an oil vehicle.M1237.70139WO00 69 / 111#13711954v1

[0184] Compositions for rectal or vaginal administration are typically suppositories, which in some embodiments are prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0185] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In some embodiments, in the case of capsules, tablets, and pills, the dosage form includes a buffering agent.

[0186] In some embodiments, solid compositions of a similar type are employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. In some embodiments, the solid dosage forms of tablets, dragees, capsules, pills, and granules are prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. In some embodiments, they optionally comprise opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions include polymeric substances and waxes. In some embodiments, solid compositions of a similar type are employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0187] In some embodiments, the active ingredient is in a micro-encapsulated form with one or more excipients as noted above. In some embodiments, the solid dosage forms of tablets, dragees, capsules, pills, and granules are prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In some embodiments, in such solid dosage forms the active ingredient isM1237.70139WO00 70 / 111#13711954v1admixed with at least one inert diluent such as sucrose, lactose, or starch. In some embodiments, such dosage forms comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In some embodiments, in the case of capsules, tablets and pills, the dosage forms comprise buffering agents. In some embodiments, they optionally comprise opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents include polymeric substances and waxes.

[0188] In some embodiments, dosage forms for topical and / or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. In some embodiments, such dosage forms are prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, in some embodiments, the rate is controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0189] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. In some embodiments, intradermal compositions are administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, in some embodiments, conventional syringes are used in the classical Mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0190] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. In some embodiments, topically administrable formulations comprise, for example, from about 1% to about 10% (w / w) active ingredient. In some embodiments, the concentration of theM1237.70139WO00 71 / 111#13711954v1active ingredient is as high as the solubility limit of the active ingredient in the solvent. In some embodiments, formulations for topical administration further comprise one or more of the additional ingredients described herein.

[0191] In some embodiments, a pharmaceutical composition described herein is prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. In some embodiments, such a formulation comprises dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. In some embodiments, such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant is directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. In some embodiments, dry powder compositions include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0192] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. In some embodiments, the propellant constitutes 50 to 99.9% (w / w) of the composition, and the active ingredient constitutes 0.1 to 20% (w / w) of the composition. In some embodiments, the propellant further comprises additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which, in some embodiments, have a particle size of the same order as particles comprising the active ingredient).

[0193] In some embodiments, pharmaceutical compositions described herein formulated for pulmonary delivery provide the active ingredient in the form of droplets of a solution and / or suspension. In some embodiments, such formulations are prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient. In some embodiments, the formulations are administered using any nebulization and / or atomization device. In some embodiments, such formulations further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or aM1237.70139WO00 72 / 111#13711954v1preservative such as methylhydroxybenzoate. In some embodiments, the droplets provided by this route of administration have an average diameter in the range from about 0.1 to about 200 nanometers.

[0194] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0195] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and, in some embodiments, comprise one or more of the additional ingredients described herein. In some embodiments, a pharmaceutical composition described herein is prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and, in some embodiments, contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, in some embodiments, formulations for buccal administration comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. In some embodiments, such powdered, aerosolized, and / or aerosolized formulations, when dispersed, have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and, in some embodiments, further comprise one or more of the additional ingredients described herein.

[0196] In some embodiments, a pharmaceutical composition described herein is prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. In some embodiments, such drops further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically- administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.M1237.70139WO00 73 / 111#13711954v1

[0197] Although the descriptions of pharmaceutical compositions disclosed herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0198] Compounds disclosed herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0199] In some embodiments, the compounds and compositions disclosed herein are administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.M1237.70139WO00 74 / 111#13711954v1

[0200] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. In some embodiments, an effective amount is included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 µg and 1 µg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein.M1237.70139WO00 75 / 111#13711954v1In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0201] Dose ranges as described herein provide guidance for the administration of disclosed pharmaceutical compositions to an adult. In some embodiments, the amount to be administered to, for example, a child or an adolescent is determined by a medical practitioner or person skilled in the art. In some embodiments, the amount to be administered to, for example, a child or an adolescent is lower or the same as that administered to an adult.

[0202] In some embodiments, a compound or composition provided herein is administered as a standalone therapy. In some embodiments, a compound or composition provided herein is administered as a standalone therapy for cancer. In some embodiments, a compound or composition provided herein is administered as a standalone therapy for TOX-dependent cancer types (e.g., T-ALL and CTCL). In some embodiments, a compound or composition provided herein is administered as a standalone therapy for immunotherapy. In some embodiments, a compound or composition provided herein is administered as a standalone therapy for auto-immune-related T-cell exhaustion. In some embodiments, a compound or composition provided herein is administered as a standalone therapy for viral infection. In some embodiments, a compound or composition provided herein is administered as a standalone therapy for long-term infection. In some embodiments, a compound or composition provided herein is administered as a standalone therapy for chronic infection.

[0203] In some embodiments, a compound or composition, as described herein, is administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). In some embodiments, the compounds or compositions are administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and / or in inhibiting the activity of TOX in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. In some embodiments, the therapy employed achieves a desired effect for the same disorder, and / or it achieves different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including oneM1237.70139WO00 76 / 111#13711954v1of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0204] In some embodiments, the compound or composition is administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease. In some embodiments, each additional pharmaceutical agent is administered at a dose and / or on a time schedule determined for that pharmaceutical agent. In some embodiments, the additional pharmaceutical agents are administered together with each other and / or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0205] The additional pharmaceutical agents include, but are not limited to, anti- proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti-pyretics, hormones, and prostaglandins. InM1237.70139WO00 77 / 111#13711954v1certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions described herein are administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. In some embodiments, the compounds or compositions provided herein are administered in combination with chemotherapy. In some embodiments, the compounds or compositions provided herein are administered in combination with immunotherapy (e.g., adoptive T Cell therapy or immune checkpoint blockage therapy). Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. In certain embodiments, the additional pharmaceutical agent is a CAR-T.

[0206] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). In some embodiments, the kits disclosed herein 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, disclosed kits 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, theM1237.70139WO00 78 / 111#13711954v1pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0207] Thus, in one aspect, disclosed herein are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., an immune disease, a proliferative disease, or a viral infection) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., an immune disease, a proliferative disease, or a viral infection) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., an immune disease, a proliferative disease, or a viral infection) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting TOX.

[0208] In certain embodiments, a kit described herein further includes instructions for using the kit. In some embodiments, a kit described herein also includes information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., an immune disease, a proliferative disease, or a viral infection) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., an immune disease, a proliferative disease, or a viral infection) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., an immune disease, a proliferative disease, or a viral infection) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting TOX. In some embodiments, a kit described herein includes one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment and Uses

[0209] In another aspect, the present disclosure provides a method of inhibiting the activity of TOX protein in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with an effective amount of a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.

[0210] In another aspect, the present disclosure provides a method of treating or preventing a disease comprising administering to a subject in need thereof an effective amount of a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceuticallyM1237.70139WO00 79 / 111#13711954v1acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.

[0211] In another aspect, the present disclosure provides method of inhibiting the activity of TOX protein in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with an effective amount of a compound of the formula: ,, ,M1237.70139WO00 80 / 111#13711954v1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof.

[0212] In another aspect, the present disclosure provides method of treating or preventing a disease mediated by TOX protein comprising administering to a subject in need thereof an effective amount of a compound of the formula: ,, ,M1237.70139WO00 81 / 111#13711954v1, , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof.

[0213] In some embodiments, the disease is associated with T cell exhaustion. In some embodiments, the disease is an autoimmune disease, a proliferative disease, or a viral infection. In some embodiments, the disease is an autoimmune disease. In some embodiments, the disease is a proliferative disease. In some embodiments, the disease is a viral infection. In some embodiments, the proliferative disease is cancer.

[0214] In some embodiments, the method induces recovery of exhausted T cells.

[0215] In some embodiments, the method further comprises administration of an additional therapy. In some embodiments, the additional therapy is administration of an immune checkpoint inhibitor or adoptive cell therapy. In some embodiments, the additional therapy is administration of an immune checkpoint inhibitor. In some embodiments, the additional therapy is administration of an adoptive cell therapy. In some embodiments, inhibition ofM1237.70139WO00 82 / 111#13711954v1TOX restores potency of the additional therapy. In some embodiments, inhibition of TOX improves potency of the additional therapy. EXAMPLES

[0216] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods disclosed herein and are not to be construed in any way as limiting in their scope. Example 1. Discovery of TOX Inhibitors

[0217] Exhausted CD8+ T-cells exhibit reduced proliferative capacity, reduced production of effector cytokines, reduced cytotoxicity, and elevated and sustained expression of multiple inhibitory receptors (FIGs. 1A-1B). Chronic viral infections and tumors trigger the NFAT pathway (FIGs. 2A-2B).

[0218] Compounds were screened for TOX inhibitory activity in five stages: SMM screening, ELSA-based screening, ELISA-dose-dependent, target engagement, and lead inhibitors. Small molecule microarrays were used for the screenings (FIGs. 3A-3C). ELISA and cytotoxicity tests were used to assess compound activity (FIGs. 5A-5D). FIG. 4 shows compounds identified via compound screening. Target validation was then performed (FIGs. 6A-6D), and KI-TOX-A3 was identified as a potent TOX inhibitor (FIGs. 7A-7F). Further compounds were prepared (FIG. 8) and assessed for cytotoxicity (FIGs. 9B- 9D). The TOX-KAT7 interaction was simulated using Alphafold v3, and docking on the C- terminal was simulated using Autodock 1.5.3 with PYRX (FIG. 9A). KI-TOX-A3 showed binding with hydrogen bond formation and pi-pi interactions with the C-terminal of TOX (FIG. 9A).

[0219] The activity of compounds KI-TOX-A3, KI-TOX-P14, and KI-TOX-D22 was assessed in T-cells (FIGs. 10A-10K). In a cell cycle arrest experiment, high concentrations of compound KI-TOX-D22 induced cell cycle arrest at the G2 / M phase (FIGs. 10C-10F).

[0220] Compounds were capable of down-regulating biomarkers of T cells. After 15 days of stimulation, T cell exhaustion was induced, and T cells were treated with compound (FIG. 11A). Compounds KI-TOX-A3, KI-TOX-D22, and KI-TOX-P14 induced recovery from T- cell exhaustion (FIGs. 11B-11C). Compound KI-TOX-A3 was capable of significantly reducing the biomarkers.M1237.70139WO00 83 / 111#13711954v1

[0221] Downregulation of IRs, upregulation of cytokines, and lower levels of TOX and NR4A were observed in T-cells after treatment with KI-TOX-D22 became toxic (FIG. 12). Example 2. Synthetic Protocolhydroxy-2,3-dihydro-1H-inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1)solution. The compound was eluted with 2M ammonia in methanol (30 ml), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. KI-TOX-A3 was obtained as a yellow powder (yield: 63 mg, 20%).

[0223] Additional compounds provided herein may be synthesized according to the methods disclosed in International Patent Application Publication No. WO 2004 / 054505 A2 toHO KI-TOX-A3-0186

[0224] 4-hydroxybenzaldehyde (146 mg, 1.2 equiv) was combined with 5-hydroxy-2,3- dihydro-1H-inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol:toluene (1:1, 5 mL) and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution wasM1237.70139WO00 84 / 111#13711954v1stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. Yellow powder with yield of 203mg (0.64 mmol, 64%).1H NMR (500 MHz, DMSO) δ 7.68 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 1.8 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.87 (dd, J = 8.4, 2.2 Hz, 1H), 6.69 (s, 2H), 3.64 (s, 2H).13C NMR (126 MHz, DMSO) δ 162.9, 162.3, 160.1, 158.7, 149.7, 149.0, 131.4, 130.6, 126.7, 123.0, 122.9, 118.7, 115.8, 115.6, 112.5, 84.9, 33.6. HPLC retention time: 3.8 minutes. MS: [M+H]+= 316.1 m / z.KI-TOX-A3-0185

[0225] 1H-pyrrole-2-carbaldehyde (114 mg, 1.2 equiv) was combined with 5-hydroxy-2,3- dihydro-1H-inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol:toluene (1:1, 5 mL) and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. Brown powder with yield of 23 mg (0.08 mmol, 8%).1H NMR (500 MHz, DMSO) δ 7.66 (d, J = 8.3 Hz, 1H), 7.08 (q, J = 2.6 Hz, 2H), 7.00 (d, J = 1.7 Hz, 1H), 6.87 (dd, J = 8.3, 2.1 Hz, 1H), 6.74 (t, J = 3.6 Hz, 2H), 6.65 (s, 2H), 6.30 – 6.27 (m, 1H), 3.87 (s, 2H).13C NMR (126 MHz, DMSO) δ 163.1, 162.5, 160.1, 148.7, 140.7, 131.4, 125.9, 122.9, 122.1, 121.0, 119.3, 115.5, retention time: 3.9 minutes. MS: [M+H]+= 289.1 m / z.M1237.70139WO00 85 / 111#13711954v1KI-TOX-A3-0181

[0226] 5-methylfuran-2-carbaldehyde (132 mg, 1.2 equiv) was combined with 5-hydroxy- 2,3-dihydro-1H-inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol:toluene (1:1, 5 mL) and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. Yellow powder with yield of 52 mg (0.172 mmol, 17.2%).1H NMR (500 MHz, DMSO) δ 10.02 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 3.4 Hz, 1H), 6.88 (dd, J = 8.3, 2.1 Hz, 1H), 6.73 (s, 2H), 6.46 – 6.41 (m, 1H), 3.96 (s, 2H), 2.45 (s, 3H).13C NMR (126 MHz, DMSO) δ 163.8, 162.6, 160.4, 154.9, 148.9, 147.4, 135.8, 131.1, 122.9, 119.6, 119.1, 115.7, 115.6, 112.3, 109.3, 35.4, 14.0. HPLC retention time: 4.3 minutes. MS: [M+H]+= 304.1 m / z.KI-TOX-A3-0180

[0227] 4-fluorobenzaldehyde (148 mg, 1.2 equiv) was combined with 5-hydroxy-2,3- dihydro-1H-inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol:toluene (1:1, 5 mL) and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. Yellow powderwith yield of 95 mg (0.3 mmol, 30%) 1H NMR (500 MHz, DMSO) δ 7.72 – 7.64 (m, 2H),7.44 – 7.35 (m, 2H), 6.97 (d, J = 1.8 Hz, 1H), 6.92 – 6.83 (m, 1H), 6.81 (s, 1H), 5.76 (s, 0H), 3.62 (s, 2H).13C NMR (126 MHz, DMSO) δ 163.9, 163.2, 162.2, 161.9, 160.3, 149.0, 148.5,M1237.70139WO00 86 / 111#13711954v1132.7, 131.3, 123.1, 118.3, 116.2, 115.7, 112.5, 84.8, 33.3.HPLC retention time: 4.4minutes. MS: [M+H]+= 318.1 m / z. KI-

[0228] Benzaldehyde (127 mg, 1.2 equiv) was combined with 5-hydroxy-2,3-dihydro-1H- inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol:toluene (1:1, 5 mL) and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. Yellow powder with yield of 155 mg (0.52 mmol, 52%)1H NMR (500 MHz, DMSO) δ 7.70 (d, J = 8.3 Hz, 1H), 7.63 – 7.49 (m, 7H), 6.96 (d, J = 1.8 Hz, 2H), 6.88 (dd, J = 8.3, 2.2 Hz, 1H), 6.79 (s, 2H), 3.62 (s, 2H), 2.09 (s, 2H).13C NMR (126 MHz, DMSO) δ 163.2, 162.2, 160.2, 149.5, 149.0, 136.3, 131.3, 129.5, 129.5, 129.1, 129.0, 128.9, 123.1, 123.0, 118.3, 115.7, 112.5, 84.8, 33.4, MS: [M+H]+=300.1 m / z.KI-TOX-A3-0176

[0229] 5-(hydroxymethyl)furan-2-carbaldehyde (151 mg, 1.2 equiv) was combined with 6- hydroxy-3,4-dihydronaphthalen-1(2H)-one (176 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol:toluene (1:1, 5 mL) and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin.M1237.70139WO00 87 / 111#13711954v1The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. Dark yellow powder with yield of 22 mg (0.067 mmol, 6.7%)1H NMR (500 MHz, DMSO) δ 9.92 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 3.3 Hz, 1H), 6.75 (dd, J = 8.5, 2.4 Hz, 1H), 6.68 – 6.63 (m, 4H), 6.54 (d, J = 3.3 Hz, 1H), 5.38 (t, J = 5.8 Hz, 1H), 4.49 (d, J = 5.6 Hz, 2H), 2.81 – 2.66 (m, 6H).13C NMR (126 MHz, DMSO) δ 160.1, 159.8, 157.5, 155.6, 147.1, 141.7, 140.5, 128.2, 125.2, 117.8, 117.3, 114.6, 114.6, 114.5, 109.1, 85.3, 56.2, 28.0, 24.6, 0.6. HPLC retention time: 4.0 minutes. MS: [M+H]+= 334.1 m / z.KI-TOX-A3-0177

[0230] 5-(hydroxymethyl)furan-2-carbaldehyde (151 mg, 1.2 equiv) was combined with 7- hydroxy-2,3-dihydro-1H-inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. Yellow powder with yield of 33 mg (0.103 mmol, 10.3%)1H NMR (500 MHz, DMSO) δ 7.44 (d, J = 3.5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.08 (s, 2H), 6.86 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 3.5 Hz, 1H), 5.49 (s, 1H), 4.57 (s, 2H), 4.10 (s, 2H), 3.17 (s, 1H).13C NMR (126 MHz, DMSO) δ 164.0, 161.9, 158.8, 155.0, 147.8, 147.3, 136.5, 132.4, 124.3, 119.2, 118.6, 116.9, 115.7, 113.7, 109.9, 79.6, 56.3, 36.0. HPLC retention time: 4.4 minutes. MS: [M+H]+= 320.1 m / z.M1237.70139WO00 88 / 111#13711954v1KI-TOX-A3-0182

[0231] Thiophene-2-carbaldehyde (151 mg, 1.2 equiv) was combined with 5-hydroxy-2,3- dihydro-1H-inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol:toluene (1:1, 5 mL) and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent.Yellow powder with yield of 15 mg (0.049 mmol, 4.9%).1H NMR (500 MHz, DMSO) δ 7.44 (d, J = 3.5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.08 (s, 2H), 6.86 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 3.5 Hz, 1H), 5.49 (s, 1H), 4.57 (s, 2H), 4.10 (s, 2H), 3.17 (s, 1H).13C NMR (126 MHz, DMSO) δ 164.0, 161.9, 158.8, 155.0, 147.8, 147.3, 136.5, 132.4, 124.3, 119.2, 118.6, 116.9, 115.7, 113.7, 109.9, 79.6, 56.3, 40.5, 40.4, 40.3, 40.2, 40.2, 40.1, 40.0, 39.8, 39.7, 39.5, 36.0. HPLC retention time: 4.3 minutes. MS: [M+H]+= 306.0 m / z.KI-TOX-A3-0174

[0232] 5-(hydroxymethyl)furan-2-carbaldehyde (151 mg, 1.2 equiv) was combined with 5- Methoxy-2,3-dihydro-1H-inden-1-one (162 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol:toluene (1:1, 5 mL) and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1)solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. Yellow powder with yield of 25 mg (0.075 mmol, 7.5%)1H NMR (500 MHz, DMSO) δ 7.77 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 3.5 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.5, 2.3 Hz, 2H), 6.83 (s, 2H), 6.63 (d, J = 3.5 Hz, 1H), 4.57 (s, 2H), 4.06 (s, 2H), 3.86 (s, 2H).13C NMR (126 MHz, DMSO) δ 163.5, 162.6, 161.9, 158.4, 148.9, 148.0, 136.1, 132.5, 122.8,M1237.70139WO00 89 / 111#13711954v1120.2, 115.2, 114.7, 110.6, 109.8, 56.3, 56.0, 35.7. HPLC retention time: 4.2 minutes. MS: [M+H]+= 334.1 m / z. KI-

[0233] Compound KI-TOX-A3 (320 mg, 1 mmol, 1 equiv) was first protected by Tert- Butyldimethylsilyl chloride (1.2 g, 8 mmol, 8 equiv) with DMF (5 mL) and imidazole (544 mg, 8 mmol, 8 equiv). The reaction was finished after 6 hr stirring according to the TLC. The solution was purified by Ethyl acetate:Hexane=3:7 in column chromatography and the protected intermediate (500 mg, 0.91 mmol, 91%) was a pale yellow solid. This intermediate (55 mg, 0.1 mmol) was then dissolved into DMF (1 mL) and mixed with isocyanopropane (20 mg, 0.23 mmol, 2.3 equiv) and followed with piperidine addition (20 mg, 0.23 mmol, 2.3 equiv). The reaction turn dark yellow overnight and was quenched by adding sodium bicarbonate solution, followed by DCM extraction. The organic layer was collected and dried by sodium sulfate. The compound was purified with chromatography by gradient DCM:Methanol solution. The final product was a yellow paste (8.3 mg, 0.0169 mmol, 16.9%).1H NMR (500 MHz, DMSO) δ 8.18 (s, 1H), 7.92 – 7.57 (m, 2H), 7.07 – 6.98 (m, 2H), 6.70 (t, J = 5.5 Hz, 2H), 6.63 (d, J = 3.5 Hz, 1H), 5.46 (t, J = 5.7 Hz, 2H), 5.09 (d, J = 5.8 Hz, 2H), 4.53 (d, J = 5.1 Hz, 2H), 3.04 (q, J = 6.4 Hz, 3H), 1.54 (dq, J = 14.9, 7.4 Hz, 4H), 1.39 (dh, J = 21.5, 7.3 Hz, 4H), 1.24 (s, 2H), 0.82 (q, J = 7.3 Hz, 6H). 13C NMR (126 MHz, DMSO) δ 177.9, 170.1, 162.8, 151.4, 146.8, 139.3, 122.2, 119.9, 109.9, 94.1, 83.8, 72.1, 62.9, 56.4, 48.3, 42.4, 23.6, 22.0, 11.7. HPLC retention time: 4.5 minutes. MS: [M+H]+=M1237.70139WO00 90 / 111#13711954v1KI-TOX-A3-0190

[0234] Compound KI-TOX-A3 (32 mg, 0.1 mmol, 1 equiv) dissolved into DMF (1 mL) and HATU (76 mg, 0.2 mmol, 2 equiv) and stirred. Then pentanoic acid (20 mg, 0.19 mmol, 1.9 equiv) was mixed with Hunig’s base (0.1 mL) and DMF (0.5 mL) and stirred in another flask for 5 minutes. Then, the mixture was added dropwise to the KI-TOX-A3 mixture, and the solution turned bright yellow. The reaction finished after overnight stirring, and the solution was washed by sodium bicarbonate (50 mL) and extracted by DCM (30 mL*2). The organic layer was collected and dried by sodium sulfate. The compound was purified with chromatography by gradient DCM:Methanol solution. The final product was a dark yellow solid (10 mg, 0.024 mmol, 24%).1H NMR (500 MHz, DMSO) δ 10.70 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 3.5 Hz, 1H), 7.10 (s, 1H), 6.94 (dd, J = 8.4, 2.1 Hz, 2H), 6.67 (d, J = 3.5 Hz, 1H), 5.52 (t, J = 6.0 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 4.20 (s, 1H), 1.63 (dt, J = 15.0, 7.4 Hz, 4H), 1.40 (dq, J = 14.6, 7.4 Hz, 4H), 0.92 (t, J = 7.4 Hz, 2H).13C NMR (126 MHz, DMSO) δ 172.3, 163.5, 160.9, 159.2, 154.8, 148.9, 136.0, 130.3, 128.5, 123.3, 116.3, 116.1, 112.4, 110.1, 56.3, 35.6, 27.5, 22.2, 14.3. HPLC retention time: 4.1 minutes. MS: [M+H]+= 404.1 m / z.KI-TOX-A3-0179

[0235] 5-(hydroxymethyl)furan-2-carbaldehyde (151 mg, 1.2 equiv) was combined with 4- hydroxy-2,3-dihydro-1H-inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent.Yellow powder with yield of 23 mg (0.072 mmol, 7.2%).1H NMR (500 MHz, DMSO) δ 7.30 (td, J = 7.8, 2.6 Hz, 2H), 7.16 (d, J = 3.4 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 11.6 Hz, 2H), 6.64 (d, J = 3.5 Hz, 1H), 6.06 (s, 1H), 5.45 – 5.39 (m, 2H), 4.55 (d, J = 5.2 Hz, 2H), 3.90 (d, J = 2.5 Hz, 2H).13C NMR (126 MHz, DMSO) δ 190.3, 167.8, 163.8, 162.5, 158.5, 157.3, 154.3, 149.1,M1237.70139WO00 91 / 111#13711954v1144.1, 141.5, 139.7, 136.8, 132.0, 130.9, 129.2, 128.3, 120.7, 118.7, 113.6, 112.8, 109.5, 90.1, 56.3, 52.4, 32.9. HPLC retention time: 3.9 minutes. MS: [M+H]+= 320.1 m / z. KI-

[0236] 5-(hydroxymethyl)furan-2-carbaldehyde (151 mg, 1.2 equiv) was combined with 6- hydroxy-2,3-dihydro-1H-inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia in methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. Yellow powder with yield of 50 mg (0.156 mmol, 15.6%)1H NMR (500 MHz, DMSO) δ 7.46 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 3.5 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 6.92 (dd, J = 8.1, 2.4 Hz, 1H), 6.87 (s, 2H), 6.62 (d, J = 3.5 Hz, 1H), 4.56 (s, 2H), 3.95 (s, 2H).13C NMR (126 MHz, DMSO) δ 163.6, 162.5, 158.5, 157.4, 147.9, 141.0, 136.9, 136.6, 126.4, 121.7, 118.8, 118.5, 115.4, 109.9, 107.5, 80.8, 56.3, 40.5, 40.4, 40.3, 40.2, 40.1, 40.0, 39.8, 39.6, 39.5, 34.8. HPLC retention + = 320.1 m / z.KI-TOX-A3

[0237] 5-(hydroxymethyl)furan-2-carbaldehyde (151 mg, 1.2 equiv) was combined with 5- hydroxy-2,3-dihydro-1H-inden-1-one (148 mg, 1 equiv), ammonium acetate (350 mg, 4.5 equiv), and malonitrile (66 mg, 1 equiv). The mixture was dissolved in ethanol and heated to 90-100 ºC overnight. The reaction solution was dried via rotary evaporation, and the crude compound was redissolved in a DCM:methanol (1:1) solution. The solution was stirred with 0.5 g of Amberlyst 15 strongly acidic cation exchange resin. The resin was washed three times with a DCM:methanol (1:1) solution. The compound was eluted with 2M ammonia inM1237.70139WO00 92 / 111#13711954v1methanol (30 mL), and the filtrate was dried. The filtrate was purified by column chromatography with DCM:Methanol (10:1) gradient as the eluent. The product was obtained as a yellow powder (yield: 63 mg, 0.0197 mmol, 19.7%).1H NMR (500 MHz, DMSO) δ 7.68 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 3.5 Hz, 1H), 7.03 (s, 1H), 6.88 (dd, J = 8.3, 2.1 Hz, 2H), 6.77 (s, 2H), 6.61 (d, J = 3.5 Hz, 1H), 4.56 (s, 2H), 4.31 (s, 1H), 3.99 (s, 2H).13C NMR (126 MHz, DMSO) δ 160.4, 158.3, 148.1, 146.2, 125.8, 123.0, 120.0, 119.1, 115.6, 115.1, 112.3, 109.8, 108.0, 107.1, 79.2, 56.3, 46.1, 29.5. HPLC retention time: 3.8 minutes. MS: [M+H]+= 320.1 m / z. Example 3: T Cell Exhaustion and Treatment Protocol

[0238] T cells were isolated using the STEMCELL CD8+ T cell isolation kit and cultured in RPMI media with 10% FBS and 30 ng / mL IL-2. The T cells were stimulated starting from day 2 to day 4 with CD3 / 28 Dynabeads (Thermofisher). The culture media was renewed without removing the bead. The media was changed on day 6 and day 8. The T cells started to show phenotypes of exhaustion (slower grow rate and lower viability). The T cells were de-beaded for 24 h at day 8 and then re-stimulated by CD3 / 28 bead. The media were changed every 2 days until day 14. The cells were exhausted and treated with compounds of interest (KI-TOX-A3, KI-TOX-D22, KI-TOX-P14) for 24 h. The cells were de-beaded and then underwent the T cell staining process. Cells were analyzed on days 15 (FIGs. 13 and 14A- 14D), 17 (FIGs. 15 and 16A-16F), and 21 (FIGs. 17 and 18A-18F) of treatment. Example 4: T Cell Staining Protocol

[0239] FACS buffer of 1 mL was mixed with 1 µL of live / dead (Alexa488) staining, then576 µL of the mixture was pipetted into a new tube. 6 µL of each antibody (FITC-CD8, PE-PD1, PE / CY7-LAG3, APC-TIM3) was added and vortexed. 100 µL of T cells (0.5 M / mL) were distributed to each well of a V shape 96 well plate. The plate was then centrifuged with 300 x g at 25 ºC for 5 minutes. When the cell pellets were observed, the medium was removed, and the master mix antibody solution was added and incubated at 4 ºC for 15 minutes. Afterwards, the plate was centrifuged and the master mix solution was removed. To wash the non-specific antibodies, 180 µL FACS was added to the wash and centrifuging was repeated. The solution was removed again and the cell pellet was resuspended by adding 150 µL FACS buffer to prepare for detection.M1237.70139WO00 93 / 111#13711954v1Example 5: Proximity Ligation Assay Protocol

[0240] A proximity ligation assay (PLA) of TOX / KAT7 was performed on Molt-4 cells (see FIGs. 19C-19E).

[0241] Molt-4 cells were pre-treated with TOX inhibitors at different concentrations for 24h. Then, the cells were collected and washed by twice with 1x cold PBS. Subsequently, the cells were fixed by 3.7% formaldehyde in PBS with 15 minutes incubation at room temperature. The cells were centrifuged and washed by PBS again to remove the fixation buffer. The cells were then incubated with TOX antibody (CST) and KAT7 (Invitrogen) antibody with 1:100 dilution in antibody diluent buffer provided by Sigma. The incubation ran overnight at 4 ºC. Then the cells were washed by PLA buffer A three times by centrifugation and re-suspension. The cells were stained by secondary antibody staining (Sigma Rabbit plus and Mouse minus) according to the PLA manufacturing protocol. The cells were incubated for 1 hour at room temperature followed by washing 3 times with PLA wash buffer A. The cells were ready to be ligated by ligase provided in the PLA kit. The ligation lasted for 30 minutes at 37 °C, and the cells were washed by PLA wash buffer A. Then, the last step was to amplify the signal. Cells were assembled with fluorescent substrate and polymerase that were provided in the PLA kit. The fluorescent incubation lasted for 100 minutes at 37 ºC. The cells were washed by PLA wash buffer A 2 times and wash buffer B one time. The last wash was performed using 0.01x Wash Buffer B for 1 minute. Subsequently, the cells were resuspended by 50 µL of 2% gelatin in PBS and coated onto the microscopy plate (MatTek P35GC-1.5-14-C). The cells were mounted by DAPI mounting buffer and gentle pipetting. The plates were then imaged by confocal microscopy.

[0242] Molt-4 cells were treated with 1% DMSO, or 1% DMSO solution of KI-TOX-A3, KI-TOX-D22, or KI-TOX-P14 at 5 or 10 µM for 24 h. The Molt-4 cells were washed, fixed, and stained by antibodies of anti-rabbit TOX1 / 2 antibody and anti-mouse KAT7 antibody. The PLA assay included a ligation kit with designed DNA and a fluorophore amplification kit. Under confocal microscopic imaging, the TOX-KAT7 interactions were qualified and quantified. After analyzing over 80 cells per treated group, KI-TOX-A3 and KI-TOX-D22 statistically reduced the TOX-KAT7 interaction at 5 and 10 µM. KI-TOX-P14 slightly engaged the TOX-KAT7 interaction at 10 µM. The Molt-4 pulldown assay showed that the TOX bound towards KI-TOX-A3-0239 on the NHS-bead, and lost its binding with KI-TOX- A3 competition at 20 and 40µM (FIG. 19F). KI-TOX-A3 downregulated TOX protein after 6 h treatment in a proteosome-dependent manner, and TOX was rescued by MG132 (FIG. 19H).M1237.70139WO00 94 / 111#13711954v1Example 6: T cell Exhaustion Recovery Experiments

[0243] FIG. 20 shows a schematic for T cell stimulation and assessing T cell exhaustion recovery. Pan CD8+ T cells were isolated by STEMCELL isolation kit at day 0 and incubated in a 37 ºC 5% CO2incubator overnight with RPMI-1640 media (contained 50 unit / mL IL-2). The cells were stimulated with 20 µL / 1 million cells of cd3 / 28 dynabeads on day 1, and the cells were stimulated for 72 hours. On day 4, the media were changed, and the cells were further diluted to maintain the 1 M / mL density. The beads were also removed on day 4. Then, the cells were repeatedly stimulated for 48 hours and unstimulated for 24 hours as a cycle. T cell expression of TOX peaks in the fifth stimulation cycle at the intermediate stage of T cell expression (FIG. 27). After 5 cycles, the cells were exhausted with high expression of PD-1, TIM-3, LAG-3, and low proliferation activities. The cells were treated with the TOXi for 24 hours while the cells were still beaded on day 20. On day 21, the cells were debeaded, and half of each group was stained with biomarker antibodies to check the expression of CD8, TIM3, LAG3, and PD1 (FIG. 28), while the other half was treated with T cell activation kit with brefeldin A for 4 hours in the culture incubator. Then, this group of cells was fixed and stained with IFN and CD8 to identify the intracellular expression level of IFN-gamma. Both groups of cells were detected by flow cytometry (FIGs. 21A-21C, 22A- 22F, 23A-23C, 24A-24F, 25A-25E, and 26A-26H). A co-culture killing assay on CD19- Ramos cells was performed on T cells after 24 hours of treatment with TOXi under the use of bispecific CD3 / CD19 antibody (FIG.29). EQUIVALENTS AND SCOPE

[0244] 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 disclosure 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 disclosure 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.

[0245] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim thatM1237.70139WO00 95 / 111#13711954v1is 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 any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the disclosure or aspects of the disclosure 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 disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0246] 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 disclosure 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 disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0247] 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 disclosure, as defined in the following claims.M1237.70139WO00 96 / 111#13711954v1

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I): , or a pharmaceutically acceptableco-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: R1and R2are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or R1and R2are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; R34R or 2; each instance of R5is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –SCN, –SRB, –SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, – C(=O)SRB, –C(=O)N(RB)2, –C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, –C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, –S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, –OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, – OC(=NRB)RB, –OC(=NRB)ORB, –OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, – OS(=O)ORB, –OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, – OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, –M1237.70139WO00 97 / 111#13711954v1NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC –NRBC –NRBC N –NRBS – –alkenyl, optionally substituted alkynyl, –CN, –SRB, –NH2, –NO2, –C(=O)ORB, –S(=O)2RB, – S(=O)2ORB, or –S(=O)2N(RB)2; each instance of R7is independently unsubstituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, – SCN, –SRB, –SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, – C – S S RB, OS OS SC –2; each instance of R8is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, – – C S OC OC 2RB,–OS(=O)2ORB, –OS(=O)2SRB, –OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, – SC(=O)SRB, –SC(=O)N(RB)2, –SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –M1237.70139WO00 98 / 111#13711954v1SC(=NRB)N(RB)2, –NRBC(=O)RB, –NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, – NRBC –NRBC –NRBC –NRBC N –optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl,–ORB, –SRB, –N(RB)2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, or –C(=O)N(RB)2; X1is –NRA–, –S–, or –O–; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and each instance of RAand RBis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAor RBattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; provided thator , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.M1237.70139WO00 99 / 111#13711954v12. The compound of claim 1, wherein the compound is of Formula (I-A), (I-B), (I-C), or (I-D): B), D),or a tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula (I-E):, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the(I-F),M1237.70139WO00 100 / 111#13711954v1or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is hydrogen.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is hydrogen.

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl.

8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled ,or .

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeledM1237.70139WO00 101 / 111#13711954v1com or .

10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeledcompound, or prodrug thereof, wherein R3is .

11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3is .M1237.70139WO00 102 / 111#13711954v112. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3is .

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled ,14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R4is –ORAor –SRA.

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R4is –ORA.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis hydrogen or optionally substituted C1-C4 alkyl.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,labeled compound, or prodrug thereof, wherein RAis hydrogen, methyl, or .M1237.70139WO00 103 / 111#13711954v118. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein m is 0.

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R6is hydrogen, halogen, or –OH.

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R6is hydrogen, –OH, or –F.

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein n is 0.

22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein X1is –O–.

23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein p is 0 or 1.

24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal,stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R8is .

25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R9aand R9bare each hydrogen.M1237.70139WO00 104 / 111#13711954v126. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: , ,,M1237.70139WO00 105 / 111#13711954v1, .

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising: a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and a pharmaceutically acceptable excipient.

29. The pharmaceutical composition of the preceding claim further comprising one or more additional pharmaceutical agents.

30. A kit comprising: a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of any one of the preceding claims; and instructions for using the compound, or a pharmaceutically acceptable salt, solvate,M1237.70139WO00 106 / 111#13711954v1hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition.

31. A method of inhibiting the activity of TOX protein in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with an effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of the preceding claims.

32. A method of treating or preventing a disease comprising administering to a subject in need thereof an effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of the preceding claims.

33. A method of inhibiting the activity of TOX protein in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with an effective amount of a compound of the formula: ,, ,M1237.70139WO00 107 / 111#13711954v1, , , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof.

34. A method of treating or preventing a disease mediated by TOX protein comprising administering to a the formula: ,, ,M1237.70139WO00 108 / 111#13711954v1, , , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof.

35. The method of claim 32 or 34, wherein the disease is associated with T cell exhaustion.M1237.70139WO00 109 / 111#13711954v136. The method of claim 32, 34, or 35, wherein the disease is an autoimmune disease, a proliferative disease, or a viral infection.

37. The method of claim 36, wherein the proliferative disease is cancer.

38. The method of any one of claims 31-37, wherein the method induces recovery of exhausted T cells.

39. The method of any one of claims 32 or 34-38, wherein the method further comprises administration of an additional therapy.

40. The method of claim 39, wherein the additional therapy is administration of an immune checkpoint inhibitor or adoptive cell therapy.

41. The method of claim 40, wherein inhibition of TOX restores or improves potency of the additional therapy.M1237.70139WO00 110 / 111#13711954v1

Images