BCL-XL / BCL-2 dual degraders and uses thereof

Abstract

The present disclosure provides compounds of Formula (I) and Formula (I'), which may be Bcl-xL and Bcl-2 dual inhibitors. The compounds may target and degrade Bcl-xL and Bcl-2. The present disclosure also provides pharmaceutical compositions, kits, and methods of using the compounds for treating a disease (e.g., cancer).

Description

BCL-XL / BCL-2 DUAL DEGRADERS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63 / 668,518, filed July 8, 2024, titled BCL-XL / BCL-2 DUAL DEGRADERS AND USES THEREOF, the contents of which are incorporated herewith by reference in their entirety. GOVERNMENT SUPPORT

[0002] This invention was made with government support under R01 CA241191 and R01 CA260239 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION

[0003] The B-cell lymphoma 2 (Bcl-2) protein family, consisting of pro- and anti-apoptotic members, plays a critical role in determining cell fate through regulation of the intrinsic apoptosis pathway. The anti-apoptotic Bcl-2 family proteins, such as Bcl-2, Bcl-xL, Bcl-w, and Mcl-1, are upregulated in many cancers and associated with tumor initiation, progression, and resistance to chemo- and targeted therapies. Thus, these anti-apoptotic Bcl-2 proteins are attractive targets for the development of novel anti-cancer agents (Lessene et al., Nat Rev Drug Discov 7: 989-1000, 2008; Vogler et al., Cell Death Differ 2009;16: 360-367; Delbridge et al., Nat Rev Cancer 16: 99-109, 2016). Numerous Bcl-2 small molecule inhibitors have been reported (Bajwa et al., Expert Opin Ther Patents 22:37-55, 2012; Vogler, Adv Med.1-14, 2014; Ashkenazi et al., 16: 273-284, 2017; Pal et al., Expert Opin Ther Patents 32:1003- 1026, 2022). The following are some of the Bcl-2 small molecule inhibitors that have been investigated at various stages of drug development: ABT-737 (US20070072860), navitoclax (ABT-263, W02009155386), venetoclax (ABT-199, W02010138588), obatoclax (GX 15-070, W02004106328), (-)- gossypol (AT-101, W02002097053), sabutoclax (BI-97C1, W02010120943), TW-37 (W02006023778), BM-1252 (APG-1252), and A-1155463 (VV02010080503).

[0004] Venetoclax, a selective Bcl-2 inhibitor, was approved by the FDA in 2016 for the treatment of chronic lymphocytic leukemia (CLL) with 17-p deletion. Venetoclax was designed to have high selectivity for Bcl-2 over Bcl-xL to avoid the on-target platelet toxicity (Souers et al., Nat Med 19: 202- 208, 2013). Platelets depend on Bcl-xL to maintain their viability, therefore dose-limiting thrombocytopenia has been observed in animals and / or humans treated with ABT-737 (Schoenwaelder et al., Blood 118: 1663-1674, 2011), ABT-263 (Tse et al., Cancer Res 68: 3421-3428, 2008; Roberts et al., Bri J Haematol 170: 669-678, 2015), BM-1197 (Bai et al., PLoS ONE 9:e99404, 2014), or A-1155463 (Tao et al., ACS Med Chem Lett 5:1088-1093,2014), due to their inhibition of Bcl-xL. However, many CLL patients are resistant to venetoclax (Roberts et al., N Engl J Med 374: 311-322, 2016) and upregulation of Bcl-xL by microenvironmental survival signals has been identified as the major component accountable for the resistance, consistent with the high efficacy of Bcl-2 / Bcl-xL dual inhibitor ABT-263 in killing venetoclax resistant CLL cells (Oppermann et al., Blood 128: 934-947,U1197.70246WO00 1 / 221 #14171685v12016). In addition, Bcl-xL is generally more frequently overexpressed than Bcl-2 in solid tumors. Importantly, promising results have been documented from preclinical and clinical studies of ABT-263, as a single-agent or in combination with other antitumor agents, against several solid and hematologic malignancies (Delbridge et al., Nat Rev Cancer 16: 99-109, 2016). Therefore, there is a need to develop compounds that can retain the antitumor versatility and efficacy of the Bcl-xL / Bcl-2 dual inhibitors, while their on-target platelet toxicity. SUMMARY OF THE INVENTION

[0005] In one aspect, provided herein is a compound of Formula (I):, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, L1, L2, Y, m1, and m2 are as defined herein.

[0006] In another aspect, provided herein is a compound of Formula (I′):, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, L1, L2, Y, m1, and m2 are as defined herein.

[0007] In certain embodiments, the compound of Formula (I) or Formula (I′), or pharmaceutically acceptable salt thereof, includes a Bcl-xL and / or Bcl-2 binding moiety (e.g.,moiety that is capable of binding to an E3 ubiquitin ligase (e.g., Y), and a linker (e.g., –L2–L1–) connecting the Bcl-xL and / or Bcl-2 binding moiety and the moiety that is capable of binding to an E3 ubiquitin ligase.U1197.70246WO00 2 / 221 #14171685v1

[0008] Compared to known Bcl-xL and / or Bcl-2 inhibitors (e.g., ABT-263:the provided compounds and pharmaceutical compositions may have unexpected advantages (e.g., increased potency and / or efficacy in inhibiting the activity and / or production of Bcl-xL and / or Bcl-2, increased bioavailability, reduced toxicity, increased safety, increased therapeutic window, reduced resistance, and / or increased subject compliance). In some embodiments, the oral bioavailability of the provided compounds and pharmaceutical compositions is increased. In some embodiments, the oral bioavailability of the provided compounds and pharmaceutical compositions is increased while the potency is not decreased (i.e., the potency stays the same or is increased).

[0009] The compounds may promote the degradation of the anti-apoptotic Bcl-2 family of proteins. The compounds may also promote the degradation of the anti-apoptotic Bcl-xL family of proteins. The compounds may be Bcl-xL / Bcl-2 dual inhibitors. The compounds may connect a Bcl-2 or Bcl-xL small molecule inhibitor or ligand to an E3 ligase binding moiety. The compounds may actively recruit anti- apoptotic Bcl-2 family of proteins to E3 ligase, resulting in their degradation by ubiquitin proteasome system.

[0010] In another aspect, provided herein is a pharmaceutical composition comprising a provided compound (e.g., a compound of Formula (I) or Formula (I′)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] In another aspect, provided herein is a kit comprising: a provided compound (e.g., a compound of Formula (I) or Formula (I′)), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition; and instructions for using the provided compound (e.g., a compound of Formula (I) or Formula (I′)), or pharmaceutically acceptable salt thereof, or pharmaceutical composition.

[0012] In another aspect, provided herein is a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a provided compound (e.g., a compound of Formula (I) or Formula (I′)) or pharmaceutical composition.

[0013] In another aspect, provided herein is a method of degrading a Bcl-2 protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound (e.g., a compound of Formula (I) or Formula (I′)) or pharmaceutical composition.U1197.70246WO00 3 / 221 #14171685v1

[0014] In another aspect, provided herein is a method of degrading a Bcl-xL protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound (e.g., a compound of Formula (I) or Formula (I′)) or pharmaceutical composition.

[0015] In another aspect, provided herein is a method of selectively killing one or more cancer cells in a tissue or biological sample, the method comprising contacting the tissue or biological sample with an effective amount of a provided compound (e.g., a compound of Formula (I) or Formula (I′)) or pharmaceutical composition.

[0016] In another aspect, provided herein is a method of selectively killing one or more cancer cells in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a provided compound (e.g., a compound of Formula (I) or Formula (I′)) or pharmaceutical composition.

[0017] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments. DEFINITIONS

[0018] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0019] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. 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, INU1197.70246WO00 4 / 221 #14171685v11972). The disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0020] In a formula, the bond is a single bond, the dashed line is a single bond or absent, and the bond or is a single or double bond.

[0021] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C- enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0022] 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.

[0023] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C1-6alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0024] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0025] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 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,U1197.70246WO00 5 / 221 #14171685v1e.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)).

[0026] 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 (“C1–7haloalkyl”).In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1–6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1–5haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1–4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1–3haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1–2haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0027] 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 (“heteroC1–20alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–12alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–11 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 heteroatomsU1197.70246WO00 6 / 221 #14171685v1within the parent chain (“heteroC1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1–12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12alkyl.

[0028] 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 (“C1-20alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1–12alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1–11alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1–10alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1–9alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1–8alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1–7alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1–6alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1–5alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1–4alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1–3alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1–2alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1alkenyl”). In some embodiments, the one or more carbon-carbon double bonds is internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C1–4alkenyl 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 C1–6alkenyl 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 some embodiments, in an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3or(E)- or (Z)-configuration.

[0029] 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.U1197.70246WO00 7 / 221 #14171685v1In 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 (“heteroC1–8alkenyl”). 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 (“heteroC1–7alkenyl”). 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 (“heteroC1–6alkenyl”). 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 (“heteroC1–5alkenyl”). 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 (“heteroC1–4alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–3alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–2alkenyl”). 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 (“heteroC1–6alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC1–20alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1–20alkenyl.

[0030] 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 (“C1-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“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 is internal (such as in 2-U1197.70246WO00 8 / 221 #14171685v1butynyl) 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.

[0031] 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 (“heteroC1–20alkynyl”). 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 (“heteroC1–10alkynyl”). 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 (“heteroC1–9alkynyl”). 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 (“heteroC1–8alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7alkynyl”). 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 (“heteroC1–5alkynyl”). 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 (“heteroC1–4alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–3alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–2alkynyl”). 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.

[0032] 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 (“C3-13U1197.70246WO00 9 / 221 #14171685v1carbocyclyl”). 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 C3-8carbocyclyl groups include the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-10carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and 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.

[0033] 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 groupsU1197.70246WO00 10 / 221 #14171685v1include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0034] 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 either saturated or contains one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0035] In some embodiments, a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selectedU1197.70246WO00 11 / 221 #14171685v1from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0036] 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, tetrahydrobenzo- thienyl, 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-tetrahydro- pyrano[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.

[0037] 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 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.U1197.70246WO00 12 / 221 #14171685v1

[0038] “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.

[0039] 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 π 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. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In some embodiments, in polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment is on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6- membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0040] 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 5-14U1197.70246WO00 13 / 221 #14171685v1membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0041] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom 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.

[0042] “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.

[0043] The term “unsaturated bond” refers to a double or triple bond.

[0044] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0045] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.

[0046] 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.

[0047] 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 orU1197.70246WO00 14 / 221 #14171685v1“substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

[0048] Carbon atoms of the groups and moieties described herein are substituted or unsubstituted, as valency permits. Exemplary carbon atom substituents include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3−C(=S)N(Rbb)2, −C(=O)SRaa, −C(=S)SRaa, −SC(=S)SRaa,−NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3+X−, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5- 14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; or two geminal hydrogens on a carbon atom are replaced with the group =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 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl,U1197.70246WO00 15 / 221 #14171685v1heteroalkyl, 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, C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =O or =S; each instance of Reeis, independently, selected from C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3- 10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–10 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,U1197.70246WO00 16 / 221 #14171685v1alkynyl, 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(C1–6alkyl), −SO2NH2, −SO2C1–6alkyl, −SO2OC1–6alkyl, −OSO2C1–6alkyl, −SOC1–6alkyl, −Si(C1–6alkyl)3, −OSi(C1–6alkyl)3−C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, −C(=O)S(C1–6alkyl), −C(=S)SC1–6alkyl, −SC(=S)SC1–6alkyl, −P(=O)(OC1–6alkyl)2, −P(=O)(C1–6alkyl)2, −OP(=O)(C1–6alkyl)2, −OP(=O)(OC1–6alkyl)2, C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents are joined to form =O or =S; and each X−is a counterion.

[0049] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, −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 C1–10alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 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 unsubstitutedU1197.70246WO00 17 / 221 #14171685v1C1–10 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).

[0050] Nitrogen atoms of the groups and moieties described herein 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, C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, hetero C1–20alkyl, hetero C1–20alkenyl, hetero C1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 5-14 membered heteroaryl, or oxo, 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.

[0051] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −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 C1-10alkyl, −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 C1-10alkyl, 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 C1-10alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or a nitrogen protecting group.

[0052] 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 independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.U1197.70246WO00 18 / 221 #14171685v1

[0053] 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-nitrophenylacetamide, 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.

[0054] 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-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p- nitrobenzyl 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-U1197.70246WO00 19 / 221 #14171685v1decyloxybenzyl 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.

[0055] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0056] 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-U1197.70246WO00 20 / 221 #14171685v1cyclohexenyl)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.

[0057] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0058] Oxygen atoms of the groups and moieties described herein are substituted or unsubstituted as valency permits. 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 C1-6alkyl, −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 C1-10alkyl, 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 C1-10alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or an oxygen protecting group.

[0059] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb)2)2, wherein X−, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0060] 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-methoxytetrahydropyranylU1197.70246WO00 21 / 221 #14171685v1(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4- methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1- ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p- phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″- tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 4,4'-Dimethoxy-3"'-[N- (imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4'-Dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9- phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2- iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4- (methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1- dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2- butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4- dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0061] 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.U1197.70246WO00 22 / 221 #14171685v1

[0062] Sulfur atoms of the groups and moieties described herein are substituted or unsubstituted as valency permits. 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. In certain embodiments, at least one sulfur atom substituent is oxo.

[0063] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0064] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0065] 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). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−, HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5– sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–,U1197.70246WO00 23 / 221 #14171685v1B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−, B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0066] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0072] 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.

[0073] The term “sulfonyl” refers to a group selected from –SO2N(Rbb)2, –SO2Raa, and –SO2ORaa, wherein Raaand Rbbare as defined herein.U1197.70246WO00 24 / 221 #14171685v1

[0074] The term “sulfinyl” refers to the group –S(=O)Raa, wherein Raais as defined herein.

[0075] The term “acyl” refers to a group having the general formula −C(=O)Raa, −C(=O)ORaa, N(Rbb)2, and −C(=S)S(Raa),, wherein Raaand Rbbare as defined herein. In some embodiments, the term “acyl” refers to a group having the general formula −C(=O)Raa, −C(=O)ORaa, −C(=O)−O−C(=O)Raa, −C(=O)SRaa, or −C(=O)N(Rbb)2.

[0076] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (–C(=O)Raa), carboxylic acids (–CO2H), aldehydes (–CHO), esters (–CO2Raa, –C(=O)SRaa, – C(=S)SRaa), amides (–C(=O)N(Rbb)2, –C(=O)NRbbSO2Raa, −C(=S)N(Rbb)2), and imines (–C(=NRbb)Raa, – C(=NRbb)ORaa), –C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0077] The term “silyl” refers to the group –Si(Raa)3, wherein Raais as defined herein.

[0078] 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.

[0079] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0080] 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 using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4 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.U1197.70246WO00 25 / 221 #14171685v1

[0081] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(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.

[0082] 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”.

[0083] 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 embodiments, 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). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0084] The terms “composition” and “formulation” are used interchangeably.U1197.70246WO00 26 / 221 #14171685v1

[0085] 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.

[0086] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels. In some embodiments, “tissue” is the object to which a compound, particle, and / or composition of the disclosure is delivered. In some embodiments, a tissue is an abnormal or unhealthy tissue, which may need to be treated. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented.

[0087] 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.

[0088] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound provided herein, a compound useful in a provided method, or a pharmaceutical composition provided herein, in or on a subject.

[0089] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0090] 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). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0091] 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 atU1197.70246WO00 27 / 221 #14171685v1a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0092] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0093] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease.

[0094] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease.

[0095] The term “inhibit” or “inhibition”, for example, in the context of a Bcl-xL or Bcl-2, refers to a reduction in activity or production. In some embodiments, the term refers to a reduction of the level of activity and / or production, e.g., Bcl-xL or Bcl-2 activity and / or production, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of activity and / or production. In some embodiments, the term refers to a reduction of the level of activity and / or production, e.g., Bcl-xL or Bcl-2 activity and / or production, 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 thanU1197.70246WO00 28 / 221 #14171685v18%, 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 and / or production.

[0096] The term “Bcl-2 family” refers to a family consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family may be able to regulate apoptosis at the mitochondrion. The Bcl-2 family may promote or inhibit apoptosis, or control apoptosis by governing mitochondrial outer membrane permeabilization (MOMP), which is a key step in the intrinsic pathway of apoptosis. In certain embodiments, the Bcl-2 family is a human Bcl-2 family.

[0097] The term “Bcl-2” refers to a protein of the Bcl-2 family and, when in humans, is encoded by the BCL2 gene.

[0098] The term “Bcl-xL” refers to a protein of the Bcl-2 family and, when in humans, is encoded by the BCL2-like 1 gene.

[0099] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0100] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0101] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distantU1197.70246WO00 29 / 221 #14171685v1sites. Exemplary benign neoplasms include lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0102] 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. The cancer may be a solid tumor. The cancer may be a hematological malignancy. Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cellU1197.70246WO00 30 / 221 #14171685v1lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B- cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0103] The term “genetic disease” refers to a disease caused by one or more abnormalities in the genome of a subject, such as a disease that is present from birth of the subject. Genetic diseases may beU1197.70246WO00 31 / 221 #14171685v1heritable and may be passed down from the parents’ genes. A genetic disease may also be caused by mutations or changes of the DNAs and / or RNAs of the subject. In such cases, the genetic disease will be heritable if it occurs in the germline. Exemplary genetic diseases include Aarskog-Scott syndrome, Aase syndrome, achondroplasia, acrodysostosis, addiction, adreno-leukodystrophy, albinism, ablepharon- macrostomia syndrome, alagille syndrome, alkaptonuria, alpha-1 antitrypsin deficiency, Alport’s syndrome, Alzheimer’s disease, asthma, autoimmune polyglandular syndrome, androgen insensitivity syndrome, Angelman syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention deficit hyperactivity disorder (ADHD), autism, baldness, Batten disease, Beckwith-Wiedemann syndrome, Best disease, bipolar disorder, brachydactyl), breast cancer, Burkitt lymphoma, chronic myeloid leukemia, Charcot-Marie-Tooth disease, Crohn’s disease, cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer, congenital adrenal hyperplasia, Cornelia de Lange syndrome, Costello syndrome, Cowden syndrome, craniofrontonasal dysplasia, Crigler-Najjar syndrome, Creutzfeldt-Jakob disease, cystic fibrosis, deafness, depression, diabetes, diastrophic dysplasia, DiGeorge syndrome, Down’s syndrome, dyslexia, Duchenne muscular dystrophy, Dubowitz syndrome, ectodermal dysplasia Ellis-van Creveld syndrome, Ehlers-Danlos, epidermolysis bullosa, epilepsy, essential tremor, familial hypercholesterolemia, familial Mediterranean fever, fragile X syndrome, Friedreich’s ataxia, Gaucher’s disease, glaucoma, glucose galactose malabsorption, glutaricaciduria, gyrate atrophy, Goldberg Shprintzen syndrome (velocardiofacial syndrome), Gorlin syndrome, Hailey-Hailey disease, hemihypertrophy, hemochromatosis, hemophilia, hereditary motor and sensory neuropathy (HMSN), hereditary non polyposis colorectal cancer (HNPCC), Huntington’s disease, immunodeficiency with hyper-IgM, juvenile onset diabetes, Klinefelter’s syndrome, Kabuki syndrome, Leigh’s disease, long QT syndrome, lung cancer, malignant melanoma, manic depression, Marfan syndrome, Menkes syndrome, miscarriage, mucopolysaccharide disease, multiple endocrine neoplasia, multiple sclerosis, muscular dystrophy, myotrophic lateral sclerosis, myotonic dystrophy, neurofibromatosis, Niemann-Pick disease, Noonan syndrome, obesity, ovarian cancer, pancreatic cancer, Parkinson’s disease, paroxysmal nocturnal hemoglobinuria, Pendred syndrome, peroneal muscular atrophy, phenylketonuria (PKU), polycystic kidney disease, Prader-Willi syndrome, primary biliary cirrhosis, prostate cancer, REAR syndrome, Refsum disease, retinitis pigmentosa, retinoblastoma, Rett syndrome, Sanfilippo syndrome, schizophrenia, severe combined immunodeficiency, sickle cell anemia, spina bifida, spinal muscular atrophy, spinocerebellar atrophy, sudden adult death syndrome, Tangier disease, Tay-Sachs disease, thrombocytopenia absent radius syndrome, Townes-Brocks syndrome, tuberous sclerosis, Turner syndrome, Usher syndrome, von Hippel-Lindau syndrome, Waardenburg syndrome, Weaver syndrome, Werner syndrome, Williams syndrome, Wilson’s disease, xeroderma piginentosum, and Zellweger syndrome.

[0104] The term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronicU1197.70246WO00 32 / 221 #14171685v1inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, dermatitis (e.g., stasis dermatitis, allergic contact dermatitis, atopic dermatitis, irritant contact dermatitis, neurodermatitis perioral dermatitis, seborrheic dermatitis), hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, necrotizing enterocolitis, inflammatory rosacea. An ocular inflammatory disease includes post-surgical inflammation.

[0105] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis,U1197.70246WO00 33 / 221 #14171685v1microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0106] A “hematological disease” includes a disease which affects a hematopoietic cell or tissue. Hematological diseases include diseases associated with aberrant hematological content and / or function. Examples of hematological diseases include diseases resulting from bone marrow irradiation or chemotherapy treatments for cancer, diseases such as pernicious anemia, hemorrhagic anemia, hemolytic anemia, aplastic anemia, sickle cell anemia, sideroblastic anemia, anemia associated with chronic infections such as malaria, trypanosomiasis, HTV, hepatitis virus or other viruses, myelophthisic anemias caused by marrow deficiencies, renal failure resulting from anemia, anemia, polycythemia, infectious mononucleosis (EVI), acute non-lymphocytic leukemia (ANLL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), polycythemia vera, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, Wilm’s tumor, Ewing’s sarcoma, retinoblastoma, hemophilia, disorders associated with an increased risk of thrombosis, herpes, thalassemia, antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red blood cells such as micro-angiopathic hemolytic anemias, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation, infections by parasites such as Plasmodium, chemical injuries from, e.g., lead poisoning, and hypersplenism.

[0107] The term “neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease. Examples of neurological diseases include headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; bbrain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm;U1197.70246WO00 34 / 221 #14171685v1cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease- neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi- infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease;U1197.70246WO00 35 / 221 #14171685v1paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0108] A “painful condition” includes neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post–operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre–operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre–term labor, pain associated with withdrawl symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter’s arthritis), lumbosacral pain, musculo–skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental / maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g. nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more typesU1197.70246WO00 36 / 221 #14171685v1of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[0109] The term “metabolic disease” refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors affecting metabolism include the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

[0110] The term “psychiatric disorder” refers to a condition or disorder relating to the functioning of the brain and the cognitive processes or behavior. Psychiatric disorders may be further classified based on the type of neurological disturbance affecting the mental faculties. Psychiatric disorders are expressed primarily in abnormalities of thought, feeling, emotion, and / or behavior producing either distress or impairment of function (for example, impairment of mental function such with dementia or senility). The term “psychiatric disorder” is, accordingly, sometimes used interchangeably with the term “mental disorder” or the term “mental illness”.

[0111] A psychiatric disorder is often characterized by a psychological or behavioral pattern that occurs in an individual and is thought to cause distress or disability that is not expected as part of normal development or culture. Definitions, assessments, and classifications of mental disorders can vary, but guideline criteria listed in the International Classification of Diseases and Related Health Problems (ICD, published by the World Health Organization, WHO), or the Diagnostic and Statistical Manual of Mental Disorders (DSM, published by the American Psychiatric Association, APA) and other manuals are widely accepted by mental health professionals. Individuals may be evaluated for various psychiatric disorders using criteria set forth in these and other publications accepted by medical practitioners in the field and the manifestation and severity of a psychiatric disorder may be determined in an individual using these publications.

[0112] Categories of diagnoses in these schemes may include dissociative disorders, mood disorders, anxiety disorders, psychotic disorders, eating disorders, developmental disorders, personality disorders, and other categories. There are different categories of mental disorder, and many different facets of human behavior and personality that can become disordered.

[0113] One group of psychiatric disorders includes disorders of thinking and cognition, such as schizophrenia and delirium. A second group of psychiatric disorders includes disorders of mood, such as affective disorders and anxiety. A third group of psychiatric disorders includes disorders of social behavior, such as character defects and personality disorders. And a fourth group of psychiatric disorders includes disorders of learning, memory, and intelligence, such as mental retardation and dementia. Accordingly, psychiatric disorders encompass schizophrenia, delirium, attention deficit disorder (ADD), schizoaffective disorder, depression (e.g., lithium-resistant depression), mania, attention deficit disorders,U1197.70246WO00 37 / 221 #14171685v1drug addiction, dementia, agitation, apathy, anxiety, psychoses, personality disorders, bipolar disorders, unipolar affective disorder, obsessive-compulsive disorders, eating disorders, post-traumatic stress disorders, irritability, adolescent conduct disorder and disinhibition.

[0114] Some diseases classified as neurodegenerative diseases, for example Alzheimer’s disease, also sometimes show aspects of psychiatric disorders as listed herein, for example disorders of memory or dementia. Some neurodegenerative diseases or manifestations thereof can, accordingly, also be referred to as psychiatric disorders. These terms are, therefore, not mutually exclusive.

[0115] The state of anxiety or fear can become disordered, so that it is unusually intense or generalized over a prolonged period of time. Commonly recognized categories of anxiety disorders include specific phobia, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive- compulsive disorder, post-traumatic stress disorder.

[0116] Relatively long lasting affective states can also become disordered. Mood disorder involving unusually intense and sustained sadness, melancholia or despair is known as clinical depression (or major depression), and may more generally be described as emotional dysregulation. Milder but prolonged depression can be diagnosed as dysthymia. Bipolar disorder involves abnormally “high” or pressured mood states, known as mania or hypomania, alternating with normal or depressed mood.

[0117] Patterns of belief, language use and perception can become disordered. Psychotic disorders centrally involving this domain include schizophrenia and delusional disorder. schizoaffective disorder is a category used for individuals showing aspects of both schizophrenia and affective disorders. Schizotypy is a category used for individuals showing some of the traits associated with schizophrenia but without meeting cut-off criteria.

[0118] The fundamental characteristics of a person that influence his or her cognitions, motivations, and behaviors across situations and time - can be seen as disordered due to being abnormally rigid and maladaptive. Categorical schemes list a number of different personality disorders, such as those classed as eccentric (e.g., paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder), those described as dramatic or emotional (antisocial personality disorder, Borderline personality disorder, histrionic personality disorder, narcissistic personality disorder) or those seen as fear-related (avoidant personality disorder, dependent personality disorder, obsessive-compulsive personality disorder). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0119] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.U1197.70246WO00 38 / 221 #14171685v1Compounds

[0120] In one aspect, provided herein is a compound of Formula (I):, or a pharmaceutically acceptable salt thereof, wherein: R1is –O(optionally substituted alkyl) or –N(Ra)2, wherein each instance of Rais independently optionally substituted alkyl or optionally substituted carbocyclyl, or two instances of Raare joined with the nitrogen atom to which they are attached to form optionally substituted heterocyclyl; R2is –NO2or –SO2CF3; R3is of formula:, wherein Rbis hydrogen, halogen, or optionally substituted alkyl; each of m1 and m2 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0; L1is optionally substituted C1-12 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, – S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; L2is absent or optionally substituted C1-12alkylene, optionally substituted C1-12alkenylene, optionally substituted C2-12alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene, optionally substituted C1-12alkenylene, or optionally substituted C2-12alkynylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R4is independently hydrogen or optionally substituted alkyl; and Y is a moiety that is capable of binding to an E3 ubiquitin ligase.U1197.70246WO00 39 / 221 #14171685v1

[0121] In another aspect, provided herein is a compound of Formula (I′):, or a pharmaceutically acceptable salt thereof, wherein: R1is –O(optionally substituted alkyl) or –N(Ra)2, wherein each instance of Rais independently optionally substituted alkyl or optionally substituted carbocyclyl, or two instances of Raare joined with the nitrogen atom to which they are attached to form optionally substituted heterocyclyl; R2is –NO2or –SO2CF3; R3is of formula:, wherein Rbis hydrogen, halogen, or optionally substituted alkyl; each of m1 and m2 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0; L1is optionally substituted C1-12 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, – S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; L2is absent or optionally substituted C1-12 alkylene, optionally substituted C1-12 alkenylene, optionally substituted C2-12alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene, optionally substituted C1-12alkenylene, or optionally substituted C2-12alkynylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R4is independently hydrogen or optionally substituted alkyl; and Y is of formula:,U1197.70246WO00 40 / 221 #14171685v1U1197.70246WO00 41 / 221 #14171685v1U1197.70246WO00 42 / 221 #14171685v1Moiety Y

[0122] As generally described herein for compounds of Formula (I), Y is a moiety that is capable of binding to an E3 ubiquitin ligase.

[0123] In some embodiments of Formula (I), Y is of formula:U1197.70246WO00 43 / 221 #14171685v1U1197.70246WO00 44 / 221 #14171685v1

[0124] As generally described herein for compounds of Formula (I′), Y is of formula:U1197.70246WO00 45 / 221 #14171685v1U1197.70246WO00 46 / 221 #14171685v1

[0125] In some embodiments of Formula (I) or Formula (I′), Y is of formula: (y-1), (y-13), (y-14), (y- 15), (y-17), (y-18), (y-19), (y-22), (y-25), (y-26), (y-28), (y-32), (y-33), (y-36), (y-41), or (y-45). In some embodiments of Formula (I), Y is of formula: (y-1), (y-13), (y-14), (y-15), (y-17), (y-18), (y-19), (y-22), (y-25), (y-26), (y-28), (y-32), (y-33), (y-36), (y-41), or (y-45). In some embodiments of Formula (I′), Y is of formula: (y-1), (y-13), (y-14), (y-15), (y-17), (y-18), (y-19), (y-22), (y-25), (y-26), (y-28), (y-32), (y-33), (y-36), (y-41), or (y-45).

[0126] In some embodiments of Formula (I) or Formula (I′), Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formula (I), Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formula (I′), Y is of formula: (y-1), (y-13), (y-14), or (y-17).

[0127] In some embodiments of Formula (I), Y is of formula (y-1). In some embodiments of Formula (I), Y is of formula (y-13). In some embodiments of Formula (I), Y is of formula (y-14). In some embodiments of Formula (I), Y is of formula (y-15). In some embodiments of Formula (I), Y is of formula (y-17). In some embodiments of Formula (I), Y is of formula (y-18). In some embodiments of Formula (I), Y is of formula (y-19). In some embodiments of Formula (I), Y is of formula (y-22). In some embodiments of Formula (I), Y is of formula (y-25). In some embodiments of Formula (I), Y is ofU1197.70246WO00 47 / 221 #14171685v1formula (y-26). In some embodiments of Formula (I), Y is of formula (y-28). In some embodiments of Formula (I), Y is of formula (y-32). In some embodiments of Formula (I), Y is of formula (y-33). In some embodiments of Formula (I), Y is of formula (y-36). In some embodiments of Formula (I), Y is of formula (y-41). In some embodiments of Formula (I), Y is of formula (y-45).

[0128] In some embodiments of Formula (I′), Y is of formula (y-1). In some embodiments of Formula (I′), Y is of formula (y-13). In some embodiments of Formula (I′), Y is of formula (y-14). In some embodiments of Formula (I′), Y is of formula (y-15). In some embodiments of Formula (I′), Y is of formula (y-17). In some embodiments of Formula (I′), Y is of formula (y-18). In some embodiments of Formula (I′), Y is of formula (y-19). In some embodiments of Formula (I′), Y is of formula (y-22). In some embodiments of Formula (I′), Y is of formula (y-25). In some embodiments of Formula (I′), Y is of formula (y-26). In some embodiments of Formula (I′), Y is of formula (y-28). In some embodiments of Formula (I′), Y is of formula (y-32). In some embodiments of Formula (I′), Y is of formula (y-33). In some embodiments of Formula (I′), Y is of formula (y-36). In some embodiments of Formula (I′), Y is of formula (y-41). In some embodiments of Formula (I′), Y is of formula (y-45). Moieties R1, R2, R3, Ra, and Rb

[0129] As generally described herein, R1is –O(optionally substituted alkyl) or –N(Ra)2, wherein each instance of Rais independently optionally substituted alkyl or optionally substituted carbocyclyl, or two instances of Raare joined with the nitrogen atom to which they are attached to form optionally substituted heterocyclyl.

[0130] In some embodiments, R1is –O(optionally substituted alkyl). In some embodiments, R1is –O(optionally substituted C1-6alkyl). In some embodiments, R1is –O(optionally substituted C1-3alkyl). In some embodiments, R1is –O(unsubstituted alkyl). In some embodiments, R1is –O(unsubstituted C1-6alkyl). In some embodiments, R1is –O(unsubstituted C1-3alkyl). In some embodiments, R1is –O(substituted alkyl). In some embodiments, R1is –O(substituted C1-6alkyl). In some embodiments, R1is –O(substituted C1-3alkyl). In some embodiments, R1is –O(alkyl substituted with an optionally substituted heterocyclyl containing at least 1 ring N atom). In some embodiments, R1is –O(C1-3alkyl substituted with an optionally substituted heterocyclyl containing at least 1 ring N atom).

[0131] In some embodiments, R1is –N(Ra)2, wherein each instance of Rais independently optionally substituted alkyl or optionally substituted carbocyclyl.

[0132] In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais optionally substituted alkyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais optionally substituted C1-6 alkyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais optionally substituted methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl. In some embodiments, R1is –N(Ra)2, wherein least one instance of Rais optionally substituted C1-3 alkyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais unsubstituted alkyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais unsubstituted C1-6 alkyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais unsubstituted C1-3 alkyl. In some embodiments, R1is –N(Ra)2, wherein at leastU1197.70246WO00 48 / 221 #14171685v1one instance of Rais methyl or ethyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais methyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais ethyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais substituted alkyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais substituted C1-6 alkyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais substituted C1-3 alkyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais alkyl substituted with –OH. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais C1-3 alkyl substituted with –OH. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais alkyl substituted with 4-7 membered heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais alkyl substituted with 4-7 membered heterocyclyl containing at least one 1 ring N atom. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais C1-3 alkyl substituted with 4-7 membered heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais C1-3alkyl substituted with 4-7 membered heterocyclyl containing at least one 1 ring N atom.

[0133] In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais optionally substituted carbocyclyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais optionally substituted C3-6carbocyclyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais optionally substituted C3-4carbocyclyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais unsubstituted carbocyclyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais unsubstituted C3-6carbocyclyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais unsubstituted C3-4carbocyclyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais cyclopropyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais cyclobutyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais substituted carbocyclyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais substituted C3-6carbocyclyl. In some embodiments, R1is –N(Ra)2, wherein at least one instance of Rais substituted C3-4carbocyclyl.

[0134] In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted heterocyclyl.

[0135] In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted monocyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered monocyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered monocyclic heterocyclyl containing at least 1 ring N atom. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered monocyclicU1197.70246WO00 49 / 221 #14171685v1heterocyclyl containing at least 1 ring N atom and at least 1 ring O atom. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted monocyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted 4-7 membered monocyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted 4-7 membered monocyclic heterocyclyl containing at least 1 ring N atom. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted 4-7 membered monocyclic heterocyclyl containing at least 1 ring N atom and at least 1 ring O atom. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted monocyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted 4-7 membered monocyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted 4-7 membered monocyclic heterocyclyl containing at least 1 ring N atom. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted 4-7 membered monocyclic heterocyclyl containing at least 1 ring N atom and at least 1 ring O atom.

[0136] In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted fused bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted 6-10 membered fused bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted 6-10 membered fused bicyclic heterocyclyl having 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted fused bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted 6-10 membered fused bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted 6-10 membered fused bicyclic heterocyclyl having 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted fused bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted 6-10 membered fused bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted 6-10 membered fused bicyclic heterocyclyl having 1 or 2 ring heteroatoms selected from O and N.U1197.70246WO00 50 / 221 #14171685v1

[0137] In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted bridged bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted 6-10 membered bridged bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted 6-10 membered bridged bicyclic heterocyclyl having 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted bridged bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted 6-10 membered bridged bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted 6-10 membered bridged bicyclic heterocyclyl having 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted bridged bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted 6-10 membered bridged bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted 6-10 membered bridged bicyclic heterocyclyl having 1 or 2 ring heteroatoms selected from O and N.

[0138] In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted spiro bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted 6-10 membered spiro bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted 6-10 membered spiro bicyclic heterocyclyl having 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted spiro bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted 6-10 membered spiro bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an unsubstituted 6-10 membered spiro bicyclic heterocyclyl having 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted spiro bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted 6-10 membered spiro bicyclic heterocyclyl. In some embodiments, R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form a substituted 6-10 membered spiro bicyclic heterocyclyl having 1 or 2 ring heteroatoms selected from O and N.U1197.70246WO00 51 / 221 #14171685v1

[0139] In some embodiments, R1is of formula:U1197.70246WO00 52 / 221 #14171685v1, wherein: each q is independently 1, 2, or 3; each r is independently 1 or 2; each s is independently 1, 2, 3, or 4; and each u is independently 0, 1, 2, 3, 4, or 5. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.

[0140] In some embodiments, R1is of formula:, wherein r is 1 or 2. In some embodiments, R1is of formula:. In some embodiments, R1is of formula:. In some embodiments, R1is of formula.

[0141] As generally described herein, R2is –NO2or –SO2CF3.

[0142] In some embodiments, R2is –NO2. In some embodiments, R2is –SO2CF3.

[0143] As generally described herein, R3is of formula:, wherein Rbis hydrogen, halogen, or optionally substituted alkyl.

[0144] In some embodiments, R3is of formula:. In some embodiments, R3is of formula:, wherein Rbis –F, –Cl, –CH3, –CH2F, –CHF2, or –CF3. In some embodiments, R3is of formula:U1197.70246WO00 53 / 221 #14171685v1some embodiments, R3is of formula:..

[0147] As generally described herein, Rbis hydrogen, halogen, or optionally substituted alkyl.

[0148] In some embodiments, Rbis halogen or optionally substituted alkyl. In some embodiments, Rbis halogen or optionally substituted C1-6alkyl. In some embodiments, Rbis halogen or optionally substituted C1-3alkyl. In some embodiments, Rbis halogen or optionally substituted methyl.

[0149] In some embodiments, Rbis hydrogen.

[0150] In some embodiments, Rbis halogen. In some embodiments, Rbis –F, –Cl, –Br, or –I. In some embodiments, Rbis –F, –Cl, or –Br. In some embodiments, Rbis –F or –Cl. In some embodiments, Rbis –F. In some embodiments, Rbis –Cl.

[0151] In some embodiments, Rbis optionally substituted alkyl. In some embodiments, Rbis optionally substituted C1-6 alkyl. In some embodiments, Rbis optionally substituted C1-3 alkyl. In some embodiments, Rbis optionally substituted methyl.

[0152] In some embodiments, Rbis unsubstituted alkyl. In some embodiments, Rbis unsubstituted C1-6 alkyl. In some embodiments, Rbis unsubstituted C1-3 alkyl. In some embodiments, Rbis –CH3.

[0153] In some embodiments, Rbis substituted alkyl. In some embodiments, Rbis substituted C1-6 alkyl. In some embodiments, Rbis substituted C1-3 alkyl. In some embodiments, Rbis substituted methyl. In some embodiments, Rbis alkyl substituted only with one or more instances of –F. In some embodiments, Rbis C1-6 alkyl substituted only with one or more instances of –F. In some embodiments, Rbis C1-3 alkyl substituted only with one or more instances of –F. In some embodiments, Rbis methyl substituted onlyU1197.70246WO00 54 / 221 #14171685v1with one or more instances of –F. In some embodiments, Rbis –CH2F, –CHF2, or –CF3. In some embodiments, Rbis –CH2F. In some embodiments, Rbis –CHF2. In some embodiments, Rbis –CF3.

[0154] In some embodiments, Rbis –F, –Cl, –CH3, –CH2F, –CHF2, or –CF3. Moieties m1, m2, L1, L2, and R4

[0155] As generally described herein, each of m1 and m2 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0.

[0156] In some embodiments, m1 is 0, 1, 2, or 3. In some embodiments, m1 is 0, 1, or 2. In some embodiments, m1 is 0 or 1. In some embodiments, m1 is 1, 2, or 3. In some embodiments, m1 is 1 or 2. In some embodiments, m1 is 0. In some embodiments, m1 is 1. In some embodiments, m1 is 2. In some embodiments, m1 is 3.

[0157] In some embodiments, m2 is 0, 1, 2, or 3. In some embodiments, m2 is 0, 1, or 2. In some embodiments, m2 is 0 or 1. In some embodiments, m2 is 1, 2, or 3. In some embodiments, m2 is 1 or 2. In some embodiments, m2 is 0. In some embodiments, m2 is 1. In some embodiments, m2 is 2. In some embodiments, m2 is 3.

[0158] In some embodiments, m1 is 0 and m2 is 1, or m1 is 1 and m2 is 0. In some embodiments, m1 is 0 and m2 is 1. In some embodiments, m1 is 1 and m2 is 0.

[0159] In some embodiments, each of m1 and m2 is independently 1. In some embodiments, m1 is 0 and m2 is 2, or m1 is 2 and m2 is 0. In some embodiments, m1 is 0 and m2 is 2. In some embodiments, m1 is 2 and m2 is 0.

[0160] In some embodiments, m1 is 1 and m2 is 2, or m1 is 2 and m2 is 1. In some embodiments, m1 is 1 and m2 is 2. In some embodiments, m1 is 2 and m2 is 1. In some embodiments, m1 is 0 and m2 is 3, or m1 is 3 and m2 is 0. In some embodiments, m1 is 0 and m2 is 3. In some embodiments, m1 is 3 and m2 is 0.

[0161] In some embodiments, each of m1 and m2 is independently 2. In some embodiments, m1 is 1 and m2 is 3, or m1 is 3 and m2 is 1. In some embodiments, m1 is 1 and m2 is 3. In some embodiments, m1 is 3 and m2 is 1. In some embodiments, m1 is 0 and m2 is 4, or m1 is 4 and m2 is 0. In some embodiments, m1 is 0 and m2 is 4. In some embodiments, m1 is 4 and m2 is 0.

[0162] In some embodiments, m1 is 2 and m2 is 3, or m1 is 3 and m2 is 2. In some embodiments, m1 is 2 and m2 is 3. In some embodiments, m1 is 3 and m2 is 2. In some embodiments, m1 is 1 and m2 is 4, or m1 is 4 and m2 is 1. In some embodiments, m1 is 1 and m2 is 4. In some embodiments, m1 is 4 and m2 is 1. In some embodiments, m1 is 0 and m2 is 5, or m1 is 5 and m2 is 0. In some embodiments, m1 is 0 and m2 is 5. In some embodiments, m1 is 5 and m2 is 0.

[0163] In some embodiments, each of m1 and m2 is independently 3. In some embodiments, m1 is 2 and m2 is 4, or m1 is 4 and m2 is 2. In some embodiments, m1 is 2 and m2 is 4. In some embodiments, m1 is 4 and m2 is 2. In some embodiments, m1 is 1 and m2 is 5, or m1 is 5 and m2 is 1. In some embodiments, m1 is 1 and m2 is 5. In some embodiments, m1 is 5 and m2 is 1. In some embodiments, m1 is 0 and m2U1197.70246WO00 55 / 221 #14171685v1is 6, or m1 is 6 and m2 is 0. In some embodiments, m1 is 0 and m2 is 6. In some embodiments, m1 is 6 and m2 is 0., . , iety

[0165] As generally described herein, L1is optionally substituted C1-12alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0166] In some embodiments, L1comprises optionally substituted C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L1comprises optionally substituted C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises optionally substituted C1-12 alkylene, optionallyU1197.70246WO00 56 / 221 #14171685v1wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

[0167] In some embodiments, L1comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L1comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises substituted C1-12alkylene, wherein one or more backbone carbon atoms in the substituted C1-12alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises substituted C1-12alkylene, wherein one or more backbone carbon atoms in the substituted C1-12alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

[0168] In some embodiments, L1comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprisesU1197.70246WO00 57 / 221 #14171685v1unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

[0169] In some embodiments, L1comprises optionally substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises optionally substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises substituted C1-3alkylene, wherein one or more backbone carbon atoms in the substituted C1-3alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises unsubstituted C1-3alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L1comprises unsubstituted C1-3alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

[0170] In some embodiments, L1comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with –NR4–. In some embodiments, L1comprises substituted C1-12alkylene, wherein one or more backbone carbon atoms in the substituted C1-12alkylene are independently replaced with –NR4–. In some embodiments, L1comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with –NR4–. In some embodiments, L1comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with –NR4–. In some embodiments, L1comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with –NR4–. In some embodiments, L1comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with –NR4–. In some embodiments, L1comprises optionally substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3 alkylene are independently replaced with –NR4–. In some embodiments, L1comprises substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with –NR4–. In some embodiments, L1comprises unsubstituted C1-3 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3 alkylene are independently replaced with –NR4–.U1197.70246WO00 58 / 221 #14171685v1

[0171] In some embodiments, L1comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –NH–. In some embodiments, L1comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with –NH–. In some embodiments, L1comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with –NH–. In some embodiments, L1comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with –NH–. In some embodiments, L1comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with –NH–. In some embodiments, L1comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with –NH–. In some embodiments, L1comprises optionally substituted C1-3alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3alkylene are independently replaced with –NH–. In some embodiments, L1comprises substituted C1-3alkylene, wherein one or more backbone carbon atoms in the substituted C1-3alkylene are independently replaced with –NH–. In some embodiments, L1comprises unsubstituted C1-3alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3alkylene are independently replaced with –NH–.

[0172] In some embodiments, L1comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with –C(=O)–. In some embodiments, L1comprises substituted C1-12alkylene, wherein one or more backbone carbon atoms in the substituted C1-12alkylene are independently replaced with –C(=O)–. In some embodiments, L1comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with –C(=O)–. In some embodiments, L1comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with –C(=O)–. In some embodiments, L1comprises substituted C1-6alkylene, wherein one or more backbone carbon atoms in the substituted C1-6alkylene are independently replaced with –C(=O)–. In some embodiments, L1comprises unsubstituted C1-6alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6alkylene are independently replaced with –C(=O)–. In some embodiments, L1comprises optionally substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3 alkylene are independently replaced with –C(=O)–. In some embodiments, L1comprises substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with –C(=O)–. In some embodiments, L1comprises unsubstituted C1-3 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3 alkylene are independently replaced with –C(=O)–.

[0173] In some embodiments, L1comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, L1comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replacedU1197.70246WO00 59 / 221 #14171685v1with optionally substituted heterocyclylene. In some embodiments, L1comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with optionally substituted 4-10 membered heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with optionally substituted 4-10 membered heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with optionally substituted 4-10 membered heterocyclylene containing 1 or 2 ring N atoms.

[0174] In some embodiments, L1comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises substituted C1-12alkylene, wherein one or more backbone carbon atoms in the substituted C1-12alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises substituted C1-12alkylene, wherein one or more backbone carbon atoms in the substituted C1-12alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms.

[0175] In some embodiments, L1comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced withU1197.70246WO00 60 / 221 #14171685v1unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms.

[0176] In some embodiments, L1comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with a moiety of formula:, wherein each of m3 and m4 is independently 0, 1, or 2, provided that m1 and m2 are not both 0. In some embodiments, L1comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene aresubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with a moiety of formula:each instance of X is independently CH or N. In some embodiments, L1comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with a moiety of formula:In some embodiments, L1comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with a moiety of formula:.

[0177] In some embodiments, L1comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with a moiety of formula:, wherein each of m3 and m4 is independently 0, 1, or 2, provided thatU1197.70246WO00 61 / 221 #14171685v1m1 and m2 are not both 0. In some embodiments, L1comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with a moiety of formula:,, . In some embodiments, L1comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with a moiety of formula:, wherein each instance of X is independently CH or N. In some embodiments, L1comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon at independently replaced with a moiety of formula:some embodiments, L1comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with a moiety of formula:.

[0178] In some embodiments, L1comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with optionally substituted arylene. In some embodiments, L1comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with optionally substituted arylene. In some embodiments, L1comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with optionally substituted arylene. In some embodiments, L1comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with unsubstituted phenylene. In some embodiments, L1comprises substituted C1-12alkylene, wherein one or more backbone carbon atoms in the substituted C1-12alkylene are independently replaced with unsubstituted phenylene. In some embodiments, L1comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with unsubstituted phenylene. In some embodiments, L1comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with unsubstituted phenylene. In some embodiments, L1comprises substituted C1-6alkylene, wherein one or more backbone carbon atoms in the substituted C1-6alkylene are independently replaced with unsubstituted phenylene. In some embodiments, L1comprises unsubstitutedU1197.70246WO00 62 / 221 #14171685v1C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with unsubstituted phenylene. In some embodiments, L1comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced.

[0179] In some embodiments, L1comprises optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises optionally substituted 4-10 membered heterocyclylene. In some embodiments, L1comprises optionally substituted 4-10 membered heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises optionally substituted 4-10 membered heterocyclylene containing 1 ring N atom. In some embodiments, L1comprises optionally substituted 4-10 membered heterocyclylene containing 2 ring N atoms.

[0180] In some embodiments, L1comprises optionally substituted 4-6 membered monocyclic heterocyclylene. In some embodiments, L1comprises optionally substituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises optionally substituted 4-6 membered monocyclic heterocyclylene containing 1 ring N atom. In some embodiments, L1comprises optionally substituted 4-6 membered monocyclic heterocyclylene containing 2 ring N atoms. In some embodiments, L1comprises substituted 4-6 membered monocyclic heterocyclylene. In some embodiments, L1comprises substituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises substituted 4-6 membered monocyclic heterocyclylene containing 1 ring N atom. In some embodiments, L1comprises substituted 4-6 membered monocyclic heterocyclylene containing 2 ring N atoms. In some embodiments, L1comprises unsubstituted 4-6 membered monocyclic heterocyclylene. In some embodiments, L1comprises unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 ring N atom. In some embodiments, L1comprises unsubstituted 4-6 membered monocyclic heterocyclylene containing 2 ring N atoms.

[0181] In some embodiments, L1comprises optionally substituted 6-10 membered bridged bicyclic heterocyclylene. In some embodiments, L1comprises optionally substituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises optionally substituted 6-10 membered bridged bicyclic heterocyclylene containing 1 ring N atom. In some embodiments, L1comprises optionally substituted 6-10 membered bridged bicyclic heterocyclylene containing 2 ring N atoms. In some embodiments, L1comprises substituted 6-10 membered bridged bicyclic heterocyclylene. In some embodiments, L1comprises substituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises substituted 6-10 membered bridged bicyclic heterocyclylene containing 1 ring N atom. In some embodiments, L1comprises substituted 6-10 membered bridged bicyclic heterocyclylene containing 2 ring N atoms. InU1197.70246WO00 63 / 221 #14171685v1some embodiments, L1comprises unsubstituted 6-10 membered bridged bicyclic heterocyclylene. In some embodiments, L1comprises unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L1comprises unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 ring N atom. In some embodiments, L1comprises unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 2 ring N atoms.

[0182] In some embodiments, L1comprises a moiety of formula:, wherein each of m3 and m4 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0. In some embodiments, L1comprises a moiety of formula:, wherein each of m3 and m4 is independently 0, 1, or 2, provided that m1 and m2 are not both 0. In some embodiments, L1comprises a moiety of formula:

[0183] In some embodiments, L1comprises a moiety of formula:, wherein each instance of X is independently CH or N. In some embodiments, L1comprises a moiety of formula:

[0184] In some embodiments, L1comprises a moiety of formula:.

[0185] In some embodiments, L1comprises optionally substituted arylene. In some embodiments, L1comprises optionally substituted C6-10arylene. In some embodiments, L1comprises optionally substituted phenylene. In some embodiments, L1comprises substituted arylene. In some embodiments, L1comprises substituted C6-10arylene. In some embodiments, L1comprises substituted phenylene. In some embodiments, L1comprises unsubstituted arylene. In some embodiments, L1comprises unsubstituted C6-10arylene. In some embodiments, L1comprises unsubstituted phenylene. In some embodiments, L1.U1197.70246WO00 64 / 221 #14171685v1

[0186] In certain embodiments, L1is –(optionally substituted monocyclic heterocyclylene)–(optionally substituted C1-2 alkylene)–, –(optionally substituted bicyclic heterocyclylene)–(optionally substituted C1-2 alkylene)–, –(optionally substituted monocyclic heteroarylene)–(optionally substituted C1-2 alkylene)–, –(optionally substituted C1-2 alkylene)–(optionally substituted monocyclic heterocyclylene)–, –(optionally substituted C1-2 alkylene)–(optionally substituted bicyclic heterocyclylene)–, or –(optionally substituted C1-2 alkylene)–(optionally substituted monocyclic heteroarylene)–, optionally wherein one or two backbone carbon atoms in the optionally substituted C1-2 alkylene are independently replaced with –O–, –NR4–, or –C(=O)–.

[0187] In certain embodiments, L1is –(optionally substituted C1-2 alkylene)–(optionally substituted monocyclic heterocyclylene)–(optionally substituted C1-2 alkylene)–, –(optionally substituted C1-2 alkylene)–(optionally substituted bicyclic heterocyclylene)–(optionally substituted C1-2 alkylene)–, or –(optionally substituted C1-2alkylene)–(optionally substituted monocyclic heteroarylene)–(optionally substituted C1-2alkylene)–, optionally wherein one or two backbone carbon atoms in each instance of the optionally substituted C1-2alkylene are independently replaced with –O–, –NR4–, or –C(=O)–.

[0188] In certain embodiments, L1is –(optionally substituted monocyclic heterocyclylene)2–(optionally substituted C1alkylene)–, –(optionally substituted C1alkylene)–(optionally substituted monocyclic heterocyclylene)2–, –(optionally substituted C1alkylene)–(optionally substituted monocyclic heterocyclylene)2–(optionally substituted C1alkylene)–, –(optionally substituted monocyclic heterocyclylene)–(optionally substituted monocyclic carbocyclylene)–(optionally substituted C1alkylene)–, –(optionally substituted monocyclic carbocyclylene)–(optionally substituted monocyclic heterocyclylene)–(optionally substituted C1alkylene)–, –(optionally substituted C1alkylene)–(optionally substituted monocyclic heterocyclylene)–(optionally substituted monocyclic carbocyclylene)–, or –(optionally substituted C1alkylene)–(optionally substituted monocyclic carbocyclylene)–(optionally substituted monocyclic heterocyclylene)–, optionally wherein the backbone carbon atom in each instance of the optionally substituted C1alkylene is independently replaced with –O–, –NR4–, or –C(=O)–.

[0189] In some embodiments, L1isU1197.70246WO00 65 / 221 #14171685v1, , , W , , , , , , , , , ,U1197.70246WO00 66 / 221 #14171685v1H H, , , , , , , , O N X N , O , ,U1197.70246WO00 67 / 221 #14171685v1U1197.70246WO00 68 / 221 #14171685v1wherein: each instance of X is independently CH or N; each instance of W is independently –CH2–, –NH–, or –O–; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each r is independently 1 or 2;

[0190] In some embodiments, L1is of formula:,U1197.70246WO00 69 / 221 #14171685v1wherein: each instance of X is independently CH or N; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 1, 2, 3, or 4; and each of m3 and m4 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0.

[0191] In some embodiments, L1is of formula: (x-1), (x-2), or (x-6).

[0192] In some embodiments, L1is of formula (x-1). In some embodiments, L1is of formula (x-1), wherein n is 7 or 8. In some embodiments, L1is of formula (x-1), wherein n is 7. In some embodiments, L1is of formula (x-1), wherein n is 8.

[0193] In some embodiments, L1is of formula (x-2). In some embodiments, L1is of formula (x-2), wherein n is 3, 4, 5, 6, or 7. In some embodiments, L1is of formula (x-2), wherein n is 3 or 7. In someU1197.70246WO00 70 / 221 #14171685v1embodiments, L1is of formula (x-2), wherein n is 3. In some embodiments, L1is of formula (x-2), wherein n is 7.

[0194] In some embodiments, L1is of formula (x-6). In some embodiments, L1is of formula (x-6), wherein each of m3 and m4 is independently 2.

[0195] In some embodiments, L1is of formula:U1197.70246WO00 71 / 221 #14171685v1of formula:. some embodiments, L1is of formula:. In some embodiments, L1is of formula:. In some embodiments, L1is of formula:.

[0197] As generally described herein, L2is absent or optionally substituted C1-12 alkylene, optionally substituted C1-12 alkenylene, optionally substituted C2-12 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene, optionally substituted C1-12 alkenylene, or optionally substituted C2- 12 alkynylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0198] In some embodiments, L2is absent.

[0199] In some embodiments, L2comprises optionally substituted C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene, are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0200] In some embodiments, L2comprises optionally substituted C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises optionally substituted C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

[0201] In some embodiments, L2comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted C1-12alkylene, wherein one or more backboneU1197.70246WO00 72 / 221 #14171685v1carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

[0202] In some embodiments, L2comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises substituted C1-6alkylene, wherein one or more backbone carbon atoms in the substituted C1-6alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises substituted C1-6alkylene, wherein one or more backbone carbon atoms in the substituted C1-6alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises unsubstituted C1-6alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

[0203] In some embodiments, L2comprises optionally substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises optionally substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3 alkylene are independently replaced with –NR4–, –C(=O)–,U1197.70246WO00 73 / 221 #14171685v1optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises unsubstituted C1-3 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises unsubstituted C1-3 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3 alkylene are independently replaced with –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

[0204] In some embodiments, L2comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with –NR4–. In some embodiments, L2comprises substituted C1-12alkylene, wherein one or more backbone carbon atoms in the substituted C1-12alkylene are independently replaced with –NR4–. In some embodiments, L2comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with –NR4–. In some embodiments, L2comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with –NR4–. In some embodiments, L2comprises substituted C1-6alkylene, wherein one or more backbone carbon atoms in the substituted C1-6alkylene are independently replaced with –NR4–. In some embodiments, L2comprises unsubstituted C1-6alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6alkylene are independently replaced with –NR4–. In some embodiments, L2comprises optionally substituted C1-3alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3alkylene are independently replaced with –NR4–. In some embodiments, L2comprises substituted C1-3alkylene, wherein one or more backbone carbon atoms in the substituted C1-3alkylene are independently replaced with –NR4–. In some embodiments, L2comprises unsubstituted C1-3alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3 alkylene are independently replaced with –NR4–.

[0205] In some embodiments, L2comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –NH–. In some embodiments, L2comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with –NH–. In some embodiments, L2comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with –NH–. In some embodiments, L2comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with –NH–. In some embodiments, L2comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6U1197.70246WO00 74 / 221 #14171685v1alkylene are independently replaced with –NH–. In some embodiments, L2comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with –NH–. In some embodiments, L2comprises optionally substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3 alkylene are independently replaced with –NH–. In some embodiments, L2comprises substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with –NH–. In some embodiments, L2comprises unsubstituted C1-3 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3 alkylene are independently replaced with –NH–.

[0206] In some embodiments, L2comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –C(=O)–. In some embodiments, L2comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12alkylene are independently replaced with –C(=O)–. In some embodiments, L2comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with –C(=O)–. In some embodiments, L2comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with –C(=O)–. In some embodiments, L2comprises substituted C1-6alkylene, wherein one or more backbone carbon atoms in the substituted C1-6alkylene are independently replaced with –C(=O)–. In some embodiments, L2comprises unsubstituted C1-6alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6alkylene are independently replaced with –C(=O)–. In some embodiments, L2comprises optionally substituted C1-3alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3alkylene are independently replaced with –C(=O)–. In some embodiments, L2comprises substituted C1-3alkylene, wherein one or more backbone carbon atoms in the substituted C1-3alkylene are independently replaced with –C(=O)–. In some embodiments, L2comprises unsubstituted C1-3alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3alkylene are independently replaced with –C(=O)–.

[0207] In some embodiments, L2comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, L2comprises substituted C1-12alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, L2comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, L2comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with optionally substituted 4-10 membered heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with optionally substituted 4-10 membered heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbonU1197.70246WO00 75 / 221 #14171685v1atoms in the unsubstituted C1-12 alkylene are independently replaced with optionally substituted 4-10 membered heterocyclylene containing 1 or 2 ring N atoms.

[0208] In some embodiments, L2comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted C1-12alkylene, wherein one or more backbone carbon atoms in the substituted C1-12alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises unsubstituted C1-12alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms.

[0209] In some embodiments, L2comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted C1-6alkylene, wherein one or more backbone carbon atoms in the substituted C1-6alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises unsubstituted C1-6alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms.

[0210] In some embodiments, L2comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with aU1197.70246WO00 76 / 221 #14171685v1moiety of formula:, wherein each of m3 and m4 is independently 0, 1, or 2, provided that m1 and m2 are not both 0. In some embodiments, L2comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with a moiety of formula:,, , . In some embodiments, L2comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with a moiety of formula:each instance of X is independently CH or N. In some embodiments, L2comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with a moiety of formula:In some embodiments, L2comprises optionally substituted C1-12alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with a moiety of formula:.

[0211] In some embodiments, L2comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with a moiety of formula:, wherein each of m3 and m4 is independently 0, 1, or 2, provided that m1 and m2 are not both 0. In some embodiments, L2comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene are independently replaced with a moiety of formula: ,,, . In some embodiments, L2comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6alkylene areU1197.70246WO00 77 / 221 #14171685v1independently replaced with a moiety of formula:, wherein each instance of X is independently CH or N. In some embodiments, L2comprises optionally substituted C1-6alkylene, wherein one or more backbone carbon a independently replaced with a moiety of formula:some embodiments, L2comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with a moiety of formula:.

[0212] In some embodiments, L2comprises optionally substituted C1-12alkenylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkenylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted C1-12alkenylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkenylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises substituted C1-12alkenylene, optionally wherein one or more backbone carbon atoms in the substituted C1-12alkenylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises unsubstituted C1-12alkenylene, optionally wherein one or more backbone carbon atoms in the unsubstituted C1-12alkenylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises optionally substituted C2-6 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-6 alkynylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises substituted C2-6 alkynylene, optionally wherein one or more backbone carbon atoms in the substituted C2-6 alkynylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises unsubstituted C2-6 alkynylene, optionally wherein one or more backbone carbon atoms in the unsubstituted C2-6 alkynylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

[0213] In some embodiments, L2comprises optionally substituted C2-12 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-12 alkynylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substitutedU1197.70246WO00 78 / 221 #14171685v1carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted C2-12 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-12 alkynylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises substituted C2-12 alkynylene, optionally wherein one or more backbone carbon atoms in the substituted C2-12 alkynylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises unsubstituted C2-12 alkynylene, optionally wherein one or more backbone carbon atoms in the unsubstituted C2-12 alkynylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises optionally substituted C2-6 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-6alkynylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises substituted C2-6alkynylene, optionally wherein one or more backbone carbon atoms in the substituted C2-6alkynylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L2comprises unsubstituted C2-6alkynylene, optionally wherein one or more backbone carbon atoms in the unsubstituted C2-6alkynylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

[0214] In some embodiments, L2comprises optionally substituted heterocyclylene. In some embodiments, L2comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises optionally substituted 4-10 membered heterocyclylene. In some embodiments, L2comprises optionally substituted 4-10 membered heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises optionally substituted 4-10 membered heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises optionally substituted 4-10 membered heterocyclylene containing 2 ring N atoms.

[0215] In some embodiments, L2comprises optionally substituted 4-6 membered monocyclic heterocyclylene. In some embodiments, L2comprises optionally substituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises optionally substituted 4-6 membered monocyclic heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises optionally substituted 4-6 membered monocyclic heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises substituted 4-6 membered monocyclic heterocyclylene. In some embodiments, L2comprises substituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted 4-6 membered monocyclic heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises substituted 4-6 membered monocyclic heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises unsubstituted 4-6 membered monocyclic heterocyclylene. In some embodiments, L2comprises unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In someU1197.70246WO00 79 / 221 #14171685v1embodiments, L2comprises unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises unsubstituted 4-6 membered monocyclic heterocyclylene containing 2 ring N atoms.

[0216] In some embodiments, L2comprises optionally substituted 6-10 membered bridged bicyclic heterocyclylene. In some embodiments, L2comprises optionally substituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises optionally substituted 6-10 membered bridged bicyclic heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises optionally substituted 6-10 membered bridged bicyclic heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises substituted 6-10 membered bridged bicyclic heterocyclylene. In some embodiments, L2comprises substituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted 6-10 membered bridged bicyclic heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises substituted 6-10 membered bridged bicyclic heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises unsubstituted 6-10 membered bridged bicyclic heterocyclylene. In some embodiments, L2comprises unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises unsubstituted 6-10 membered bridged bicyclic heterocyclylene containing 2 ring N atoms.

[0217] In some embodiments, L2comprises a moiety of formula:, wherein each of m3 and m4 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0. In some embodiments, L2comprises a moiety of formula:, wherein each of m3 and m4 is independently 0, 1, or 2, provided that m1 and m2 are not both 0. In some embodiments, L2comprises a moiety of formula:

[0218] In some embodiments, L2comprises a moiety of formula:, wherein each instance of X is independently CH or N. In some embodiments, L2comprises a moiety of formula:U1197.70246WO00 80 / 221 #14171685v1

[0219] In some embodiments, L2comprises a moiety of formula:.

[0220] In certain embodiments, L2is –(optionally substituted monocyclic heterocyclylene)–(optionally substituted C1alkylene)–, –(optionally substituted bicyclic heterocyclylene)–(optionally substituted C1alkylene)–, –(optionally substituted C1alkylene)–(optionally substituted monocyclic heterocyclylene)–, –(optionally substituted C1alkylene)–(optionally substituted bicyclic heterocyclylene)–, –(optionally substituted C2alkylene)–(optionally substituted bicyclic carbocyclylene)–,or –(optionally substituted bicyclic carbocyclylene)–(optionally substituted C2alkylene)–, optionally wherein one backbone carbon atom in the optionally substituted C1alkylene or C2alkylene is replaced with –O–, –NR4–, or –C(=O)–.

[0221] In certain embodiments, L2is –(optionally substituted C1alkylene)–(optionally substituted monocyclic heterocyclylene)–(optionally substituted C1alkylene)– or –(optionally substituted C1alkylene)–(optionally substituted bicyclic heterocyclylene)–(optionally substituted C1alkylene)–, optionally wherein the backbone carbon atom in each instance of the optionally substituted C1 alkylene is independently replaced with –O–, –NR4–, or –C(=O)–.

[0222] In certain embodiments, L2is –(optionally substituted C1alkylene)–(optionally substituted monocyclic heterocyclylene)– or –(optionally substituted monocyclic heterocyclylene)–(optionally substituted C1 alkylene)–.

[0223] In certain embodiments, L2is –(optionally substituted monocyclic heterocyclylene)2–, –(optionally substituted monocyclic heterocyclylene)2–(optionally substituted C1 alkylene)–, –(optionally substituted C1 alkylene)–(optionally substituted monocyclic heterocyclylene)2–, –(optionally substituted C1 alkylene)–(optionally substituted monocyclic heterocyclylene)2–(optionally substituted C1 alkylene)–, –(optionally substituted monocyclic heterocyclylene)–(optionally substituted monocyclic carbocyclylene)–, or –(optionally substituted monocyclic carbocyclylene)–(optionally substituted monocyclic heterocyclylene)–, optionally wherein the backbone carbon atom in each instance of the optionally substituted C1 alkylene is independently replaced with –O–, –NR4–, or –C(=O)–.

[0224] In some embodiments, L2is:U1197.70246WO00 81 / 221 #14171685v1U1197.70246WO00 82 / 221 #14171685v1U1197.70246WO00 83 / 221 #14171685v1wherein: each instance of R5is independently hydrogen or optionally substituted alkyl; each instance of X is independently CH or N; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 0, 1, 2, 3, or 4; each r is independently 1 or 2; and each s is independently 1, 2, 3, or 4.

[0225] In some embodiments, L2is absent or is of formula:U1197.70246WO00 84 / 221 #14171685v1wherein: each instance of X is independently CH or N; each p is independently 1, 2, 3, or 4; and each of m3 and m4 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0.

[0226] In some embodiments, L2is of formula:

[0227] As generally described herein, each instance of R4is independently hydrogen or optionally substituted alkyl.

[0228] In some embodiments, at least one instance of R4is hydrogen. In some embodiments, each instance of R4is independently hydrogen.

[0229] In some embodiments, at least one instance of R4is optionally substituted alkyl. In some embodiments, at least one instance of R4is optionally substituted C1-6 alkyl. In some embodiments, atU1197.70246WO00 85 / 221 #14171685v1least one instance of R4is optionally substituted C1-3 alkyl. In some embodiments, at least one instance of R4is optionally substituted methyl. In some embodiments, at least one instance of R4is unsubstituted alkyl. In some embodiments, at least one instance of R4is unsubstituted C1-6 alkyl. In some embodiments, at least one instance of R4is unsubstituted C1-3 alkyl. In some embodiments, at least one instance of R4is substituted alkyl. In some embodiments, at least one instance of R4is substituted C1-6 alkyl. In some embodiments, at least one instance of R4is substituted C1-3 alkyl. Additional Subgeneric Embodiments

[0230] In some embodiments, L1is of formula:,U1197.70246WO00 86 / 221 #14171685v1L2is absent or is of formula:,U1197.70246WO00 87 / 221 #14171685v1wherein: each instance of X is independently CH or N; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 1, 2, 3, or 4; and each of m3 and m4 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0.

[0231] In some embodiments, L1is of formula: (x-1), (x-2), or (x-6); and L2is absent.

[0232] In some embodiments, L1is of formula (x-1); and L2is absent. In some embodiments, L1is of formula (x-1), wherein n is 7 or 8; and L2is absent. In some embodiments, L1is of formula (x-1), wherein n is 7; and L2is absent. In some embodiments, L1is of formula (x-1), wherein n is 8; and L2is absent.

[0233] In some embodiments, L1is of formula (x-2); and L2is absent. In some embodiments, L1is of formula (x-2), wherein n is 3, 4, 5, 6, or 7; and L2is absent. In some embodiments, L1is of formula (x-2), wherein n is 3 or 7; and L2is absent. In some embodiments, L1is of formula (x-2), wherein n is 3; and L2is absent. In some embodiments, L1is of formula (x-2), wherein n is 7; and L2is absent.

[0234] In some embodiments, L1is of formula (x-6); and L2is absent. In some embodiments, L1is of formula (x-6), wherein each of m3 and m4 is independently 2; and L2is absent.

[0235] In some embodiments, L1is of formula:U#14171685v1U1197.70246WO00 89 / 221 #14171685v1is absent. In some embodiments, L1is of formula: ; and L2is absent. In some embodiments, L1is of formula:; and L2is absent. In some embodiments, L1is of formula:; and L2is absent. In some embodiments, L1is of formula:; and L2is absent.

[0237] In some embodiments, the compound of Formula (I) or Formula (I′) is of Formulae (II-a), (II-b), or (II-c):or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the compound of Formula (I) is of Formula (II-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (II-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (II-c), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (II-a), or a pharmaceutically acceptable salt thereof. In some embodiments,U1197.70246WO00 90 / 221 #14171685v1the compound of Formula (I′) is of Formula (II-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (II-c), or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments of Formulae (II-a), (II-b), or (II-c), L1is of formula: (x-1), (x-2), or (x-6). In some embodiments of Formulae (II-a), (II-b), or (II-c), L1is of formula: (x-1), wherein n is 7 or 8; (x- 2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2. In some embodiments of Formulae (II-a), (II-b), or (II-c), L1is of formula: (x-1), (x-2), or (x-6); and L2is absent. In some embodiments of Formulae (II-a), (II-b), or (II-c), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; and L2is absent. In some embodiments of Formulae (II-a), (II-b), or (II-c), Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (II-a), (II-b), or (II-c), L1is of formula: (x-1), (x-2), or (x-6); and Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (II-a), (II-b), or (II-c), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; and Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (II-a), (II-b), or (II-c), L1is of formula: (x-1), (x-2), or (x-6); L2is absent; and Y is of formula: (y-1), (y- 13), (y-14), or (y-17). In some embodiments of Formulae (II-a), (II-b), or (II-c), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; L2is absent; and Y is of formula: (y-1), (y-13), (y-14), or (y-17).

[0240] In some embodiments, the compound of Formula (I) or Formula (I′) is of Formulae (III-a) or (III-b):U1197.70246WO00 91 / 221 #14171685v1or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the compound of Formula (I) is of Formula (III-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (III-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (III-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (III-b), or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments of Formulae (III-a) or (III-b), L1is of formula: (x-1), (x-2), or (x-6). In some embodiments of Formulae (III-a) or (III-b), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2. In some embodiments of Formulae (III-a) or (III-b), L1is of formula: (x-1), (x-2), or (x-6); and L2is absent. In some embodiments of Formulae (III-a) or (III-b), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; and L2is absent. In some embodiments of Formulae (III-a) or (III-b), Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (III-a) or (III-b), L1is of formula: (x-1), (x-2), or (x-6); and Y is of formula: (y-1), (y-13), (y- 14), or (y-17). In some embodiments of Formulae (III-a) or (III-b), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; and Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (III-a) or (III-b), L1is of formula: (x-1), (x-2), or (x-6); L2is absent; and Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (III-a) or (III-b), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; L2is absent; and Y is of formula: (y- 1), (y-13), (y-14), or (y-17).

[0243] In some embodiments, the compound of Formula (I) or Formula (I′) is of Formulae (IV-a), (IV-U1197.70246WO00 92 / 221 #14171685v1or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the compound of Formula (I) is of Formula (IV-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (IV-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (IV-b-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (IV-b-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (IV-c), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (IV-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (IV-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (IV-b-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (IV-b-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (IV-c), or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments of Formulae (IV-a), (IV-b), (IV-b-1), (IV-b-2), or (IV-c), L1is of formula: (x-1), (x-2), or (x-6). In some embodiments of Formulae (IV-a), (IV-b), (IV-b-1), (IV-b-2), or (IV-c), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2. In some embodiments of Formulae (IV-a), (IV-b), (IV-b-1), (IV-b-2), or (IV-c), L1is of formula: (x-1), (x-2), or (x-6); and L2is absent. In some embodiments of Formulae (IV-U1197.70246WO00 93 / 221 #14171685v1a), (IV-b), (IV-b-1), (IV-b-2), or (IV-c), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; and L2is absent. In some embodiments of Formulae (IV-a), (IV-b), (IV-b-1), (IV-b-2), or (IV-c), Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (IV-a), (IV-b), (IV-b-1), (IV-b-2), or (IV-c), L1is of formula: (x-1), (x-2), or (x-6); and Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (IV-a), (IV-b), (IV-b-1), (IV-b-2), or (IV-c), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; and Y is of formula: (y-1), (y-13), (y- 14), or (y-17). In some embodiments of Formulae (IV-a), (IV-b), (IV-b-1), (IV-b-2), or (IV-c), L1is of formula: (x-1), (x-2), or (x-6); L2is absent; and Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (IV-a), (IV-b), (IV-b-1), (IV-b-2), or (IV-c), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; L2is absent; and Y is of formula: (y-1), (y-13), (y-14), or (y-17).

[0246] In some embodiments, the compound of Formula (I) or Formula (I′) is of Formulae (V-a), (V-b),,U1197.70246WO00 94 / 221 #14171685v1(V-c), (V-d),U1197.70246WO00 95 / 221 #14171685v1or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the compound of Formula (I) is of Formula (V-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (V-b), or aU1197.70246WO00 96 / 221 #14171685v1pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (V-b-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (V-b-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (V-c), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (V-d), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (V-e), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (V-e-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (V-e-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (V-f), or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the compound of Formula (I′) is of Formula (V-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (V-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (V-b-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (V-b-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (V-c), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (V-d), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (V-e), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (V-e-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (V-e-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (V-f), or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments of Formulae (V-a), (V-b), (V-b-1), (V-b-2), (V-c), (V-d), (V-e), (V-e-1), (V-e-2), or (V-f), L1is of formula: (x-1), (x-2), or (x-6). In some embodiments of Formulae (V-a), (V-b), (V-b-1), (V-b-2), (V-c), (V-d), (V-e), (V-e-1), (V-e-2), or (V-f), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2. In some embodiments of Formulae (V-a), (V-b), (V-b-1), (V-b-2), (V-c), (V-d), (V-e), (V-e-1), (V-e-2), or (V-f), L1is of formula: (x-1), (x-2), or (x-6); and L2is absent. In some embodiments of Formulae (V-a), (V-b), (V-b-1), (V-b-2), (V-c), (V-d), (V-e), (V-e-1), (V-e-2), or (V-f), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; and L2is absent. In some embodiments of Formulae (V-a), (V-b), (V-b-1), (V-b-2), (V-c), (V-d), (V-e), (V-e-1), (V-e-2), or (V-f), Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (V-a), (V-b), (V-b-1), (V-b-2), (V-c), (V-d), (V-e), (V-e-1), (V-e-2), or (V-f), L1is of formula: (x-1), (x-2), or (x-6); and Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (V-a), (V-b), (V- b-1), (V-b-2), (V-c), (V-d), (V-e), (V-e-1), (V-e-2), or (V-f), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; and Y is of formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (V-a), (V-b), (V-b-1), (V-b-2), (V-c), (V-d), (V-e), (V-e-1), (V-e-2), or (V-f), L1is of formula: (x-1), (x-2), or (x-6); L2is absent; and Y is ofU1197.70246WO00 97 / 221 #14171685v1formula: (y-1), (y-13), (y-14), or (y-17). In some embodiments of Formulae (V-a), (V-b), (V-b-1), (V-b- 2), (V-c), (V-d), (V-e), (V-e-1), (V-e-2), or (V-f), L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2; L2is absent; and Y is of formula: (y-1), (y-13), (y-14), or (y-17).

[0250] In some embodiments, the compound of Formula (I) or Formula (I′) is of Formulae (VI-a), (VI- b), (VI-b-1), (VI-b-2), (VI-c), (VI-d), (VI-e), (VI-e-1), (VI-e-2), or (VI-f):,U1197.70246WO00 98 / 221 #14171685v1-2), ,-e),U1197.70246WO00 99 / 221 #14171685v1or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, the compound of Formula (I) is of Formula (VI-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (VI-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (VI-b-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (VI-b-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (VI-c), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (VI-d), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (VI-e), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (VI-e-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is ofU1197.70246WO00 100 / 221 #14171685v1Formula (VI-e-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (VI-f), or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, the compound of Formula (I′) is of Formula (VI-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (VI-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (VI-b-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (VI-b-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (VI-c), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (VI-d), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (VI-e), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (VI-e-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (VI-e-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is of Formula (VI-f), or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments of Formulae (VI-a), (VI-b), (VI-b-1), (VI-b-2), (VI-c), (VI-d), (VI-e), (VI-e-1), (VI-e-2), or (VI-f), Y is of formula: (y-1), (y-13), (y-14), or (y-17).

[0254] In some embodiments, the compound of Formula (I) or Formula (I′) is a compound provided in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound provided in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I′) is a compound provided in Table 1, or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, the compound of Formula (I) or Formula (I′) is a compound provided in Table 1. In some embodiments, the compound of Formula (I) is a compound provided in Table 1. In some embodiments, the compound of Formula (I′) is a compound provided in Table 1.

[0256] In some embodiments, the compound of Formula (I) or Formula (I′) is a pharmaceutically acceptable salt of a compound provided in Table 1. In some embodiments, the compound of Formula (I) is a pharmaceutically acceptable salt of a compound provided in Table 1. In some embodiments, the compound of Formula (I′) is a pharmaceutically acceptable salt of a compound provided in Table 1.U1197.70246WO00 101 / 221 #14171685v1Table 1. Non-Limiting Compounds of Formula (I) and Formula (I′)U1197.70246WO00 102 / 221 #14171685v1U1197.70246WO00 103 / 221 #14171685v1U1197.70246WO00 104 / 221 #14171685v1U1197.70246WO00 105 / 221 #14171685v1U1197.70246WO00 106 / 221 #14171685v1U1197.70246WO00 107 / 221 #14171685v1U1197.70246WO00 108 / 221 #14171685v1U1197.70246WO00 109 / 221 #14171685v1U1197.70246WO00 110 / 221 #14171685v1U1197.70246WO00 111 / 221 #14171685v1U1197.70246WO00 112 / 221 #14171685v1U1197.70246WO00 113 / 221 #14171685v1U1197.70246WO00 114 / 221 #14171685v1U1197.70246WO00 115 / 221 #14171685v1U1197.70246WO00 116 / 221 #14171685v1U1197.70246WO00 117 / 221 #14171685v1U1197.70246WO00 118 / 221 #14171685v1

[0257] In some embodiments, a provided compound (a compound of the present disclosure, a compound provided herein) is a compound of Formula (I) or Formula (I′), or a pharmaceutically acceptable salt thereof. In some embodiments, a provided compound (a compound of the present disclosure, a compound provided herein) is a compound of Formula (I) or Formula (I′), or a salt thereof. In some embodiments, a provided compound (a compound of the present disclosure, a compound provided herein) is a compound of Formula (I) or Formula (I′). In some embodiments, a provided compound is any one of Compounds 1- 82, or a pharmaceutically acceptable salt thereof. In some embodiments, a provided compound is any one of Compounds 1-82, or a salt thereof. In some embodiments, a provided compound is any one of Compounds 1-82.U1197.70246WO00 119 / 221 #14171685v1

[0258] Compounds provided herein can be obtained from natural sources or made or modified made by means known in the art of organic synthesis. Methods for optimizing reaction conditions, if necessary minimizing competing by-products, are known in the art. Reaction optimization and scale-up may advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (e.g. Design And Optimization in Organic Synthesis, 2ndEdition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Jähnisch, K et al, Angew. Chem. Int. Ed. Engl.200443: 406; and references therein). Additional reaction schemes and protocols may be determined by the skilled artesian by use of commercially available structure-searchable database software, for instance, SciFinder® (CAS division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searching using an internet search engine such as Google® or keyword databases such as the US Patent and Trademark Office text database. For example, compounds of formulae herein can be made using methodology known in the art, including Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0259] The compounds of the formulae herein can be synthesized using methodology similarly to that described in Chen, Q. Y.; Liu, Y.; Cai, W.; Luesch, H. Improved Total Synthesis and Biological Evaluation of Potent Apratoxin S4 Based Anticancer Agents with Differential Stability and Further Enhanced Activity. J. Med. Chem.2014, 57 (7):p.3011–302; and in WO2012 / 158933.

[0260] In certain embodiments, the provided compounds bind to Bcl-2 with a dissociation constant (Kd) of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM.

[0261] In certain embodiments, the provided compounds inhibit the activity of Bcl-2 with an IC50of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM.

[0262] In certain embodiments, the provided compounds inhibit the production of Bcl-2 with an IC50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM.

[0263] In certain embodiments, the provided compounds bind to Bcl-xL with a dissociation constant (Kd) of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM.U1197.70246WO00 120 / 221 #14171685v1

[0264] In certain embodiments, the provided compounds inhibit the activity of Bcl-xL with an IC50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM.

[0265] In certain embodiments, the provided compounds inhibit the production of Bcl-xL with an IC50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM.

[0266] In certain embodiments, the provided compounds are able to bind to both Bcl-2 and Bcl-xL. In certain embodiments, the provided compounds inhibit the activity of both Bcl-2 and Bcl-xL. In certain embodiments, the provided compounds inhibit the production of both Bcl-2 and Bcl-xL.

[0267] In certain embodiments, the selectivity (e.g., as determined by Kdor IC50) of the provided compounds for Bcl-2 over a different Bcl-2 family protein (e.g., Bcl-xL) is between 2 and 3, between 3 and 5, between 5 and 10, between 10 and 30, between 30 and 100, between 100 and 300, or between 300 and 1000 folds, or greater than 1000 folds.

[0268] In certain embodiments, the selectivity (e.g., as determined by Kdor IC50) of the provided compounds for Bcl-xL over a different Bcl-2 family protein (e.g., Bcl-2) is between 2 and 3, between 3 and 5, between 5 and 10, between 10 and 30, between 30 and 100, between 100 and 300, or between 300 and 1000 folds, or greater than 1000 folds.

[0269] In certain embodiments, a compound provided herein has reduced platelet toxicity relative to other Bcl-2 and / or Bcl-xL inhibitors. In certain embodiments, the ratio of human platelet toxicity (IC50) to anticancer activity (IC50) of the compound the present disclosure provides less than that of other Bcl-2 and / or Bcl-xL inhibitors (e.g., the another Bcl-2 inhibitor and the another Bcl-xL inhibitor described herein).

[0270] The provided compounds may be prepared by methods known in the art, e.g., the methods described in U.S. Patent Application Publication No.2022-0169628. Pharmaceutical Compositions and Kits

[0271] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I) or Formula (I′), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I′), or pharmaceutically acceptable salt thereof. In another aspect, provided herein is a pharmaceutical composition comprising any one of Compounds 1 to 82, or a pharmaceutically acceptable salt thereof. and a pharmaceutically acceptable carrier.

[0272] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an additional pharmaceutical agent.U1197.70246WO00 121 / 221 #14171685v1

[0273] In some embodiments, the pharmaceutical composition comprises an effective amount of the provided compound. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In some embodiments, the effective amount is an amount effective for treating a disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective for preventing a disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective for reducing the risk of developing a disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective for binding Bcl-xL and / or Bcl-2 (e.g., in a subject, tissue, biological sample, or cell). In some embodiments, the effective amount is an amount effective for inhibiting the production of Bcl-xL and / or Bcl-2 (e.g., in a subject, tissue, biological sample, or cell). In some embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of Bcl-xL and / or Bcl-2 (e.g., in a subject, tissue, biological sample, or cell).

[0274] In some embodiments, the effective amount is an amount effective for binding Bcl-xL and / or Bcl-2 by between 0.1% and 10%, between 10% and 20%, between 20% and 30%, between 30% and 40%, between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 95%, between 95% and 98%, between 98% and 99%, or greater than 99%.

[0275] In some embodiments, the effective amount is an amount effective for inhibiting the production of Bcl-xL and / or Bcl-2 by between 0.1% and 10%, between 10% and 20%, between 20% and 30%, between 30% and 40%, between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 95%, between 95% and 98%, between 98% and 99%, or greater than 99%.

[0276] In some embodiments, the effective amount is an amount effective for inhibiting the activity of Bcl-xL and / or Bcl-2 by between 0.1% and 10%, between 10% and 20%, between 20% and 30%, between 30% and 40%, between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 95%, between 95% and 98%, between 98% and 99%, or greater than 99%.

[0277] In some embodiments, the pharmaceutical composition is for use in treating a disease. In some embodiments, the pharmaceutical composition is for use in preventing a disease. In some embodiments, the pharmaceutical composition is for use in inhibiting the activity of Bcl-xL and / or Bcl-2. In some embodiments, the pharmaceutical composition is for use in inhibiting the production of Bcl-xL and / or Bcl-2. In some embodiments, the pharmaceutical composition is for use in inhibiting the activity of Bcl- xL and / or Bcl-2.

[0278] A provided compound or pharmaceutical composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The provided compounds or pharmaceutical compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing aU1197.70246WO00 122 / 221 #14171685v1disease in a subject in need thereof, and / or in reducing the risk of developing a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the additional pharmaceutical agents employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a provided compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the provided compounds and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0279] In some embodiments, provided herein the pharmaceutical composition further comprising an additional pharmaceutical agent. The provided compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound or pharmaceutical composition and may be useful as, e.g., combination therapies.

[0280] Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides, synthetic proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease.

[0281] Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or pharmaceutical composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0282] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, cytotoxic agents, anti-angiogenesis agents, anti-inflammatory agents, and immunosuppressants. In certain embodiments, the additional pharmaceutical agent is an anti- inflammatory agent. In certain embodiments, the additional pharmaceutical agent is an immunotherapy. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certainU1197.70246WO00 123 / 221 #14171685v1embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the anti-cancer agents include, but are not limited to, epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, HDAC inhibitors, lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), 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, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g., vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g., busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound- paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9- aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycin (e.g., actinomycin D, dactinomycin), bleomycin (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca2+ATPase inhibitors (e.g., thapsigargin), thalidomide, lenalidomide, pomalidomide, tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cediranib (RECENTINTM), dasatinib (SPRYCEL®), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®), lapatinib (TYKERB®, TYVERB®), lestaurtinib, neratinib, nilotinib (TASIGNA®), semaxanib, sunitinib (SUTENT®), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869,U1197.70246WO00 124 / 221 #14171685v1MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine.

[0283] In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments the anti-cancer agent is an alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof. In some embodiments, the additional pharmaceutical agent is an alkylating agent. In some embodiments, the additional pharmaceutical agent is an anti-metabolite. In some embodiments, the additional pharmaceutical agent is an anti-tumor antibiotic. In some embodiments, the additional pharmaceutical agent is an anti-cytoskeletal agent. In some embodiments, the additional pharmaceutical agent is a topoisomerase inhibitor. In some embodiments, the additional pharmaceutical agent is an anti-hormonal agent. In some embodiments, the additional pharmaceutical agent is a targeted therapeutic agent. In some embodiments, the additional pharmaceutical agent is a photodynamic therapeutic agent. In some embodiments, the additional pharmaceutical agent is a combination of anticancer agents.

[0284] Non-limiting examples of suitable alkylating agents include altretamine, benzodopa, busulfan, carboplatin, carboquone, carmustine (BCNU), chlorambucil, chlornaphazine, cholophosphamide, chlorozotocin, cisplatin, cyclosphosphamide, dacarbazine (DTIC), estramustine, fotemustine, ifosfamide, improsulfan, lipoplatin, lomustine (CCNU), mafosfamide, mannosulfan, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, meturedopa, mustine (mechlorethamine), mitobronitol, nimustine, novembichin, oxaliplatin, phenesterine, piposulfan, prednimustine, ranimustine, satraplatin, semustine, temozolomide, thiotepa, treosulfan, triaziquone, triethylenemelamine, triethylenephosphoramide (TEPA), triethylenethiophosphaoramide (thiotepa), trimethylolomelamine, trofosfamide, uracil mustard and uredopa.

[0285] Suitable anti-metabolites include, but are not limited to aminopterin, ancitabine, azacitidine, 8- azaguanine, 6-azauridine, capecitabine, carmofur (1-hexylcarbomoyl-5-fluorouracil), cladribine, clofarabine, cytarabine (cytosine arabinoside (Ara-C)), decitabine, denopterin, dideoxyuridine, doxifluridine, enocitabine, floxuridine, fludarabine, 5-fluorouracil, gemcetabine, hydroxyurea (hydroxycarbamide), leucovorin (folinic acid), 6-mercaptopurine, methotrexate, nafoxidine, nelarabine, oblimersen, pemetrexed, pteropterin, raltitrexed, tegofur, tiazofurin, thiamiprine, tioguanine (thioguanine), and trimetrexate.U1197.70246WO00 125 / 221 #14171685v1

[0286] Non-limiting examples of suitable anti-tumor antibiotics include aclacinomysin, aclarubicin, actinomycins, adriamycin, aurostatin (for example, monomethyl auristatin E), authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, epoxomicin, esorubicin, idarubicin, marcellomycin, mitomycins, mithramycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, plicamycin, potfiromycin, puromycin, quelamycin, rodorubicin, sparsomycin, streptonigrin, streptozocin, tubercidin, valrubicin, ubenimex, zinostatin, and zorubicin.

[0287] Non-limiting examples of suitable anti-cytoskeletal agents include cabazitaxel, colchicines, demecolcine, docetaxel, epothilones, ixabepilone, macromycin, omacetaxine mepesuccinate, ortataxel, paclitaxel (for example, DHA-paclitaxel), taxane, tesetaxel, vinblastine, vincristine, vindesine, and vinorelbine.

[0288] Suitable topoisomerase inhibitors include, but are not limited to, amsacrine, etoposide (VP-16), irinotecan, mitoxantrone, RFS 2000, teniposide, and topotecan.

[0289] Non-limiting examples of suitable anti-hormonal agents such as aminoglutethimide, antiestrogen, aromatase inhibiting 4(5)-imidazoles, bicalutamide, finasteride, flutamide, fluvestrant, goserelin, 4- hydroxytamoxifen, keoxifene, leuprolide, LY117018, mitotane, nilutamide, onapristone, raloxifene, tamoxifen, toremifene, and trilostane.

[0290] Examples of targeted therapeutic agents include, without limit, monoclonal antibodies such as alemtuzumab, cartumaxomab, edrecolomab, epratuzumab, gemtuzumab, gemtuzumab ozogamicin, glembatumumab vedotin, ibritumomab tiuxetan, reditux, rituximab, tositumomab, and trastuzumab; protein kinase inhibitors such as bevacizumab, cetuximab, crizonib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, mubritinib, nilotinib, panitumumab, pazopanib, sorafenib, sunitinib, toceranib, and vandetanib; angiogeneisis inhibitors such as angiostatin, bevacizumab, denileukin diftitox, endostatin, everolimus, genistein, interferon alpha, interleukin-2, interleukin-12, pazopanib, pegaptanib, ranibizumab, rapamycin (sirolimus), temsirolimus, and thalidomide; and growth inhibitory polypeptides such as bortazomib, erythropoietin, interleukins (e.g., IL-1, IL-2, IL-3, IL-6), leukemia inhibitory factor, interferons, romidepsin, thrombopoietin, TNF-α, CD30 ligand, 4-1BB ligand, and Apo-1 ligand.

[0291] Non-limiting examples of photodynamic therapeutic agents include aminolevulinic acid, methyl aminolevulinate, retinoids (alitretinon, tamibarotene, tretinoin), and temoporfin.

[0292] Other antineoplastic agents include anagrelide, arsenic trioxide, asparaginase, bexarotene, bropirimine, celecoxib, chemically linked Fab, efaproxiral, etoglucid, ferruginol, lonidamide, masoprocol, miltefosine, mitoguazone, talapanel, trabectedin, and vorinostat.

[0293] In certain embodiments, the additional pharmaceutical agent is another Bcl-2 inhibitor. In certain embodiments, the another Bcl-2 inhibitor is ABT-737, navitoclax (ABT-263), venetoclax (ABT-199), obatoclax (GX 15-070), (-)-gossypol (AT-101), sabutoclax (BI-97C1), TW-37, BM-1252 (APG-1252), or A-1155463. In certain embodiments, the other Bcl-2 inhibitor is venetoclax or ABT-263. In certain embodiments, the additional pharmaceutical agent is another Bcl-xL inhibitor. In certain embodiments,U1197.70246WO00 126 / 221 #14171685v1the another Bcl-xL inhibitor is ABT-263, ABT-737, A-1155463, A-1331852, AZD4320, WEHI-539, (-)- gossypol, BH3I-1, berberine, flavokawain A, sabutoclax, TW-37, or gambogic acid.

[0294] In certain embodiments, the additional pharmaceutical agent is an immunotherapy. In certain embodiments, the immunotherapy is useful in the treatment of a cancer. Exemplary immunotherapies include, but are not limited to, T-cell therapies, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and / or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies. In certain embodiments, the immunotherapy is a T-cell therapy. In certain embodiments, the T-cell therapy is chimeric antigen receptor T cells (CAR-T). In certain embodiments, the immunotherapy is an antibody. In certain embodiments, the antibody is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIM3 antibody, an anti-OX40 antibody, an anti-GITR antibody, an anti-LAG-3 antibody, an anti-CD137 antibody, an anti-CD27 antibody, an anti-CD28 antibody, an anti-CD28H antibody, an anti-CD30 antibody, an anti-CD39 antibody, an anti-CD40 antibody, an anti-CD47 antibody, an anti-CD48 antibody, an anti-CD70 antibody, an anti-CD73 antibody, an anti-CD96 antibody, an anti-CD160 antibody, an anti-CD200 antibody, an anti-CD244 antibody, an anti-ICOS antibody, an anti-TNFRSF25 antibody, an anti- TMIGD2 antibody, an anti-DNAM1 antibody, an anti-BTLA antibody, an anti-LIGHT antibody, an anti- TIGIT antibody, an anti-VISTA antibody, an anti-HVEM antibody, an anti-Siglec antibody, an anti- GAL1 antibody, an anti-GAL3 antibody, an anti-GAL9 antibody, an anti-BTNL2 (butrophylins) antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody, an anti-B7-H5 antibody, an anti-B7-H6 antibody, an anti-KIR antibody, an anti-LIR antibody, an anti-ILT antibody, an anti-MICA antibody, an anti-MICB antibody, an anti-NKG2D antibody, an anti-NKG2A antibody, an anti-TGFβ antibody, an anti-TGFβR antibody, an anti-CXCR4 antibody, an anti-CXCL12 antibody, an anti-CCL2 antibody, an anti-IL-10 antibody, an anti-IL-13 antibody, an anti-IL-23 antibody, an anti-phosphatidylserine antibody, an anti-neuropilin antibody, an anti-GalCer antibody, an anti-HER2 antibody, an anti-VEGFA antibody, an anti-VEGFR antibody, an anti-EGFR antibody, or an anti-Tie2 antibody. In certain embodiments, the antibody is pembrolizumab, nivolumab, pidilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab, avelumab, PF-06801591, utomilumab, PDR001, PBF-509, MGB453, LAG525, AMP-224, INCSHR1210, INCAGN1876, INCAGN1949, samalizumab, PF-05082566, urelumab, lirilumab, lulizumab, BMS-936559, BMS-936561, BMS-986004, BMS-986012, BMS-986016, BMS-986178, IMP321, IPH2101, IPH2201, varilumab, ulocuplumab, monalizumab, MEDI0562, MEDI0680, MEDI1873, MEDI6383, MEDI6469, MEDI9447, AMG228, AMG820, CC-90002, CDX-1127, CGEN15001T, CGEN15022, CGEN15029, CGEN15049, CGEN15027, CGEN15052, CGEN15092, CX-072, CX-2009, CP-870893, lucatumumab, dacetuzumab, Chi Lob 7 / 4, RG6058, RG7686, RG7876, RG7888, TRX518, MK-4166, MGA271, IMC-CS4, emactuzumab, pertuzumab, obinutuzumab, cabiralizumab, margetuximab, enoblituzumab, mogamulizumab, carlumab, bevacizumab, trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), alemtuzumab (CAMPATH®), or ranibizumab (Lucentis®).U1197.70246WO00 127 / 221 #14171685v1

[0295] In certain embodiments, at least one of the additional pharmaceutical agents is a cytotoxic agent. In certain embodiments, at least one of the additional pharmaceutical agents is venetoclax, azacitidine, bortezomib, cladribine, cytarabine, doxorubicin, eribulin, etoposide, everolimus, ixabepilone, mitoxantrone, ixazomib, panobinostat, pemetrexed, SN-38, or topotecan. In certain embodiments, at least one of the additional pharmaceutical agents is nivolumab, pidilizumab, pembrolizumab, MEDI-0680, REGN2810, AMP-224, atezolizumab, durvalumab, BMS-936559, avelumab, CA-170, ipilimumab, or tremelimumab.

[0296] In certain embodiments, at least one of the additional pharmaceutical agents is an immune check- point inhibitor. In certain embodiments, at least one of the additional pharmaceutical agents is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. In certain embodiments, at least one of the additional pharmaceutical agents is a programmed cell death 1 protein (PD-1) inhibitor. In certain embodiments, at least one of the additional pharmaceutical agents is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor. In certain embodiments, at least one of the additional pharmaceutical agents is a stimulator of interferon genes (STING) agonist. In certain embodiments, the additional pharmaceutical agents include pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co- crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrug thereof.

[0297] In certain embodiments, the provided compounds or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

[0298] In certain embodiments, the provided compound or pharmaceutical composition is a solid. In certain embodiments, the provided compound or pharmaceutical composition is a powder. In certain embodiments, the provided compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In certain embodiments, the provided compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parental injection. In certain embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for subcutaneous injection.

[0299] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the composition comprising a provided compound (i.e., the “active ingredient”) into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0300] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the activeU1197.70246WO00 128 / 221 #14171685v1ingredient 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.

[0301] Relative amounts of the provided compound, pharmaceutically acceptable excipient, agent, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the pharmaceutical composition is to be administered. The pharmaceutical composition may comprise between 0.1% and 100% (w / w) agent.

[0302] Pharmaceutically acceptable excipients used in manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients and accessory ingredients, such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents, may also be present in the pharmaceutical composition.

[0303] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0304] 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.

[0305] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween®20), polyoxyethylene sorbitan monostearate (Tween®60), polyoxyethylene sorbitan monooleate (Tween®80), sorbitan monopalmitate (Span®40), sorbitan monostearate (Span®60), sorbitan tristearate (Span®65), glyceryl monooleate, sorbitan monooleate (Span®80), polyoxyethylene esters (e.g., polyoxyethyleneU1197.70246WO00 129 / 221 #14171685v1monostearate (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.

[0306] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0312] 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.U1197.70246WO00 130 / 221 #14171685v1

[0313] 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®.

[0314] 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.

[0315] 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.

[0316] 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.

[0317] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. InU1197.70246WO00 131 / 221 #14171685v1certain 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.

[0318] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0319] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0320] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0321] Pharmaceutical compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0322] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.U1197.70246WO00 132 / 221 #14171685v1

[0323] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes.

[0324] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0325] Dosage forms for topical and / or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0326] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0327] Suitable devices for use in delivering injectable pharmaceutical compositions described herein include short needle devices. Injectable pharmaceutical compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally,U1197.70246WO00 133 / 221 #14171685v1conventional syringes can be used in the classical mantoux method of administration. Jet injection devices which deliver liquid formulations via a liquid jet injector and / or via a needle. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form are suitable.

[0328] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such pharmaceutical compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder pharmaceutical compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0329] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w / w) of the pharmaceutical composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the pharmaceutical composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0330] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0331] 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.U1197.70246WO00 134 / 221 #14171685v1

[0332] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0333] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically- administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0334] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such pharmaceutical compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the pharmaceutical compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0335] Provided compounds are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.U1197.70246WO00 135 / 221 #14171685v1

[0336] The provided compounds and pharmaceutical compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarticular, intra- arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically, contemplated routes are intraarticular administration, oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0337] The exact amount of a provided compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound of the disclosure, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses of the multiple doses include different or substantially the same amounts of an agent described herein.

[0338] In certain embodiments, a pharmaceutical composition comprising a provided compound is administered, orally or parenterally, at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg in one or more dose administrations for one or several days (depending on th...

Claims

1. CLAIMS What is claimed is:

1. A compound of Formula (I): , or a pharmaceutically acceptable salt thereof, wherein: R1is –O(optionally substituted alkyl) or –N(Ra)2, wherein each instance of Rais independently optionally substituted alkyl or optionally substituted carbocyclyl, or two instances of Raare joined with the nitrogen atom to which they are attached to form optionally substituted heterocyclyl; R2is –NO2 or –SO2CF3; R3is of formula: substituted alkyl; each of m1 and m2 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0; L1is optionally substituted C1-12 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; L2is absent or optionally substituted C1-12alkylene, optionally substituted C1-12alkenylene, optionally substituted C2-12alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene, optionally substituted C1-12alkenylene, or optionally substituted C2-12alkynylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R4is independently hydrogen or optionally substituted alkyl; and Y is a moiety that is capable of binding to an E3 ubiquitin ligase.U1197.70246WO00 202 / 221 #14171685v12. The compound of claim 1, wherein Y is of formula:U1197.70246WO00 203 / 221 #14171685v1U1197.70246WO00 204 / 221 #14171685v13. A compound of Formula (I′):, or a pharmaceutically acceptable salt thereof, wherein: R1is –O(optionally substituted alkyl) or –N(Ra)2, wherein each instance of Rais independently optionally substituted alkyl or optionally substituted carbocyclyl, or two instances of Raare joined with the nitrogen atom to which they are attached to form optionally substituted heterocyclyl; R2is –NO2or –SO2CF3; R3is of formula:, wherein Rbis hydrogen, halogen, or optionally substituted alkyl; each of m1 and m2 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0; L1is optionally substituted C1-12alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, – S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; L2is absent or optionally substituted C1-12alkylene, optionally substituted C1-12alkenylene, optionally substituted C2-12alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene,U1197.70246WO00 205 / 221 #14171685v1optionally substituted C1-12 alkenylene, or optionally substituted C2-12 alkynylene are independently replaced with –O–, –NR4–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R4is independently hydrogen or optionally substituted alkyl; and Y is of formula:U1197.70246WO00 206 / 221 #14171685v1U1197.70246WO00 207 / 221 #14171685v14. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Y is of formula: (y-1), (y-13), (y-14), (y-15), (y-17), (y-18), (y-19), (y-22), (y-25), (y-26), (y-28), (y-32), (y-33), (y-36), (y-41), or (y-45).

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Y is of formula: (y-1), (y-13), (y-14), or (y-17).

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1is –O(optionally substituted alkyl).

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1is –O(alkyl substituted with an optionally substituted heterocyclyl containing at least 1 ring N atom).

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1is –N(Ra)2, wherein each instance of Rais independently optionally substituted alkyl or optionally substituted carbocyclyl.

9. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl.

10. The compound of any one of claims 1-5 or 9, or a pharmaceutically acceptable salt thereof, wherein R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted monocyclic heterocyclyl.U1197.70246WO00 208 / 221 #14171685v111. The compound of any one of claims 1-5 or 9, or a pharmaceutically acceptable salt thereof, wherein R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted fused bicyclic heterocyclyl.

12. The compound of any one of claims 1-5 or 9, or a pharmaceutically acceptable salt thereof, wherein R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted bridged bicyclic heterocyclyl.

13. The compound of any one of claims 1-5 or 9, or a pharmaceutically acceptable salt thereof, wherein R1is –N(Ra)2, wherein two instances of Raare joined with the nitrogen atom to which they are attached to form an optionally substituted spiro bicyclic heterocyclyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R1is of formula:U1197.70246WO00 209 / 221 #14171685v1wherein: each q is independently 1, 2, or 3; each r is independently 1 or 2; each s is independently 1, 2, 3, or 4; and each u is independently 0, 1, 2, 3, 4, or 5.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein, wherein r is 1 or 2.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R1is of formula:.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R2is –NO2.

18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R2is –SO2CF3.U1197.70246WO00 210 / 221 #14171685v119. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R3is of formula:.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein Rbis halogen.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein Rbis Cl.

23. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein Rbis optionally substituted alkyl.

24. The compound of any one of claims 1-20 or 23, or a pharmaceutically acceptable salt thereof, wherein Rbis alkyl substituted only with one or more instances of –F.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R3is:

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein each of m1 and m2 is independently 1.U1197.70246WO00 211 / 221 #14171685v128. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein m1 is 1 and m2 is 2, or m1 is 2 and m2 is 1.

29. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein each of m1 and m2 is independently 2.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein the moietyf formula:

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted C1-12alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with –O–, –NR4–, =N–, – N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted C1-12alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted heterocyclylene.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted 4-10 membered heterocyclylene.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms.U1197.70246WO00 212 / 221 #14171685v137. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted arylene.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted phenylene.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein L1is of formula:U1197.70246WO00 213 / 221 #14171685v1wherein: each instance of X is independently CH or N; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 1, 2, 3, or 4; and each of m3 and m4 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein L1is of formula: (x-1), (x-2), or (x-6).

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein L1is of formula: (x-1), wherein n is 7 or 8; (x-2), wherein n is 3 or 7; or (x-6), wherein each of m3 and m4 is independently 2:

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein L1is of formula: ,U1197.70246WO00 214 / 221 #14171685v144. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein L1is of formula:

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein L2is absent.

46. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein L2comprises optionally substituted C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12alkylene, are independently replaced with –O–, –NR4–, =N–,U1197.70246WO00 215 / 221 #14171685v1–N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

47. The compound of any one of claims 1-44 or 46, or a pharmaceutically acceptable salt thereof, wherein L2comprises optionally substituted C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with –O–, –NR4–, –C(=O)–, optionally substituted heterocyclylene, or optionally substituted arylene.

48. The compound of any one of claims 1-44, 46, or 47, or a pharmaceutically acceptable salt thereof, wherein L2comprises optionally substituted heterocyclylene.

49. The compound of any one of claims 1-44 or 46-48, or a pharmaceutically acceptable salt thereof, wherein L2comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms.

50. The compound of any one of claims 1-44 or 46-49, or a pharmaceutically acceptable salt thereof, wherein L2comprises optionally substituted 4-10 membered heterocyclylene.

51. The compound of any one of claims 1-44 or 46-50, or a pharmaceutically acceptable salt thereof, wherein L2comprises optionally substituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms.

52. The compound of any one of claims 1-44 or 46-51, or a pharmaceutically acceptable salt thereof, wherein L2comprises optionally substituted 6-10 membered bridged bicyclic heterocyclylene containing 1 or 2 ring N atoms.

53. The compound of any one of claims 1-44 or 46-52, or a pharmaceutically acceptable salt thereof, wherein L2is of formula:U1197.70246WO00 216 / 221 #14171685v1wherein: each instance of X is independently CH or N; each p is independently 1, 2, 3, or 4; and each of m3 and m4 is independently 0, 1, 2, or 3, provided that m1 and m2 are not both 0.

54. The compound of any one of claims 1-44 or 46-53, or a pharmaceutically acceptable salt thereof, wherein L2is of formula:

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound provided in Table 1, or a pharmaceutically acceptable salt thereof.U1197.70246WO00 217 / 221 #14171685v156. A pharmaceutical composition comprising the compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

57. The pharmaceutical composition of claim 56 further comprising an additional pharmaceutical agent.

58. The pharmaceutical composition of claim 57, wherein the additional pharmaceutical agent is an anti-cancer agent.

59. The pharmaceutical composition of claim 58, wherein the anti-cancer agent is an alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof.

60. A method of degrading a Bcl-2 protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of the compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 56-59.

61. A method of degrading a Bcl-xL protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of the compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 56-59.

62. The method of claim 60 or claim 61, wherein the cell is a cancer cell.

63. A method of selectively killing one or more cancer cells in a tissue or biological sample, the method comprising contacting the tissue or biological sample with an effective amount of the compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 56-59.

64. The method of any one of claims 60-63, wherein the cell, tissue, biological sample, or cancer cell is in vitro.

65. The method of any one of claims 60-63, wherein the cell, tissue, biological sample, or cancer cell is in a subject.U1197.70246WO00 218 / 221 #14171685v166. A method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 56-59.

67. The method of claim 66, wherein the disease is an age-related disease.

68. The method of claim 66 or claim 67, wherein the disease is an age-related cognitive dysfunction, age-related intervertebral disc disease, age-related muscle loss, Alzheimer’s disease, amyotrophic lateral sclerosis, ataxia, AV fistulae, bone marrow transplant complication, cardiac dysfunction, cataracts, chemotherapy complication, chronic obstructive, cirrhosis, COVID-19 complication, diabetes, frailty, glaucoma, hepatic steatosis, hyperoxic lung damage, idiopathic pulmonary fibrosis, macular degeneration, MGUS, myeloma, obesity, obesity-related neuropsychiatric dysfunction, organ transplantation complication, osteoarthritis, osteoporosis, Parkinson’s disease, pre-eclampsia, primary biliary cirrhosis, progerias, prostatic hypertrophy, psoriasis, pulmonary disease, radiation complication, renal dysfunction, urinary incontinence, vascular calcification, or vascular hyporeactivity.

69. The method of claim 66, wherein the disease is cancer.

70. A method of selectively killing one or more cancer cells in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of the compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 56-59.

71. The method of any one of claims 62-65, 69, and 70, wherein the cancer is a Bcl-2-mediated cancer.

72. The method of any one of claims 62-65, 69, and 70, wherein the cancer is a Bcl-xL-mediated cancer.

73. The method of any one of claims 62-65, 69, and 70, wherein the cancer is a hematological malignancy.

74. The method of claim 73, wherein the cancer is leukemia.

75. The method of claim 73, wherein the cancer is acute myeloid leukemia, chronic lymphocytic leukemia, or acute lymphoblastic leukemia.U1197.70246WO00 219 / 221 #14171685v176. The method of claim 73, wherein the cancer is lymphoma.

77. The method of claim 73, wherein the cancer is T-cell lymphoma.

78. The method of any one of claims 62-65, 69, and 70, wherein the cancer is a solid tumor.

79. The method of any one of claims 65-78, wherein the subject is a mammal.

80. The method of claim 79, wherein the subject is a human.

81. A kit comprising: the compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 56-59; and instructions for its use.U1197.70246WO00 220 / 221 #14171685v1

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