BCL-2 degraders

Abstract

The present disclosure provides compounds of any one of Formulae (I"), (I), (I"'), and (I'), which may be selective Bcl-2 inhibitors. The compounds may target and degrade 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-2 DEGRADERSRELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 727560, filed December 3, 2024, which is incorporated herein by reference in its entirety.GOVERNMENT SUPPORT

[0002] This invention was made with government support under Grant No. R01 CA241191, 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 e.g., Bcl-2, Bcl-xL, 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). Among the anti-apoptotic Bcl-2 family of proteins, only Bcl-2 has been clinically validated as an anti-cancer target. Currently, there are at least seven Bcl-2 selective inhibitors at various stages of clinical trials.

[0004] Venetoclax is the only Bcl-2 selective inhibitor approved by the FDA, having been approved in 2016 for the treatment of chronic lymphocytic leukemia (CLL) with 17-p deletion. However, many CLL patients develop resistance to venetoclax (Roberts et al., N Engl J Med 374: 311-322, 2016), some driven by Bcl-2 mutations which disrupt the binding of venetoclax (Blombery et al., Br J Haematol 186: e!63-e225, 2019; Blombery et al., Cancer Discov 9: 342-353, 2019; Tausch et al., Haematologica 104: e434-e437, 2019). In addition, upregulation of Bcl-xL by microenvironmental survival signals has been identified as a 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, 2016). 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., Br J Haematol 170: 669-678,1 / 411U1197.70255WO002015), BM-1197 (Bai et al., PLoS ONE 9:e99404, 2014), or A-l 155463 (Tao et al., ACS Med Chem Lett 5: 1088-1093, 2014), due to their inhibition of Bcl-xL.SUMMARY OF THE INVENTION

[0005] The development of Bcl-2 selective degraders would allow for the antitumor versatility, efficacy, and promise in degrading Bcl-2 mutants of previous Bcl-2 / Bcl-xL dual degraders to be retained, without the corresponding high platelet toxicity in vivo associated with Bcl-xL targeting. Compounds of the present disclosure are highly potent Bcl-2 degraders that have moderate, minimal, or no impact on Bcl-xL. The most potent compounds are over 100-fold more potent than venetoclax in killing Bcl-2 dependent RS4; 11 cells, and may have similar effects on Bcl-2 mutant cells.

[0006] In one aspect, provided herein is a compound of Formula (I"):or a pharmaceuticallyacceptable salt thereof, wherein R1, R2, R4, Lla, Llb, L2, L3, L4, Y, and Z are as defined herein.

[0007] In one aspect, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, Lla, Llb, L2, L3, L4, Y, and Z are as defined herein.

[0008] In another aspect, provided herein is a compound of Formula (I'"):or a pharmaceuticallyacceptable salt thereof, wherein R1, R2, R4, Lia, Llb, L2, L3, L4, Y, and Z are as defined herein.2 / 411U1197.70255WO00

[0009] In another aspect, provided herein is a compound of Formula (I'):or a pharmaceuticallyacceptable salt thereof, wherein R1, R2, R4, Lia, Llb, L2, L \ L4, Y, and Z are as defined herein.

[0010] Compared to known Bcl-xL and / or Bcl-2 inhibitors, 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-2, increased selectivity for Bcl-2 compared to Bcl-xL, 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).

[0011] The compounds may promote the degradation of the anti-apoptotic Bcl-2 family of proteins. The compounds may be selective for promoting the degradation of Bcl-2 compared to Bcl-xL. The compounds may connect a Bcl-2 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.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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 3 / 411U1197.70255WO00sample 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 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.

[0017] 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.

[0018] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 shows Bel -2 Degradation (DCso) in Hela Cells as described in Example 30.DEFINITIONS

[0020] 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 moi eties 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.

[0021] 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 4 / 411U1197.70255WO00high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers are prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0022] 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.

[0023] 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 al3C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0024] 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.

[0025] 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 tzo ends of the range unless otherwise provided. For example “Ci-6 alkyl” encompasses. Ci,G. C4, C5, C, C1-6, C1-5, Ci^, C1-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C4-6, C4-5, and C5-6 alkyl.

[0026] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0027] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“CI-JO alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Cj- 9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci 4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci -3 alkyl”). In 5 / 411U1197.70255WO00some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of Ct-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., zz-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, ec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, / ert-amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include zz-heptyl (C7), zz-octyl (Cs), / / -dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted Ci-12 alkyl (such as unsubstituted Ct-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted / / -butyl (zz-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted ec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z-Bu)). In certain embodiments, the alkyl group is a substituted Ci-12 alkyl (such as substituted Ci-6 alkyl, e.g., -CH2F, -CHF2, CF3, CH2CH2F, --CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0028] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.“Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“Ci-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms “Ci-10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1-9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“Ci-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“Ci-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1-5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“Ci^ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“Ci -3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCh, -CF2CI, and the like.6 / 411U1197.70255WO00

[0029] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi -20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-n alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-n 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 (“heteroCi-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 (“heteroCi-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-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 (“heteroCi-7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“heteroCi-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“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 heteroCi-12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi 12 alkyl.

[0030] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“Cj -12 alkenyl”). In 7 / 411U1197.70255WO00some embodiments, an alkenyl group has 1 to 11 carbon atoms (“Ci-n alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“Cj io alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“Cj -9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“Ci-s alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“Ci-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1-6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“Ci-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“CM alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“Ci alkenyl”). In some embodiments, the one or more carbon-carbon double bonds is internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C1-4 alkenyl groups include methylidenyl (Cj), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1 6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted Ct-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=CHCH3 or) isjnthe (E)- or (Z)-configuration.

[0031] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-n 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 (“heteroCi-io 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 8 / 411U1197.70255WO00(“heteroCi-9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-8 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkenyl”). In some embodiments, a heteroalkenyl group has Ito 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi 4 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroCi-20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroCi-20 alkenyl.

[0032] 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 (“Ci-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C j -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 (“Ci-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 (“Cj alkynyl”). In some embodiments, the one or more carbon-carbon triple bonds is internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C1-4 alkynyl groups include, without limitation, methylidynyl (Ci), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (CT), and the like. Examples of Ci-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (Cs), hexynyl (CT), and the like. Additional examples of alkynyl 9 / 411U1197.70255WO00include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently un substituted (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.

[0033] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCt 9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-s alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkynyl”). 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 (“heteroCi-5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroCi-4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi 6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “un substituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroCj-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroCi-20 alkynyl.

[0034] 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 10 / 411U1197.70255WO00heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Cs), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like.Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H- indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplar}' C3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and is saturated or contains one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.11 / 411U1197.70255WO00

[0035] In some embodiments, “carbocyciyl” is a monocyclic, saturated carbocyciyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3 -14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyciyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0036] 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 carbocyciyl groups wherein the point of attachment is either on the carbocyciyl 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 “un substituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3- 12 / 411U1197.70255WO0014 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.

[0037] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5—10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5 -6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0038] 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, oxadi azolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary’ 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary’ 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroi soquinolinyl, decahydroquinolinyl, decahydroi soquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8-naphthyridinyl,13 / 411U1197.70255WO00octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1 H- benzo [e][ 1,4] di azepinyl, l,4,5,7-tetrahydropyrano[3,4-b|pyrrolyl, 5,6-dihydro-4H-furo[3,2-bjpyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo|2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2- b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0039] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Cs-i4 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“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 G5-14 aryl. In certain embodiments, the aryl group is a substituted Cg-14 aryl.

[0040] “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.

[0041] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In 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)14 / 411U1197.70255WO00ring 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.

[0042] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0043] 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 15 / 411U1197.70255WO00groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotri azolyl, 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.

[0044] “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.

[0045] The term “unsaturated bond” refers to a double or triple bond.

[0046] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0047] 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.

[0048] 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.

[0049] 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 “un substituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.16 / 411U1197.70255WO00Unless 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.

[0050] 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, -0Si(Raa>3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2. -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc) 2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X", -P(ORCC)3+X", -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X“, -OP(RCC)4, -OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-20 alkenyl, Cu 20 alkynyl, heteroCi-20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-1 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbh)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC;wherein:each instance of Raais, independently, selected from C1-20 alkyl, Ci-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, 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,17 / 411U1197.70255WO00wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, ~CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC. -C(=S)SRCC, -P(=O)(Raa)2, ~P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, Ci-20 alkyl, Ci-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, heteroCi-2oalkyl, heteroCi-2oalkenyl, heteroCi -2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Co-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rccis, independently, selected from hydrogen, C1-20 alkyl, C1-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCj -20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X“, -N(ORfte)Rff, -SH, -SRee, -SSReft, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rfl)2, -NRflC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, Ci-10 alkyl, C1-10 perhaloalkyl, Ci-10 alkenyl, C1-10 alkynyl, heteroCi-ioalkyl, heteroCi-ioalkenyl, heteroCi-joalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C&io aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =0 or =S;each instance of Reeis, independently, selected from Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCj-10 alkyl, heteroCi-w alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, Cfi-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein 18 / 411U1197.70255WO00each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R88groups;each instance of Rffis, independently, selected from hydrogen, Ci-io alkyl, CI JO perhaloalkyl, Ci-io alkenyl, Ci-io alkynyl, heteroCi-io alkyl, heteroCi-io alkenyl, heteroCi-io alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R88groups;each instance of R88is, independently, halogen, -CN, -NO2, -N3, -SOIL -SO3H, -OH, -OCi 6 alkyl, -ON(Ci-6 alkyl)2, -N(Ci-6 alkyl)2, -N(Ci-6 alkyl 3+X~, -NH(CI-6 alkyl)2aX”, -NH2(Ci-6 alkyl) ^X”, -NH3+X“, -N(OCi-6alkyl)(Ci-6alkyl), -N(OH)(Ci-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6 alkyl), -C(=O)(Ci-6 alkyl), -CO2H, -CO2(Ci-6 alkyl), -OC(=O)(Cj 6 alkyl), -OCO2(Ci-6 alkyl), -C(=O)NH2, -C(=O)N(Ci-6alkyl)2, -OC(=O)NH(Cj- 6 alkyl), -NHC(=O)( Ci-6alkyl), -N(CL-6 alkyl)C(=O)( Ci-6alkyl), -NHCO2(Ci^ alkyl), -NHC(=O)N(CI-6 alkyl)2, -NHC(=O)NH(Ci-f alkyl), -NHC(=0)NH2, -C(=NH)O(CJ_6alkyl), -OC(=NH)(CI 6 alkyl), -OC(=NH)OCi6alkyl, -C(=NH)N(Ci^ alkyl)2, -C(=NH)NH(Ci-6 alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6alkyl)2, -OC(NH)NH(Ci-6 alkyl), -OC(NH)NH2, -NHC(NH)N(CJ 6 alkyl)2, -NHC(=NH)NH2, -NHSO2(Ci..6alkyl), -SO2N(Cj-6 alkyl)2, -SO2NH(CI^ alkyl), -SO2NH2, -SO2C1-6 alkyl, -SChOCi^ alkyl, -OSO2Ci_6alkyl, -SOCi-6alkyl, -Si(Ci-6 alkyl)s, ~OSi(Ci-6 alkyl)? -C(=S)N(Ci-6 alkylh, C(=S)NH(Ci-e alkyl), C(=S)NH2, -C(=O)S(CI-6 alkyl), -C(=S)SCi-6 alkyl, -SC(=S)SCm> alkyl. -P(=O)(OCi^> alkyl)2, -P(=O)(Ci-6 alkyl)’, -OP(=O)(Ci-6 alkyl)2, -OP(=O)(OCi-6 alkyl)2, Ci-10 alkyl, Cj-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-io alkenyl, heteroCi-io alkynyl, C3-10 carbocyclyl, Ce- aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rsgsubstituents are joined to form =0 or =S; andeach X” is a counterion.

[0051] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, ~C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa. -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted 19 / 411U1197.70255WO00(e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -OR88, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted Ci-10 alkyl, -OR88, -SR88, -N(Rbb)2, ~CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Cj-io alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0052] 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. “SO2R88, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOR88, -C(=S N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, “P(=O)(ORCC)2, “P(=O)(Raa)2, -P(=O)(N(RCC)2)2, Ci-20 alkyl, Cj-2operhaloalkyl, Cj_ 20 alkenyl, Ci-20 alkynyl, hetero Ci-20 alkyl, hetero Ci-20 alkenyl, hetero Ci-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C -14 aryl, 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 R88, Rbb, Rccand Rddare as defined above.

[0053] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, ~CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Cno alkyl, -C(=O)Raa, ~CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group,20 / 411U1197.70255WO00wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Cj-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a nitrogen protecting group.

[0054] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, CI-IO alkyl (e.g., aralkyl, heteroaralkyl), Ci-2o alkenyl, Cj-2o alkynyl, hetero Ci~2o alkyl, hetero Cj-2o alkenyl, hetero Ci-2o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Cg-i4 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, bb RCCanddare asjefinej 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.

[0055] 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- benzoyl phenyl alanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (p- 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.

[0056] 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, is21 / 411U1197.70255WO00independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl- [ 9-( 10, 10-dioxo- 10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l -methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1, 1 -dimeth yl-2, 2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l -methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido)ethyl carbamate, / -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-methoxy benzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2, 4- dichloro benzyl carbamate, 4-methylsulfmylbenzyl 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), l,l-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, / -amyl carbamate, 5-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o- N -dimethylcarboxamido)benzyl carbamate, 1, 1 -dimethyl-3-(A, A-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p ’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, l-methyl-l-(p-phenylazophenyl)ethyl carbamate, 1-methyl-l-phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-r-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.22 / 411U1197.70255WO00

[0057] 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 ofp-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfon amide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2.3.5.6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2.4.6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P~ trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0058] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A’-p-toluenesulfonylaminoacyl derivatives, A' ’-phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, A-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, AT-phthalimide, A ithiasuccinimide (Dts), N-2. - dipheny Imai eimide, A-2,5-dimethylpyrrole, A- 1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3- dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, Ar-methylamine, N-allylamine, A-[2-(trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, A-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, A-di(4-methoxyphenyl)methyl amine, A'-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenylfluorenylamine (PhF), A 2,7- dichloro-9-fluorenylmethyleneamine, A-ferrocenylmethylamino (Fem), A-2-picolylamino N’~ oxide, A- 1,1 -dimethylthiomethyleneamine, A-benzylideneamine, A-p-methoxybenzylideneamine, A-diphenylmethyleneamine, A-[(2-pyridyl)mesityl|methyleneamine, A-(A’, A’-dimethylaminomethylene)amine, A-p-nitrobenzylideneamine, A- salicylideneamine, N- 5-chlorosalicylideneamine, A-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, A-cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, A-borane derivatives, N- diphenylborinic acid derivatives, A-[phenyl(pentaacylchromium- or tungsten) acyl] amine, A-copper chelate, A- zinc chelate, A-nitroamine, A-nitrosoamine, amine A-oxide, diphenylphosphinamide (Dpp), dimethylthiopho sphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate,23 / 411U1197.70255WO00benzenesulfenamide, <? -nitrobenzene sulfenamide (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 areAjV’-isopropylidenediamine.

[0059] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0060] 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 Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom: and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ct-6 alkyl or an oxygen protecting group.

[0061] 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(Rbh)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)3iX”, -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.

[0062] 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 24 / 411U1197.70255WO00(SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyrany I S, S-dioxide, 1 - | (2-chloro-4-methyl)phenyl] -4-methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2, 3, 3a, 4, 5, 6, 7,7 a- 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, / -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 / V-oxido, diphenylmethyl, p,p ’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)pheny Imethyl, 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) Jtrityl Ether (IDTr-OR), 4,4'-Dimethoxy-3'"-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), l,l-bis(4-methoxyphenyl)- l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl 5,5-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropyl silyl (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, phenoxy acetate, 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, / -butyl carbonate (BOC or Boc),p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3, 4- dimethoxy benzyl carbonate, o -nitrobenzyl carbonate, p- nitrobenzyl carbonate, 5-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6- 25 / 411U1197.70255WO00dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-( 1, 1,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis( l,l-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl M ) ”,r- tetramethylphosphorodiamidate, alkyl ALphenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzyl sulfonate, and tosylate (Ts).

[0063] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, / -Bu. Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0064] 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 Ci-io alkyl, -C(=O)Raa, -CO2Raa, ~C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, ~C(=O)Raa, -CC>2Raa, -~C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Cj-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Cis alkyl or a sulfur protecting group. In certain embodiments, at least one sulfur atom substituent is oxo.

[0065] 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.

[0066] 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 26 / 411U1197.70255WO00embodiments, 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.

[0067] 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., R, CE, Br, E), NCR, CICR, OH; H2PO4, HCCR, HSO4, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, -toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2- sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BFR, PF4", PFR, AsFR, SbFR, B[3,5-(CF3)2C6H3]4]", BfCeFsCr, BPh4, A1 OC(CF3)3R, and carborane anions (e.g., CB11H12 or (HCBnMesBre) ). Exemplary counterions which may be multivalent include COs2-, HPC2-, PO43-, B4O?2-, SCU2-, 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.

[0068] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, —Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0069] 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.

[0070] 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)?, and -SC(=O)Raa, wherein Raaand Rccare as defined herein.27 / 411U1197.70255WO00

[0071] The term “amino” refers to the group -NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a tri substituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0072] 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, -NI ICO2Raa, -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.

[0073] 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, -NRhhC(=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.

[0074] 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.

[0075] The term “sulfonyl” refers to a group selected from -SO2N(Rbb)2, -SO2Raa, and - SChOR, wherein Raaand Rbbare as defined herein.

[0076] The term “sulfinyl” refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0077] 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, -C(=O)N(Rbb)2, -C(=S)Raa, -C(=S)N(Rbb)2, and -C(=S)S(Raa), -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)SRaa, and -C(=NRbb)N(Rbb)2, 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.

[0078] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (-C(=O)Raa), carboxylic acids ( -CO2H), aldehydes (-CHO), esters (-CO2Raa,-C(=O)SRaa, -C(=S)SRaa), amides (-C(=O)N(Rbb)2, -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.

[0079] The term “silyl” refers to the group -Si(Raa)3, wherein Raais as defined herein.28 / 411U1197.70255WO00

[0080] 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.

[0081] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0082] 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, -toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI-4 alky 1)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.

[0083] 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 29 / 411U1197.70255WO00addition 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+(C j -4 alkyl)4” salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0084] 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”.

[0085] 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 (z.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0086] The terms “composition” and “formulation” are used interchangeably.

[0087] A “subject” to which administration is contemplated refers to a human ( / .<?., 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 30 / 411U1197.70255WO00embodiments, 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0092] 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 / or31 / 411U1197.70255WO00in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0093] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0094] 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).

[0095] 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.

[0096] 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 32 / 411U1197.70255WO00benefit 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.

[0097] The term “inhibit” or “inhibition”, for example, in the context of, e.g., 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-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-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 than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of activity and / or production.

[0098] 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.

[0099] The term “Bcl-2” refers to a protein of the Bcl-2 family and, when in humans, is encoded by the BCL2 gene.

[0100] 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.

[0101] 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.33 / 411U1197.70255WO00

[0102] 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 (<?.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0103] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include 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.

[0104] 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 34 / 411U1197.70255WO00body 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-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T- lym pho blastic 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 35 / 411U1197.70255WO00of 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).

[0105] 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 be heritable 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, adrenoleukodystrophy, albinism, ablepharon-macrostomia syndrome, alagille syndrome, alkaptonuria,36 / 411U1197.70255WO00alpha- 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, brachy dactyl), 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-Najj r 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 pigmentosum, and Zellweger syndrome.

[0106] 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 37 / 411U1197.70255WO00can be either an acute or chronic inflammatory 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.

[0107] 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 38 / 411U1197.70255WO00membrane 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, microscopic poly angiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0108] 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.

[0109] 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, neuroophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and 39 / 411U1197.70255WO00disorders 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; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt- Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine- Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden- Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid 40 / 411U1197.70255WO00storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau- Kleffner syndrome; lateral medullary’ (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II);Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge- 41 / 411U1197.70255WO00Weber 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 (VEIL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0110] 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 types of 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.

[0111] 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 42 / 411U1197.70255WO00(e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

[0112] 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”.

[0113] 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.

[0114] 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.

[0115] 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, drug 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.43 / 411U1197.70255WO00

[0116] 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.

[0117] 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.

[0118] 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 dysreg ulation. 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.

[0119] 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.

[0120] 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 ie.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

[0121] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vane The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.44 / 411U1197.70255WO00Compounds

[0122] In one aspect, provided herein is a compound of Formula (I"):or a pharmaceutically acceptable salt thereof, wherein:R1is -(Ci-3 alkylene) -Rla, wherein the alkylene is unsubstituted, and Rlais optionally substituted 4-10 membered heterocyclyl, -OR°, -N(N)2, or optionally substituted C4-10 carbocyclyl;R2is -NO2, -SO2CF3, or -CN;attached to Z at the ring N atom of Q1;Q2is CH or N;Q3is C, CH, or N, as valency permits;X1is -CH2- or absent;X2is absent or Cl k. wherein X2is attached to the aryl ring of (z-5), (z-6), or (z-7); p i s 0 or 1;R3is aryl, carbocyclyl, heteroaryl,, or alkenyl, wherein the carbocyclyl,45 / 411U1197.70255WO00aryl, heteroaryl, or alkenyl is substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits;each instance of R3ais independently optionally substituted alkyl, optionally substituted cycloalkyl, -OR°, halogen, -CN, or -NO2;R3bis optionally substituted alkyl, hydrogen, or halogen;R4is optionally substituted heteroaryl or optionally substituted heterocyclyl;Llais optionally substituted heterocyclylene;Libis absent or optionally substituted heterocyclylene;L2is absent or optionally substituted C1-12 alkylene or optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -O-, -NRN~, =N~, -N=, -S-, — S(=O)—, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is absent or optionally substituted Ci-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 Cj-12 alkylene, optionally substituted C1-12 alkenylene, or optionally substituted C2-12 alkynylene are independently replaced with -O-, ~NRN~, =N~, -N=, -S-, -S(=O)~, -S(=O)2~, - C(=O)~, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally- substituted arylene, or optionally substituted heteroarylene;L4is -O-, absent, or -NH-;each instance of R° is independently hydrogen or optionally substituted alkyl;each instance of RNis independently hydrogen or optionally substituted alkyl, or two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl; andY is a moiety that is capable of binding to an E3 ubiquitin ligase.

[0123] In one aspect, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is -(Ci-3 alkylene) -Rla, wherein the alkylene is unsubstituted, and Rlais optionally substituted 4-10 membered heterocyclyl, -OR°, -N(N)2, or optionally substituted C4-1046 / 411U1197.70255WO00carbocyclyl;R2is -NO2, -SO2CF3, or -CN;attached to Z at the ring N atom of Q1;Q2is CH orN;Q3is C, CH, or N, as valency permits;X1is -CH2 - or absent;X2is absent or -CH2-, wherein X2is attached to the aryl ring of (z-5), (z-6), or (z-7); p is 0 or 1;R3is aryl, carbocyclyl, heteroaryl, orR3b, wherein the carbocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits;each instance of R3ais independently optionally substituted alkyl, optionally substituted cycloalkyl, -OR°, halogen, -CN, or -NO2;R3bis optionally substituted alkyl, hydrogen, or halogen;R4is optionally substituted heteroaryl or optionally substituted heterocyclyl;Llais optionally substituted heterocyclylene;Llbis absent or optionally substituted heterocyclylene;L2is absent or optionally substituted Ci-12 alkylene or optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -O-, -NRN-=N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;47 / 411U1197.70255WO00L3is absent or optionally substituted Ci-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-, ~NRN~, =N~, -N=, -S-, -S(=O)~, -S(=O)2~, - C(=O)~, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L4is O -, absent, or -NHeach instance of R° is independently hydrogen or optionally substituted alkyl;each instance of RNis independently hydrogen or optionally substituted alkyl, or two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl; andY is a moiety that is capable of binding to an E3 ubiquitin ligase.

[0124] In another aspect, provided herein is a compound of Formula (I'");or a pharmaceutically acceptable salt thereof, wherein:R1is — (C1-3 alkylene) -Rla, wherein the alkylene is unsubstituted, and Rlais optionally substituted 4-10 membered heterocyclyl, -OR°, -N(RN)2, or optionally substituted C4-10 carbocyclyl;R2is -NO2, -SO2CF3, or -CN;48 / 411U1197.70255WO00Q1is CH, CCH3, or N; or Q1is wherein ml is 1 or 2, m2 is 0 or 1, and L2is attached to Z at the ring N atom of Q1;Q2is CH orN;Q3is C, CH, or N, as valency permits;X1is -CH2 - or absent;X2is absent or -CH2-, wherein X2is attached to the aryl ring of (z-5), (z-6), or (z-7); p is 0 or 1;R3is aryl, carbocyclyl, heteroaryl,R3b, or alkenyl, wherein the carbocyclyl, aryl, heteroaryl, or alkenyl is substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits;each instance of R3ais independently optionally substituted alkyl, optionally substituted cycloalkyl, -OR°, halogen, -CN, or -NCh;R3bis optionally substituted alkyl, hydrogen, or halogen;R4is optionally substituted heteroaryl or optionally substituted heterocyclyl;Llais optionally substituted heterocyclylene;Llbis absent or optionally substituted heterocyclylene;L2is absent or optionally substituted C1-12 alkylene or optionally substituted heterocyclylene, or a combination thereof, optionally w'herein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -O-, -NRN- =N-, -N=, -S-, — S(=O)—, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is 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 NRN, =N -N=, -S -, -S(=O) -, -S(=O)2 ---C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L4is -O-, absent, or -NH-;each instance of R° is independently hydrogen or optionally substituted alkyl;49 / 411U1197.70255WO00each instance of RNis independently hydrogen or optionally substituted alkyl, or two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl; andY is of formula:50 / 411U1197.70255WO00.0,051 / 411U1197.70255WO00U1197.70255WO00(y-44q), (y-44r),53 / 411U1197.70255WO00wherein:each instance of Q4is independently CH or N;each instance of R5is independently H, F, Cl, Br, -CN, -OMe, Me, -CH2F, -CHF2, or - CF3; andeach instance of v is independently 1 or 2.In another aspect, the present disclosure provides a compound is of Formula (I'):54 / 411U1197.70255WO00or a pharmaceutically acceptable salt thereof, wherein:R1is ~(Ci-3 alkylene)-Rla, wherein the alkylene is unsubstituted, and Rlais optionally substituted 4-10 membered heterocyclyl, -OR°, -N(RN)2, or optionally substituted C4-10 carbocyclyl;R2is -NO2, -SO2CF3, or -CN;attached to Z at the ring N atom of Q1;Q2is CH orN;Q3is C, CH, or N, as valency permits;X1is -CH2 - or absent;X2is absent or -CH2-, wherein X2is attached to the aryl ring of (z-5), (z-6), or (z-7); p is 0 or 1;R3is aryl, carbocyclyl, heteroaryl, or^^^^R36, wherein the carbocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits;each instance of R3ais independently optionally substituted alkyl, optionally substituted cycloalkyl, OR°, halogen, -CN, or -NO2;R3bis optionally substituted alkyl, hydrogen, or halogen;R4is optionally substituted heteroaryl or optionally substituted heterocyclyl;Llais optionally substituted heterocyclylene;55 / 411U1197.70255WO00Llbis absent or optionally substituted heterocyclylene;L2is absent or optionally substituted C1-12 alkylene or optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -O-, -NRN- =N- -N=, -S-, — S(=O)—, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is 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-, -NRN~, =N~, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L4is O -, absent, or -NH-;each instance of R° is independently hydrogen or optionally substituted alkyl;each instance of RNis independently hydrogen or optionally substituted alkyl, or two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl; andY is of formula:56 / 411U1197.70255WO00U1197.70255WO00U1197.70255WO00wherein:each instance of Q4is independently CH or N; andeach instance of v is independently 1 or 2.Moiety Y

[0125] As generally described herein for compounds of Formula (I), Y is a moiety that is capable of binding to an E3 ubiquitin ligase.In certain embodiments, Y is of formula:59 / 411U1197.70255WO00U1197.70255WO00U1197.70255WO00U1197.70255WO00wherein:each instance of Q4is independently CH or N;each instance of R5is independently H, F, CI, Br, -CN, -OMe, Me, -CH2F, -CHF₂, or - CF3; andeach instance of v is independently 1 or 2.63 / 411U1197.70255WO00

[0126] In some embodiments of Formula (I), Y is of formula:64 / 411U1197.70255WO00(y-34), H (y-35), H (y-36),65 / 411U1197.70255WO00U1197.70255WO00U1197.70255WO00wherein:each instance of Q4is independently CH or N;each instance of v is independently 1 or 2; andeach instance of R is independently -CH₃, -CH2CH3, -CH(CH₃)₂, -CH(CH3)CH2CH3, - C(CH3)3, -CHF2, cyclopropyl, or cyclobutyl.

[0127] In some embodiments of Formula (I), Y is of formula (y-1), (y-2), (y-3), (y-4), (y-5), (y-6), (y-7), (y-8), (y-9), (y-10), (y-11). (y-12), (y-13), (y-14), (y-15). (y-16), (y-17), (y-18), (y-19), (y-20), (y-21), (y-22), (y-23), (y-24), (y-25), (y-26), (y-27), (y-28), (y-29), (y-30), (y-31), (y-32), (y-33), (y-34), (y-35). (y-36), (y-37), (y-38), (y-39). (y-40), (y-41), (y-42), (y-43). (y-44), (y-45), (y-46), (y-47), (y-48), (y-49), (y-50), (y-51), (y-52), (y-53), (y-54), (y-55), (y-56), (y-57), (y-58), (y-59), (y-60), (y-61), (y-62), (y-63), or (y-64).

[0128] In some embodiments of Formula (I), Y is of formula (y-1). In some embodiments of Formula (I), Y is of formula (y-2). In some embodiments of Formula (I), Y is of formula (y-3). In some embodiments of Formula (I), Y is of formula (y-4). In some embodiments of Formula (I), Y is of formula (y-5). In some embodiments of Formula (I), Y is of formula (y-6). In some embodiments of Formula (I), Y is of formula (y-7). In some embodiments of Formula (I), Y is of formula (y-8). In some embodiments of Formula (I), Y is of formula (y-9). In some embodiments of Formula (I), Y is of formula (y-10). In some embodiments of Formula (I), Y is of formula (y-11). In some embodiments of Formula (I), Y is of formula (y-12). 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-16). 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-20). In some embodiments of Formula (I), Y is of formula (y-21). In some embodiments of Formula (I), Y is of formula (y-22). In some embodiments of Formula (I), Y is of formula (y-23). In some embodiments of Formula (I), Y is of formula (y-24). 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-27). In some embodiments of Formula (I), Y is of formula (y-28). In some embodiments of Formula (I), Y is of formula (y-29). In some embodiments of Formula (I), Y is of formula (y-30). In some embodiments of Formula (I), Y is of formula (y-31). 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-34). In some embodiments of Formula (I), Y is of formula (y-35). In some embodiments of Formula (I), Y is of formula (y-36). In some embodiments of Formula (I), Y is 68 / 411U1197.70255WO00of formula (y-37). In some embodiments of Formula (I), Y is of formula (y-38). In some embodiments of Formula (I), Y is of formula (y-39). In some embodiments of Formula (I), Y is of formula (y-40). In some embodiments of Formula (I), Y is of formula (y-41). In some embodiments of Formula (I), Y is of formula (y-42). In some embodiments of Formula (I), Y is of formula (y-43). In some embodiments of Formula (I), Y is of formula (y-44). In some embodiments of Formula (I), Y is of formula (y-45). In some embodiments of Formula (I), Y is of formula (y-46). In some embodiments of Formula (I), Y is of formula (y-47). In some embodiments of Formula (I), Y is of formula (y-48). In some embodiments of Formula (I), Y is of formula (y-49). In some embodiments of Formula (I), Y is of formula (y-50). In some embodiments of Formula (I), Y is of formula (y-51). In some embodiments of Formula (I), Y is of formula (y-52). In some embodiments of Formula (I), Y is of formula (y-53). In some embodiments of Formula (I), Y is of formula (y-54). In some embodiments of Formula (I), Y is of formula (y-55). In some embodiments of Formula (I), Y is of formula (y-56). In some embodiments of Formula (I), Y is of formula (y-57). In some embodiments of Formula (I), Y is of formula (y-58). In some embodiments of Formula (I), Y is of formula (y-59). In some embodiments of Formula (I), Y is of formula (y-60). In some embodiments of Formula (I), Y is of formula (y-61). In some embodiments of Formula (I), Y is of formula (y-62). In some embodiments of Formula (I), Y is of formula (y-63). In some embodiments of Formula (I), Y is of formula (y-64).

[0129] In some embodiments of Formula (I), Y is of formula (y-30), (y-58), (y-59), (y-62), or (y-63), wherein Q4is CH. In some embodiments of Formula (I), Y is of formula (y-30), (y-58), (y-59), (y-62), or (y-63), wherein Q4is N.

[0130] In some embodiments of Formula (I), Y is of formula (y-31 ), (y-32), (y-33), (y-34), (y-35), (y-36), (y-53), (y-54), or (y-55), wherein at least one instance of Q4is CH. In some embodiments of Formula (I), Y is of formula (y-31), (y-32), (y-33), (y-34), (y-35), (y-36), (y-53), (y-54), or (y-55), wherein at least one instance of Q4is N.

[0131] In some embodiments of Formula (I), Y is of formula (y-56) or (y-57), wherein v is 1. In some embodiments of Formula (I), Y is of formula (y-56) or (y-57), wherein v is 2.

[0132] In some embodiments of Formula (I), Y of formula (y-31) is of formula:HN / I" N(y-31a). In some embodiments of Formula (I), Y of formula (y-56) is of69 / 411U1197.70255WO00formula:(y-56a). In some embodiments of Formula (I), Y of formula F(y-57) is of formula:(y-57a). In some embodiments of Formula (I),Y of formula (y-58) is of formula:(y-58a). In some embodiments ofFormula (I), Y of formula (y-59) is of formula:(y-59a).

[0133] In some embodiments of Formula (I), Y is of formula (y-65), (y-66), (y-67), (y-68), (y-69), (y-70), (y-71), (y-72), (y-73), (y-74), (y-75), (y-76), (y-77), (y-78), (y-79), (y-80), (y-81), (y-82), (y-83), or (y-84).

[0134] In some embodiments of Formula (I), Y is of formula (y-65). In some embodiments of Formula (I), Y is of formula (y-66). In some embodiments of Formula (I), Y is of formula (y-67). In some embodiments of Formula (I), Y is of formula (y-68). In some embodiments of Formula (I), Y is of formula (y-69). In some embodiments of Formula (I), Y is of formula (y-70). In some embodiments of Formula (I), Y is of formula (y-71). In some embodiments of Formula (I), Y is of formula (y-72). In some embodiments of Formula (I), Y is of formula (y-73). In some embodiments of Formula (I), Y is of formula (y-74). In some embodiments of Formula (I), Y is of formula (y-75). In some embodiments of Formula (I), Y is of formula (y-76). In some embodiments of Formula (I), Y is of formula (y-77). In some embodiments of Formula (I), Y is of formula (y-78). In some embodiments of Formula (I), Y is of formula (y-79). In some embodiments of Formula (I), Y is of formula (y-80). In some embodiments of Formula (I), Y is of formula (y-81). In some embodiments of Formula (I), Y is of formula (y-82). In some embodiments of Formula (I), Y is of formula (y-83). In some embodiments of Formula (I), Y is of formula (y-84).

[0135] In some embodiments of Formula (I), Y is of formula (y-65), (y-66), (y-67), (y-68), (y-69), (y-70). (y-71), (y-72), (y-73), (y-74). (y-75), (y-76), (y-77), (y-78), or (y-79), wherein RYis -C(CH3)3. In some embodiments of Formula (I), Y is of formula (y-65), wherein R is -CfCFFh.

[0136] In some embodiments of Formula (I), Y is of formula (y-65), (y-66), (y-67), (y-68), (y-70 / 411U1197.70255WO0069), (y-70), (y-71), (y-72), (y-73), (y-74), (y-75), (y-76), (y-77), (y-78), or (y-79), wherein the o omoietyrYis of formularY. In some embodiments of Formula (I), Y is of formula (y-65), (y-66), (y-67), (y-68), (y-69), (y-70), (y-71), (y-72), (y-73), (y-74), (y-75), (y-76), (y-77), (y-78), or (y-79), wherein the moietyrYis of formulaI. In some Oembodiments of Formula (I), Y is of formula (y-65), wherein the moietyrYis offormulaI

[0137] In some embodiments of Formula (I), Y is of formula (y-6), (y-7), (y-10), (y-20), (y-31), (y-41), (y-43), (y-56), (y-58), (y-59), (y-60), or (y-65). In some embodiments of Formula (I), Y is of formula (y-6), (y-7), (y-10), (y-20), (y-31a), (y-41), (y-43), (y-56a), (y-58a), (y-59a), (y-60), or (y-65). In some embodiments of Formula (I), Y is of formula (y-6), (y-7), (y-10), (y-20), (y- 31), (y-41), (y-43), (y-56), (y-58), (y-59), or (y-60). In some embodiments of Formula (I), Y is of formula (y-6), (y-7), (y-10), (y-20), (y-31a), (y-41), (y-43), (y-56a), (y-58a), (y-59a), or (y-60). In some embodiments of Formula (I), Y is of formula (y-6), (y-10), or (y-43).

[0138] As generally described herein for compounds of Formula (I"), Y is of formula:71 / 411U1197.70255WO00U1197.70255WO00U1197.70255WO00HN—Z HN--Zo (y-63), or o (y-64), wherein:each instance of Q4is independently CH or N; andeach instance of v is independently 1 or 2.

[0139] In some embodiments of Formula (I'), Y is of formula (y-1). In some embodiments of Formula (I'), Y is of formula (y-2). In some embodiments of Formula (I'), Y is of formula (y-3). In some embodiments of Formula (I'), Y is of formula (y-4). In some embodiments of Formula (T), Y is of formula (y-5). In some embodiments of Formula (I'), Y is of formula (y-6). In some embodiments of Formula (I'), Y is of formula (y-7). In some embodiments of Formula (I'), Y is of formula (y-8). In some embodiments of Formula (I'), Y is of formula (y-9). In some embodiments of Formula (I'), Y is of formula (y-10). In some embodiments of Formula (I'), Y is of formula (y- 11). In some embodiments of Formula (I'), Y is of formula (y-12). 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-16). 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 (Th Y is of formula (y-19). In some embodiments of Formula (I'), Y is of formula (y-20). In some embodiments of Formula (I'), Y is of formula (y-21). In some embodiments of Formula (I'), Y is of formula (y-22). In some embodiments of Formula ( )?Y is of formula (y-23). In some embodiments of Formula (I'), Y is of formula (y-24). In some embodiments of Formula (Th 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-27). In some embodiments of Formula (I'), Y is of formula (y-28). In some embodiments of Formula ( ), Y is of formula (y-29). In some embodiments of Formula (I'), Y is of formula (y-30). In some embodiments of Formula (I'), Y is of formula (y-31). 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-34). In some embodiments of Formula (I'), Y is of formula (y-35). In some embodiments of Formula (I'), Y is of formula (y-36). In some embodiments of Formula (I'), Y is of formula (y-37). In some embodiments of Formula (I'), Y is of formula (y-38). In some embodiments of Formula (I'), Y is of formula (y-39). In some embodiments of Formula (I’), Y is of formula (y-40). In some embodiments of Formula (I'), Y is of formula (y-41). In some embodiments of Formula (I'), Y is of formula (y-42). In some embodiments of Formula (I'), Y is of formula (y-43). In some embodiments of Formula (I'), Y is 74 / 411U1197.70255WO00of formula (y-44). In some embodiments of Formula (I'), Y is of formula (y-45). In some embodiments of Formula (I'), Y is of formula (y-46). In some embodiments of Formula (I'), Y is of formula (y-47). In some embodiments of Formula (I'), Y is of formula (y-48). In some embodiments of Formula (I'), Y is of formula (y-49). In some embodiments of Formula (I'), Y is of formula (y-50). In some embodiments of Formula (I'), Y is of formula (y-51 ). In some embodiments of Formula (I'), Y is of formula (y-52). In some embodiments of Formula (F), Y is of formula (y-53). In some embodiments of Formula (I'), Y is of formula (y-54). In some embodiments of Formula (I'), Y is of formula (y-55). In some embodiments of Formula (I'), Y is of formula (y-56). In some embodiments of Formula (I'), Y is of formula (y-57). In some embodiments of Formula (I'), Y is of formula (y-58). In some embodiments of Formula (I'), Y is of formula (y-59). In some embodiments of Formula (I'), Y is of formula (y-60). In some embodiments of Formula (I'), Y is of formula (y-61 ). In some embodiments of Formula (I'), Y is of formula (y-62). In some embodiments of Formula (I'), Y is of formula (y-63). In some embodiments of Formula (I’), Y is of formula (y-64).

[0140] In some embodiments of Formula (I'), Y is of formula (y-30), (y-58), (y-59), (y-62), or (y-63), wherein Q4is CH. In some embodiments of Formula (F), Y is of formula (y-30), (y-58), (y-59), (y-62), or (y-63), wherein Q4is N.

[0141] In some embodiments of Formula (I'), Y is of formula (y-31), (y-32), (y-33), (y-34), (y-35), (y-36), (y-53), (y-54), or (y-55), wherein at least one instance of Q4is CH. In some embodiments of Formula (I'), Y is of formula (y-31), (y-32), (y-33), (y-34), (y-35), (y-36), (y-53), (y-54), or (y-55), wherein at least one instance of Q4is N.

[0142] In some embodiments of Formula (I'), Y is of formula (y-56) or (y-57), wherein v is 1. In some embodiments of Formula (I'), Y is of formula (y-56) or (y-57), wherein v is 2.

[0143] In some embodiments of Formula (I'), Y of formula (y-31) is of formula:In some embodiments of Formula (I1'), Y of formula (y-56) is ofN1(y-56a). In some embodiments of Formula (I'), Y of F HO. NNformula (y-57) is of formula:H (v-57a). In some embodiments of 75 / 411U1197.70255WO00

[0144] In some embodiments of Formula (I'), ¥ is of formula (y-6), (y-7), (y-10), (y-20), (y-31), (y-41), (y-43), (y-56), (y-58), (y-59), or (y-60). In some embodiments of Formula (I'), Y is of formula (y-6), (y-7), (y-10), (y-20), (y-31a), (y-41), (y-43), (y-56a), (y-58a), (y-59a), or (y-60). In some embodiments of Formula (T), Y is of formula (y-6), (y-10), or (y-43). In certain embodiments, Y is of formula (y-43).

[0145] As generally described herein, each instance of Q4is independently CH or N.

[0146] In some embodiments, at least one instance of Q4is CH. In some embodiments, at least one instance of Q4is N.

[0147] As generally described herein, each instance of v is independently 1 or 2.

[0148] In some embodiments, at least one instance of v is 1. In some embodiments, at least one instance of v is 2.

[0149] As generally described herein, each instance of RYis independently CH3, -CH2CH3, - CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CHF2, cyclopropyl, or cyclobutyl.

[0150] In some embodiments, at least one instance of RYis -CH3. In some embodiments, at least one instance of RYis -CH2CH3. In some embodiments, at least one instance of RYis -CHtCHs)?. In some embodiments, at least one instance of R^ is -CH(CH3 CH2CH3. In some embodiments, at least one instance of RYis -C(CH3)3. In some embodiments, at least one instance of RYis - CHF2. In some embodiments, at least one instance ofis cyclopropyl. In some embodiments, at least one instance of R^ is cyclobutyl.Moieties Z, Q1, Q2, Q3, X1, X2, ml, m2, p, R3, R3a, and R3b

[0151] As generally described herein, Z is of formula:76 / 411U1197.70255WO00wherein:Q1is CH, CCH3, or N; or Q1is wherein ml is 1 or 2, m2 is 0 or 1, and L2is attached to Z at the ring N atom of Q1;Q2is CH orN;Q3is C, CH, or N, as valency permits;X1is absent or -CH2-;X2is absent or -CH2-, wherein X2is attached to the aryl ring of (z-5), (z-6), or (z-7); and p is 0 or 1.

[0153] In some embodiments, Z is of formula (z-1), (z-2), (z-3), or (z-4). In some embodiments, Z is of formula (z-2), (z-3), or (z-4). In some embodiments, Z is of formula (z-1), (z-2), or (z-3).In some embodiments, Z is of formula (z-2) or (z-3).77 / 411U1197.70255WO00

[0154] In some embodiments, Z is of formula (z-4), (z-5), (z-6), or (z-7). In some embodiments, Z is of formula (z-5), (z-6), or (z-7).

[0155] In some embodiments, Z is of formula (z-1). In some embodiments, Z is of formula (z-2). In some embodiments, Z is of formula (z-3). In some embodiments, Z is of formula (z-4). In some embodiments, Z is of formula (z-5). In some embodiments, Z is of formula (z-6). In some embodiments, Z is of formula (z-7).

[0156] In some embodiments, Z is of formula:l 9l H 9i -Jpy

[0157] In certain embodiments, Z is of formulaR° (z-9a), R3(z-lOa), orR3(z-lOb). In some embodiments, Z is of formula (z-1) is of formula (z-la), (z-lb), (z-lc), or (z-ld). In some embodiments, Z is of formula (z-2) is of formula (z-2a), (z-2b), (z-2c), or (z-2d). In some embodiments, Z is of formula (z-3) is of formula (z-3a). In some78 / 411U1197.70255WO00embodiments, Z is of formula (z-4) is of formula (z-4a). In some embodiments, Z is of formula (z-5) is of formula (z-5a) or (z-5b). In some embodiments, Z is of formula (z-6) is of formula (z-6a). In some embodiments, Z is of formula (z-7) is of formula (z-7a).

[0158] In some embodiments, Z is of formula (z-la), (z-lb), (z-lc), (z-ld), (z-2a), (z-2b), (z-2c), (z-2d), (z-3a), or (z-4a). In some embodiments, Z is of formula (z-2a), (z-2b), (z-2c), (z-2d), (z-3a), or (z-4a). In some embodiments, Z is of formula (z-la), (z-lb), (z-lc), (z-ld), (z-2a), (z-2b), (z-2c), (z-2d), or (z-3a). In some embodiments, Z is of formula (z-2a), (z-2b), (z-2c), (z-2d), or (z-3a).

[0159] In some embodiments, Z is of formula (z-la), (z-lb), (z-lc), or (z-ld). In some embodiments, Z is of formula (z-2a), (z-2b), (z-2c), or (z-2d). In some embodiments, Z is of formula (z-la) or (z-2a). In some embodiments, Z is of formula (z-lb) or (z-2b). In some embodiments, Z is of formula (z-lc) or (z-2c). In some embodiments, Z is of formula (z-ld) or (z-2d).

[0160] In some embodiments, Z is of formula (z-4a), (z-5a), (z-5b), (z-6a), or (z-7a). In some embodiments, Z is of formula (z-5a), (z-5b), (z-6a), or (z-7a). In some embodiments, Z is of formula (z-5b), (z-6a), or (z-7a).

[0161] In some embodiments, Z is of formula (z-la). In some embodiments, Z is of formula (z-1b). In some embodiments, Z is of formula (z-lc). In some embodiments, Z is of formula (z-ld). In some embodiments, Z is of formula (z-2a). In some embodiments, Z is of formula (z-2b). In some embodiments, Z is of formula (z-2c). In some embodiments, Z is of formula (z-2d). In some embodiments, Z is of formula (z-3a). In some embodiments, Z is of formula (z-4a). In some embodiments, Z is of formula (z-5a). In some embodiments, Z is of formula (z-5b). In some embodiments, Z is of formula (z-6a). In some embodiments, Z. is of formula (z-7a).10a).79 / 411U1197.70255WO00m2

[0163] As generally described herein, Q1is CH, CCH3, or N; or Q1is, wherein ml is 1 or 2, m2 is 0 or 1, and L2is attached to Z at the ring N atom of Q1.

[0164] In some embodiments, Q1is CH, CCH3, or N. In some embodiments, Q1is CH or CCH In some embodiments, Q1is CH or N. In some embodiments, Q1is CCH3 or N.

[0165] In some embodiments, Q1is CH. In some embodiments, Q1is CCH3. In some embodiments, Q1is N.

[0166] In some embodiments, Q1is wherein ml is 1 or 2, m2 is 0 or 1, and L2is attached to Z at the ring N atom of Q1.

[0167] It is understood that when Q1is denotes attachment of the specified ring C atom of Q1to the ring in (z-1) or (z-2), thereby forming a spirocyclic heterocyclic ring,and does not denote attachment to L2, whereas' denotes attachment of the ring N atom of Q1to L2.In some embodiments, the moietyis of formula:80 / 411U1197.70255WO00

[0169] As generally described herein, ml is 1 or 2.

[0170] In some embodiments, ml is 1, In some embodiments, ml is 2.

[0171] As generally described herein, m2 is 0 or 1.

[0172] In some embodiments, m2 is 0. In some embodiments, m2 is 1.

[0173] In some embodiments, ml is 1 and m2 is 0, In some embodiments, ml is 2 and m2 is 0. In some embodiments, ml is 1 and m2 is 1. In some embodiments, ml is 2 and m2 is 1.

[0174] As generally described herein, Q2is CH or N.

[0175] In some embodiments, Q2is CH. In some embodiments, Q2is N.

[0176] As generally described herein, Q3is C, CH, or N, as valency permits.

[0177] In some embodiments, Q3is C or N, as valency permits. In some embodiments, Q3is CH or N, as valency permits.

[0178] In some embodiments, Q3is C. In some embodiments, Q3is CH. In some embodiments, Q3is N.

[0179] As generally described herein, X1is absent or -CH2-.

[0180] In some embodiments, X1is absent. In some embodiments, X1is -CH2-.

[0181] As generally described herein, X2is absent or -CH2-, wherein X2is attached to the aryl ring of (z-5), (z-6), or (z-7).

[0182] In some embodiments, X2is absent. In some embodiments, X2is -CI I2-.

[0183] As generally described herein, p is 0 or 1.

[0184] In some embodiments, p is 0. In some embodiments, p is 1.

[0185] As generally described herein, R3is carbocyclyl, aryl, heteroaryl,or, wherein the carbocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits; each instance of R3ais independently optionally substituted alkyl, optionally substituted cycloalkyl, -OR°, halogen, -CN, or -NO2; and R3bis hydrogen, halogen, or optionally substituted alkyl.81 / 411U1197.70255WO00

[0186] In some embodiments, R3is carbocyclyl, aryl, heteroaryl, or R3b, wherein the carbocyclyl, aryl, or heteroaryl is substituted with 0, I, or 2, instances of R3a, as valency permits.In some embodiments, R3is carbocyclyl, aryl, heteroaryl, orR3b, wherein the carbocyclyl, aryl, or heteroaryl is substituted with 0 or 1 instances of R3a, as valency permits.

[0187] In some embodiments, R3is carbocyclyl substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits. In some embodiments, R3is carbocyclyl substituted with 0, 1, or 2 instances of R3a, as valency permits. In some embodiments, R3is C5-6 carbocyclyl substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits. In some embodiments, R3is C5-6 carbocyclyl substituted with 0, 1, or 2 instances of R3a, as valency permits. In some embodiments, R3is C5-6 carbocyclyl substituted with 0 instances of R3a. In some embodiments, R3is cyclopentyl substituted with 0 instances of R3a. In some embodiments, R3is cyclohexyl substituted with 0 instances of R3a.

[0188] In some embodiments, R3is aryl substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits. In some embodiments, R3is aryl substituted with 0, 1, or 2 instances of Rja, as valency permits. In some embodiments, R3is phenyl substituted with 0, 1, 2, 3, 4, or 5 instances of R3a. In some embodiments, R3is phenyl substituted with 0, 1, or 2 instances of R3a. In some embodiments, R3is phenyl substituted with 0 instances of R3a.

[0189] In some embodiments, R3is phenyl substituted with 1 instance of R3a. In some embodiments, R3is phenyl substituted with 1 instance of R3a, wherein R3ais optionally substituted Ci-6 alkyl, optionally substituted C3-6 cycloalkyl, -OR°, halogen, -CN, or -NO?. In some embodiments, R3is phenyl substituted with 1 instance of R3a, wherein R3ais optionally substituted C1-3 alkyl or halogen. In some embodiments, R3is phenyl substituted with 1 instanceof R3a, wherein R3ais unsubstituted C1-3 alkyl or halogen. In some embodiments, R3is7 / a 5 5 f’ In certain embodiments, R3is of formula:82 / 411U1197.70255WO00

[0190] In some embodiments, R3is heteroaryl substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits. In some embodiments, R3is heteroaryl substituted with 0, 1, or 2 instances of R3a, as valency permits. In some embodiments, R3is heteroaryl substituted with 0 or 1 instances of R3a, as valency permits. In some embodiments, R3is 5-6 membered heteroaryl substituted with 0, 1, or 2 instances of R3a, as valency permits. In some embodiments, R3is 5-6 membered heteroaryl substituted with 0 or 1 instances of R3a, as valency permits.

[0191] In some embodiments, R3is 5-6 membered heteroaryl substituted with 0 instances of Rja. In some embodiments, R3is 5-6 membered heteroaryl substituted with 1 instance of R3a, as valency permits. In some embodiments, R3is 5-6 membered heteroaryl substituted with 1 instance of R3a, as valency permits, wherein R3ais optionally substituted C1-3 alkyl. In someembodiments,R3is

[0192] In some embodiments, R3is of formulaR3b. In some embodiments, R3is offormulaR3b, wherein R3bis halogen or optionally substituted alkyl. In someembodiments, R3is of formulaR3b, wherein R3bis halogen or optionally substitutedCi-3 alkyl. In some embodiments, R3is of formulaR3b, wherein R3bis unsubstituted Ci-3 alkyl or C1-3 alkyl substituted only with one or more instances of -F. In some embodiments,83 / 411U1197.70255WO00substituted alkyl.

[0194] In some embodiments, R3is of formula (c-1), (c-2), (c-3), (c-4), (c-5), (c-6), or (c-7).

[0195] In some embodiments, R3is of formula (c-1), (c-2), (c-3), or (c-4). In some embodiments, R3is of formula (c-2), (c-3), or (c-4). In some embodiments, R3is of formula (c-5) or (c-6).

[0196] In some embodiments, R3is of formula (c-1). In some embodiments, R3is of formula (c- 2). In some embodiments, R3is of formula (c-3). In some embodiments, R3is of formula (c-4). In some embodiments, R3is of formula (c-5). In some embodiments, R3is of formula (c-6). In some embodiments, R3is of formula (c-7).

[0197] In some embodiments, R3is oi formula:SoSSrcr„^F3. in certain embodiments, R3is of formula:C|.

[0198] As generally described herein, each instance of R3ais independently optionally substituted alkyl, optionally substituted cycloalkyl, -OR°, halogen, -CN, or --NO2.

[0019] In some embodiments, at least one instance of R3ais optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, -OR°, halogen, -CN, or -NO2. In some embodiments, at least one instance of R3ais optionally substituted C1-4 alkyl, optionally substituted C3-4 cycloalkyl, -OR°, halogen, -CN, or -NO2.

[0200] In some embodiments, at least one instance of R3ais optionally substituted alkyl. In some embodiments, at least one instance of R3ais optionally substituted C1-6 alkyl. In some embodiments, at least one instance of R3ais optionally substituted Ci-4 alkyl.84 / 411U1197.70255WO00

[0201] In some embodiments, at least one instance of Rjais unsubstituted Ci-6 alkyl. In some embodiments, at least one instance of R3ais unsubstituted C1-4 alkyl. In some embodiments, at least one instance of R3ais -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, or -CH(CH3)CH2CH3. In some embodiments, at least one instance of R3ais -CH3. In some embodiments, at least one instance of R3ais -CH2CH3. In some embodiments, at least one instance of R3ais -CH(CH3)2. In some embodiments, at least one instance of R3ais -C(CH3)3. In some embodiments, at least one instance of R3ais -CH(CH3)CH2CH3.

[0202] In some embodiments, at least one instance of R3ais substituted Cue alkyl. In some embodiments, at least one instance of R3ais substituted C1-4 alkyl. In some embodiments, at least one instance of R3ais C1-4 alkyl substituted only with one or more instances of halogen. In some embodiments, at least one instance of R3ais C1-4 alkyl substituted only with one or more instances of -F. In some embodiments, at least one instance of R3ais -CF3, -CHF2, or -CHFCH3. In some embodiments, at least one instance of R3ais -CF3. In some embodiments, at least one instance of R3ais -CHF2. In some embodiments, at least one instance of R ';‘ is -CHFCH3.

[0203] In some embodiments, at least one instance of Rjais optionally substituted cycloalkyl. In some embodiments, at least one instance of R3ais optionally substituted C3-6 cycloalkyl. In some embodiments, at least one instance of R3ais optionally substituted C3-4 cycloalkyl. In some embodiments, at least one instance of R3ais substituted cycloalkyl.

[0204] In some embodiments, at least one instance of R1ais unsubstituted cycloalkyl. In some embodiments, at least one instance of R3ais unsubstituted C3-6 cycloalkyl. In some embodiments, at least one instance of R3ais unsubstituted C3-4 cycloalkyl. In some embodiments, at least one instance of R3ais cyclopropyl or cyclobutyl. In some embodiments, at least one instance of R3ais cyclopropyl. In some embodiments, at least one instance of R3ais cyclobutyl.

[0205] In some embodiments, at least one instance of Rjais -OR°. In some embodiments, at least one instance of R3ais -OH.

[0206] In some embodiments, at least one instance of R3ais halogen. In some embodiments, at least one instance of R3ais -Cl, -Br, or -F. In some embodiments, at least one instance of R3ais -Cl or -F. In some embodiments, at least one instance of R3ais -Cl. In some embodiments, at least one instance of R3ais -Br. In some embodiments, at least one instance of R3ais -F.

[0207] In some embodiments, at least one instance of R3ais -CN.

[0208] In some embodiments, at least one instance of R3ais -NO2.

[0209] In some embodiments, at least one instance of R3ais -CH3, -CH2CH3, -CH(CH3)2, - C(CH3)3, -CH(CH3)CH2CH3, -CF3, -CHF2, -CHFCH3, cyclopropyl, cyclobutyl, -OH, -Cl, -Br, -F, -CN, or -NO2.85 / 411U1197.70255WO00

[0210] In some embodiments, each instance of R3ais independently -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, -CF3. -CHF2, -CHFCH3, cyclopropyl, cyclobutyl, -OH, -Cl, -Br, -F, -CN, or -NO2.

[0211] As generally described herein, R3bis hydrogen, halogen, or optionally substituted alkyl.

[0212] In some embodiments, R3bis halogen or optionally substituted alkyl. In some embodiments, R3bis halogen or optionally substituted Cue alkyl. In some embodiments, R3bis halogen or optionally substituted C1-3 alkyl. In some embodiments, R3bis halogen or optionally substituted methyl.

[0213] In some embodiments, R3bis hydrogen.

[0214] In some embodiments, R3bis halogen. In some embodiments, R3bis -F, -Cl, -Br, or -I. In some embodiments, R3bis -F, -Cl, or -Br. In some embodiments, R3bis -F or -CL In some embodiments, R3bis -F. In some embodiments, R3bis -Cl.

[0215] In some embodiments, R3bis optionally substituted alkyl. In some embodiments, R3bis optionally substituted C1-6 alkyl. In some embodiments, R3bis optionally substituted C1-3 alkyl. In some embodiments, R3bis optionally substituted methyl.

[0216] In some embodiments, R3bis unsubstituted alkyl. In some embodiments, R3bis unsubstituted C1-6 alkyl. In some embodiments, R3bis unsubstituted C1-3 alkyl. In some embodiments, R3bis -CH3.

[0217] In some embodiments, R3bis substituted alkyl. In some embodiments, R3bis substituted C1-6 alkyl. In some embodiments, R3bis substituted C1-3 alkyl. In some embodiments, R3bis substituted methyl. In some embodiments, R3bis alkyl substituted only with one or more instances of -F. In some embodiments, R3bis C1-6 alkyl substituted only with one or more instances of -F. In some embodiments, R3bis C1-3 alkyl substituted only with one or more instances of -F. In some embodiments, R3bis methyl substituted only with one or more instances of-F. In some embodiments, R3bis -CH2F, -CHF2, or -CF3. In some embodiments, R3bis -CH2F. In some embodiments, R3bis -CHF2. In some embodiments, R3bis -CF3.

[0218] In some embodiments, R3bis -F, -Cl, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R3bis -CH3, -CHF2, or -CF3.Moieties R1, R2, R4, and L4

[0219] As generally described herein, R1is -(C1-3 alkylene)-Rla, wherein the alkylene is unsubstituted, and R,ais -OR°, -N(RN)2, optionally substituted C4-10 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl.

[0220] In some embodiments, R1is — (C1-2 alkylene)-R1a, wherein Rlais -OR°, -N(RN)2, optionally substituted C4-10 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl. In86 / 411U1197.70255WO00some embodiments, R1is -(C2-3 alkylene)-Rla, wherein Rlais OR°, -N(RN)2, optionally substituted C4-10 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl.

[0221] In some embodiments, R1is -CH2Rla, wherein Rlais -OR°, -N(RN)2, optionally substituted C4-10 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl. In some embodiments, R1is -(CH2)2R1a, wherein R1ais -OR°, -N(RN)2, optionally substituted C4-10 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl. In some embodiments, R1is -(CH2)sRla, wherein Rlais -OR°, -N(RN)’, optionally substituted C4-10 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl.

[0222] In some embodiments, R1is — (C1-3 alkylene)-ORo. In some embodiments, R1is -(Ct-2 alkylene)--OR°. In some embodiments, R1is -(C2-3 alkylene)-ORo. In some embodiments, R1is -CH2OR0. In some embodiments, R1is ~(CH2)2OR°. In some embodiments, R1is -(CFkhOR0.

[0223] In some embodiments, R1is -(C1-3 alkylene)-ORo, wherein R° is hydrogen. In some embodiments, R1is -(C1-3 alkylene)-OR°, wherein R° is optionally substituted alkyl. In some embodiments, R1is -(C1-3 alkylene)-OR°, wherein R° is optionally substituted Ci-3 alkyl. In some embodiments, R1is -(C1-3 alkylene)-OR°, wherein R° is substituted alkyl. In some embodiments, R1is -(C1-3 alkylene)-OR°, wherein R° is substituted C1-3 alkyl. In some embodiments, R1is -(C1-3 alkylene) -OR°, wherein R° is unsubstituted alkyl. In some embodiments, R1is -(C1-3 alkylene)-OR°, wherein R° is unsubstituted C1-3 alkyl. In some embodiments, R1is -(C1-3 alkylene)-OR°, wherein R° is -CH3 or -CH2CH3. In some embodiments, R1is -(C2-3 alkylene)-OR°, wherein R° is optionally substituted C1-3 alkyl. In some embodiments, R1is -(C2-3 alkylene)-OR°, wherein R° is unsubstituted C1-3 alkyl. In some embodiments, R1is -(C2-3 alkylene)-OR°, wherein R° is -CH3 or -CH2CH3.

[0224] In some embodiments, R1is, or.

[0225] In some embodiments, R1is -(C1-3 alkylene)-N(RN)2. In some embodiments, R1is -(Ct-2 alkylene)-N(RN)2. In some embodiments, R1is -(C2-3 alkylene)-N(RN)2. In some embodiments, R1is -CH2N(RN)2. In some embodiments, R1is -(CH2)2N(RN)2. In some embodiments, R1is -(CH2)3N(RN)2.

[0226] In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein each instance of RNis independently C1-3 alkyl substituted with 0 or 1 instances of -OH, or two instances of R ' are joined with the nitrogen atom to which they are attached to form an optionally substituted 4-10 membered heterocyclyl.

[0227] In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein at least one instance of RNis hydrogen. In some embodiments, R1is -(Ct-3 alkylene)-N(RN)2, wherein at least one instance of RNis optionally substituted alkyl. In some embodiments, R1is -(C1-3 alkylene) -N(RN)2,87 / 411U1197.70255WO00wherein least one instance of RNis optionally substituted C1-3 alkyl. In some embodiments, R1is - (C1-3 alkylene )-N(RN)2, wherein at least one instance of RNis unsubstituted alkyl. In some embodiments, R1is -(Ct-3 alkylene)-N(RN)2, wherein at least one instance of RNis unsubstituted C1-3 alkyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein at least one instance of RNis -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R1is -(Ct-3 alkylene)-N(RN)2, wherein at least one instance of RNis -CH3. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein at least one instance of RNis -CH2CH3. In some embodiments, R1is -(C1-3 alkylene >-N(RN)2, wherein at least one instance of RNis -CH(CH3)2. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein at least one instance of RNis substituted alkyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein at least one instance of RNis substituted C1-3 alkyl.

[0228] In some embodiments, R1is -(Ci.3 alkyleiie)-N(RN)2, wherein each instance of RNis independently optionally substituted alkyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein each instance of RNis independently optionally substituted C j -3 alkyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein each instance of RNis independently unsubstituted alkyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein each instance of RNis independently unsubstituted C1-3 alkyl. In some embodiments, R1is -(C1-3 alkylene) -N(RN)2, wherein each instance of RNis independently -CH3. In some embodiments, R1is -(C1-3 alkylene )-N(RN)2, wherein each instance of R. is independently substituted alkyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein each instance of RNis independently substituted C1-3 alkyl.

[0229] In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein at least one instance of RNis alkyl substituted with 0 or 1 instances of -OH. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein each instance of RNis independently C1-3 alkyl substituted with 0 or 1 instances of -OH.

[0230] In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein at least one instance of RNis alkyl substituted with 1 instance of -OH. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein at least one instance of RNis C1-3 alkyl substituted with 0 or 1 instances of -OH. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein at least one instance of RNis C1-3 alkyl substituted with 1 instance of -OH. In some embodiments, R1is -(Ci-3 alkylene)-N(RN)2, wherein at least one instance of RNis -CH2CH2OH.

[0231] In some embodiments, R1is - (C1-3 alkylene)-N(RN)2, wherein I instance of RNis alkyl substituted with 1 instance of -OH; and 1 instance of RNis Cl h. -CH2CH3, or -CH(CH3)2. In some embodiments, R1is - (C1-3 alkylene)-N(RN)2, wherein I instance of RNis C1-3 alkyl substituted with 1 instance of -OH; and 1 instance of RNis -CH3, -CH2CH3, or -CH(CH3)2. In 88 / 411U1197.70255WO00some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein 1 instance of RNis -CH2CH2OH; and 1 instance of RNis -CH3, -CH2CH3, or -CH(CHs)2.

[0232] In some embodiments, R1is -(CH2)2N(RN)2, wherein 1 instance of RNis alkyl substituted with 1 instance of -OH; and 1 instance of RNis -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R1is ~(CH2)2N(RN)2, wherein 1 instance of R" is C1..3 alkyl substituted with 1 instance of -OH; and 1 instance of RNis -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R1is -(CH2)2N(RN)2, wherein 1 instance of RNis -CH2CH2OH; and 1 instance of R" is -CH3, -CH2CH3, or -CH(CH3)2.

[0233] In some embodiments, R1is

[0234] In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 4-10 membered heterocyclyl.

[0235] In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl. In some embodiments, R1is -(C1-3 alkylene) -N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted heterocyclyl. In some embodiments, R1is — (C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted heterocyclyl.

[0236] In some embodiments, R1is -(C1.3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted monocyclic heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered monocyclic heterocyclyl. In some embodiments, R1is -(Cv 3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(Ci 3 alkylene)- N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted monocyclic heterocyclyl. In some embodiments, R1is -(C1.3 alkylene)- N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 4-7 membered monocyclic heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which 89 / 411U1197.70255WO00they are attached to form an unsubstituted 4-7 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(Cns alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted monocyclic heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)- N(RN)?, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 4-7 membered monocyclic heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 4-7 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O.

[0237] In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted monocyclic heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered monocyclic heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted monocyclic heterocyclyl. In some embodiments, R1is ~(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 4-7 membered monocyclic heterocyclyl. In some embodiments, R1is ~(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 4-7 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted monocyclic heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 4-7 membered monocyclic heterocyclyl. In some embodiments, R1is ~(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 4-7 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O.

[0238] In some embodiments, R1is ((': =. aikylene)--N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted bridged heterocyclyl. In some embodiments, R1is --(Ci-3 alkylene)--N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered bridged heterocyclyl. In some embodiments, R1is — (Ci-390 / 411U1197.70255WO00alkylene) -N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from N and (). In some embodiments, R1is -(Ci -3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted bridged heterocyclyl. In some embodiments, R1is -(Ci 3 alkylene)- N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered bridged heterocyclyl. In some embodiments, R1is — (Ci- 3 alkylene)-- N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(C1-3 alkylene) -N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted bridged heterocyclyl. In some embodiments, R1is -(C13 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered bridged heterocyclyl. In some embodiments, R1is -(C1.3 alkylene)- N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N.

[0239] In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted bridged heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered bridged heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted bridged heterocyclyl. In some embodiments, R1is ~(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered bridged heterocyclyl. In some embodiments, R1is ~(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(CH2)2N(RN)’, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted bridged heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered 91 / 411U1197.70255WO00bridged heterocyclyl. In some embodiments, R1is --(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N.

[0240] In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted fused heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)~N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5- 10 membered fused heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(C1-3 alkylene)~N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted fused heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)~N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered fused heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)- N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is — (C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted fused heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered fused heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)~N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N.

[0241] In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted fused heterocyclyl. In some embodiments, R1is ~(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered fused heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted fused heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of R" are joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered fused heterocyclyl. In 92 / 411U1197.70255WO00some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an un substituted 5-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is ~(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted fused heterocyclyl. In some embodiments, R1is - (CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered fused heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N.

[0242] In some embodiments, R1is -(C1-3 alkylene)~N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted spirocyclic heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)~N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered spirocyclic heterocyclyl. In some embodiments, R1is -(Ci-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is - (C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted spirocyclic heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)- N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered spirocyclic heterocyclyl. In some embodiments, R1is - (C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted spirocyclic heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)- N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered spirocyclic heterocyclyl. In some embodiments, R1is -(C1-3 alkylene)-N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N.

[0243] In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted spirocyclic heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare 93 / 411U1197.70255WO00joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered spirocyclic heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is ~(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted spirocyclic heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered spirocyclic heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form an unsubstituted 5-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is ~(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted spirocyclic heterocyclyl. In some embodiments, R1is ~(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered spirocyclic heterocyclyl. In some embodiments, R1is -(CH2)2N(RN)2, wherein two instances of RNare joined with the nitrogen atom to which they are attached to form a substituted 5-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N.

[0244] In some embodiments, R1is^OH94 / 411U1197.70255WO00

[0245] In some embodiments, R1is / 95 / 411U1197.70255WO00

[0246] In some embodiments, R1is — (C1-3 alkylene)-(optionally substituted C4-10 carbocyclyl). In some embodiments, R1is -(C1-2 alkylene)-(optionally substituted C4-10 carbocyclyl). In some embodiments, R1is -(C2-3 alkylene)-(optionally substituted C4-10 carbocyclyl). In some embodiments, R1is -CH2-(optionally substituted C4-10 carbocyclyl). In some embodiments, R1is -(CH’)2-(optionally substituted C4-10 carbocyclyl). In some embodiments, R1is -(CH2)3-(optionally substituted C4-10 carbocyclyl).

[0247] In some embodiments, R1is -(C1-3 alkylene)~(optionally substituted C5-6 carbocyclyl). In some embodiments, R1is — (C1-2 alkylene)-(optionally substituted C5-6 carbocyclyl). In some embodiments, R1is -(C2-3 alkylene)~-(optionally substituted C5-6 carbocyclyl). In some embodiments, R1is -CH2-(optionally substituted C5-6 carbocyclyl). In some embodiments, R1is -(CH2)2-(optionally substituted C5-6 carbocyclyl). In some embodiments, R1is -(CH2)3-(optionally substituted C5-6 carbocyclyl).96 / 411U1197.70255WO00

[0248] In some embodiments, R1is -(C1-3 alkylene)- (unsubstituted C5-6 carbocyclyl). In some embodiments, R1is -CH2-(unsubstituted C5-6 carbocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(substituted C5-6 carbocyclyl). In some embodiments, R1is -CH2-(substituted C5-6 carbocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, or 3 instances of C1..3 alkyl, halogen, or -OH. In some embodiments, R1is -(C1-3 alkylene)-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 or 2 instances of C1-3 alkyl, halogen, or -OH. In some embodiments, R1is -(C1-3 alkylene)-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 instance of Ci-3 alkyl, halogen, or -OH. In some embodiments, R1is -(C1-3 alkylene)-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 2 instances of Ci-3 alkyl, halogen, or -OH.

[0249] In some embodiments, R1is -CH2-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, or 3 instances of C1..3 alkyl, halogen, or -OH. In some embodiments, R1is — CH2— (C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 or 2 instances of C1-3 alkyl, halogen, or -OH. In some embodiments, R1is -CH2-(Cs 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 instance of C1-3 alkyl, halogen, or -OH. In some embodiments, R1is — CH ’— (C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 2 instances of C1-3 alkyl, halogen, or -OH.

[0250] In some embodiments, R1is - (C1-3 alkylene)-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 instance of C1-3 alkyl. In some embodiments, R1is -(C1-3 alkylene)-(C56 carbocyclyl), wherein the carbocyclyl is substituted with 1 instance of -OH. In some embodiments, R1is -(C1-3 alkylene)-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 instance of C1-3 alkyl and 1 instance of -OH. In some embodiments, R1is -(C1-3 alkylene)-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 or 2 instances of halogen. In some embodiments, R1is -(C1-3 alkylene) --(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 or 2 instances of -F. In some embodiments, R1is -(C1-3 alkylene) -(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 or 2 instances of --F.

[0251] In some embodiments, R1is -CH2-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 instance of C1-3 alkyl. In some embodiments, R1is -CH2-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 instance of -OH. In some embodiments, R1is -CH2-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 instance of C1-3 alkyl and 1 instance of -OH. In some embodiments, R1is -CH2 -(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 or 2 instances of halogen. In some embodiments, R1is -CH2-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 or 2 instances of -F. In some embodiments, R1is -CH2-(C5-6 carbocyclyl), wherein the carbocyclyl is substituted with 1 or 2 instances of -F.97 / 411U1197.70255WO00

[0252] In some embodiments, R1is

[0253] In some embodiments, R1is -(C1-3 alkylene) -(optionally substituted 4-10 membered heterocyclyl). In some embodiments, R1is -(C1-2 alkylene)-(optionally substituted 4-10 membered heterocyclyl). In some embodiments, R1is -(C2-3 alkylene)-- (optionally substituted 4- 10 membered heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(substituted 4-10 membered heterocyclyl). In some embodiments, R1is -(C1-2 alkylene) -(substituted 4-10 membered heterocyclyl). In some embodiments, R1is -(C2-3 alkylene)-(substituted 4-10 membered heterocyclyl). In some embodiments, R1is -(C1-3 alkylene )-(unsubstituted 4-10 membered heterocyclyl). In some embodiments, R1is -(C1-2 alkylene)-(unsubstituted 4-10 membered heterocyclyl). In some embodiments, R1is -(C2-3 alkylene)-(unsubstituted 4-10 membered heterocyclyl).

[0254] In some embodiments, R1is -CH ’-(optionally substituted 4-10 membered heterocyclyl). In some embodiments, R1is -(CH2)2-(optionally substituted 4-10 membered heterocyclyl). In some embodiments, R1is -(CH2)3-(optionally substituted 4-10 membered heterocyclyl). In some embodiments, R1is -CH2-( substituted 4-10 membered heterocyclyl). In some embodiments, R1is -(CH2)2-(substituted 4-10 membered heterocyclyl). In some embodiments, R1is -(CH2)3- (substituted 4-10 membered heterocyclyl). In some embodiments, R1is -CH2-(unsubstituted 4- 10 membered heterocyclyl). In some embodiments, R1is -(CH2)2-(unsubstituted 4-10 membered heterocyclyl). In some embodiments, R1is -(CH2)3-(unsubstituted 4-10 membered heterocyclyl).

[0255] In some embodiments, R1is -(C1-3 alkylene)- (4-7 membered monocyclic heterocyclyl), - (C1-3 alkylene)-(5-10 membered bridged heterocyclyl), -(C1-3 alkylene)-(5- 10 membered fused heterocyclyl), or -(C1-3 alkylene)-(7-10 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of - OR° or -N(RN)2. In some embodiments, R1is -(C1-3 alkylene )-(4-7 membered monocyclic heterocyclyl), -(Ci-3 alkylene)-(5-10 membered bridged heterocyclyl), -(C1-3 alkylene)-(5-10 membered fused heterocyclyl), or -(C1-3 alkylene)- (7- 10 membered spirocyclic heterocyclyl).98 / 411U1197.70255WO00wherein the heterocyclyl is substituted with 0, 1, or 2 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or-N(RN)2. In some embodiments, R1is — (C1-3 alkylene)-(4-7 membered monocyclic heterocyclyl), -(Ci-3 alkylene)-(5-10 membered bridged heterocyclyl), -(C1-3 alkylene )-(5- 10 membered fused heterocyclyl), or -(C1-3 alkylene)-(7-10 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, ~(C=O)~ (Cj-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2.

[0256] In some embodiments, R1is -(C1-3 alkylene)-(4-7 membered monocyclic heterocyclyl), -(C1-3 alkylene) -(5- 10 membered bridged heterocyclyl), -(Ci-3 alkylene)- (5- 10 membered fused heterocyclyl), or-(Ci-3 alkylene)-(7-10 membered spirocyclic heterocyclyl), wherein the heterocyclyl is un substituted. In some embodiments, R1is -(C1-3 alkylene)-(4-7 membered monocyclic heterocyclyl), -(C1-3 alkylene)-(5-10 membered bridged heterocyclyl), -(C1-3 alkylene )-(5- 10 membered fused heterocyclyl), or -(C1-3 alkylene)-(7-10 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 1 instance of C1-3 alkyl, -(C=O) -(C1-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2.

[0257] In some embodiments, R1is - (C1-3 alkylene)-(optionally substituted 4-10 membered monocyclic heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(optionally substituted 4-7 membered monocyclic heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(optionally substituted 4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(C1-3 alkylene)- (unsubstituted 4-10 membered monocyclic heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)--(unsubstituted 4-7 membered monocyclic heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(unsubstituted 4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(C1-3 alkylene)-(substituted 4-10 membered monocyclic heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(substituted 4-7 membered monocyclic heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(substituted 4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0258] In some embodiments, R1is -(CH2)2-(optionally substituted 4-10 membered monocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(optionally substituted 4-7 membered monocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(optionally substituted 4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(CH2)2-(unsubstituted 4-10 membered 99 / 411U1197.70255WO00monocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(unsubstituted 4-7 membered monocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(unsubstituted 4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(CH2)2-(substituted 4-10 membered monocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(substituted 4-7 membered monocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(substituted 4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0259] In some embodiments, R1is -(C1-3 alkylene)-(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is -(C1-3 alkylene )— (4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is -(C1-3 alkylene)-(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(C1-3 alkyl), halogen, -OR°, or-N(RN)2, wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0260] In some embodiments, R1is — (C1-3 alkylene)-(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of -CH3, -CH2OH, - CH2N(CH3)2, -(C=O)CH33, -OH, or -N(CH3)2. In some embodiments, R1is -(Ci 3 alkylene)-(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of-CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH33, -OH, or -N(CH3)2. In some embodiments, R1is -(C1-3 alkylene) -(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH33, -OH, or -N(CH3)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0261] In some embodiments, R1is -(CH2)2-(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or-N(RN)2. In some embodiments, R1is -(CH2)2-(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)- (C1-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is -(CH2)2-(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(C1-3 alkyl), halogen, -OR°, or -N(RN)2, wherein each alkyl is independently 100 / 411U1197.70255WO00substituted with 0 or 1 instances of -OR° or -N(RN)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0262] In some embodiments, R1is -(CH2)2-(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of -CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH3, -OH, or -N(CH3)2. In some embodiments, R1is -(CH2)2-(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, - CH2N(CH3)2, -(C=O)CH3, -OH, or -N(CH3)2. In some embodiments, R1is -(CH2)2-(4-7 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH33, -OH, or -N(CH3)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0263] In some embodiments, R1is101 / 411U1197.70255WO00

[0264] In some embodiments, R1is -(C1-3 alkylene)-(optionally substituted 4-10 membered bridged heterocyclyl). In some embodiments, R1is — (C1-3 alkylene)-(optionally substituted 5-8 membered bridged heterocyclyl). In some embodiments, R1is —(Ci-3 alkylene)~(optionally substituted 5-8 membered bridged heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(C1-3 alkylene)-(unsubstituted 4-10 membered bridged heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)- (unsubstituted 5-8 membered bridged heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)--(unsubstituted 5-8 membered bridged heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(C1-3 alkylene)-(substituted 4-10 membered bridged heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)-- (substituted 5-8 membered bridged heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)- (substituted 5-8 membered bridged heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N.

[0265] In some embodiments, R1is -(CH2)2-(optionally substituted 4-10 membered bridged heterocyclyl). In some embodiments, R1is -(CH2)2-(optionally substituted 5-8 membered bridged heterocyclyl). In some embodiments, R1is -(CH2)2-(optionally substituted 5-8 membered bridged heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O. In some embodiments, R1is -(CH2)2-(unsubstituted 4-10 membered bridged heterocyclyl). In some embodiments, R1is -(CH2)2-(unsubstituted 5-8 membered bridged heterocyclyl). In some embodiments, R1is -(CH2)2-(unsubstituted 5-8 membered 102 / 411U1197.70255WO00bridged heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(CH2)2-( substituted 4-10 membered bridged heterocyclyl). In some embodiments, R1is -(CH2)2-(substituted 5-8 membered bridged heterocyclyl). In some embodiments, R1is -(CH2)2-(substituted 5-8 membered bridged heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N.

[0266] In some embodiments, R1is -(C1-3 alkylene)-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or-N(RN)2. In some embodiments, R1is -(C1-3 alkylene)-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is — (Cj -3 alkylene)-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(C1-3 alkyl), halogen, -OR°, or -N(RN)2, wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0267] In some embodiments, R1is -(C1-3 alkylene)-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of -CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH3, -OH, or -N(CH3)2. In some embodiments, R1is -(Ci-3 alkylene)-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH33, -OH, or -N(CH3)2. In some embodiments, R1is - (C1-3 alkylene)-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, -CH’N(CH3)2, -(C=O)CH33, -OH, or-N(CH3)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0268] In some embodiments, R1is -(CH2)2-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is -(CH2)2-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is -(CH2)2-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(C1-3 alkyl), halogen, OR°, or -N(RN)2, wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.103 / 411U1197.70255WO00

[0269] In some embodiments, R1is -(CH2)2-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of -CH3, -CH2OH, -Cl hNlCHs)’, -(C=O)CH3s, -OH, or -N(CH3)2. In some embodiments, R1is -(CH2)2-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH₃, -CH2OH, -CH2N(CH3)2, -(C=O)CH3J, -OH, or -N(CH3)2. In some embodiments, R1is -(CH2)2-(5-8 membered bridged heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, -CH2N(CH?)2, -(C=O)CH3, -OH, or -N(CH3)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0270] In some embodiments, R1is

[0271] In some embodiments, R1is -(C1-3 alkylene)-(optionally substituted 4-10 membered fused heterocyclyl). In some embodiments, R1is -(Ci-3 alkylene)-(optionally substituted 5-8 membered fused heterocyclyl). In some embodiments, R1is - (Ci-3 alkylene)- (optionally substituted 5-8 membered fused heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(C1-3 alkylene)- (unsubstituted 4-10 membered fused heterocyclyl). In some embodiments, R1is -(Ci-3 alkylene )-(unsubstituted 5-8 membered fused heterocyclyl). In some embodiments, R1is -(Ci-3 alkylene)-(unsubstituted 5-8 membered fused heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is — (C1-3 alkylene)-(substituted 4-10 membered fused heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(substituted 5-8 membered fused heterocyclyl). In some embodiments, R1is -(Ci-3 alkylene)-(substituted 5-8 membered fused heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N.

[0272] In some embodiments, R1is -(CH2)2-(optionally substituted 4-10 membered fused heterocyclyl). In some embodiments, R1is -(CH2)2-(optionally substituted 5-8 membered fused heterocyclyl). In some embodiments, R1is -(CH2)2-(optionally substituted 5-8 membered fused heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(CH2)2-(unsubstituted 4-10 membered fused heterocyclyl). In some embodiments, R1is -(CH2)2- (unsubstituted 5-8 membered fused heterocyclyl). In some embodiments, R1is -(CH2)2-(unsubstituted 5-8 membered fused heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1104 / 411U1197.70255WO00is -(CH2)2-(substituted 4-10 membered fused heterocyclyl). In some embodiments, R1is -(CH2)2-(substituted 5-8 membered fused heterocyclyl). In some embodiments, R1is -(CH2)2-(substituted 5-8 membered fused heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N.

[0273] In some embodiments, R1is — (C1-3 alkylene)-(5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is -(C1-3 alkylene)- (5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is -(C1-3 alkylene)-(5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0274] In some embodiments, R1is -(C1-3 alkylene)-(5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of -CH3, -CH2OH, - CH2N(CH3)2, -(C=O)CH3, -OH, or -N(CH3)2. In some embodiments, R1is — (C1-3 alkylene)-(5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of - CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH3, -OH, or -N(CH3)2. In some embodiments, R1is -(Ci-3 alkylene)-(5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH33, -OH, or -N(CH3)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0275] In some embodiments, R1is -(CH2)2-(5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of - OR° or -N(RN)2. In some embodiments, R1is -(CH2)2-(5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of Ci-3 alkyl, -(C=O)-(C1-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or-N(RN)2. In some embodiments, R1is -(CH2)2-(5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(C1-3 alkyl), halogen, -OR°, or -N(RN)2, wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.105 / 411U1197.70255WO00

[0276] In some embodiments, R1is -(CH2)2 — (5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of -CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH3s, -OH, or -N(CH3)2. In some embodiments, R1is -(CH2)2-(5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH₃, -CH2OH, -CH2N(CH3)2, -(C=O)CH3J, -OH, or -N(CH3)2. In some embodiments, R1is -(CH2)2-(5-8 membered fused heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH3, -OH, or -N(CH3)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0277] In some embodiments, R1is

[0278] In some embodiments, R1is -(C1-3 alkylene)- (optionally substituted 4-10 membered spirocyclic heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(optionally substituted 7-9 membered spirocyclic heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)-(optionally substituted 7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is — (C1-3 alkylene)-(unsubstituted 4-10 membered spirocyclic heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)- (un substituted 7-9 membered spirocyclic heterocyclyl). In some embodiments, R1is -(C1-3 alkylene)--(unsubstituted 7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(C1-3 alkylene)-(substituted 4-10 membered spirocyclic heterocyclyl). In some embodiments, R1is - (C1-3 alkylene)-(substituted 7-9 membered spirocyclic heterocyclyl). In some embodiments, R1is -(Ci-3 alkylene)-(substituted 7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N.

[0279] In some embodiments, R1is -(CH2)2-(optionally substituted 4-10 membered spirocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(optionally substituted 7-9 membered spirocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(optionally substituted 7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(CH2)2”(unsubstituted 4-10 membered 106 / 411U1197.70255WO00spirocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(unsubstituted 7-9 membered spirocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(unsubstituted 7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N. In some embodiments, R1is -(CH2)2“(substituted 4-10 membered spirocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(substituted 7-9 membered spirocyclic heterocyclyl). In some embodiments, R1is -(CH2)2-(substituted 7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from O and N.

[0280] In some embodiments, R1is -(C1-3 alkylene)-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is -(C1-3 alkylene )-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is -(C1-3 alkylene)-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(C1-3 alkyl), halogen, -OR°, or-N(RN)2, wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0281] In some embodiments, R1is -(C1-3 alkylene)-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of -CH3, -CH2OH, - CH2N(CH3)2, -(C=O)CH33, -OH, or -N(CH3)2. In some embodiments, R1is -(Ci-3 alkylene)-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of-CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH33, -OH, or-N(CH3)2. In some embodiments, R1is -(C1-3 alkylene)-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of-CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH33, -OH, or -N(CH3)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0282] In some embodiments, R1is -(CH2)2-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or-N(RN)2. In some embodiments, R1is -(CH2)2-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)- (C1-3 alkyl), halogen, -OR°, or -N(RN)2, and wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2. In some embodiments, R1is -(CH2)2-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, wherein each alkyl is independently 107 / 411U1197.70255WO00substituted with 0 or 1 instances of -OR° or -N(RN)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0283] In some embodiments, R1is -(CH2)2-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of -CH3, -CH2OH, -CH2N(CH3)2, - (C=O)CH, -OH, or -N(CH3)2. In some embodiments, R1is -(CH2)2-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, - CH2N(CH3)2, -(C=O)CH3, -OH, or -N(CH3)2. In some embodiments, R1is -(CH2)2-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, -CH2N(CH3)2, -(C=O)CH33, -OH, or -N(CH3)2, and wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

[0284] In some embodiments, R1is108 / 411U1197.70255WO00U1197.70255WO00U1197.70255WO00U1197.70255WO00embodiments, R1embodiments, R1is. In someembodiments, R1is. In someembodiments, R1is. In someembodiments, R1. In some embodiments, R1isembodiments, R1isembodiments, R1isembodiments,R1is

[0289] As generally described herein, R2is -NOz, -SO2CF3, or -CN.

[0290] In some embodiments, R2is -NO2. In some embodiments, R2is -SO2CF3. In some embodiments, R2is -CN.

[0291] As generally described herein, R4is optionally substituted heterocyclyl or optionally substituted heteroaryl.

[0292] In some embodiments, R4is optionally substituted 5-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, R4is optionally substituted 5-10 membered monocyclic heterocyclyl, wherein the heterocyclyl further comprises fused thereto an optionally substituted 5-10 membered bicyclic heteroaryl; or R4is optionally substituted 5-10 membered bicyclic heteroaryl.

[0293] In some embodiments, R4is optionally substituted 6-8 membered monocyclic heterocyclyl, wherein the heterocyclyl further comprises fused thereto an optionally substituted 112 / 411U1197.70255WO008-10 membered bicyclic heteroaryl; or R4is optionally substituted 8-10 membered bicyclic heteroaryl. In some embodiments, R4is optionally substituted 6-8 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O, wherein the heterocyclyl further comprises fused thereto an optionally substituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms: or R4is optionally substituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms.

[0294] In some embodiments, R4is unsubstituted 5-10 membered heterocyclyl or unsubstituted 5-10 membered heteroaryl. In some embodiments, R4is unsubstituted 5-10 membered monocyclic heterocyclyl, wherein the heterocyclyl further comprises fused thereto an unsubstituted 5-10 membered bicyclic heteroaryl; or R4is unsubstituted 5-10 membered bicyclic heteroaryl.

[0295] In some embodiments, R4is unsubstituted 6-8 membered monocyclic heterocyclyl, wherein the heterocyclyl further comprises fused thereto an unsubstituted 8-10 membered bicyclic heteroaryl; or R4is unsubstituted 8-10 membered bicyclic heteroaryl. In some embodiments, R4is unsubstituted 6-8 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O, wherein the heterocyclyl further comprises fused thereto an unsubstituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms; or R4is unsubstituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms.

[0296] In some embodiments, R4is optionally substituted heterocyclyl. In some embodiments, R4is unsubstituted heterocyclyl. In some embodiments, R4is substituted heterocyclyl.

[0297] In some embodiments, R4is optionally substituted 5-10 membered heterocyclyl. In some embodiments, R4is substituted 5-10 membered heterocyclyl. In some embodiments, R4is unsubstituted 5-10 membered heterocyclyl. In some embodiments, R4is optionally substituted 5- 10 membered monocyclic heterocyclyl, wherein the heterocyclyl further comprises fused thereto an optionally substituted 5-10 membered bicyclic heteroaryl. In some embodiments, R4is unsubstituted 5-10 membered monocyclic heterocyclyl, wherein the heterocyclyl further comprises fused thereto an unsubstituted 5-10 membered bicyclic heteroaryl.

[0298] In some embodiments, R4is optionally substituted 6-8 membered monocyclic heterocyclyl, wherein the heterocyclyl further comprises fused thereto an optionally substituted 8-10 membered bicyclic heteroaryl. In some embodiments, R4is unsubstituted 6-8 membered monocyclic heterocyclyl, wherein the heterocyclyl further comprises fused thereto an unsubstituted 8-10 membered bicyclic heteroaryl.

[0299] In some embodiments, R4is optionally substituted 6-8 membered monocyclic heterocyclyl containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, wherein the heterocyclyl further comprises fused thereto an optionally substituted 8-10 membered bicyclic 113 / 411U1197.70255WO00heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, R4is unsubstituted 6-8 membered monocyclic heterocyclyl containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, wherein the heterocyclyl further comprises fused thereto an unsubstituted 8-10 membered bicyclic heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S.

[0300] In some embodiments, R4is optionally substituted 6-8 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O, wherein the heterocyclyl further comprises fused thereto an optionally substituted 8-10 membered bicyclic heteroaryl containing 1, 2, 3, or 4 ring N atoms. In some embodiments, R4is unsubstituted 6-8 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O, wherein the heterocyclyl further comprises fused thereto an unsubstituted 8-10 membered bicyclic heteroaryl containing 1, 2, 3, or 4 ring N atoms.

[0301] In some embodiments, R4is optionally substituted 6-8 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O, wherein the heterocyclyl further comprises fused thereto an optionally substituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms. In some embodiments, R4is unsubstituted 6-8 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O, wherein the heterocyclyl further comprises fused thereto an unsubstituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms.

[0303] In some embodiments, R4is optionally substituted heteroaryl. In some embodiments, R4is unsubstituted heteroaryl. In some embodiments, R4is substituted heteroaryl. In some embodiments, R4is optionally substituted 5-10 membered heteroaryl. In some embodiments, R4is unsubstituted 5-10 membered heteroaryl. In some embodiments, R4is substituted 5-10 membered heteroaryl.

[0304] In some embodiments, R4is optionally substituted 5-10 membered bicyclic heteroaryl. In some embodiments, R4is unsubstituted 5-10 membered bicyclic heteroaryl. In some embodiments, R4is substituted 5-10 membered bicyclic heteroaryl. In some embodiments, R4is optionally substituted 8-10 membered bicyclic heteroaryl. In some embodiments, R4is unsubstituted 8-10 membered bicyclic heteroaryl. In some embodiments, R4is substituted 8-10114 / 411U1197.70255WO00membered bicyclic heteroaryl.

[0305] In some embodiments, R4is optionally substituted 8-10 membered bicyclic heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, R4is unsubstituted 8-10 membered bicyclic heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, R4is substituted 8-10 membered bicyclic heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S.

[0306] In some embodiments, R4is optionally substituted 8-10 membered bicyclic heteroaryl containing 1, 2, 3, or 4 ring N atoms. In some embodiments, R4is unsubstituted 8-10 membered bicyclic heteroaryl containing 1, 2, 3, or 4 ring N atoms. In some embodiments, R4is substituted 8-10 membered bicyclic heteroaryl containing 1, 2, 3, or 4 ring N atoms.

[0307] In some embodiments, R4is optionally substituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms. In some embodiments, R4is unsubstituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms. In some embodiments, R4is substituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms.

[0310] As generally described herein, L4is absent, O -, or -NH-.

[0311] In some embodiments, L4is absent. In some embodiments, L4is -O-. In some embodiments, L4is -NH -.115 / 411U1197.70255WO00

[0313] In some embodiments, R4isis -0 - or NH -. In someMoieties Lla, Llb, L2, and L3

[0315] As generally described herein, Llais optionally substituted heterocyclylene.

[0316] In some embodiments, Llais unsubstituted heterocyclylene. In some embodiments, Llais substituted heterocyclylene.

[0317] In some embodiments, Liais optionally substituted 5-6 membered monocyclic heterocyclylene, optionally substituted 6-10 membered bridged heterocyclylene, optionally substituted 8-10 membered fused heterocyclylene, or optionally substituted 7-12 membered spirocyclic heterocyclylene. In some embodiments, Llais unsubstituted 5-6 membered monocyclic heterocyclylene, unsubstituted 6-10 membered bridged heterocyclylene, unsubstituted 8-10 membered fused heterocyclylene, or unsubstituted 7-12 membered spirocyclic heterocyclylene.

[0318] In some embodiments, Llais optionally substituted monocyclic heterocyclylene, optionally substituted bridged heterocyclylene, optionally substituted fused heterocyclylene, or optionally substituted spirocyclic heterocyclylene, wherein the heterocyclylene contains 1 or 2 ring N atoms. In some embodiments, Liais unsubstituted monocyclic heterocyclylene,116 / 411U1197.70255WO00unsubstituted bridged heterocyclylene, unsubstituted fused heterocyclylene, or unsubstituted spirocyclic heterocyclylene, wherein the heterocyclylene contains 1 or 2 ring N atoms.

[0319] In some embodiments, Llais optionally substituted 5-6 membered monocyclic heterocyclylene, optionally substituted 6-10 membered bridged heterocyclylene, optionally substituted 8-10 membered fused heterocyclylene, or optionally substituted 7-12 membered spirocyclic heterocyclylene, wherein the heterocyclylene contains 1 or 2 ring N atoms. In some embodiments, Llais unsubstituted 5-6 membered monocyclic heterocyclylene, unsubstituted 6-10 membered bridged heterocyclylene, unsubstituted 8-10 membered fused heterocyclylene, or unsubstituted 7-12 membered spirocyclic heterocyclylene, wherein the heterocyclylene contains 1 or 2 ring N atoms.

[0320] In some embodiments, Liais optionally substituted monocyclic heterocyclylene. In some embodiments, Llais optionally substituted monocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais optionally substituted monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, Liais unsubstituted monocyclic heterocyclylene. In some embodiments, Llais unsubstituted monocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Liais unsubstituted monocyclic heterocyclylene containing 1 or 2 ring N atoms.

[0321] In some embodiments, Liais optionally substituted 5-6 membered monocyclic heterocyclylene. In some embodiments, Llais optionally substituted 5-6 membered monocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais optionally substituted 5-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, Llais unsubstituted 5-6 membered monocyclic heterocyclylene, In some embodiments, Llais unsubstituted 5-6 membered monocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais unsubstituted 5-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms.

[0322] In some embodiments,Liais *.

[0323] In some embodiments, Llais optionally substituted bridged heterocyclylene, In some embodiments, Llais optionally substituted bridged heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais optionally substituted bridged heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, Llais unsubstituted bridged heterocyclylene. In some embodiments, Llais unsubstituted bridged 117 / 411U1197.70255WO00heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais unsubstituted bridged heterocyclylene containing 1 or 2 ring N atoms.

[0324] In some embodiments, Llais optionally substituted 6-10 membered bridged heterocyclylene. In some embodiments, Llais optionally substituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais optionally substituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, Llais unsubstituted 6-10 membered bridged heterocyclylene. In some embodiments, Llais unsubstituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, L1ais unsubstituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms.

[0326] In some embodiments, Liais optionally substituted fused heterocyclylene. In some embodiments, Llais optionally substituted fused heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais optionally substituted fused heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, Llais unsubstituted fused heterocyclylene. In some embodiments, Llais unsubstituted fused heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais unsubstituted fused heterocyclylene containing 1 or 2 ring N atoms.

[0327] In some embodiments, Llais optionally substituted 8-10 membered fused heterocyclylene. In some embodiments, Llais optionally substituted 8-10 membered fused heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais optionally substituted 8-10 membered fused heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, Llais unsubstituted 8-10 membered fused heterocyclylene. In some embodiments, Llais unsubstituted 8-10 membered fused heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some118 / 411U1197.70255WO00embodiments, L1ais unsubstituted 8-10 membered fused heterocyclylene containing 1 or 2 ring N atoms.H HI— N I N-| |—N I N— II I 8 I

[0328] In some embodiments, Llais H or H

[0329] In some embodiments, Liais optionally substituted spirocyclic heterocyclylene. In some embodiments, Llais optionally substituted spirocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais optionally substituted spirocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, Llais unsubstituted spirocyclic heterocyclylene. In some embodiments, L1ais unsubstituted spirocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais unsubstituted spirocyclic heterocyclylene containing 1 or 2 ring N atoms.

[0330] In some embodiments, Llais optionally substituted 7-12 membered spirocyclic heterocyclylene. In some embodiments, L,ais optionally substituted 7-12 membered spirocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais optionally substituted 7-12 membered spirocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, Llais unsubstituted 7-12 membered spirocyclic heterocyclylene. In some embodiments, Llais unsubstituted 7-12 membered spirocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llais unsubstituted 7-12 membered spirocyclic heterocyclylene containing 1 or 2 ring N atoms.

[0331] In some embodiments, Llais119 / 411U1197.70255WO00embodiments, Llais

[0333] As generally described herein, Llbis absent or optionally substituted heterocyclylene.

[0334] In some embodiments, Llbis absent.

[0335] In some embodiments, Libis optionally substituted heterocyclylene. In some embodiments, Llbis substituted heterocyclylene. In some embodiments, Llbis unsubstituted heterocyclylene.

[0336] In some embodiments, Llbis optionally substituted monocyclic heterocyclylene. In some embodiments, L1bis optionally substituted monocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llbis optionally substituted monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, Llbis unsubstituted monocyclic heterocyclylene. In some embodiments, Libis unsubstituted monocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llbis unsubstituted monocyclic heterocyclylene containing 1 or 2 ring N atoms.

[0337] In some embodiments, Llbis optionally substituted 5-6 membered monocyclic heterocyclylene. In some embodiments, Llbis optionally substituted 5-6 membered monocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, Llbis optionally substituted 5-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, Llbis unsubstituted 5-6 membered monocyclic heterocyclylene. In some embodiments, Llbis unsubstituted 5-6 membered monocyclic heterocyclylene containing 1 or 2 ring heteroatoms selected from N, O, and S. In some 120 / 411U1197.70255WO00embodiments, L1bis unsubstituted 5-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms.

[0338] In some embodiments, L1bisor. In some embodiments, L1bisabsent,

[0339] In some embodiments, Llais unsubstituted monocyclic heterocyclylene, un substituted bridged heterocyclylene, unsubstituted fused heterocyclylene, or unsubstituted spirocyclic heterocyclylene, wherein the heterocyclylene contains 1 or 2 ring N atoms; and Llbis absent. In some embodiments, Llais unsubstituted 5-6 membered monocyclic heterocyclylene, unsubstituted 6-10 membered bridged heterocyclylene, unsubstituted 8-10 membered fused heterocyclylene, or unsubstituted 7-12 membered spirocyclic heterocyclylene: and Libis absent. In some embodiments, Llais unsubstituted 5-6 membered monocyclic heterocyclylene, unsubstituted 6-10 membered bridged heterocyclylene, unsubstituted 8-10 membered fused heterocyclylene, or unsubstituted 7-12 membered spirocyclic heterocyclylene, wherein the heterocyclylene contains 1 or 2 ring N atoms; and Llbis absent.

[0340] In some embodiments, Llais unsubstituted monocyclic heterocyclylene; and Llbis unsubstituted monocyclic heterocyclylene. In some embodiments, Llais unsubstituted 5-6 membered monocyclic heterocyclylene; and Libis unsubstituted 5-6 membered monocyclic heterocyclylene. In some embodiments, Llais unsubstituted 5-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms; and Libis unsubstituted 5-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms.121 / 411U1197.70255WO00. In some embodiments, -Llb-some embodiments, -L1b-L1a- is ' In certain embodiments, -L1b-L1a- is

[0342] In some embodiments,is or. In certain embodiments, -

[0343] As generally described herein, L2is absent or optionally substituted C1-12 alkylene or optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with O -, -NRN-, =N -, -N=, -S -, -S(=O) -S(=O)2- -C(=O) -, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0344] In some embodiments, L2is absent.

[0345] 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-, -NRN-, =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 C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -O-, -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted C1-12 alkylene, optionally wherein one or more 122 / 411U1197.70255WO00backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene.

[0346] In some embodiments, L2comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted Ct-12 alkylene are independently replaced with -O-, ~NRN~, =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 C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -O-, -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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-, -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -O-, -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene.

[0347] In some embodiments, L2comprises optionally substituted Ci-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted Ci-e alkylene are independently replaced with -O-, -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. In some embodiments, L2comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6123 / 411U1197.70255WO00alkylene are independently replaced with -O-, -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -O-, -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene.

[0348] 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-, -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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-, -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted hetero 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-, -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene. 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 -NRN-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted heteroarylene.

[0349] 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 -NRN-. 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 -NRN~. In some embodiments, L2comprises unsubstituted C1-12 alkylene, wherein one or 124 / 411U1197.70255WO00more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with -NRN-. 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 -NRN-. 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 -NRN-. 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 -NRN-. 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 -NRN-. 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 -NRN-. 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 - NRN-.

[0350] 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 Ci-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 Cue 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 C1-6 alkylene are independently replaced with -NH-. In some embodiments, L2comprises unsubstituted Cj-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 Ci-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 un substituted C1-3 alkylene are independently replaced with -NH-.

[0351] 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 -S(=O)2-. In some embodiments, L2comprises substituted C1-12 alkylene, wherein 125 / 411U1197.70255WO00one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with -S(=O)’-. 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 -S(=O)2-. 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 -S(=O)2-. 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 -S(=O)2-. 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 -S(=O)2-. 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 -S(=O)2-. 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 -S(=O)2-. 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 - S(=O)2-.

[0352] 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 Cj -12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with -C(=O)-. In some embodiments, L2comprises unsubstituted Cj-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with -C(=O)-. 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 -C(=O)-. 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 -C(=O)-. In some embodiments, L2comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted Cj-6 alkylene are independently replaced with -C(=O)-. 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 -C(=O)-. 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 -C(=O)- 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 -C(=O)-.126 / 411U1197.70255WO00

[0353] 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 heterocyclylene. 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 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 Ci-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 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.

[0354] 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 C1-12 alkylene are independently replaced with unsubstituted 6-10 membered bridged 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 6-10 membered bridged 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 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms.127 / 411U1197.70255WO00

[0355] In some embodiments, L2comprises optionally substituted Ci-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted Cj-6 alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted Ci-6 alkylene, wherein one or more backbone carbon atoms in the substituted Ci-6 alkylene are independently replaced with unsubstituted 4-6 membered monocyclic 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 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. 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 unsubstituted 6-10 membered bridged 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 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 C1-66 alkylene are independently replaced with unsubstituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms.

[0356] In some embodiments, L2comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independentlyreplaced with a moiety of formula:' or ', wherein 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:', ', or

[0357] In some embodiments, L2comprises optionally substituted Cj-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently128 / 411U1197.70255WO00replaced with a moiety of formula:f or *, wherein each instance of X is independently CH or N. In some embodiments, L2comprises optionally substituted Ci-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted Ci-6 alkylene areindependently replaced with a moiety of formula:', <, or / .

[0358] In some embodiments, L2comprises optionally substituted Cj -12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with optionally substituted heteroarylene. 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 heteroarylene. 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 heteroarylene. In some embodiments, L2comprises optionally substituted Ci -6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with unsubstituted heteroarylene. 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 heteroarylene. In some embodiments, L2comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted Ci-6 alkylene are independently replaced with unsubstituted heteroarylene.

[0359] 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.

[0360] 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 4-6129 / 411U1197.70255WO00membered 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 some embodiments, 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.

[0361] In some embodiments, L2comprises optionally substituted 6-10 membered bridged heterocyclylene. In some embodiments, L2comprises optionally substituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises optionally substituted 6-10 membered bridged heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises optionally substituted 6-10 membered bridged heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises substituted 6-10 membered bridged heterocyclylene. In some embodiments, L2comprises substituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted 6-10 membered bridged heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises substituted 6-10 membered bridged heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises unsubstituted 6-10 membered bridged heterocyclylene. In some embodiments, L2comprises unsubstituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises unsubstituted 6-10 membered bridged heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises un substituted 6-10 membered bridged heterocyclylene containing 2 ring N atoms.

[0362] In some embodiments, L2comprises optionally substituted 6-10 membered fused heterocyclylene. In some embodiments, L2comprises optionally substituted 6-10 membered fused heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises optionally substituted 6-10 membered fused heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises optionally substituted 6-10 membered fused heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises substituted 6-10 membered fused heterocyclylene. In some embodiments, L2comprises substituted 6-10 membered fused heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted 6-10 membered fused heterocyclylene containing 1 ring N atom. In some embodiments, L2130 / 411U1197.70255WO00comprises substituted 6-10 membered fused heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises unsubstituted 6-10 membered fused heterocyclylene. In some embodiments, L2comprises unsubstituted 6-10 membered fused heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises unsubstituted 6-10 membered fused heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises unsubstituted 6- 10 membered fused heterocyclylene containing 2 ring N atoms.

[0363] In some embodiments, L2comprises optionally substituted 6-12 membered spirocyclic heterocyclylene. In some embodiments, L2comprises optionally substituted 6-12 membered spirocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises optionally substituted 6-12 membered spirocyclic heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises optionally substituted 6-12 membered spirocyclic heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises substituted 6-12 membered spirocyclic heterocyclylene. In some embodiments, L2comprises substituted 6-12 membered spirocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises substituted 6-12 membered spirocyclic heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises substituted 6-12 membered spirocyclic heterocyclylene containing 2 ring N atoms. In some embodiments, L2comprises unsubstituted 6-12 membered spirocyclic heterocyclylene. In some embodiments, L2comprises unsubstituted 6-12 membered spirocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2comprises unsubstituted 6-12 membered spirocyclic heterocyclylene containing 1 ring N atom. In some embodiments, L2comprises unsubstituted 6-12 membered spirocyclic heterocyclylene containing 2 ring N atoms.

[0364] In some embodiments, L2comprises a moiety of formula:wherein each instance of X is independently CH or N. In some embodiments, L2comprises amoiety of formula:

[0365] In some embodiments, L2comprises a moiety of formula:embodiments, L2comprises a moiety of formula:. In some embodiments, L2131 / 411U1197.70255WO00< N N"~\. In some embodiments, L2comprises a f-N.moiety of formula: In some embodiments, L2comprises a moiety of formula:. In some embodiments, L2comprises a moiety of formula: ^NDN”A.

[0366] In certain embodiments, L2is -(optionally substituted monocyclic heterocyclylene)- (optionally substituted C1-2 alkylene) -, -(optionally substituted bicyclic heterocyclylene) - (optionally substituted C1-2 alkylene)-, -(optionally substituted monocyclic heteroarylene)- (optionally substituted Ct-2 alkylene)-, -(optionally substituted C1-2 alkylene)-(optionally substituted monocyclic heterocyclylene)-, -(optionally substituted C1-2 alkylene)-(optionally substituted bicyclic heterocyclylene)-, or -(optionally substituted Cj-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-, -NRN-, or -C(=O)

[0367] In certain embodiments, L2is -(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 Ct-2 alkylene)-, or -(optionally substituted Cj -2 alkylene)-(optionally substituted monocyclic heteroarylene)-(optionally substituted C1-2 alkylene)-, optionally wherein one or two backbone carbon atoms in each instance of the optionally substituted C1-2 alkylene are independently replaced with O -, -NRN-, or -C(=O)

[0368] In certain embodiments, L2is -(optionally substituted monocyclic heterocyclylene) - (optionally substituted Ci alkylene) -, -(optionally substituted Ci alkylene) --(optionally substituted monocyclic heterocyclylene)’-, -(optionally substituted Ci alkylene [-(optionally substituted monocyclic heterocyclylene)2-(optionally substituted Ci alkylene)-, -(optionally substituted monocyclic heterocyclylene )-(optionally substituted monocyclic carbocyclylene)- (optionally substituted Ct alkylene)-, -(optionally substituted monocyclic carbocyclylene)- (optionally substituted monocyclic heterocyclylene)-(optionally substituted Ci alkylene)-, - (optionally substituted Cj alkylene)-! optionally substituted monocyclic heterocyclylene)- (optionally substituted monocyclic carbocyclylene) --, or --(optionally substituted Ci alkylene) - (optionally substituted monocyclic carbocyclylene)-(optionally substituted monocyclic heterocyclylene) --, optionally wherein the backbone carbon atom in each instance of the optionally substituted Cj alkylene is independently replaced with -O-, -NRN-, or -C(=O)-.132 / 411U1197.70255WO00

[0369] In some embodiments, L2is absent orrwherein each instance of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each instance of m3133 / 411U1197.70255WO00is independently 1 or 2.7, 8, 9, or 10; and each instance of m3 is independently 1 or 2.

[0371] In some embodiments, L2is:134 / 411U1197.70255WO00U1197.70255WO00

[0373] As generally described herein, L3is absent or optionally substituted C1-12 alkylene, optionally substituted Cm 2 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 Cj-12 alkenylene, or optionally substituted C2-12 alkynylene are independently replaced with O -, -NRN-, =N -, - N=, S. -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0374] In some embodiments, L3is absent.

[0375] In some embodiments, L3comprises optionally substituted C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene, are independently replaced with O -NRN=N -, -N==, --S-, -S(=O) -, -S(=O)2- -C(=O) -, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0376] In some embodiments, L3comprises optionally substituted Cj-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NRN-, -C(=O)~-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises optionally substituted C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci- 12 alkylene are independently replaced with -NRN-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene.

[0377] In some embodiments, L3comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -O-, ~NRN~, =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, L3comprises optionally substituted Ci j 2 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with O -, -NRN-, -C(=O) -, optionally substituted 136 / 411U1197.70255WO00heterocyclylene, or optionally substituted arylene. In some embodiments, LJcomprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -NRN- -C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with -O-, -NRN~, ~-C(=O)~, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, I? comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with -NRN-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1.12 alkylene are independently replaced with -O-, -NRN~, -C(=O)~, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises unsubstituted C1.12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with --NRN-C(=O) -, optionally substituted heterocyclylene, or optionally substituted arylene.

[0378] In some embodiments, L3comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with -O-, -~NRN-, -~C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with -NRN~, -C(=O)~, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises substituted Cj-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with -O-, -NRN-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with -NRN~, — C(=O)-~, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with O. ~NRN~, -C(=O)~, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with --NRN-C(=O) -, optionally substituted heterocyclylene, or optionally substituted arylene.137 / 411U1197.70255WO00

[0379] In some embodiments, I? comprises optionally substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3 alkylene are independently replaced with -O-, -NRN~, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises optionally substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the optionally substituted Ci 3 alkylene are independently replaced with ~NRN~, ~-C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with -O-, -NRN-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with ~NRN~ — C(=O)—, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises unsubstituted C1-3 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3 alkylene are independently replaced with -O-, -NRN~, - C(=O) -, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises un substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3 alkylene are independently replaced with -NRN-, -C(=O) optionally substituted heterocyclylene, or optionally substituted arylene.

[0380] In some embodiments, L3comprises optionally substituted C1- J2 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently- replaced with -NRN- In some embodiments, L3comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with -NN-. In some embodiments, L3comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with -NRN-. In some embodiments, L3comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with -NRN~. In some embodiments, L3comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with -NRN~. In some embodiments, L3comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with - NRNIn some embodiments, L3comprises optionally substituted Ci-3 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-3 alkylene are independently replaced with -NRNIn some embodiments, I? comprises substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with ~NN~. In some embodiments, 1 / comprises unsubstituted Ci 3 alkylene, wherein one or more 138 / 411U1197.70255WO00backbone carbon atoms in the unsubstituted C1-3 alkylene are independently replaced with --NRN-.

[0381] In some embodiments, L3comprises optionally substituted Cj -12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -NH-. In some embodiments, L3comprises substituted Ci -12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with -NH-. In some embodiments, L3comprises unsubstituted Cj-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with ---NH-. In some embodiments, L3comprises optionally substituted Cj-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted Cue alkylene are independently replaced with -NH-. In some embodiments, L3comprises substituted Ci-e alkylene, wherein one or more backbone carbon atoms in the substituted C j -6 alkylene are independently replaced with -NH-. In some embodiments, L3comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted Ct-6 alkylene are independently replaced with -NH-. In some embodiments, L3comprises 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, L3comprises substituted C1-3 alkylene, wherein one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with -Nil-. In some embodiments, L3comprises unsubstituted C1-3 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-3 alkylene are independently replaced with -NH-.

[0382] In some embodiments, L3comprises optionally substituted Cj-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, L3comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with -C(=O)-. In some embodiments, L3comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkylene are independently replaced with -C(=O)~. In some embodiments, L3comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1- alkylene are independently replaced with -C(=O)-. In some embodiments, L3comprises substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the substituted Ct-6 alkylene are independently replaced with -C(=O) In some embodiments, L3comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C1-6 alkylene are independently replaced with -C(=O) In some embodiments, L3comprises 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, L3comprises substituted C1-3 alkylene, wherein 139 / 411U1197.70255WO00one or more backbone carbon atoms in the substituted C1-3 alkylene are independently replaced with -C(=O)-. In some embodiments, L3comprises unsubstituted C1-3 alkylene, wherein one or more backbone carbon atoms in the unsubstituted C13 alkylene are independently replaced with - C(=O)-.

[0383] In some embodiments, L3comprises 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, L3comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, LJcomprises 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, L3comprises optionally substituted C j -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, L3comprises 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, L3comprises unsubstituted Ci-j 2 alkylene, wherein one or more backbone carbon atoms in the unsubstituted Ci j 2 alkylene are independently replaced with optionally substituted 4-10 membered heterocyclylene containing 1 or 2 ring N atoms.

[0384] In some embodiments, L3comprises optionally substituted Cj -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, L3comprises 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, L3comprises unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted Ci j 2 alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L3comprises optionally substituted C1- J2 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with unsubstituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L3comprises substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the substituted C1-12 alkylene are independently replaced with unsubstituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L? comprises 140 / 411U1197.70255WO00unsubstituted C1-12 alkylene, wherein one or more backbone carbon atoms in the unsubstituted Cj-12 alkylene are independently replaced with unsubstituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms.

[0385] In some embodiments, L3comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted Ct-6 alkylene are independently replaced with unsubstituted 4-6 membered monocyclic heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L3comprises substituted Ct-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, LJcomprises 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, L3comprises optionally substituted C1-6 alkylene, wherein one or more backbone carbon atoms in the optionally substituted Cis alkylene are independently replaced with unsubstituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, LJcomprises substituted Ct-6 alkylene, wherein one or more backbone carbon atoms in the substituted C1-6 alkylene are independently replaced with unsubstituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L3comprises unsubstituted C1-6 alkylene, wherein one or more backbone carbon atoms in the unsubstituted Ct- 6 alkylene are independently replaced with unsubstituted 6-10 membered bridged heterocyclylene containing 1 or 2 ring N atoms.

[0386] In some embodiments, L3comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently Xx^ XN^k^Ny k^xyreplaced with a moiety of formula:' or ', wherein each instance of X is independently CH or N. In some embodiments, L3comprises optionally substituted C1-12 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkyleneXN*^! XN^^I k^Ny kXy are independently replaced with a moiety of formula:', ', or

[0387] In some embodiments, L3comprises optionally substituted C1-6 alkylene, wherein one or141 / 411U1197.70255WO00more backbone carbon atoms in the optionally substituted Cue alkylene are independently Xx^ XN^replaced with a moiety of formula: / or / , wherein each instance of X is independently CH or N. In some embodiments, L3comprises optionally substituted Cue alkylene, wherein one or more backbone carbon atoms in the optionally substituted Cue alkylene are XN^ XN-^ XX^ independently replaced with a moiety of formula: / , k^Xy / , or k^Ny / .

[0388] In some embodiments, L3comprises optionally substituted Cj-12 alkenylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkenylene are independently replaced with -O-, ~NRN~, =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, L3comprises optionally substituted C1-12 alkenylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkenylene are independently replaced with -O-, -NN-, -C(=O)~, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises substituted C1-12 alkenylene, optionally wherein one or more backbone carbon atoms in the substituted Cui2 alkenylene are independently replaced with -O~, ~NRN~, -C(=O)~, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises unsubstituted Cm2 alkenylene, optionally wherein one or more backbone carbon atoms in the unsubstituted C1-12 alkenylene are independently replaced with -O-, -NRN-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, I? comprises 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-, ~NRN~, -C(=O)~, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises substituted C2-6 alkynylene, optionally wherein one or more backbone carbon atoms in the substituted C2-6 alkynylene are independently replaced with -O-, -NRN-, -C(=O)~-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises unsubstituted C2-6 alkynylene, optionally wherein one or more backbone carbon atoms in the unsubstituted C2-6 alkynylene are independently replaced with -O-, -NRN-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene.

[0389] In some embodiments, L3comprises optionally substituted C2-12 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C212 alkynylene are 142 / 411U1197.70255WO00independently replaced with O -NRN=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, L3comprises optionally substituted C2-12 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C212 alkynylene are independently replaced with -O-, NR''. - C(=O)~, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises substituted C2-12 alkynylene, optionally wherein one or more backbone carbon atoms in the substituted C2-12 alkynylene are independently replaced with O -NRN-, — C(=O)—, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises unsubstituted C2-12 alkynylene, optionally wherein one or more backbone carbon atoms in the unsubstituted C2-12 alkynylene are independently replaced with - O- -NRN- -C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3comprises 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 -NRN-C(=O) -, optionally substituted heterocyclylene, or optionally substituted arylene. In some embodiments, L3com...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I"):or a pharmaceutically acceptable salt thereof, wherein:R1is -(Cj-3 alkylene)-Rla, wherein the alkylene is unsubstituted, and Rlais optionally substituted 4-10 membered heterocyclyl. OR°, --N(RN)2, or optionally substituted C4-10 carbocyclyl;R2is -NO2, -SO2CF3, or -CN;Q1is CH, CCH3, or N; or Q1is, wherein ml is 1 or 2, m2 is 0 or 1, and L2is attached to Z at the ring N atom of Q1;Q2is CH orN;Q3is C, CH, or N, as vaiency permits;X1is --CH2-- or absent;X2is absent or -CH2-, wherein X2is attached to the aryl ring of (z-5), (z-6), or (z-7); p is 0 or 1;370 / 411U1197.70255WO00R3is aryl, carbocyclyl, heteroaryl, R3b, or alkenyl, wherein the carbocyclyl, aryl, heteroaryl, or alkenyl is substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits;each instance of R3ais independently optionally substituted alkyl, optionally substituted cycloalkyl, -OR°, halogen, -CN, or -NO2;R3bis optionally substituted alkyl, hydrogen, or halogen;R4is optionally substituted heteroaryl or optionally substituted heterocyclyl;Llais optionally substituted heterocyclylene;Llbis absent or optionally substituted heterocyclylene;L2is absent or optionally substituted C1-12 alkylene or optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -O-, -NRN- =N-, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is 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-, -NRN~, =N~, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)~, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L4is O -, absent, or -NH-;each instance of R° is independently hydrogen or optionally substituted alkyl;each instance of RNis independently hydrogen or optionally substituted alkyl, or two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl; andY is a moiety that is capable of binding to an E3 ubiquitin ligase.371 / 411U1197.70255WO002. The compound of claim 1, wherein the compound is of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is -(Ci-3 alkylene)-Rla, wherein the alkylene is unsubstituted, and Rlais optionally substituted 4-10 membered heterocyclyl, -OR°, -N(RN)2, or optionally substituted C4-10 carbocyclyl;R2is -NO2, --SO2CF3, or -CN;attached to Z at the ring N atom of Q1;Q2is CH orN;Q3is C, CH, or N, as valency permits;X1is -CH2- or absent;X2is absent or -CH2-, wherein X2is attached to the aryl ring of (z-5), (z-6), or (z-7); p is 0 or 1;R3is aryl, carbocyclyl, heteroaryl,or, wherein the carbocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 instances of R311, as valency permits;each instance of R3ais independently optionally substituted alkyl, optionally substituted cycloalkyl, -OR°, halogen, -CN, or -NO2;R3bis optionally substituted alkyl, hydrogen, or halogen;R4is optionally substituted heteroaryl or optionally substituted heterocyclyl;372 / 411U1197.70255WO00Llais optionally substituted heterocyclylene;Llbis absent or optionally substituted heterocyclylene;L2is absent or optionally substituted Cnn alkylene or optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NRN-, =N-, -N=, S, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;I? is 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 Cun alkylene, optionally substituted C1-12 alkenylene, or optionally substituted C2-12 alkynylene are independently replaced with -O-, -NRN~, =N~, -N=, ~S~, ~S(=O)~, ~S(=O)2”, ~ C(=O)~, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L4is O. absent, or -NH-;each instance of R° is independently hydrogen or optionally substituted alkyl;each instance of RNis independently hydrogen or optionally substituted alkyl, or two instances ofNare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl; andY is a moiety that is capable of binding to an E3 ubiquitin ligase.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is of373 / 411U1197.70255WO00U1197.70255WO00F375 / 411U1197.70255WO00U1197.70255WO00J s HO (y-75), HO (y-76).HO (y-77). HO (y-78).wherein:each instance of Q4is independently CH or N;each instance of v is independently 1 or 2; andeach instance of RYis independently -CHs, -CH2CH3, -CH(CH )2, -CH(CH3)CH2CH3, ~ C(CH3)3, -CHF2, cyclopropyl, or cyclobutyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is of formula:377 / 411U1197.70255WO00U1197.70255WO00(y-44p), (y-44q)379 / 411U1197.70255WO00wherein:each instance of Q4is independently CH or N;each instance of R5is independently H, F, Cl, Br, -CN, -OMe, Me, -CH2F, -CHF2, or - CF3; andeach instance of v is independently 1 or 2.

5. A compound of Formula (I"'):or a pharmaceutically acceptable salt thereof, wherein:R1is -(Ci.3 alkylene)-Rla, wherein the alkylene is unsubstituted, and Rlais optionally substituted 4-10 membered heterocyclyl, -OR°, -N(RN)2, or optionally substituted C4-10 carbocyclyl;R2is -NO2, --SO2CF3, or -CN;380 / 411U1197.70255WO00Q1is CH, CCH3, or N; or Q1is, wherein ml is 1 or 2, m2 is 0 or 1, and L2is attached to Z at the ring N atom of Q1;Q2is CH orN;Q3is C, CH, or N, as valency permits;X1is -CH2- or absent;X2is absent or ~-CH2-, wherein X2is attached to the aryl ring of (z-5), (z-6), or (z-7); p is 0 or 1;R3is aryl, carbocyclyl, heteroaryl,R3b, or alkenyl, wherein the carbocyclyl, aryl, heteroaryl, or alkenyl is substituted with 0, 1, 2, 3, 4, or 5 instances of R3a, as valency permits;each instance of R3ais independently optionally substituted alkyl, optionally substituted cycloalkyl, -OR°, halogen, -CN, or -NC;R3bis optionally substituted alkyl, hydrogen, or halogen;R4is optionally substituted heteroaryl or optionally substituted heterocyclyl;Llais optionally substituted heterocyclyl ene;Llbis absent or optionally substituted heterocyclylene;L2is absent or optionally substituted C1-12 alkylene or optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with -O-, -NRN-, =N- -N=, -S-, — S(=O)—, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is 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-, -NRN~, =N~, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L4is O -, absent, or -NH-;each instance of R° is independently hydrogen or optionally substituted alkyl;381 / 411U1197.70255WO00each instance of RNis independently hydrogen or optionally substituted alkyl, or two instances of RNare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl; andY is of formula:382 / 411U1197.70255WO00,0,0383 / 411U1197.70255WO00U1197.70255WO00wherein:each instance of Q4is independently CH or N;each instance of R5is independently H, F, CI, Br, -CN, -OMe, Me, -CH2F, -CHF₂, or - CF3; andeach instance of v is independently 1 or 2.386 / 411U1197.70255WO006. The compound of claim 5, wherein the compound is of Formula (I’):or a pharmaceutically acceptable salt thereof, wherein:R1is -(Ci-3 alkylene)-Rla, wherein the alkylene is unsubstituted, and Rlais optionally substituted 4-10 membered heterocyclyl, -OR°, -N(RN)2, or optionally substituted C4-10 carbocyclyl;R2is -NO2, --SO2CF3, or -CN;attached to Z at the ring N atom of Q1;Q2is CH orN;Q3is C, CH, or N, as valency permits;X1is -CH2- or absent;X2is absent or -CH2-, wherein X2is attached to the aryl ring of (z-5), (z-6), or (z-7); p is 0 or 1;R3is aryl, carbocyclyl, heteroaryl,or, wherein the carbocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 instances of R311, as valency permits;each instance of R3ais independently optionally substituted alkyl, optionally substituted cycloalkyl, -OR°, halogen, -CN, or -NO2;R3bis optionally substituted alkyl, hydrogen, or halogen;R4is optionally substituted heteroaryl or optionally substituted heterocyclyl;387 / 411U1197.70255WO00Llais optionally substituted heterocyclylene;Llbis absent or optionally substituted heterocyclylene;L2is absent or optionally substituted C1-12 alkylene or optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with -O-, -NRN-=N-, -N=, S, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;I? is 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 Cun alkylene, optionally substituted C1-12 alkenylene, or optionally substituted C2-12 alkynylene are independently replaced with -O-, -NRN~, =N~, -N=, ~S~, ~S(=O)~, ~S(=O)2~ ~ C(=O)~, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L4is O. absent, or -NH-;each instance of R° is independently hydrogen or optionally substituted alkyl;each instance of RNis independently hydrogen or optionally substituted alkyl, or two instances ofNare joined with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl; andY is of formula;388 / 411U1197.70255WO00U1197.70255WO00U1197.70255WO00wherein:each instance of Q4is independently CH or N; andeach instance of v is independently 1 or 2.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:391 / 411U1197.70255WO009. The compound of any one of claims 1-6, wherein the compound is of Formula (II):or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, wherein the compound is of Formula (II-a), (II-b), (II-c), or (II-d):or a pharmaceutically acceptable salt thereof.392 / 411U1197.70255WO0011. The compound of any one of claims 1-6, wherein the compound is of Formula (III):or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11, wherein the compound is of Formula (III-a), (III-b), (III-c), or (III-d):or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claims 1-6, wherein the compound is of Formula (IV):or a pharmaceutically acceptable salt thereof.393 / 411U1197.70255WO0014. The compound of claim 13, wherein the compound is of Formula (IV-a):or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1-6, wherein the compound is of Formula (V):or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15, wherein the compound is of Formula (V-a):or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1-6, wherein the compound is of Formula (VI):(VI) or a pharmaceutically acceptable salt thereof.394 / 411U1197.70255WO0018. The compound of claim 17, wherein the compound is of Formula (VI-a) or (VI-b):or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 1-6, wherein the compound is of Formula (VII):or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19, wherein the compound is of Formula (VII-a):or a pharmaceutically acceptable salt thereof.

21. The compound of any one of claims 1-6, wherein the compound is of Formula (VIII):(VIII),or a pharmaceutically acceptable salt thereof.395 / 411U1197.70255WO0022. The compound of claim 21, wherein the compound is of Formula (VIII-a):or a pharmaceutically acceptable salt thereof.

23. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof,25. The compound of any one of claims 1-20 and 23-24, or a pharmaceutically acceptable salt thereof, wherein each instance of R3ais independently -CH.?, -CH2CH3, -CHICHs)?, -C(CH.?).?, -CH(CH3)CH2CH3, -CF3, -CHF2, -CHFCH3, cyclopropyl, cyclobutyl, -OH, -Cl, Br, F, -CN, or -NO’.

26. The compound of any one of claims 1-18 and 23, or a pharmaceutically acceptable saltthereof, wherein R3is of formula:sooty- 5.5396 / 411U1197.70255WO00of formula: Cl28. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R3is29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R2is -NO2.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is --(C1-3 alkylene)--OR°, wherein R° is C1-3 alkyl.

31. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is -(C1-3 alkylene)-N(RN)’, wherein each instance of RNis independently C1-3 alkyl substituted with 0 or 1 instances of -OH, or two instances of R. are joined with the nitrogen atom to which they are attached to form an optionally substituted 4-10 membered heterocyclyl.

32. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is ~(Cj-3 alkylene)-(C56 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, halogen, or -OH.

33. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is -(Cj- alkylene)-(4-7 membered monocyclic heterocyclyl), -(C1-3 alkylene)-(5-8 membered bridged heterocyclyl), — (C 1-3 alkylene)-(5-8 membered fused heterocyclyl), or -(C1-3 alkylene)-(7-9 membered spirocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 instances of C1-3 alkyl, -(C=O)-(Ci-3 alkyl), halogen, -OR°, or -N(RN)2, and 397 / 411U1197.70255WO00wherein each alkyl is independently substituted with 0 or 1 instances of -OR° or -N(RN)2.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is substituted with 0 or 1 instances of -CH3, -CH2OH, -CH2N(CH3)2, ~(C=O)CH3, -OH, or -N(CH3)2.

35. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from N and O.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof,398 / 411U1197.70255WO0037. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof,399 / 411U1197.70255WO0038. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof.400 / 411U1197.70255WO0039. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R1is40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein Llais unsubstituted heterocyclylene.

41. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein Llais unsubstituted 5-6 membered monocyclic heterocyclylene, 6-10 membered bridged heterocyclylene, 8-10 membered fused heterocyclylene, or 7-12 membered spirocyclic heterocyclylene, wherein the heterocyclylene contains 1 or 2 ring N atoms.

42. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof,43. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof,44. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof,401 / 411U1197.70255WO00wherein Llais45. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof., or 46. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof.wherein -Llb-Lla- is V 'The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof.wherein -Llb-Lla- i48. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof,402 / 411U1197.70255WO0049. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof,50. The compound of any one of claims 1-49, 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 -, -NRN-, -S(=O)2-, -C(=O) optionally substituted heterocyclylene, or optionally substituted heteroarylene.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein L2comprises optionally substituted heterocyclylene.

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

53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein L2comprises optionally substituted 4-10 membered heterocyclylene.

54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein L2comprises optionally substituted 4-6 membered monocyclic heterocyclylene, optionally substituted 6-10 membered bridged heterocyclylene, optionally substituted 6-10 membered fused heterocyclylene, or optionally substituted 6-12 membered spirocyclic heterocyclylene, wherein the heterocyclylene contains 1 or 2 ring N atoms.

55. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof,403 / 411U1197.70255WO00wherein each instance of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each instance of m3 is independently 1 or 2.

56. The compound of any one of claims 1-49, or a pharmaceutic ally acceptable salt thereof,404 / 411U1197.70255WO00wherein L2is57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt thereof, wherein L3is absent.

58. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt thereof, wherein L3comprises 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.

59. The compound of any one of claims 1-56 and 58, or a pharmaceutically acceptable salt thereof, wherein L3comprises optionally substituted C1-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-12 alkylene are independently replaced with 0 -, -NR4-, -C(=O)-, optionally substituted heterocyclylene, or optionally substituted arylene.

60. The compound of any one of claims 1-56 and 58-59, or a pharmaceutically acceptable salt thereof, wherein L3comprises optionally substituted heterocyclylene.

61. The compound of any one of claims 1-56 and 58-60, or a pharmaceutically acceptable salt thereof, wherein L3comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms.

62. The compound of any one of claims 1-56 and 58-61, or a pharmaceutically acceptable salt thereof, wherein L3comprises optionally substituted 4-10 membered heterocyclylene.

63. The compound of any one of claims 1-56 and 58-62, or a pharmaceutically acceptable salt thereof, wherein L3comprises optionally substituted 4-6 membered monocyclic heterocyclylene, optionally substituted 6-10 membered bridged heterocyclylene, optionally substituted 6-10 membered fused heterocyclylene, or optionally substituted 6-12 membered spirocyclic heterocyclylene, wherein the heterocyclylene contains 1 or 2 ring N atoms.405 / 411U1197.70255WO0064. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt thereof.406 / 411U1197.70255WO00wherein each instance of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each instance of m3 is independently 1 or 2.

65. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt thereof,66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, wherein R4is optionally substituted 5-10 membered monocyclic heterocyclyl, wherein the heterocyclyl further comprises fused thereto an optionally substituted 5-10 membered bicyclic heteroaryl; or R4is optionally substituted 5-10 membered bicyclic heteroaryl.

67. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, wherein R4is optionally substituted 6-8 membered monocyclic heterocyclyl, wherein the heterocyclyl further comprises fused thereto an optionally substituted 8-10 membered bicyclic heteroaryl; or R4is optionally substituted 8-10 membered bicyclic heteroaryl.

68. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, wherein R4is optionally substituted 6-8 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from N and O, wherein the heterocyclyl further comprises fused thereto an optionally substituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms; or R4is optionally substituted 8-10 membered bicyclic heteroaryl containing 2 ring N atoms.

69. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof,wherein R4is407 / 411U1197.70255WO0070. The compound of claim 69, or a pharmaceutically acceptable salt thereof, wherein R4is71. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt thereof, wherein L4is -O -.

72. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof,73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof,74. The compound of any one of claims 1, 2, and 5-6, wherein the compound is a compound provided in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

75. The compound of any one of claims 1, 2, and 5-6, wherein the compound is a compound provided in Table 2, or a pharmaceutically acceptable salt thereof.

76. The compound of any one of claims 1, 2, and 5-6, wherein the compound is a compound provided in Table 2A, or a pharmaceutically acceptable salt thereof.

77. A pharmaceutical composition comprising the compound of any one of claims 1-76, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.408 / 411U1197.70255WO0078. The pharmaceutical composition of claim 77, further comprising an additional pharmaceutical agent.

79. The pharmaceutical composition of claim 78, wherein the additional pharmaceutical agent is an anti-cancer agent.

80. The pharmaceutical composition of claim 79, wherein the anti-cancer agent is an alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cy to skeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof.

81. 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 1-76, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 77-80.

82. The method of claim 81, wherein the degradation of the Bcl-2 protein is selective over degradation of a Bcl-xL protein.

83. The method of claim 81 or 82, wherein the cell is a cancer cell.

84. 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 1-76, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 77-80.

85. The method of any one of claims 81-84, wherein the cell, tissue, biological sample, or cancer cell is in vitro.

86. The method of any one of claims 81-84, wherein the cell, tissue, biological sample, or cancer cell is in a subject.

87. 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 1-76, or a pharmaceutically acceptable salt thereof, or the 409 / 411U1197.70255WO00pharmaceutical composition of any one of claims 77-80.

88. The method of claim 87, wherein the disease is cancer.

89. 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 1-76, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 77-80.

90. The method of any one of claims 83-86 and 88-89, wherein the cancer is a Bcl-2-mediated cancer.

91. The method of any one of claims 83-86 and 88-90, wherein the cancer is a hematological malignancy.

92. The method of claim 91, wherein the cancer is chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma, non¬ Hodgkin Lymphoma (NHL), or myelodysplastic syndromes (MDS).

93. The method of claim 91, wherein the cancer is leukemia.

94. The method of claim 91, wherein the cancer is acute myeloid leukemia, chronic lymphocytic leukemia, or acute lymphoblastic leukemia.

95. The method of claim 91, wherein the cancer is lymphoma.

96. The method of claim 91, wherein the cancer is T-cell lymphoma.

97. The method of any one of claims 86-96, wherein the subject is a mammal.

98. The method of claim 97, wherein the subject is a human.

99. A kit comprising:the compound of any one of claims 1-76, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 77-80; and instructions for its use.410 / 411U1197.70255WO00

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