Technologies for modulating CITK and cell states

Abstract

Provided herein are technologies useful for reducing polypeptide levels and inhibiting activities of CITK, PKN2, or AAK1, and compositions and methods thereof.

Description

Attorney Docket No.: 2013405-0034 TECHNOLOGIES FOR MODULATING CITK AND CELL STATES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application Nos.63 / 642513, filed May 3, 2024, and 63 / 642519, filed May 3, 2024, the entirety of each of which is incorporated herein by reference. BACKGROUND

[0002] It has been reported that Citron Kinase (CIT, CIT-K or CITK) is a product of the CIT gene and may function as an AGC-type serine / threonine kinase. See, e.g., Pallavicini, G. et al., Int. J. Mol. Sci.20, 2098 (2019). CITK has been reported as a binding partner of Rho and Rac small GTPases. See, e.g., Madaule, P. et al., FEBS Lett.377, 243–248 (1995); and Cunto, F. D. et al., J Biol Chem 273, 29706–29711 (1998). According to some reports, CITK plays an important evolutionarily conserved role in cytokinesis by regulating several steps including progression of the cleavage furrow, recruitment of proteins that form and maintain the midbody, facilitating the abscission process, and interacting with components of the chromosomal passenger complex (CPC). See, e.g., D’Avino, P. P., J Cell Sci 130, 1701–1708 (2017). CITK was also shown in some reports to regulate mitosis by controlling the orientation of the mitotic spindle and promoting the nucleation and stability of microtubules. See, e.g., Gai, M. et al., EMBO Rep. 17, 1396–1409 (2016). A role for CITK in regulating differentiation and cellular state has been reported in normal and tumor models. See, e.g., McKenzie, C. & D’Avino, P. P., Oncotarget 7, 87323–87341 (2016); Tran, T. H. Y. et al., J. Mol. Cell Biol. 11, 1006–1017 (2019). Inactivating mutations of CIT have been reported in patients with microcephaly, and CIT genetic knockout mice have been reported to display microcephaly and perinatal death due to loss of neuronal progenitors during development. Further genetic knockout studies have been reported to show that CITK also has a cytokinesis-independent role in maintenance of genomic integrity as CITK loss led to DNA damage and p53-dependent neuronal progenitor cell death. See, e.g., Bianchi, F. T. et al., Cell Reports 18, 1674–1686 (2017). SUMMARY

[0003] Among other things, the present disclosure encompasses the recognition that CITK can be targeted for modulating cell states including dysregulated cell states of various cancers. Further, in some embodiments, the present disclosure provides the insight and demonstrates that small molecule technologies targeting CITK can be dramatically improved by incorporating degradation technologies, e.g., E3 ligase binding moieties, so that the improved technologies can reduce CITK levels. For example, among other things, the present disclosure demonstrates that moieties of various CITK inhibitors which cannot Page 1 of 378 12753881v1Attorney Docket No.: 2013405-0034 produce certain effects of CIT knockdown or knockout can be combined with E3 ligase binding moieties to provide compounds that can produce various effects of CIT knockdown or knockout. In some embodiments, the present disclosure provides and demonstrates various improvements, benefits and advantages of small molecule technologies that can reduce CITK levels over technologies that inhibit CITK kinase activity but do not reduce CITK levels as much. In some embodiments, the present disclosure provides the insight and demonstrates that reducing CITK levels can provide various improvements, benefits and advantages over CITK inhibition without sufficient reduction of CITK levels, e.g., for treating various conditions, diseases or disorders including cancer.

[0004] In some embodiments, the present disclosure provides various compounds as described herein. In some embodiments, the present disclosure provides a compound of Formula I: CIM—LCL—LBM I or a pharmaceutically acceptable salt thereof, wherein CIM, LCL, and LBM are independently as defined herein.

[0005] In some embodiments, provided compounds comprise a protein binding moiety capable of binding a CITK polypeptide, and an E3 ligase binding moiety capable of binding an E3 ubiquitin ligase. In some embodiments, provided compounds can recruit a CITK polypeptide to an E3 ubiquitin ligase, and promote degradation of (or otherwise inhibiting) the CITK polypeptide.

[0006] In some embodiments, provided compounds are useful to regulate CITK, for example, to reduce CITK activity, for example, by degrading CITK. In some embodiments, provided compounds can reduce CITK levels. In some embodiments, provided compounds can inhibit CITK, e.g., kinase activity. In some embodiments, provided compounds are useful for, among other things, treating and / or preventing diseases, disorders, or conditions associated with CITK. In some embodiments, the present disclosure provides a method for preventing and / or treating a condition, disease or disorder, comprising administering or delivering to a subject susceptible thereto or suffering therefrom an effective amount of a provided compound.

[0007] In some embodiments, provided compounds comprise a protein binding moiety capable of binding a PKN2 polypeptide, and an E3 ligase binding moiety capable of binding an E3 ubiquitin ligase. In some embodiments, provided compounds can recruit a PKN2 polypeptide to an E3 ubiquitin ligase, and promote degradation of (or otherwise inhibiting) the PKN2 polypeptide.

[0008] In some embodiments, provided compounds are useful to regulate PKN2, for example, to reduce PKN2 activity, for example, by degrading PKN2. In some embodiments, provided compounds can reduce PKN2 levels. In some embodiments, provided compounds can inhibit PKN2, e.g., kinase activity. In some embodiments, provided compounds are useful for, among other things, treating and / or preventing Page 2 of 378 12753881v1Attorney Docket No.: 2013405-0034 diseases, disorders, or conditions associated with PKN2. In some embodiments, the present disclosure provides a method for preventing and / or treating a condition, disease or disorder, comprising administering or delivering to a subject susceptible thereto or suffering therefrom an effective amount of a provided compound.

[0009] In some embodiments, provided compounds comprise a protein binding moiety capable of binding an AAK1 polypeptide, and an E3 ligase binding moiety capable of binding an E3 ubiquitin ligase. In some embodiments, provided compounds can recruit an AAK1 polypeptide to an E3 ubiquitin ligase, and promote degradation of (or otherwise inhibiting) the AAK1 polypeptide.

[0010] In some embodiments, provided compounds are useful to regulate AAK1, for example, to reduce AAK1 activity, for example, by degrading AAK1. In some embodiments, provided compounds can reduce AAK1 levels. In some embodiments, provided compounds can inhibit AAK1, e.g., kinase activity. In some embodiments, provided compounds are useful for, among other things, treating and / or preventing diseases, disorders, or conditions associated with AAK1. In some embodiments, the present disclosure provides a method for preventing and / or treating a condition, disease or disorder, comprising administering or delivering to a subject susceptible thereto or suffering therefrom an effective amount of a provided compound.

[0011] In some embodiments, provided technologies, e.g., compounds, compositions, methods, etc., can selectively reduce CITK polypeptide levels over PKN2 polypeptide levels. In some embodiments, provided technologies, e.g., compounds, can selectively reduce CITK polypeptide levels over AAK1 polypeptide levels. In some embodiments, selectivity is about or at least about a certain (e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more) fold as assessed by DC50 / IC50, IC90 / DC90, etc. (e.g., concentrations for reducing polypeptide levels by 50% in a system, concentrations for reducing polypeptide levels by 90% in a system, concentrations for inhibiting cell proliferation by 50% in a system, concentrations for inhibiting cell proliferation by 90% in a system, etc.). Various technologies for assessing DC50 / IC50, IC90 / DC90, etc. can be utilized in accordance with the present disclosure. Certain useful technologies are described in the Examples. In some embodiments, selectivity of CITK over PKN2 and / or AAK1 is about or at least about 2-fold (e.g., IC50for PKN2 and / or AAK1 is about or at least about 2-fold of IC50for CITK). In some embodiments, it is about or at least about 5-fold. In some embodiments, it is about or at least about 10-fold. In some embodiments, it is about or at least about 20-fold. In some embodiments, it is about or at least about 50-fold. In some embodiments, it is about or at least about 100-fold. In some embodiments, selectivity is assessed by concentrations for reducing polypeptide levels by 50% in a system. In some embodiments, selectivity is assessed by concentrations for inhibiting cell proliferation by 50% in a system. In some embodiments, a technology can reduce CITK polypeptide levels, and PKN2 and / or AAK1 polypeptide levels. In some embodiments, Page 3 of 378 12753881v1Attorney Docket No.: 2013405-0034 selectivity for CITK polypeptides over PKN2 and / or AAK1 polypeptides is about or no more than about a certain level (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10-fold) as assessed by DC50 / IC50, IC90 / DC90, etc. (e.g., concentrations for reducing polypeptide levels by 50% in a system, concentrations for reducing polypeptide levels by 90% in a system, concentrations for inhibiting cell proliferation by 50% in a system, concentrations for inhibiting cell proliferation by 90% in a system, etc.).

[0012] In some embodiments, a system is or comprises SW48 cells. In some embodiments, a system is or comprises HCT116 cells.

[0013] In some embodiments, provided technologies, e.g., compounds, compositions, methods, etc., can bind CITK, and AAK1 and / or PKN2. In some embodiments, provided technologies can reduce levels of CITK, and AAK1 and / or PKN2 levels. In some embodiments, provided technologies can bind CITK and AAK1 polypeptides. In some embodiments, provided technologies can reduce levels of CITK and AAK1 polypeptides. In some embodiments, provided technologies can bind CITK and PKN2 polypeptides. In some embodiments, provided technologies can reduce levels of CITK and PKN2 polypeptides. In some embodiments, provided technologies can bind CITK, AAK1 and PKN2 polypeptides. In some embodiments, provided technologies can reduce levels of CITK, AAK1 and PKN2 polypeptides.

[0014] In some embodiments, reducing levels of CITK and PKN2 can provide various benefits and / or advantages (e.g., relative to reducing levels of CITK or PKN2 only) in certain instances. In some embodiments, reducing levels of CITK and PKN2 provides cellular growth inhibition, in some embodiments, more than reducing levels of CITK or PKN2 alone. In some embodiments, technologies that can reduce levels of CITK and PKN2 polypeptides may be utilized to treat a condition, disease or disorder. In some embodiments, a condition, disease or disorder is associated with CITK. In some embodiments, a condition, disease or disorder is associated with PKN2. In some embodiments, a condition, disease or disorder is associated with CITK and PKN2. In some embodiments, a condition, disease or disorder is not or is less responsive to a technology that reduces CITK or PKN2 polypeptide levels but not both. In some embodiments, technologies that can reduce levels of CITK and PKN2 polypeptide levels can provide improved efficacy relative to technologies that reduce CITK or PKN2 polypeptide levels but not both. In some embodiments, technologies that can reduce levels of CITK and PKN2 polypeptide levels can treat cancers that are not responsive or are less responsive to technologies that can reduce CITK or PKN2 polypeptide levels but not both.

[0015] In some embodiments, reducing levels of CITK and AAK1 can provide various benefits and / or advantages (e.g., relative to reducing levels of CITK or AAK1 only). In some embodiments, reducing levels of CITK and AAK1 provides cellular growth inhibition, in some embodiments, more than reducing levels of CITK or AAK1 alone. In some embodiments, technologies that can reduce levels of CITK and AAK1 polypeptides may be utilized to treat a condition, disease or disorder. In some embodiments, a Page 4 of 378 12753881v1Attorney Docket No.: 2013405-0034 condition, disease or disorder is associated with CITK. In some embodiments, a condition, disease or disorder is associated with AAK1. In some embodiments, a condition, disease or disorder is associated with CITK and AAK1. In some embodiments, a condition, disease or disorder is not or is less responsive to a technology that reduces CITK or AAK1 polypeptide levels but not both. In some embodiments, technologies that can reduce levels of CITK and AAK1 polypeptide levels can provide improved efficacy relative to technologies that reduce CITK or AAK1 polypeptide levels but not both. In some embodiments, technologies that can reduce levels of CITK and AAK1 polypeptide levels can treat cancers that are not responsive or are less responsive to technologies that can reduce CITK or AAK1 polypeptide levels but not both.

[0016] In some embodiments, provided technologies reduces levels of CITK, and AAK1 and PKN2.

[0017] For various applications, compounds described herein are provided in pharmaceutical compositions as described herein. In some embodiments, the present disclosure provides compounds and compositions useful for preventing or treating various conditions, diseases or disorders. BRIEF DESCRIPTION OF THE DRAWING

[0018] Figure 1. Provided technologies can reduce CITK levels and inhibit cell growth. (A): Provided technologies can reduce CITK levels (see “CIT”). (B): Provided technologies can reduce growth of certain cells. Top: SW48. Bottom: HCT116.

[0019] Figure 2. Provided technology can selectively degrade target polypeptides. Shown in Figure 2 is an abundance comparison between treatment with 20 nM (DC90) compound 1 and 20 nM compound 2. Among other things, global proteomics of compound 1 demonstrated high selectivity for degradation of CITK (see “CIT”) over other polypeptides. Figure 2 also showed significant degradation of two kinases, adaptor-associated kinase 1 (AAK1) and serine / threonine-protein kinase N2 (PKN2).

[0020] Figure 3. Certain provided technologies can degrade CITK selectively over PKN2. Certain data for compound 182 are shown in Figure 3.

[0021] Figure 4. Certain provided technologies can effectively degrade CITK and PKN2. Certain data for compound 169 are shown in Figure 4.

[0022] Figure 5. Certain provided technologies can degrade CITK selectively over AAK1. Certain data for compound 11 are shown in Figure 5.

[0023] Figure 6. Certain provided technologies can effectively degrade CITK and AAK1. Certain data for compound 23 are shown in Figure 6. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0024] Certain provided technologies of the disclosure, e.g., compounds, compositions, methods, Page 5 of 378 12753881v1Attorney Docket No.: 2013405-0034 include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. Definitions

[0025] Among other things, the present disclosure provides various compounds as described herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0026] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional / second one or more; (v) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included.

[0027] Unless otherwise indicated, structures depicted herein are meant to represent all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, where a stereocenter is present, in some embodiments, the R and / or S configurations of such stereocenter are contemplated as part of the disclosure. Therefore, in some embodiments, single stereochemical isomers, and / or enantiomeric, diastereomic, and / or geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. Unless otherwise indicated, tautomeric forms of provided compounds are within the scope of the disclosure.

[0028] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopes. For example, hydrogen in a compound can be1H,2H or3H, and carbon can be12C,13C, or14C. In some embodiments, in a composition an isotope is enriched at one or more positions in one or more compounds.

[0029] Aliphatic: As used herein, “aliphatic” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or combinations thereof. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon Page 6 of 378 12753881v1Attorney Docket No.: 2013405-0034 atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-9 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1, 2, 3, or 4 aliphatic carbon atoms. Certain aliphatic groups include linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0030] Alkenyl: As used herein, the term “alkenyl” refers to an aliphatic group, as defined herein, having one or more double bonds.

[0031] Alkynyl: As used herein, the term “alkynyl” refers to an aliphatic group, as defined herein, having one or more triple bonds.

[0032] Alkyl: As used herein, the term “alkyl” is given its ordinary meaning in the art and refers to an aliphatic group, e.g., a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl (alicyclic) group, an alkyl substituted cycloalkyl group, a cycloalkyl substituted alkyl group, etc., which is saturated. In some embodiments, alkyl has 1-20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-15, 1-10, etc.) carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-15, 1-10, etc.) carbon atoms in its backbone (e.g., C1-C20 for straight chain, C2-C20 for branched chain, etc.), and alternatively, about 1- 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, etc.) carbon atoms. In some embodiments, cycloalkyl rings have from about 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) carbon atoms in their ring structure where such rings are monocyclic, bicyclic, or polycyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, an alkyl group may be a lower alkyl group, wherein a lower alkyl group has 1-4 carbon atoms (e.g., C1-C4for straight chain lower alkyls).

[0033] Aryl: The term “aryl”, as used herein, used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic or polycyclic ring systems having a total of, unless otherwise specified, 5-20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 5-15, 5-14, 5- 10, 5-9, etc.) ring members, wherein at least one ring in the system is aromatic. In some embodiments, an aryl group is a monocyclic, bicyclic or polycyclic ring system having a total of five to fourteen (e.g., 5-10, 6-14, 6-10, 5, 6, 9, 10, 14, etc.) ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, each aromatic ring is independently 6-membered. In some embodiments, each aromatic ring atom is carbon. In some embodiments, each ring atom is carbon. In some embodiments, an aryl group is a biaryl group. The term “aryl” may be used interchangeably with the term Page 7 of 378 12753881v1Attorney Docket No.: 2013405-0034 “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthylmethyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0034] Characteristic portion: As used herein, the term “characteristic portion”, in the broadest sense, refers to a portion of a substance whose presence (or absence) correlates with presence (or absence) of a particular feature, attribute, or activity of the substance. In some embodiments, a characteristic portion of a substance is a portion that is found in the substance and in related substances that share the particular feature, attribute or activity, but not in those that do not share the particular feature, attribute or activity. In certain embodiments, a characteristic portion shares at least one functional characteristic with the intact substance. For example, in some embodiments, a “characteristic portion” of a protein or polypeptide is one that contains a continuous stretch of amino acids, or a collection of continuous stretches of amino acids, that together are characteristic of a protein or polypeptide. In some embodiments, each such continuous stretch generally contains at least 2, 5, 10, 15, 20, 50, or more amino acids. In general, a characteristic portion of a substance (e.g., of a protein, antibody, etc.) is one that, in addition to the sequence and / or structural identity specified above, shares at least one functional characteristic with the relevant intact substance. In some embodiments, a characteristic portion may be biologically active.

[0035] Cycloaliphatic: The term “cycloaliphatic,” “carbocycle,” “carbocyclyl,” “carbocyclic radical,” and “carbocyclic ring,” are used interchangeably, and as used herein, refer to saturated or partially unsaturated, but non-aromatic, cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having, unless otherwise specified, from 3 to 20 ring members. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, a cycloaliphatic group has 3–6 carbons. In some embodiments, a cycloaliphatic group is saturated and is cycloalkyl. The term “cycloaliphatic” may also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl. In some embodiments, a cycloaliphatic group is bicyclic. In some embodiments, a cycloaliphatic group is tricyclic. In some embodiments, a cycloaliphatic group is polycyclic. In some embodiments, “cycloaliphatic” refers to C3-C6monocyclic hydrocarbon, or C8-C10bicyclic or polycyclic hydrocarbon, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, or a C9-C16polycyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Page 8 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0036] Heteroaryl: The terms “heteroaryl” and “heteroar–”, as used herein, used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to monocyclic, bicyclic or polycyclic ring systems having a total of, unless otherwise specified, 5-20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 5-15, 5-14, 5-10, 5-9, etc.) ring members, wherein at least one ring in the system is aromatic and at least one aromatic ring atom is a heteroatom. In some embodiments, the number of ring heteroatoms in a heteroaryl group is about 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, 1-3, 1-2, etc.). In some embodiments, a heteroaryl group is a group having 5 to 10 ring atoms, in some embodiments 5, 6, 9, or 10 ring atoms. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, each aromatic monocyclic ring unit is independently 5- or 6-membered. In some embodiments, a heteroaryl ring is monocyclic and is 5-membered. In some embodiments, a heteroaryl ring is monocyclic and is 6- membered. In some embodiments, a heteroaryl ring is bicyclic and is 9-membered. In some embodiments, a heteroaryl ring is bicyclic and is 10-membered. In some embodiments, a heteroaryl group has 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In some embodiments, a heteroaryl is a heterobiaryl group, such as bipyridyl and the like. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be monocyclic, bicyclic or polycyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0037] Heteroatom: The term “heteroatom", as used herein, means an atom that is not carbon or hydrogen. In some embodiments, a heteroatom is boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon; charged forms of nitrogen (e.g., quaternized forms, forms as in iminium groups, etc.), phosphorus, sulfur, oxygen; etc.). In some embodiments, a heteroatom is silicon, phosphorus, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is silicon, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is oxygen, sulfur or Page 9 of 378 12753881v1Attorney Docket No.: 2013405-0034 nitrogen.

[0038] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring", as used herein, are used interchangeably and refer to a monocyclic, bicyclic or polycyclic ring moiety (unless otherwise specified, 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered) that is saturated or partially unsaturated and has one or more (e.g., 1-10, 1-5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heteroatom ring atoms. In some embodiments, the number of ring heteroatoms in a heterocyclyl group is about 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, 1-3, 1-2, etc.). In some embodiments, a heterocyclyl group is a stable 3-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. In some embodiments, each monocyclic ring is independently 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3- 6, 4-6, 5-6, 5-8, etc.) membered. In some embodiments, each monocyclic ring independently has 0-5 (e.g., 0, 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms wherein at least one monocyclic ring independently has 1-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms. In some embodiments, each monocyclic ring is independently 3-7 membered. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H– pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic, bicyclic or polycyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0039] Optionally Substituted: As described herein, compounds of the disclosure may contain optionally substituted, substituted and / or unsubstituted moieties. In general, the term “substituted,” means that one or more hydrogens of the designated moiety are independently replaced with a substituent. Unless otherwise indicated, an “optionally substituted” group may independently have a substituent at each Page 10 of 378 12753881v1Attorney Docket No.: 2013405-0034 substitutable position of the group, and when more than one position in any given structure may be substituted with two or more substituents, the substituents may be either the same or different at every position. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. Various substituents are described below.

[0040] Monovalent substituents are independently halogen; –(CH2)0–4R ; –(CH2)0–4OR ; −O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR )2; –(CH2)0–4Ph, which may be substituted with R°; −(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R )2; –(CH2)0–4N(R )C(O)R ; –N(R )C(S)R ; –(CH2)0–4N(R )C(O)N(R )2; −N(R )C(S)N(R )2; –(CH2)0–4N(R )C(O)OR ; –N(R )N(R )C(O)R ; −N(R )N(R )C(O)N(R )2; −N(R )N(R )C(O)OR ; –(CH2)0–4C(O)R ; –C(S)R ; –(CH2)0–4C(O)OR ; –(CH2)0–4C(O)SR ; −(CH2)0–4C(O)OSi(R )3; –(CH2)0–4OC(O)R ;–OC(O)(CH2)0–4SR°, −SC(S)SR°; −(CH2)0–4SC(O)R ; –(CH2)0–4C(O)N(R )2; –C(S)N(R )2; –C(S)SR°;−SC(S)SR°, -(CH2)0–4OC(O)N(R )2; -C(O)N(OR )R ; –C(O)C(O)R ; –C(O)CH2C(O)R ;−C(NOR )R ; -(CH2)0–4SSR ; –(CH2)0–4S(O)2R ; –(CH2)0–4S(O)2OR ; –(CH2)0–4OS(O)2R ;−S(O)2N(R )2; -(CH2)0–4S(O)R ; –N(R )S(O)2N(R )2; –N(R )S(O)2R ; –N(OR )R ; −C(NH)N(R )2; –Si(R )3; –OSi(R )3; −P(R )2; −P(OR )2; −OP(R )2; −OP(OR )2; −N(R )P(R )2; −B(R )2; −OB(R )2;−P(O)(R )2; −OP(O)(R )2; −N(R )P(O)(R )2; –(C1-4 straight or branched alkylene)O–N(R )2; or –(C1-4straight or branched alkylene)C(O)O–N(R )2; wherein each R may be independently substituted as definedbelow and is independently hydrogen, C1-10(e.g., C1-6, C1-5, C1-4, etc.) aliphatic, C1-10(e.g., C1-6, C1-5, C1-4, etc.) heteroaliphatic having 1-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, C6-10(e.g., C6, C10, etc.) aryl, 5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 (e.g., 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur, −CH2−(C6-10(e.g., C6, C10, etc.) aryl), −O(CH2)0-1(C6-10(e.g., C6, C10, etc.) aryl), −CH2−(5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 (e.g., 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur), −O(CH2)0-1(5- 10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 (e.g., 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur), a 3-10 (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, or partially unsaturated ring having 0-5 (e.g., 0, 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the definition above, two independent occurrences ofR , taken together with their intervening atom(s), form a 3-10 (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.)membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated or aromatic ring (for aromatic ring, 5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered) having, in addition to the intervening atom(s), Page 11 of 378 12753881v1Attorney Docket No.: 2013405-0034 0-5 (e.g., 0, 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined below.

[0041] Monovalent substituents on R (or the ring formed by taking two independent occurrences ofR together with their intervening atoms), are independently halogen, –(CH2)0–2R , –(haloR ), –(CH2)0–2OH, –(CH2)0–2OR , –(CH2)0–2CH(OR )2; –O(haloR ), –CN, –N3, –(CH2)0–2C(O)R , –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR , –(CH2)0–2SR , –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR , –(CH2)0–2NR 2, –NO2, –isunsu sttute or w ere prece e y a o s su sttute on y wt one or more a ogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)- membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. Divalent substituents on a saturated carbon atom of R are independently =O or =S.

[0042] Divalent substituents are independently the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, −O(C(R*2))2–3O−, or −S(C(R*2))2–3S−, wherein each independent occurrence of R*is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. Divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group are independently −O(CR*2)2–3O−, wherein each independent occurrence of R*is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0043] Substituents on the aliphatic group of R* are independently halogen, –R , -(haloR ), –OH,−OR , –O(haloR ), –CN, –C(O)OH, –C(O)OR , –NH2, –NHR , –NR 2, or –NO2, wherein each R isunsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0044] Substituents on a substitutable nitrogen are independently –R†, −NR†2, −C(O)R†, –C(O)OR†, – C(O)C(O)R†, –C(O)CH2C(O)R†, –S(O)2R†, –S(O)2NR†2, −C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, Page 12 of 378 12753881v1Attorney Docket No.: 2013405-0034 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12 (e.g., 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0045] Substituents on the aliphatic group of R† are independently halogen, −R , -(haloR ), −OH, –OR , –O(haloR ), –CN, –C(O)OH, –C(O)OR , –NH2, –NHR , –NR 2, or –NO2, wherein each R isunsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0046] Partially Unsaturated: As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

[0047] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient or subject is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0048] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, an active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release Page 13 of 378 12753881v1Attorney Docket No.: 2013405-0034 formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0049] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0050] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0051] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., 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, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salt include, but are not limited to, nontoxic acid addition salts, which 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, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable Page 14 of 378 12753881v1Attorney Docket No.: 2013405-0034 salts include, but are not limited to, 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. In some embodiments, a provided compound comprises one or more acidic groups, e.g., an oligonucleotide, and a pharmaceutically acceptable salt is an alkali, alkaline earth metal, or ammonium (e.g., an ammonium salt of N(R)3, wherein each R is independently defined and described in the present disclosure) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, a pharmaceutically acceptable salt is a sodium salt. In some embodiments, a pharmaceutically acceptable salt is a potassium salt. In some embodiments, a pharmaceutically acceptable salt is a calcium salt. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0052] Polypeptide: As used herein refers to a polymeric chain of amino acids. In some embodiments, a polypeptide has an amino acid sequence that occurs in nature. In some embodiments, a polypeptide has an amino acid sequence that does not occur in nature. In some embodiments, a polypeptide has an amino acid sequence that is engineered in that it is designed and / or produced through action of the hand of man. In some embodiments, a polypeptide may comprise or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, a polypeptide may comprise or consist of only natural amino acids or only non-natural amino acids. In some embodiments, a polypeptide may comprise D-amino acids, L- amino acids, or both. In some embodiments, a polypeptide may comprise only D-amino acids. In some embodiments, a polypeptide may comprise only L-amino acids. In some embodiments, a polypeptide may include one or more pendant groups or other modifications, e.g., modifying or attached to one or more amino acid side chains, at the polypeptide’s N-terminus, at the polypeptide’s C-terminus, or any combination thereof. In some embodiments, such pendant groups or modifications may be selected from the group consisting of acetylation, amidation, lipidation, methylation, pegylation, etc., including combinations thereof. In some embodiments, a polypeptide may be cyclic, and / or may comprise a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not comprise any cyclic portion. In some embodiments, a polypeptide is linear. In some embodiments, a polypeptide may be or comprise a stapled polypeptide. In some embodiments, the term “polypeptide” may be appended to a name of a Page 15 of 378 12753881v1Attorney Docket No.: 2013405-0034 reference polypeptide, activity, or structure; in such instances it is used herein to refer to polypeptides that share the relevant activity or structure and thus can be considered to be members of the same class or family of polypeptides. For each such class, the present specification provides and / or those skilled in the art will be aware of exemplary polypeptides within the class whose amino acid sequences and / or functions are known; in some embodiments, such exemplary polypeptides are reference polypeptides for the polypeptide class or family. In some embodiments, a member of a polypeptide class or family shows significant sequence homology or identity with, shares a common sequence motif (e.g., a characteristic sequence element) with, and / or shares a common activity (in some embodiments at a comparable level or within a designated range) with a reference polypeptide of the class; in some embodiments with all polypeptides within the class). For example, in some embodiments, a member polypeptide shows an overall degree of sequence homology or identity with a reference polypeptide that is at least about 30-40%, and is often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more and / or includes at least one region (e.g., a conserved region that may in some embodiments be or comprise a characteristic sequence element) that shows very high sequence identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%. Such a conserved region usually encompasses at least 3-4 and often up to 20 or more amino acids; in some embodiments, a conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more contiguous amino acids. In some embodiments, a relevant polypeptide may comprise or consist of a fragment of a parent polypeptide. In some embodiments, a useful polypeptide as may comprise or consist of a plurality of fragments, each of which is found in the same parent polypeptide in a different spatial arrangement relative to one another than is found in the polypeptide of interest (e.g., fragments that are directly linked in the parent may be spatially separated in the polypeptide of interest or vice versa, and / or fragments may be present in a different order in the polypeptide of interest than in the parent), so that the polypeptide of interest is a derivative of its parent polypeptide.

[0053] Specific binding: As used herein, the term “specific binding” refers to an ability to discriminate between possible binding partners in the environment in which binding is to occur. A binding agent that interacts with one particular target when other potential targets are present is said to "bind specifically" to the target with which it interacts. In some embodiments, specific binding is assessed by detecting or determining degree and / or rate of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or determining degree and / or rate of dissociation of a binding agent-partner complex; in some embodiments, specific binding is assessed by detecting or determining ability of the binding agent to compete an alternative interaction between its partner and another entity. In some embodiments, specific binding is assessed by performing such detections or determinations across a range of concentrations. Page 16 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0054] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0055] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition.

[0056] Unsaturated: The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0057] As those skilled in the art will appreciate, methods and compositions described herein relating to provided compounds (e.g., oligonucleotides) generally also apply to pharmaceutically acceptable salts of such compounds. Compounds

[0058] In some embodiments, the present disclosure provides various compounds.

[0059] In some embodiments, provided compounds can bind to CITK. In some embodiments, provided compounds are useful for modulating CITK activities and / or functions. In some embodiments, provided compounds can inhibit CITK activity. In some embodiments, provided compounds can inhibit CITK kinase activity. In some embodiments, provided compounds can bind to an E3 ubiquitin ligase. In Page 17 of 378 12753881v1Attorney Docket No.: 2013405-0034 some embodiments, provided compounds can reduce CITK levels. In some embodiments, the present disclosure provides CITK degrader compounds, comprising a CITK protein binding moiety, LCL, and an E3 ubiquitin ligase binding moiety.

[0060] In some embodiments, the present disclosure provides a compound of Formula I: CIM—LCL—LBM, I or a pharmaceutically acceptable salt thereof, wherein:, ,Page 18 of 378 12753881v1Attorney Docket No.: 2013405-0034 each of Ring A, Ring B, Ring C and Ring D is independently an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; each of a, b, c and d is independently 0, 1, 2, 3, or 4; each Rsais independently −Rsa1, −ORsa1, or −Lsa1−Lsa2−Lsa3−N(Rsa1)(Rsa2); Lsa1is a covalent bond, optionally substituted −CH2−, −O−, or −N(R’)−; Lsa2is a covalent bond, or optionally substituted −CH2−; Lsa3is a covalent bond, −R’, or −CH2−C(Rsa3)2−, wherein the −CH2− is optionally substituted; each of Rsa1, Rsa2and Rsa3is independently −R’, or Rsa2and one Rsa3are taken together with their intervening atoms to form an optionally substituted 3-14 membered ring having 1-6 heteroatoms independently selected from N, O, and S; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; each of Rsb, Rscand Rsdis independently halogen, −CN, −R’, −OR’, or −N(R’)2; each of Lband Lcis independently a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; Ring P is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Lpis a covalent bond or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −O−, −S−, −N(R’)−, −N=N−, −C(O)−, −C(S)−, −C(NR’)−, −C(NOR’)−, −C(NN(R’)2)−, −C(O)O−, −C(O)N(R’)−, −C(NR’)O−, −C(NR’)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −N(R’)C(O)S−, −N(R’)C(NR’)N(R’)−, −SC(O)−, −S(O)2−, −SO2N(R’)−, or −Cy−; each −Cy− is independently an optionally substituted, mono- or bicyclic, 3- to 11-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-4 heteroatoms independently selected from N, O, and S; Ring Q is optionally substituted ; each of Ring R and Ring S is istituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rspis independently halogen, −CN, −R’ or −OR; each Rsqis independently halogen, −CN, −R’ or −OR’, or two Rsqare taken together with their intervening atom(s) to form an optionally substituted 3-6 membered ring having 0-2 heteroatoms Page 19 of 378 12753881v1Attorney Docket No.: 2013405-0034 independently selected from N, O, and S; each of p and q is independently 0, 1, 2, 3, or 4; Rais −N(Ra1)2, −Ra1, −C(Ra1)3, or −Cy−Ra1; Rbis −Rb1, or −C(Rb1)3; each of Ra1and Rb1is independently −R’; Rcis −R’; each Rdis independently halogen, −CN, −R’ or −OR’; r is 0, 1, 2, or 3; each Reis independently halogen, −R’, or −C(O)N(R’)2; m is 1, 2, 3, 4, or 5; t is 1 or 2; Rfis −R, or one Reand one Rfare taken together with their intervening atoms to form an optionally substituted 5-10 membered ring having 1-2 heteroatoms independently selected from N, O, and S; each of Rg, Rhand Rh’is independently −R’; each of Rj, Rk, Rmand Rm’is independently −R’; each of Rn, Rp, Rq, Rr, Rs, Rtand Ruis independently halogen, −CN, −R’ or −OR’; each of n, s, u, u’, v and w is independently 0, 1, 2, 3, 4, or 5; each Rvis independently halogen, −CN, −R’ or −OR’, or one Ruand one Rvare taken together withtheir intervening atoms to form an optionally substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, −CN, −R or −OR, or one Ruand one Rware taken together with their intervening atoms to form an optionally substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; each R’ is independently −R, −C(O)R, or −S(O)2R, or two R’ attached to the same atom are taken together with the atom to which they are attached to form an optionally substituted 3-16 membered ring having 0-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen, or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1−C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0061] In some embodiments, the present disclosure provides a compound of Formula II ,Page 20 of 378 12753881v1Attorney Docket No.: 2013405-0034 II or a pharmaceutically acceptable salt thereof, wherein: Lais a covalent bond, C1-3alkylene optionally substituted with one or more halogen, or −NH−; Lbis a covalent bond, C1-3alkylene optionally substituted with one or more halogen, −C(O)NH−, −NHC(O)NH−, or −NH−; Ring C is an optionally substituted 6-membered aryl or heteroaryl; each A1is independently CH, C(R’), or N; A2is −CH2−, −NH− or −O−; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H, C1-6alkyl, or C1-6haloalkyl; Ryis H, C1-6alkyl, C1-6haloalkyl; or C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form a 4-6 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N, O, and S; and each other variable (e.g., R’, LCL, or LBM) is independently as defined and described in classes and subclasses herein, both singly and in combination.

[0062] In some embodiments, the present disclosure provides a compound of Formula IIa: ,or a pharmaceutically acceptable salt thereof, wherein Rx, A1, A2, La, Lb, Ring C, LCL, and LBM are as defined and described in classes and subclasses herein, both singly and in combination.

[0063] In some embodiments, the present disclosure provides a compound of Formula III: ,or a pharmaceutically acceptable salt thereof, wherein Y is N or CN, and each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, Lpis a covalent bond or a C1-3hydrocarbon chain wherein one methylene is optionally replaced with –O−, −S−, −N(R)−, −S(O)2−, −C(O)N(R)−, or −N(R)C(O)−, and each Rsqis Page 21 of 378 12753881v1Attorney Docket No.: 2013405-0034 independently hydrogen or optionally substituted C1-6aliphatic, or two Rsqare taken together with their intervening atom(s) to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms independently selected from N, O, and S.

[0064] In some embodiments, CIM is or comprise wherein each variable is independently as defined and described i singly and incombination. In some embodiments, CIM is or comprise wherein each variable is independently as defined and dboth singly and in combination. In some embodiments, LBM is or compris wherein each variable is independently as defined and described in claoth singly and in combination.

[0065] In some embodiments, the present disclosure provides a compound of Formula III-A: Page 22 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein each Rsp’is independently hydrogen, or two Rsp’groups on the same carbon are taken together to form =O or together with the carbon atom to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination.

[0066] In some embodiments, the present disclosure provides a compound of Formula III-B: Page 23 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein each Rsp’is independently hydrogen, or two Rsp’groups on the same carbon are taken together to form =O or together with the carbon atom to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring; each Rsais independently −R’or −OR’; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); and Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C-Rsaor N; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; Lbis a covalent bond, optionally substituted C1-3 alkylene (e.g., C1-3 haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; Lcis a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; and each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination.

[0067] In some embodiments, the present disclosure provides a compound of Formula III-C: Page 24 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein each Rsp’is independently hydrogen, or two Rsp’groups on the same carbon are taken together to form =O or together with the carbon atom to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring; each of Rsa, Rsband Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; each of a, b, and c is independently 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; Lbis a covalent bond, optionally substituted C1-3 alkylene (e.g., C1-3 haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; each of Ring A and Ring B is independently an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination. Page 25 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0068] In some embodiments, each Rsp’is hydrogen. In some embodiments, two Rsp’groups, on the same carbon, are taken together to form an oxo. In some embodiments, two Rxare taken together to form =O. In some embodiments, A3is C-Rsa. In some embodiments, Ring C is an optionally substituted 6- membered aryl or heteroaryl ring. In some embodiments, A3is N. In some embodiments, Ring C is an optionally substituted 5- or 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted 6-membered aryl ring. In some embodiments, two Rxare taken together to form =O. In some embodiments, Ryis C1-6alkyl. In some embodiments, Ryand one Rzare taken together with their intervening atoms to form a 4-6 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Rzis H. In some embodiments, Rzis C1-6alkyl. In some embodiments, Rzis C1-6haloalkyl. In some embodiments, each Rzis H.

[0069] In some embodiments, LCL , wherein each Lc isindependently a covalent bond, or an option rocarbon chain, wherein oneor more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−, and Cy1and Cy2are each independently Cy as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, LCLis , wherein each Lcis independently a covalent bond, or an optionallyon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and Cy1and Cy2are each independently Cy as defined and described in classes and subclasses herein, both singly and in combination.

[0070] In some embodiments, the present disclosure provides a compound of Formula IV: ,Page 26 of 378 12753881v1Attorney Docket No.: 2013405-0034 IV or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, Rais −H. In some embodiments, . In some embodiments, Rbis −H. In someembodiments, . In some embodiments, Rcis −H. In someembodiments, In some embodiments, an occurrence of Rdis −H. In some embodiments . In some embodiments, an occurrence of Rdis not −HM is bonded through such an occurrence Rdat a position which can be or is −H. In some embodiments, LBM is , wherein Rd’is of such a structure that −Rd’−H is −Rdas descr e ere n. n some em o ments, Rd’is a covalent bond. In some embodiments, Rd’is not a covalent bond. In some embodiments, Rd’is an optionally substituted bivalent 3-10 membered ring having 0-5 Page 27 of 378 12753881v1Attorney Docket No.: 2013405-0034 heteroatoms independently selected from N, O, and S. In some embodiments, Rd’is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O, ietyRbis −R’ or −C(R’)3; Rcis −R’; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each of Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is Page 28 of 378 12753881v1Attorney Docket No.: 2013405-0034 −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; A4is C(Ra1) or N;Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination.

[0072] In some embodiments, the present disclosure provides a compound of Formula IV-A:or a pharmaceutically acceptable salt thereof, wherein Rbis −R’ or −C(R’)3; Page 29 of 378 12753881v1Attorney Docket No.: 2013405-0034 Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each of Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; A4is C(Ra1) or N; ond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−,−NHC(O)NH−, or −NH−; Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination.

[0073] In some embodiments, the present disclosure provides a compound of Formula IV-B: Page 30 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein Rbis −R’ or −C(R’)3; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; ;bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently Page 31 of 378 12753881v1Attorney Docket No.: 2013405-0034 selected from N, O, and S; and each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination.

[0074] In some embodiments, the present disclosure provides a compound of Formula IV-C:or a pharmaceutically acceptable salt thereof, wherein Rbis −R’ or −C(R’)3; Rcis −R’; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; Page 32 of 378 12753881v1Attorney Docket No.: 2013405-0034 Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination.

[0075] In some embodiments, the present disclosure provides a compound of Formula IV-D:or a pharmaceutically acceptable salt thereof, wherein Rbis −R’ or −C(R’)3; Rcis −R’; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; Page 33 of 378 12753881v1Attorney Docket No.: 2013405-0034 A2is optionally substituted NH or O; A3is C(Rsa) or N; Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination.

[0076] In some embodiments, the present disclosure provides a compound of Formula IV-E:or a pharmaceutically acceptable salt thereof, wherein Rbis −R’ or −C(R’)3; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; A4is C(Ra1) or N; Ra1is −R’; Page 34 of 378 12753881v1Attorney Docket No.: 2013405-0034 Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; Lcis a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination.

[0077] In some embodiments, the present disclosure provides a compound of Formula IV-F:or a pharmaceutically acceptable salt thereof, wherein Rbis −R’ or −C(R’)3; Rdis halogen, −CN, −R’ or −OR’; each of Rsa, Rsband Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; each of a, b, and c is independently 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6 alkyl (e.g., C1-6 haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A4is C(Ra1) or N; Page 35 of 378 12753881v1Attorney Docket No.: 2013405-0034 Ra1is −R’; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; each of Ring A and Ring B is independently an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and each other variable is independently as defined and described in classes and subclasses herein, both singly and in combination.

[0078] Various moieties and variables are or comprise an optionally substituted ring, and certain variables can be taken together with their intervening atom(s) to form a ring. In some embodiments, unless otherwise indicated, a ring is 3-30 (e.g., 3-25, 3-20, 3-15, 3-10, 5-20, 5-15, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) membered. In some embodiments, a ring is 3-10 membered (e.g., as for certain embodiments of R). In some embodiments, a ring is substituted. In some embodiments, a ring is unsubstituted. In some embodiments, a ring is 3-membered. In some embodiments, a ring is 4-membered. In some embodiments, a ring is 5-membered. In some embodiments, a ring is 6-membered. In some embodiments, a ring is 7-membered. In some embodiments, a ring is 8- membered. In some embodiments, a ring is 9-membered. In some embodiments, a ring is 10-membered. In some embodiments, a ring is saturated. In some embodiments, a ring is partially unsaturated. In some embodiments, a ring is aromatic. In some embodiments, a ring is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, 10) membered ring which is independently saturated, partially unsaturated, or aromatic and has 0-4 (e.g., 0, 1, 2, 3, 4) heteroatoms. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-10, 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, 10) membered ring which is independently saturated, partially unsaturated, or aromatic and has 0-4 (e.g., 0, 1, 2, 3, 4) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic ring unit is independently 3-7 membered. In some embodiments, each monocyclic ring unit is independently 3-6 membered. In some embodiments, each monocyclic ring unit is independently 5- 7 membered. In some embodiments, each monocyclic unit is independently saturated or partially unsaturated. In some embodiments, at least one monocyclic unit is saturated. In some embodiments, at least one monocyclic unit is partially unsaturated. In some embodiments, at least one monocyclic unit is aromatic. In some embodiments, a ring has 0-4 (e.g., 0, 1, 2, 3, 4, 5, 6) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a ring has 0-4 (e.g., 0, 1, 2, 3, 4) heteroatoms Page 36 of 378 12753881v1Attorney Docket No.: 2013405-0034 independently selected from oxygen, nitrogen, and sulfur. In some embodiments, there are no additional heteroatoms. In some embodiments, there is one additional heteroatom. In some embodiments, there are 2 additional heteroatoms. In some embodiments, there are 3 additional heteroatoms. In some embodiments, there are 4 additional heteroatoms. In some embodiments, there are 5 additional heteroatoms. In some embodiments, there are 6 or more additional heteroatoms. In some embodiments, an additional heteroatom is nitrogen. In some embodiments, an additional heteroatom is oxygen. In some embodiments, an additional heteroatom is sulfur. In some embodiments, when moieties, groups and / or variables are taken together to form a ring, the number of intervening atoms is about no more than about 1, 2, 3, 4, 5, or 6; in some embodiments, it is 1; in some embodiments, it is 2; in some embodiments, it is 3. For example, as utilized herein, each of Ring A, Ring B, Ring C and Ring D is independently an optionally substituted 3- 14 membered ring having 0-6 heteroatoms independently selected from N, O, and S. In some embodiments, a ring is 3-10 membered. In some embodiments, a ring is 5-10 membered.

[0079] In some embodiments, Ring C is an optionally substituted heteroaryl ring having 0-4 heteroatoms independently selected from N, O, S. In some embodiments, Ring C is an optionally substituted phenyl ring. In some embodiments, Ring C is an optionally substituted pyridine ring. In some embodiments, two Rxare taken together to form =O. In some embodiments, Ryis C1-6alkyl. In some embodiments, Ryand one Rzare taken together with their intervening atoms to form a 4-6 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Rzis H. In some embodiments, Rzis C1-6 alkyl. In some embodiments, Rzis C1-6 haloalkyl. In some embodiments, each Rzis H. In some embodiments, each Rzis H. In some embodiments, A3is C-Rsa. In some embodiments, A3is N.

[0080] In some embodiments, LCL Lc isindependently a covalent bond, or an optionaein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−, and Cy1and Cy2are each independently Cy as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, LCLis , wherein each Lcis independently a covalent bond, or an optionally- 0bon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and Cy1and Cy2are each Page 37 of 378 12753881v1Attorney Docket No.: 2013405-0034 independently Cy as defined and described in classes and subclasses herein, both singly and in combination. CIM

[0081] In some embodiments, CIM is a CITK binding moiety, i.e., is a moiety that is capable of binding a CITK polypeptide. Typically, a CIM is considered to be capable of binding a CITK polypeptide if it specifically (i.e., preferentially) associates with the CITK polypeptide when contacted with the CITK polypeptide in the presence of at least one other polypeptide. In some embodiments, a CIM is considered to be capable of binding a CITK polypeptide if it specifically associates with that protein within a cell (e.g., in vitro or in vivo). In some embodiments, a CITK polypeptide is a CITK protein expressed in a cell. In some embodiments, a CITK polypeptide is or comprises a full-length CITK protein found in a cell, e.g., a human cell. In some embodiments, a CITK polypeptide is or comprises a portion of a CITK protein, e.g., one found in a cell such as a human cell. In some embodiments, a portion is a characteristic portion which can differentiate a CITK protein from one or more other proteins. In some embodiments, a portion is or comprises a kinase domain of a CITK protein. In some embodiments, a portion is or comprises an ATP domain of a CITK protein. In some embodiments, a compound competes with ATP for CITK polypeptide binding. Different CIM and compounds of the present disclosure may bind to CITK or a portion thereof with different levels of specificity. Among other things, the present disclosure encompasses the recognition reported CITK inhibitors have different specificity for CITK and certain effects of certain CITK inhibitors and certain CIM-containing compounds may be from off-target effects. Among other things, the present disclosure provides CIM and compounds having high specificity for CITK.

[0082] In some embodiments, CIM shares significant structural identity with a reference compound or moiety thereof that is capable of binding a CITK polypeptide. For example, in some embodiments, a CIM comprises the same or similar structure as a reference compound, except that a CIM comprises a point of attachment to the rest of a compound, e.g., in some embodiments, CIM comprises a point of attachment to LCL. In some embodiments, CIM has the same structure as a reference compound except that a −H of a reference compound is removed to form a point of attachment. In some embodiments, a reference compound is characterized by a Kdof less than a certain concentration, e.g., 1 μM, in a biophysical assay, such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). In some embodiments, a reference compound is characterized by a IC50of less than a certain concentration, e.g., 1 μM, in a competition or functional assay, such as time-resolved fluorescence resonance energy transfer (TR-FRET). In some embodiments, a reference compound is a compound described in, e.g., WO 2022 / 0216717A1; J. Med. Chem.2021, 64, 11090−11128; and J. Med. Chem.2022, 65, 4457−4480, the entire contents of each of which are hereby incorporated by reference. In some embodiments, a compound is Compound 2: Page 38 of 378 12753881v1Attorney Docket No.: 2013405-0034 , wherein Ring A, bclasses herein, bothsingly and in combination. In some embodiments, CIM has the structur , wherein Ring A, Ring B, La, Rsa, Rsb, a, and b are as defined and described h sesherein, both singly and in combination.

[0084] In some embodiments, a CIM has the structur , wherein Ring A, Ring B, Ring C, La, Lb, Rsa, Rsb, Rsc, a, b, an in classes and subclasses herein, both singly and in combination. In some embodiments, a CIM has the structure , wherein Ring A, Ring B, Ring C, La, Lb, Rsa, Rsb, Rsc, a, b, and c arelasses and subclasses herein, both singly and in combination.

[0085] In some embodiments, a CIM has the structure of Page 39 of 378 12753881v1Attorney Docket No.: 2013405-0034 Lc, oths ngy an n com nat on. n some em o ments, a C as t e structure of Rsa, glyand in combination.

[0086] In some embodiments, Ring A is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S.

[0087] In some embodiments , wherein A is N or optionallysubstituted CH. In some embodiments, i , wherein A is C(R’). Insome embodiments, is an optionally substituted group selected fro ,nts, andis optionally substitute . In someis optionally substituted . In some embodiments,Page 40 of 378 12753881v1Attorney Docket No.: 2013405-0034 is optionally substituted . In some embodiments,isoptionally substituted . In some embodiments is optionally substituted, ,,Page 41 of 378 12753881v1Attorney Docket No.: 2013405-0034 , nts,a is 2. In some embodiments, a is 3. In some embodiments, a is 4.

[0091] In some embodiments, an occurrence of Rsais −Lsa1−Lsa2−Lsa3−N(Rsa1)(Rsa2). In some embodiments, Lsa1is selected from −O− and −N(R’)−. In some embodiments, Lsa1is −O−. In some embodiments, Lsa1is −N(R’)−. In some embodiments, Lsa1is −NH−. In some embodiments, Lsa1is optionally substituted −CH2−. In some embodiments, Lsa1is −CH2−. In some embodiments, Lsa2is selected from optionally substituted −CH2− and −C(O)−. In some embodiments, Lsa2is optionally substituted −CH2−. In some embodiments, Lsa2is −C(O)−. In some embodiments, Lsa3is −CH2−C(Rsa3)2−, wherein the −CH2− is optionally substituted. In some embodiments, Lsa3is −CH2−CHRsa3−. In some embodiments, Lsa3is −R’ (−N(Rsa1)(Rsa2) is absent). In some embodiments, Rsais −Lsa1−Lsa2−R.

[0092] In some embodiments, Lsa1is −O− and Lsa2is optionally substituted −CH2−. In some embodiments, Lsa1is −O− and Lsa2is −CH2−. In some embodiments, such compounds are effective for reducing levels of CITK polypeptides and PKN2 polypeptides. In some embodiments, such compounds are effective for inhibiting CITK activity and for inhibiting PKN2 activity.

[0093] In some embodiments, Lsa1is −N(R’)− and Lsa2is −C(O)−. In some embodiments, Lsa1is −NH− and Lsa2is −C(O)−. In some embodiments, such compounds can reduce CITK polypeptide levels selectively over PKN2 polypeptide levels. In some embodiments, such compounds can inhibit CITK activity selectively over PKN2 activity.

[0094] In some embodiments, each of Rsa1, Rsa2and Rsa3is independently −R’. In some embodiments, Rsa1is −R’. In some embodiments, Rsa2is −R’. In some embodiments, Rsa3is −R’.

[0095] In some embodiments, Rsa2and one Rsa3are taken together with their intervening atoms to form Page 42 of 378 12753881v1Attorney Docket No.: 2013405-0034 an optionally substituted 3-14 membered ring having 1-6 heteroatoms independently selected from N, O, and S. In some embodiments, the ring formed by Rsa2and one Rsa3are taken together with their intervening atoms is an optionally substituted 5-6 membered saturated ring having no additional heteroatoms in addition to the nitrogen atom to which Rsa2is attached. In some embodiments, an occurrence of Rsais −NHC(O)CH(Rsa3)NH2. In some embodiments, an occurrence of Rsais −OCH2CH(Rsa3)NH2. In some embodiments, an occurrence of Rsa3is optionally substituted C1-8aliphatic. In some embodiments, an occurrence of Rsa3is isopropyl, t-butyl, or methylcyclopropyl. In some embodiments, an occurrence of Rsa3is isopropyl. In some embodiments, an occurrence of Rsa3is t-butyl. In some embodiments, an occurrence of Rsa3is methylcyclopropyl.

[0096] In some embodiments, Rsais optionally substituted and selected from -NH2, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, -NHC(O)R’’’, or =O; wherein R’’’is optionally substituted and selected from C1-6alkyl, C1-6cycloalkyl, 4- to 6-membered heterocycle, and 6-membered aryl. In some embodiments, Rsais- NH2. In some embodiments, Rsais optionally substituted C1-6alkyl. In some embodiments, Rsais optionally substituted C1-6heteroalkyl. In some embodiments, Rsais optionally substituted C1-6haloalkyl. In some embodiments, Rsais =O. In some embodiments, Rsais -NHC(O)R’’’. In some embodiments, R’’’is optionally substituted C1-6alkyl. In some embodiments, R’’’is optionally substituted C1-6cycloalkyl. In some embodiments, R’’’is optionally substituted 4- to 6-membered heterocycle. In some embodiments, R’’’is optionally substituted 6-membered aryl. In some embodiments, -Rsai ,or, or −N(R’)2. In some embodiments, Rsbis halogen. In some embodiments, Rsbis −CN. In some embodiments, Rsbis −R’. In some embodiments, Rsbis −OR’. In some embodiments, Rsbis −N(R’)2. In some embodiments, Rscis halogen. In some embodiments, Rscis −CN. In some embodiments, Rscis −R’. In some embodiments, Rscis −OR’. In some embodiments, Rscis −N(R’)2. In some embodiments, Rsdis halogen. In some embodiments, Rsdis −CN. In some embodiments, Rsdis −R’. In some embodiments, Rsdis −OR’. In some embodiments, Rsdis −N(R’)2. Page 43 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0098] In some embodiments, Lais selected from a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−. In some embodiments, Lais a covalent bond. In some embodiments, Lais optionally substituted C1-3alkylene. In some embodiments, Lais −(CH2)1-3−. In some embodiments, Lais −N(R’)−. In some embodiments, Lais −(CH2)1-3−. In some embodiments, Lais −NH−.

[0099] In some embodiments, Lbis selected from a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. In some embodiments, Lbis a covalent bond. In some embodiments, Lbis optionally substituted bivalent C1-3hydrocarbon chain wherein one or moremet yene un ts are opt ona y and ndependent y rep aced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. In some embodiments, Lbis −C(O)N(R’)−. In some embodiments, Lbis −NHC(O)− or −C(O)NH−. In some embodiments, Lbis −N(R’)C(O)N(R’)−. In some embodiments, Lbis −N(R’)−. In some embodiments, Lbis −NH−.

[0100] In some embodiments, Ring B is an optionally substituted 6-10 membered aromatic ring having no heteroatoms. In some embodiments, Ring B is an optionally substituted phenyl ring. In some embodiments, Ring B is an optionally substituted 5-12 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is an optionally substituted 5-9 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiment , wherein A is C(R’), N or optionally substituted CH, * denotes thetotes the attachment point to La. In some embodiments, A is CH, N or C(CH3). In some embodiments, A is CH. In some embodiments, A is N. In some embodiments, A is C(CH3).

[0101] In some embodiments, Ring B o is an optionally substituted group selected,.In some embodiments, Ring B is selectedPage 44 of 378 12753881v1Attorney Docket No.: 2013405-0034 , , * ing,ing ,Page 45 of 378 12753881v1Attorney Docket No.: 2013405-0034 , ; wherein * denotes an attachment point to Lb, and ** denotes a

[0102] In some embodiments, Ring B o is an optionally substituted group selected,.In some embodiments, Ring B is selected, , Lb,oup selected from andPage 46 of 378 12753881v1Attorney Docket No.: 2013405-0034 , an

[0103] In some embodiments, Ring B o is optionally substitute , wherein * denotes an attachment point tenotes an attachment poome embodiments, Ring B o , wherein * denotes an attachment point to Lb, and ** denotes an abodiments, compounds with such Ring B or can reduce CITK polypeptide levels selectively over AAK1 polypeptide levels. In someembodiments, the selectivity is higher than when Ring B o .

[0104] In some embodiments, Ring B o is optionally substitut , wherein * denotes an attachment point to, a enotes an attachment po. some Page 47 of 378 12753881v1Attorney Docket No.: 2013405-0034 embodiments, Ring t to Lb, and ** denotes orcan reduce AAK1 polypeptide levels. In some embodiments, compounds with such Ringorcan reduce CITK polypeptide levels and AAK1 polypeptide levels. In someembodiments, compounds with such Ring B o can inhibit CITK activity and AAK1 activity. In some embodiments, such compoundtive for reducing AAK1 polypeptide levels and / or for inhibiting AAK1 activity compared to wherein Ring B .

[0105] In some embodiments, Lsa1is −N(R’)−. In some embodiments, Lsa1is −NH−. In some embodiments, Lsa2is −C(O)−. In some embodiments, Lsa1is −N(R’)− and Lsa2is −C(O)−. In some embodiments, Lsa1is −NH− and Lsa2is −C(O)−. In some embodiments, Lsa1is −N(R’)− and Lsa2is −C(O)−, a1is nts, ted. In some embodiments, Lsa1is −NH− and Lsa2is −C(O)−, and Ring B orPage 48 of 378 12753881v1Attorney Docket No.: 2013405-0034 and 1 is−N(R’)− and Lsa2is −C(O)−, and Rin . In some embodiments,Lsa1is −NH− and Lsa2is −C(O)−, and Ring B o is optionally substitut. In some embodiments, Lsa1is −NH− and Lsa2is −C(O)−, and Ring B is, wherein A is C(R’), N or enotes the aattachment point to L . In some embodiments, each A is independently selected from CH, N or C(CH3).

[0107] In some embodiments, Ring C is an optionally substituted 6-10 membered aromatic ring having no heteroatoms. In some embodiments, Ring C is an optionally substituted phenyl ring. In some embodiments, Ring C is an optionally substituted 5-12 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted 5-9 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring , wherein A is N or optionally substituted CH, * denotes the attachment point to, attachment point to Lb. In some embodiments, A is N. In some embodiments, A is optionally substituted CH. Page 49 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0108] In some embodiments, Ring C o is optionally substituted and selected fromdI b di Ri i l d fromn *

[0109] In some embodiments, Lcis selected from a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. In some embodiments, Lcis a covalent bond. In some embodiments, Lcis optionally substituted bivalent C1-3hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. In some embodiments, Lcis −C(O)N(R’)−. In some embodiments, Lcis −NHC(O)− or −C(O)NH−. In some embodiments, Lcis −N(R’)C(O)N(R’)−. In some embodiments, Lcis −N(R’)−. In some embodiments, Lcis −NH−.

[0110] In some embodiments, Ring D is an optionally substituted phenyl ring. In some embodiments, Ring D is an optionally substituted 5-12 membered heterocyclic ring having 1-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring D is an optionally substituted 5-9 membered heterocyclic ring having 1-6 heteroatoms independently selected from N, O, and S. In some embodiments, theor * denotes the attachment point to LCL, and ** denotes the

[0111] In some embodiments, each of b, c and d is independently 0, 1, 2, 3, or 4. In some embodiments, b is 0 or 1. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4. In some embodiments, c is 0 or 1. In some Page 50 of 378 12753881v1Attorney Docket No.: 2013405-0034 embodiments, c is 0. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, c is 3. In some embodiments, c is 4. In some embodiments, d is 0 or 1. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. , , , , , ,Page 51 of 378 12753881v1Attorney Docket No.: 2013405-0034 , or me is isPage 52 of 378 12753881v1Attorney Docket No.: 2013405-0034 meembodiments, . In some embodiments, it isnts, nts,n some embodiments, in addition to be useful for CIM, such compoundss.

[0114] In some embodiments, CIM can bind to a CITK polypeptide. In some embodiments, CIM can bind to a CITK polypeptide and a PKN2 polypeptide. In some embodiments, CIM can bind to a CITK Page 53 of 378 12753881v1Attorney Docket No.: 2013405-0034 polypeptide selectively over a PKN2 polypeptide. In some embodiments, CIM can bind to a CITK polypeptide and an AAK1 polypeptide. In some embodiments, CIM can bind to a CITK polypeptide selectively over an AAK1 polypeptide. In some embodiments, CIM can bind to a CITK polypeptide and a PKN2 polypeptide. In some embodiments, CIM can bind to a CITK polypeptide selectively over an AAK1 polypeptide and a PKN2 polypeptide. In some embodiments, a compound can bind to a CITK polypeptide. In some embodiments, a compound can bind to a CITK polypeptide and a PKN2 polypeptide. In some embodiments, a compound can bind to a CITK polypeptide selectively over a PKN2 polypeptide. In some embodiments, a compound can bind to a CITK polypeptide and an AAK1 polypeptide. In some embodiments, a compound can bind to a CITK polypeptide selectively over an AAK1 polypeptide. In some embodiments, a compound can bind to a CITK polypeptide and a PKN2 polypeptide. In some embodiments, a compound can bind to a CITK polypeptide selectively over an AAK1 polypeptide and a PKN2 polypeptide. In some embodiments, a compound is CIM-H or a salt thereof. In some embodiments, a compound is a compound of formula I or a salt thereof. Linker

[0115] In some embodiments, LCLis a linking moiety (i.e., any suitable bivalent moiety that connects a CIM to a LBM). In some embodiments, LCLis a particular length (e.g., as measured by number of atoms). In some embodiments, when the length of LCLis described, the longest contiguous chain of atoms is used. In some embodiments, when the length of LCLis described, the shortest contiguous chain of atoms is used. example, in some embodiments, LCLhas the following structure, which is 14 atoms in length (counted as shown with italicized numbers): ., s 2-16 atoms in length. In some embodiments, LCLis 2-13 atoms in length. In some embodiments, LCLis 2-10 atoms in length. In some embodiments, LCLis 2-8 atoms in length. In some embodiments, LCLis 2-7 atoms in length. In some embodiments, LCLis 0-16 atoms in length. In some embodiments, LCLis 0-13 atoms in length. In some embodiments, LCLis 0-10 atoms in length. In some embodiments, LCLis 0-7 atoms in length. In some embodiments, LCLis 4-16 atoms in length. In some embodiments, LCLis 4-13 atoms in length. In some embodiments, LCLis 4-10 atoms in length. In some embodiments, LCLis 4-8 atoms in length. In some embodiments, LCLis 4-7 atoms in length. In some embodiments, LCLis less than 14 atoms in length. In some embodiments, LCLis less than 11 atoms in length. In some embodiments, LCLis less than 9 atoms in length. In some embodiments, LCLis Page 54 of 378 12753881v1Attorney Docket No.: 2013405-0034 less than 8 atoms in length.

[0117] In some embodiments, the shortest-path length of LCLis about or no more than 14 atoms. In some embodiments, the shortest-path length of LCLis about or no more than 10 atoms. In some embodiments, the number of non-ring consecutive sp3atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1. In some embodiments, the number of non-ring consecutive sp3atoms in the shortest path chain of LCLis about or no more than about 2. In some embodiments, the number of bonds between two non-ring sp3atoms in the shortest path chain of LCLis about or no more than 5, 4, 3, 2 or 1. In some embodiments, the number of bonds between two non-ring sp3atoms in the shortest path chain of LCLis about or no more than 1. In some embodiments, the number of non-ring sp3C, O, and S atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1. In some embodiments, the number of non-ring sp3C, O, and S atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1. In some embodiments, the number of non-ring sp3atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1.

[0118] In some embodiments, the number of non-ring sp3atoms in the shortest path chain of LCLis about or no more than about 1. In some embodiments, the number of non-ring atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1. In some embodiments, the number of non-ring atoms in the shortest path chain of LCLis about or no more than about 1.

[0119] In some embodiments, LCLis a covalent bond. In some embodiments, LCLis absent.

[0120] In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, - N(R)SO2-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least two methylene units are replaced by – O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0121] In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated Page 55 of 378 12753881v1Attorney Docket No.: 2013405-0034 or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, - N(R)SO2-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by – O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0122] In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)- , -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy- .

[0123] In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)- , -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy- .

[0124] In some embodiments, LCLcomprises an ether moiety (e.g., -O-). In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, Page 56 of 378 12753881v1Attorney Docket No.: 2013405-0034 wherein at least one methylene unit is replaced by –O-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-.

[0125] In some embodiments, LCLcomprises an amine moiety (e.g., -N(R)-). In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)- (e.g., -NH- or –N(C1-6alkyl)-). In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1- C10hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)- (e.g., -NH- or –N(C1-6alkyl)-).

[0126] In some embodiments, LCLcomprises a carbonyl moiety. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)-.

[0127] In some embodiments, LCLcomprises an ester moiety. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -OC(O)- or -C(O)O-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -OC(O)- or -C(O)O-.

[0128] In some embodiments, LCLcomprises an amide moiety. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)- (e.g., -C(O)NH- or –C(O)N(C1-6alkyl)-). In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)- (e.g., -C(O)NH- or –C(O)N(C1-6alkyl)-). In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)C(O)- (e.g., -N(H)C(O)- or –N(C1-6alkyl)C(O)-). In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)C(O)- (e.g., -N(H)C(O)- or –N(C1-6alkyl)C(O)-).

[0129] In some embodiments, LCLcomprises a bivalent ring moiety (e.g., -Cy-). In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1- C20hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. In some such embodiments, Cy is not Page 57 of 378 12753881v1Attorney Docket No.: 2013405-0034 phenyl.

[0130] In some embodiments, LCLcomprises a triple bond. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C20hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by – O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C10hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)- , -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C20hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, LCLis an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C10hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, - C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.

[0131] In some embodiments, LCLhas the following structure: ,independently Cy or selected from an optionally substituted 4- to 12- membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

[0132] In some embodiments, LCLhas the following structure: ,Page 58 of 378 12753881v1Attorney Docket No.: 2013405-0034 wherein each of Cy1and Cy2is independently Cy or selected from an optionally substituted 4- to 12- membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

[0133] In some embodiments, LCLhas the following structure: ,herein; and: M1and M2are each independently absent, –CH2-, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0134] In some embodiments, LCLis selected from: , , ,Page 59 of 378 12753881v1Attorney Docket No.: 2013405-0034 . om:, , , , , and,M1and M2are each independently absent, –CH2-, –O–, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O–, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - , -Page 60 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0137] In some embodiments, LCLis selected from: and,M1and M2are each independently absent, –CH2-, –O–, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and L8is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O–, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0139] In some embodiments, LCLis selected from: , and, , , , , , , , or -N(R)C(O)-. In some embodiments, M1is absent. In some embodiments, M1is –CH2-. In some embodiments, M1is –O–. In some embodiments, M1is -N(R)- (e.g., -N(H)- or –N(CH3)-). In some embodiments, M1is -C(O)-. In some embodiments, M1is -OC(O)-. In some embodiments, M1is -C(O)O- Page 61 of 378 12753881v1Attorney Docket No.: 2013405-0034 . In some embodiments, M1is -C(O)N(R)- (e.g., -C(O)N(H)- or –C(O)N(CH3)-). In some embodiments, M1is -N(R)C(O)- (e.g., -N(H)C(O)- or –N(CH3)C(O)-).

[0141] In some embodiments, M2is –CH2-, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or - N(R)C(O)-. In some embodiments, M2is absent. In some embodiments, M2is –CH2-. In some embodiments, M2is –O–. In some embodiments, M2is -N(R)- (e.g., -N(H)- or –N(CH3)-). In some embodiments, M2is -C(O)-. In some embodiments, M2is -OC(O)-. In some embodiments, M2is -C(O)O- . In some embodiments, M2is -C(O)N(R)- (e.g., -C(O)N(H)- or –C(O)N(CH3)-. In some embodiments, M2is -N(R)C(O)- (e.g., -N(H)C(O)- or –N(CH3)C(O)-).

[0142] In some embodiments, L6is a covalent bond.

[0143] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O–, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O–, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, - N(R)SO2-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by – O–, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0144] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O–, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O–, -N(R)-, -C(O)-, -OC(O)- , -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O–, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or – Cy-.

[0145] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated Page 62 of 378 12753881v1Attorney Docket No.: 2013405-0034 or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O–, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O–, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O–, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0146] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10ydrocarbon c a n, w ere n one or more met yene un ts are optionally and independently replaced by –O–. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O–. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by – O–.

[0147] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated C1-C10hydrocarbon chain. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C6hydrocarbon chain. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated C1-C6 hydrocarbon chain.

[0148] In some embodiments, L7is a covalent bond.

[0149] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, - N(R)SO2-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by – O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, Page 63 of 378 12753881v1Attorney Docket No.: 2013405-0034 -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0150] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)- , -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy- .

[0151] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0152] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by – O-.

[0153] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated C1-C10hydrocarbon chain. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C6hydrocarbon chain. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated C1-C6hydrocarbon chain.

[0154] In some embodiments, both L6and L7are a covalent bond.

[0155] In some embodiments, L8is a covalent bond. Page 64 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0156] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R-, - R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, - N(R)SO2-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least two methylene units are replaced by – O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0157] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)- , -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy- .

[0158] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0159] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and Page 65 of 378 12753881v1Attorney Docket No.: 2013405-0034 independently replaced by –O-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least two methylene units are replaced by – O-.

[0160] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated C1-C15hydrocarbon chain. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C6hydrocarbon chain. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated C1-C6hydrocarbon chain. ,,, , ,Page 66 of 378 12753881v1Attorney Docket No.: 2013405-0034 , , , , , , ,Page 67 of 378 12753881v1Attorney Docket No.: 2013405-0034 , , , , , ,Page 68 of 378 12753881v1Attorney Docket No.: 2013405-0034 , , , nd , ,Page 69 of 378 12753881v1Attorney Docket No.: 2013405-0034 , , andlic, 3- to 11-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-4 heteroatoms independently selected from N, O, and S.

[0164] In some embodiments, Cy is optionally substituted phenyl. In some embodiments, Cy is phenyl. In some embodiments, Cy is not phenyl.

[0165] In some embodiments, Cy is optionally substituted C9-10bicyclic aryl. In some embodiments, Cy is optionally substituted C13-16polycyclic aryl.

[0166] In some embodiments, Cy is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted triazole. In some embodiments, Cy is an optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted pyridine, pyridazine, or pyrimidine.

[0167] In some embodiments, Cy is an optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an Page 70 of 378 12753881v1Attorney Docket No.: 2013405-0034 optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.

[0168] In some embodiments, Cy is an optionally substituted monocyclic C3-7cycloaliphatic. In some embodiments, Cy is an optionally substituted monocyclic C3-7cycloalkyl. In some embodiments, Cy is an optionally substituted monocyclic C4-6cycloalkyl (e.g., cyclobutane, cyclopentane, or cyclohexane).

[0169] In some embodiments, Cy is an optionally substituted 6- to 10-membered bicyclic cycloaliphatic. In some embodiments, Cy is an optionally substituted bicyclic 6- to 10-membered bridged, fused, or spirocyclic cycloaliphatic.

[0170] In some embodiments, Cy is an optionally substituted monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted monocyclic 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted monocyclic 4-membered heterocyclyl having 1 heteroatom independently selected from N, O, and S. In some embodiments, Cy is azetidine. In some embodiments, Cy is an optionally substituted monocyclic 5- membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is pyrrolidine. In some embodiments, Cy is an optionally substituted monocyclic 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is piperidine or piperazine. In some embodiments, Cy is an optionally substituted monocyclic 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0171] In some embodiments, Cy is an optionally substituted bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 6- to 11-membered bridged, fused, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7- to 11-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 8-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 9-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 10-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 11-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is selected fro ,Page 71 of 378 12753881v1Attorney Docket No.: 2013405-0034 , and. , red 1-4 heteroatoms independently selected from N, O, and S.

[0172] In some embodiments, each R is independently hydrogen, N(R’)2, or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1−C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each R is independently hydrogen or optionally substituted C1-6aliphatic. In some embodiments, each R is independently hydrogen or optionally substituted C1-6alkyl. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C1-6aliphatic. In some embodiments, R is optionally substituted C1-6alkyl. In some embodiments, R is C1-6alkyl. In some embodiments, R is optionally substituted C1-2alkyl. In some embodiments, R is C1-2alkyl (methyl). In some embodiments, each R is C1-2alkyl (methyl). In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted C3-7cycloaliphatic. In some embodiments, R is optionally substituted C3-7cycloalkyl (e.g., cyclopropyl). In some embodiments, R is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 3- to 7- membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 4- to 6-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted C1−C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted C6-10aryl. In some embodiments, R is optionally substituted 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S.

[0173] In some embodiments, each R’ is independently −R, −C(O)R, or −S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to 16-membered ring having 0-5 heteroatoms independently selected from N, O, and S. In some embodiments, each R’ is independently −R, −C(O)R, or −S(O)2R. In some embodiments, R’ is −R. Page 72 of 378 12753881v1Attorney Docket No.: 2013405-0034 In some embodiments, R’ is −C(O)R. In some embodiments, R’ is −S(O)2R. In some embodiments, two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to 16-membered ring having 0-5 heteroatoms independently selected from N, O, and S.

[0174] In some embodiments, LBM is an E3 ubiquitin ligase binding moiety, i.e., is a moiety that is capable of binding an E3 ubiquitin ligase. Typically, an LBM is considered to be capable of binding an E3 ubiquitin ligase if it specifically (i.e., preferentially) associates with the E3 ubiquitin ligase when contacted with the E3 ubiquitin ligase in the presence of at least one other protein. In some embodiments, an LBM is considered to be capable of binding an E3 ubiquitin ligase if it specifically associates with that protein within a cell (e.g., in vitro or in vivo). An LBM may be capable of binding any suitable E3 ubiquitin ligase, including cereblon, Von Hippel-Lindau protein, Inhibitor of Apoptosis protein, MDM2, RNF114, DCAF16, DCAF15, KEAP1, FEM1B, Arylhydrocarbon Receptor, etc. Some moieties capable of binding an E3 ubiquitin ligase are known in the art – see, e.g., Sun, X., et al., Signal Transduction and Targeted Therapy, 2019, 4, 64; Ishida, T., et al., SLAS Discovery, 2021, 26(4), 484-502; Bricelj, A., et al., Frontiers in Chemistry, 2021, 9, Article 707317; Min, J., et al., Angew. Chem. Int. Ed., 2021, 60, 26663-70; and WO 2019 / 140387, the entire contents of each of which are hereby incorporated by reference. LBM

[0175] In some embodiments, LBM is a cereblon (CRBN) binding moiety, i.e., is a moiety that is capable of binding cereblon.

[0176] In some embodiments, LBM has the following structure:, Lp, Rsp, Rsq, p, and q are as defined and described herein in classes and subclasses herein, both singly and in combination.

[0177] In some embodiments, LBM has the following structure:g , , , p, and Rsqare as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination. Page 73 of 378 12753881v1Attorney Docket No.: 2013405-0034 m:, , . InC1-6aliphatic. In some embodiments, each Rsqis independently hydrogen or optionally substituted C1-6alkyl. In some embodiments, each Rsqis hydrogen. In some embodiments, Rsqis hydrogen. In some embodiments, Rsqis optionally substituted C1-6aliphatic. In some embodiments, Rsqis optionally substituted C1-6alkyl. In some embodiments, Rsqis C1-6alkyl. In some embodiments, Rsqis optionally substituted C1-2alkyl. In some embodiments, Rsqis C1-2alkyl (methyl). In some embodiments, two Rsqgroups, together with the atom to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently Page 74 of 378 12753881v1Attorney Docket No.: 2013405-0034 selected from N, O, and S). In some embodiments, two Rsqgroups, together with the atom to which they are attached, combine to form a 3- to 6-membered saturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently selected from N, O, and S). In some embodiments, two Rsqgroups, together with the atom to which they are attached, combine to form a 3- to 4-membered saturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently selected from N, O, and S).

[0181] In some embodiments, Y is N. In some embodiments, Y is CH.

[0182] In some embodiments, Lpis a covalent bond or a straight or branched C1-3hydrocarbon chain. In some embodiments, Lpis a covalent bond or a straight or branched C1-3hydrocarbon chain wherein one methylene is replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, Lpis a covalent bond. In some embodiments, Lpis a straight or branched C1-3hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, Lpis a C1hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, - N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, Lpis a straight or branched C2hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)- , or -N(R)C(O)-. In some embodiments, Lpis a straight or branched C3hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, Lpis –CH2-. In some embodiments, Lpis –CH2-, -O-, or –N(R)-. In some embodiments, Lpis –CH2-, -O-, or –N(H)-. In some embodiments, Lpis –O- or –S-. In some embodiments, Lpis –O-. In some embodiments, Lpis -S-. In some embodiments, Lpis –N(R)-. In some embodiments, Lpis –N(H)-. In some embodiments, Lpis –SO2-. In some embodiments, Lpis -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, Lpis –C(O)N(R)-. In some embodiments, Lpis –N(R)C(O)-. In some embodiments, Lpis - Cy-. In some embodiments, Lpis -Cy-, wherein -Cy- is aromatic.

[0183] In some embodiments, Ring P is an optionally substituted, mono- or multicyclic 3- to 16- membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is optionally substituted phenyl, C5-6cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1- 2 heteroatoms independently selected from N, O, and S, or 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is optionally substituted phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, or 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is optionally substituted phenyl or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is optionally substituted C3-C7cycloaliphatic or 3- to 7-membered heterocyclyl having 1-2 heteroatoms Page 75 of 378 12753881v1Attorney Docket No.: 2013405-0034 independently selected from N, O, and S.

[0184] In some embodiments, Ring P is optionally substituted phenyl. In some embodiments, Ring P is phenyl.

[0185] In some embodiments, Ring P is optionally substituted 5- to 6-membered heteroaryl having 1- 4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is optionally substituted 5- to 6-membered heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is optionally substituted 5-membered heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is a pyrrole. In some embodiments, Ring P is optionally substituted 6-membered heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is a pyridine.

[0186] In some embodiments, Ring P is optionally substituted C3-C7cycloaliphatic. In some embodiments, Ring P is optionally substituted C3-C7cycloalkyl. In some embodiments, Ring P is optionally substituted C5-C6cycloaliphatic. In some embodiments, Ring P is optionally substituted C5-C6cycloalkyl. In some embodiments, Ring P is a cyclohexane.

[0187] In some embodiments, Ring P is optionally substituted 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is optionally substituted 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is a 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is a piperidine or piperazine.

[0188] In some embodiments, Ring P is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is optionally substituted phthalimide, isoindolin-1-one, indazole, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-benzo[d]imidazole-2-one, or isoquinoline. In some embodiments, Ring P is optionally substituted phthalimide or isoindolin-1-one. In some embodiments, Ring P is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.

[0189] In some embodiments, Ring P is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring P is an optionally substituted 11-membered tricyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (e.g., 6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione). Page 76 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0190] In some embodiments, Rin , wherein: each A is independently N, C, or CH, provided that no more than two A groups are N; each Rsp’is hydrogen, or two Rsp’groups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rspis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and p is 0, 1, 2, or 3.

[0191] In some embodiments, Rin .

[0192] In some embodiments, Ring P is selected from .

[0193] In some embodiments, Rin , wherein: each B is independently selected fr, provided that no more than two B are N; each Rspis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and p is 0, 1, 2, or 3.

[0194] In some embodiments, Rin .

[0195] In some embodiments, Ring P is selected from , andPage 77 of 378 12753881v1Attorney Docket No.: 2013405-0034 .

[0196] In some embodiments, Ring Q is optionally substitute . Insome embodiments, Ring Q is optionally substituted . In some embodiments, Ring Q isoptionally substituted . In some embodiments, Ring . In someembodiments, Ring .

[0197] In som ch A is CH. In some embodiments, one A is N and the other A groupsare CH. In some embodiments, two A groups are N, and the other A groups are CH. It will be appreciated that when A is CH, it may be substituted with Rsp, as defined herein, such that the ring contains a –C(Rsp)- moiety. It will also be appreciated that A is C, when it is the point of attachment to the rest of the molecule.

[0198] In some embodiments, each Rsp’is hydrogen. In some embodiments, two Rsp’groups, on the same carbon, are taken together to form an oxo. In some embodiments, two Rsp’groups, on the same carbon, combine to form a 3- to 6-membered saturated or partially unsaturated ring (e.g., a C3-6cycloaliphatic or 3- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S). In some embodiments, two Rsp’groups, on the same carbon, combine to form C3-6cycloalkyl (e.g., cyclopropyl). In some embodiments, two Rsp’groups, on the same carbon, combine to form a 3- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0199] In some embodiments, each B is CH, C-Rsp, or C. In some embodiments, one B is N and the other B groups are CH or C. In some embodiments, two B groups are N and the other B groups are CH or C. In some embodiments, B is N. In some embodiments, B is CH. In some embodiments, B is C-Rsp. In some embodiments, B is C. It will be appreciated that B is C, when it is the point of attachment to the rest of the molecule. Page 78 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0200] In some embodiments, each Rspis independently selected from halogen, -CN, -R’, or -OR’. In some embodiments, Rspis halogen (e.g., fluoro or chloro). In some embodiments, Rspis –OR’ (e.g., -OH or -O(C1-6alkyl)). In some embodiments, Rspis -N(R)2(e.g., -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)2). In some embodiments, Rspis –CN. In some embodiments, Rspis optionally substituted C1-6aliphatic. In some embodiments, Rspis optionally substituted C1-6alkyl. In some embodiments, Rspis C1-6alkyl optionally substituted with one or more halogen. In some embodiments, Rspis C1-6alkyl. In some embodiments, Rspis optionally substituted C1-2alkyl. In some embodiments, Rspis optionally substituted C1-2alkyl optionally substituted with one or more halogen. In some embodiments, Rspis C1-2alkyl (e.g., methyl). In some embodiments, Rspis C1-6haloalkyl. In some embodiments, Rspis C1-2haloalkyl (e.g., -CF3).

[0201] In some embodiments, each Rsqis independently selected from halogen, -CN, -R’, or -OR’. In some embodiments, Rsqis halogen (e.g., fluoro or chloro). In some embodiments, Rsqis –OR’ (e.g., -OH or -O(C1-6alkyl)). In some embodiments, Rsqis -N(R)2(e.g., -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)2). In some embodiments, Rsqis –CN. In some embodiments, Rsqis optionally substituted C1-6aliphatic. In some embodiments, Rsqis optionally substituted C1-6alkyl. In some embodiments, Rsqis C1-6alkyl optionally substituted with one or more halogen. In some embodiments, Rsqis C1-6alkyl. In some embodiments, Rsqis optionally substituted C1-2alkyl. In some embodiments, Rsqis optionally substituted C1-2alkyl optionally substituted with one or more halogen. In some embodiments, Rsqis C1-2alkyl (e.g., methyl). In some embodiments, Rsqis C1-6haloalkyl. In some embodiments, Rsqis C1-2haloalkyl (e.g., -CF3).

[0202] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0203] In some embodiments, LBM is a Von Hippel-Lindau protein (VHL) binding moiety, i.e., is a moiety that is capable of binding Von Hippel-Lindau protein.

[0204] In some embodiments, LBM has the following structure: , were n , , , , an r are as e ned herein for Formula IV and described in classes and subclasses herein, both singly and in combination. Page 79 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0205] In some embodiments, Rais −H. In some embodiments, LBM is is is meembodiments, In some embodiments, an occurrence of Rdis not −H bded through such an occurrence of R at a position which can be or is −H. In some embodiment , wherein Rd’is of such a structure that −Rd’−H is −Ris a covalent bond. In some embodiments, Rd’is not a covalent bond. In some embodiments, Rd’is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from N, O, and S. In some embodiments, Rd’is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 3 Page 80 of 378 12753881v1Attorney Docket No.: 2013405-0034 heteroatoms independently selected from N, O, and S. In some embodiments is. In some embodiments, in a reference compound is. me embodiments, LBM moiety (e.g., VHL binding moiety) is attached to LCLat Ra. Insome embodiments, LBM moiety (e.g., VHL binding moiety) is attached to LCLat Rb. In some embodiments, LBM moiety (e.g., VHL binding moiety) is attached to LCLat Rc. In some embodiments, LBM moiety (e.g., VHL binding moiety) is attached to LCLat a Rd. In some embodiments, LBM moiety (e.g., VHL binding moiety) is attached to LCLat a point on one Rd.

[0207] In some embodiments, Rais −N(Ra1)2, −Ra1, −C(Ra1)3, or −Cy−Ra1. In some embodiments, Rais −N(Ra1)2. In some embodiments, Rais −Ra1. In some embodiments, Rais −C(Ra1)3. In some embodiments, Rais −Cy−Ra1. In some embodiments, Cy is a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, each Ra1is independently a point of attachment for LCLor −R’. In some embodiments, Ra1is −R’. In some embodiments, Ra1is a point of attachment for LCL.

[0208] In some embodiments, Rbis a point of attachment for LCL, −Rb1, or −C(Rb1)3. In some embodiments, each Rb1is independently a point of attachment for LCLor −R’. In some embodiments, Rbis −Rb1. In some embodiments, Rbis −C(Rb1)3. In some embodiments, each Rb1−R’. In some embodiments, Ra1is −R’. In some embodiments, Rb1is a point of attachment for LCL.

[0209] In some embodiments, Rcis independently a point of attachment for LCLor -R’. In some embodiments, Rcis a point of attachment for LCL. In some embodiments, Rcis -R’.

[0210] In some embodiments, each Rdis independently a point of attachment for LCL, halogen, -R’ or -OR’. In some embodiments, LCLis attached to a point on one Rd. In some embodiments, Rdis is –OR’ (e.g., -OH or -O(C1-6alkyl)). In some embodiments, Rdis -N(R)2(e.g., -NH2, -NH(C1-6alkyl), or -N(C1-6alkyl)2). In some embodiments, Rdis –CN. In some embodiments, Rdis optionally substituted C1-6aliphatic. In some embodiments, Rdis alkynyl. In some embodiments, Rdis optionally substituted C1-6alkyl. In some embodiments, Rdis C1-6alkyl optionally substituted with one or more halogen. In some embodiments, Rdis C1-6alkyl. In some embodiments, Rdis optionally substituted C1-2alkyl. In some Page 81 of 378 12753881v1Attorney Docket No.: 2013405-0034 embodiments, Rdis optionally substituted C1-2alkyl optionally substituted with one or more halogen. In some embodiments, Rdis C1-2alkyl (e.g., methyl). In some embodiments, Rdis C1-6haloalkyl. In some embodiments, Rdis C1-2haloalkyl (e.g., -CF3). In some embodiments, Rdis an optionally substituted 3- to 16-membered ring having 0-5 heteroatoms independently selected from N, O, and S. In some embodiments, Rdis a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S (e.g., thiazoyl).

[0211] In some embodiments, each R’ is independently −R, −C(O)R, or −S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to 16-membered ring having 0-5 heteroatoms independently selected from N, O, and S. In some embodiments, each R’ is independently −R. In some embodiments, each R’ is independently −C(O)R. In some embodiments, each R’ is independently −S(O)2R. In some embodiments, two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to 16-membered ring having 0-5 heteroatoms independently selected from N, O, and S.

[0212] In some embodiments, each R is independently hydrogen, N(R’)2, or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1−C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C1-8 aliphatic. In some embodiments, R is an optionally substituted C3-10cycloaliphatic. In some embodiments, R is an optionally substituted C1−C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted C6-10aryl. In some embodiments, R is an optionally substituted 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0213] In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 0 or 1. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3.

[0214] In some embodiments, Ring R is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring R is an optionally substituted 3- to 10-membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring R is an optionally substituted phenyl. In some embodiments, Ring R is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Ring R is a 4- to 8-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring R is a 3- to 8- Page 82 of 378 12753881v1Attorney Docket No.: 2013405-0034 membered carbocyclic ring.

[0215] In some embodiments, LBM is an Inhibitor of Apoptosis protein (IAP) binding moiety, i.e., is a moiety that is capable of binding Inhibitor of Apoptosis protein.

[0216] In some embodiments, LBM is or comprises ,, orPage 83 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0217] In some embodiments, LBM has the following structure: , are as defined and described herein in classes and subclasses herein,both singly and in combination.

[0218] In some embodiments, LBM has the following structure: , as defined and described herein in classes and subclasses herein, bothsingly and in combination.

[0219] In some embodiments, each Reis independently a point of attachment of LCL, halogen, −R’, or −C(O)N(R’)2. In some embodiments, Reis a point of attachment of LCL. In some embodiments, Reis halogen. In some embodiments, Reis −R’, or −C(O)N(R’)2. In some embodiments, Reis −R’. In some embodiments, Reis −C(O)N(R’)2.

[0220] In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, t is 1 or 2. In some embodiments, t is 1. In some embodiments, t is 2.

[0221] In some embodiments, Rfis a point of attachment for LCL, −R, or one Reand one Rfare taken together with their intervening atoms to form an optionally substituted 5-10 membered ring having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Rfis a point of attachment for LCL. In some embodiments, Rfis −R. In some embodiments, one Reand one Rfare taken together with their intervening atoms to form an optionally substituted 5-10 membered ring having 1-2 heteroatoms independently selected from N, O, and S.

[0222] In some embodiments, each of Rg, Rhand Rh’is independently a point of attachment for LCLor −R’. In some embodiments, is Rgis a point of attachment for LCL. In some embodiments, Rgis −R’. In some embodiments, is Rhis a point of attachment for LCL. In some embodiments, Rhis −R’. In some embodiments, is Rh’is a point of attachment for LCL. In some embodiments, Rh’is −R’.

[0223] In some embodiments, each of Rj, Rk, Rmand Rm’is independently −R’. In some embodiments, Rjis −R’. In some embodiments, Rkis −R’. In some embodiments, Rmis −R’. In some embodiments, Rm’is −R’. Page 84 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0224] In some embodiments, each Rnis independently halogen, −CN, −R’ or −OR’. In some embodiments, Rnis halogen. In some embodiments, Rnis −CN. In some embodiments, Rnis −R’. In some embodiments, Rnis −OR’.

[0225] In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0226] In some embodiments, Ring S is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring S is an optionally substituted 3- to 10-membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring S is an optionally substituted phenyl. In some embodiments, Ring S is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Ring S is a 4- to 8-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring S is a 3- to 8-membered carbocyclic ring.

[0227] In some embodiments, LBM is a MDM2 binding moiety, i.e., is a moiety that is capable of binding MDM2.

[0228] In some embodiments, LBM has the following structure: ,d u’ are as defined and described herein in classes and subclasses herein, both singly and in combination.

[0229] In some embodiments, LBM has the following structure: , were n , , , , w, and v are as defined and described herein in classes and subclasses herein, both Page 85 of 378 12753881v1Attorney Docket No.: 2013405-0034 singly and in combination.

[0230] In some embodiments, each of Rp, Rq, Rr, Rs, Rtand Ruis independently halogen, −CN, −R’ or −OR’. In some embodiments, each Rpis independently halogen, −CN, −R’ or −OR’. In some embodiments, each Rqis independently halogen, −CN, −R’ or −OR’. In some embodiments, each Rris independently halogen, −CN, −R’ or −OR’. In some embodiments, each Rsis independently halogen, −CN, −R’ or −OR’. In some embodiments, each Rtis independently halogen, −CN, −R’ or −OR’. In some embodiments, each Ruis independently halogen, −CN, −R’ or −OR’. In some embodiments, Rpis halogen. In some embodiments, Rpis −CN. In some embodiments, Rpis −R’. In some embodiments, Rpis −OR’. In some embodiments, Rqis halogen. In some embodiments, Rqis −CN. In some embodiments, Rqis −R’. In some embodiments, Rqis −OR’. In some embodiments, Rris halogen. In some embodiments, Rris −CN. In some embodiments, Rris −R’. In some embodiments, Rris −OR’. In some embodiments, Rsis halogen. In some embodiments, Rsis −CN. In some embodiments, Rsis −R’. In some embodiments, Rsis −OR’. In some embodiments, Rtis halogen. In some embodiments, Rtis −CN. In some embodiments, Rtis −R’. In some embodiments, Rtis −OR’. In some embodiments, Ruis halogen. In some embodiments, Ruis −CN. In some embodiments, Ruis −R’. In some embodiments, Ruis −OR’.

[0231] In some embodiments, each of s, u, u’, v and w is independently 0, 1, 2, 3, 4, or 5. In some embodiments, s is 0 or 1. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, s is 5. In some embodiments, u is 0 or 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, u’ is 0 or 1. In some embodiments, u’ is 0. In some embodiments, u’ is 1. In some embodiments, u’ is 2. In some embodiments, u’ is 3. In some embodiments, u’ is 4. In some embodiments, u’ is 5. In some embodiments, v is 0 or 1. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. In some embodiments, v is 5.

[0232] In some embodiments, each Rvis independently halogen, −CN, −R’ or −OR’, or one Ruand one Rvare taken together with their intervening atoms to form an optionally substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, Rvis halogen, −CN, −R’ or −OR’. In some embodiments, Rvis halogen. In some embodiments, Rvis −CN. In some embodiments, Rvis −R’. In some embodiments, Rvis −OR’. In some embodiments, one Ruand one Rvare taken together with their intervening atoms to form an optionally substituted 3-7 membered ring having 0- 2 heteroatoms independently selected from N, O, and S.

[0233] In some embodiments, each Rwis independently halogen, −CN, −R or −OR, or one Ruand one Rware taken together with their intervening atoms to form an optionally substituted 3-7 membered ring Page 86 of 378 12753881v1Attorney Docket No.: 2013405-0034 having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, Rwis halogen, −CN, −R’ or −OR’. In some embodiments, Rwis halogen. In some embodiments, Rwis −CN. In some embodiments, Rwis −R’. In some embodiments, Rwis −OR’. In some embodiments, one Ruand one Rware taken together with their intervening atoms to form an optionally substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S.

[0234] In some embodiments, the present disclosure provides compounds selected from Table 1, or a pharmaceutically acceptable salt thereof. Table 1. Certain Compounds. Compound No. Structureage o 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 88 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 89 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 90 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 91 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 92 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 93 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 94 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 95 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 96 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 97 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 98 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 99 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 100 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 101 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 102 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 103 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 104 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 105 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 106 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 107 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 108 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 109 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 110 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 111 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 112 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 113 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 114 o 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 115 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 116 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 117 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 118 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 119 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 120 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 121 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 122 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 123 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 124 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 125 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 126 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 127 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 128 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 129 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 130 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 131 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 132 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 133 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 134 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 135 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 136 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 137 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 138 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 139 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 140 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 141 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 142 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 143 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 144 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 145 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 146 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 147 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 148 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 149 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 150 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 151 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 152 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 153 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 154 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 155 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 156 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 157 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 158 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 159 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 160 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 161 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 162 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 163 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 164 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 165 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 166 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 167 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 168 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 169 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 170 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 171 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 172 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. StructurePage 173 of 378 12753881v1Attorney Docket No.: 2013405-0034 Compound No. Structure

[0235] In some embodiments, the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds. For example, in some embodiments, provided compounds are more potent than certain known compounds in one or more assays described herein. In some embodiments, provided compounds are more soluble than certain known compounds, as measured by, e.g., kinetic and / or thermodynamic solubility assays. In some embodiments, provided compounds have improved metabolic stability than certain known compounds, as measured by, e.g., intrinsic clearance using an in vitro liver microsomal stability assay and / or an in vivo pharmacokinetic analysis. In some embodiments, provided compounds have improved permeability, as measured by, e.g., a MDCK and / or Caco2 permeability assays. Without wishing to be bound by theory, it will be appreciated that provided compounds that display a suitable balance of any two or more of these Page 174 of 378 12753881v1Attorney Docket No.: 2013405-0034 properties may be particularly suitable for development as a drug, as evidenced, in some embodiments, by pharmacokinetic properties, such as AUC, T1 / 2, MRT, or CL.

[0236] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977).

[0237] It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of Formula I is intended to also include Formulae I’, I, II, IIa, III, and IV and compound species of such formulas disclosed herein.

[0238] As described herein, various groups may be optionally substituted. Substituents are routinely utilized in chemistry including in development of various therapeutics. Many substituents can be utilized in accordance with the present disclosure. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. In some embodiments, substituents are those that result in the formation of compounds for a desired property, activity, use, etc., as described herein. In some embodiments, compounds are stable for therapeutic use as described herein. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a substituent is a hydrocarbon group. In some embodiments, a substituent comprises a heteroatom. In some embodiments, a substituent comprises multiple heteroatoms. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus and silicon. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, fluorine, chlorine, bromine, iodine, nitrogen, oxygen, and sulfur. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in a substituent is about or no more than about 1; in some embodiments, it is about or no more than about 2; in some embodiments, it is about or no more than about 3; in some embodiments, it is about or no more than about 4; in some embodiments, it is about or no more than about 5; in some embodiments, it is about or no more than about 6; in some embodiments, it is about or no more than about 7; in some embodiments, it is about or no more than about 8; in some embodiments, it is about or no more than about 9; in some embodiments, it is about or no more than about 10; in some embodiments, it is about or no more than about 11; in some embodiments, it is about or no more than about 12; in some embodiments, it is about or no more than about 13; in some embodiments, it is about or no more than about 14; in some embodiments, it is about or no more than about Page 175 of 378 12753881v1Attorney Docket No.: 2013405-0034 15; in some embodiments, it is about or no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 15. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 10. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 6. Substituents of various sizes are described herein including exemplified in various compounds. In some embodiments, each optional substituent on a substitutable group (e.g., Ring A, Ring B, R, etc.) is independently halogen, C1-4alkyl, −OH, −CN, −NO2, C1-4haloalkyl (e.g., −CF3), −ORSB, − N(RSB)2, −C(O)ORSB, −C(O)N(RSB)2, or −S(O)2N(RSB)2wherein each RSBis independently −H, C1-4alkyl or C1-4haloalkyl. In some embodiments, each optional substituent on a substitutable group (e.g., Ring A, Ring B, R, etc.) is independently halogen, C1-4alkyl, C1-4haloalkyl, or –OH. In some embodiments, each optional substituent on a substitutable group (e.g., Ring A, Ring B, R, etc.) is independently halogen or C1-4alkyl. As examples, many substituents are exemplified in compounds described herein, e.g., in Table 1. Compositions

[0239] The present disclosure also provides compositions that comprise or deliver a compound as provided herein. In some embodiments, the present disclosure provides compositions comprising a compound provided herein with one or more other components.

[0240] In some embodiments, provided compositions comprise and / or deliver a compound described herein (e.g., compounds of Formulae I’, I, II, IIa, III, and IV).

[0241] In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a compound provided herein (e.g., compounds of Formulae I’, I, II, IIa, III, and IV) and further comprises a pharmaceutically acceptable carrier. In some embodiments, a compound in a composition, e.g., a pharmaceutical composition, is in a salt form, e.g., a pharmaceutically acceptable salt form. In some embodiments, a compound may be in two or more forms, e.g., in two or more pharmaceutically acceptable salt forms.

[0242] Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and / or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and / or inhaler, eye drops, intraocular Page 176 of 378 12753881v1Attorney Docket No.: 2013405-0034 injection forms, depot forms, as well as injectable and infusible solutions.

[0243] Provided pharmaceutical compositions can be prepared with any appropriate available technologies.

[0244] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0245] Provided compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that is (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and / or decreasing incidence and / or intensity of) a disease or disorder, for example as described herein.

[0246] The present disclosure also provides methods of preparing pharmaceutical compositions provided herein. In some embodiments, provided methods comprise (i) providing a provided compound or a pharmaceutically acceptable salt thereof; and (ii) formulating the compound with suitable excipients to give a pharmaceutical composition. Uses

[0247] In some embodiments, the present disclosure provides a method for preventing a condition, disease or disorder, comprising administering or delivering to a subject susceptible thereto an effective amount of a provided compound. In some embodiments, the present disclosure provides a method for treating a condition, disease or disorder, comprising administering or delivering to a subject suffering therefrom an effective amount of a provided compound. In some embodiments, the present disclosure provides a compound or composition useful for preventing or treating various conditions, diseases or disorders. In some embodiments, the present disclosure provides use of a provided compound for the manufacture of a medicament for the prevention or treatment of a condition, disease or disorder. In some embodiments, the present disclosure provides use of a provided compound for degrading CITK in a subject. Page 177 of 378 12753881v1Attorney Docket No.: 2013405-0034 In some embodiments, the present disclosure provides use of a provided compound for reducing levels of CITK in a subject. In some embodiments, the present disclosure provides use of a provided compound for reducing CITK activity in a subject. In some embodiments, the present disclosure provides use of a provided compound for treating cancer by reducing CITK in a subject. In some embodiments, the present disclosure provides use of a provided compound for treating a disease, disorder, or condition associated with CITK in a subject. In some embodiments, the present disclosure provides use of a provided compound for treating a disease, disorder, or condition selected from medulloblastoma, multiple myeloma, prostate, bladder, breast, ovarian, cervical, brain, head and neck, lung, gastrointestinal, colorectal, sarcoma, liver malignancies, small cell lung, neuroblastoma, neuroendocrine tumors, non-small cell lung, breast, and colorectal cancer. In some embodiments, a provided compound is administered or delivered in or using a pharmaceutical composition.

[0248] Among other things, the present disclosure provides the insight, and demonstrate, that reduction of CITK levels can be utilized to modulate cell states, e.g., change cancer cell states to cell states less or not associated with cancer, and are useful for preventing or treating various diseases, disorders, or conditions associated with CITK including various cancers. It has been reported that temporally controlled CITK depletion in a transgenic mouse model of medulloblastoma led to decreased tumor growth, increased survival, with no increased mortality or gross behavioral consequences one year after CITK depletion. See, e.g., Pallavicini, G. et al., Cancer Res 78, canres.4060.2017 (2018). It has also been reported that CITK is overexpressed in several tumors as compared to normal tissues, and certain reports have proposed that CITK could be a target in various oncology indications including multiple myeloma, prostate, bladder, breast, ovarian, cervical, brain, head and neck, lung, gastrointestinal, colorectal, sarcoma, and liver malignancies. See, e.g., Mishra, R. et al., Cancer Res.83, 4008–4009 (2023); Pallavicini, G. et al., Cancers 12, 542 (2020). Additionally, dependency on CITK has been reported to be enriched in tumors of neural crest (small cell lung, neuroblastoma, and neuroendocrine tumors) and epithelial (non-small cell lung, breast, and colorectal tumors) origin. However, prior to invention(s) described herein, there remained questions whether CITK can be a viable therapeutic target, e.g., in view of various CITK functions in normal cells, tissues, organs, etc., and failures to reproduce various biological effects using small molecule compounds. Using its AURIGIN platform, Applicant has identified CITK can be a therapeutic target, particularly for various cancers, and Applicant has established and demonstrated that CITK can be targeted using various technologies including various compounds for therapeutic purposes, e.g., for treatment of various cancers.

[0249] In some embodiments, the present disclosure provides various improvements. In some embodiments, the present disclosure provides, in a method of reducing levels of CITK in a subject, the improvement that comprises administering or delivering a compound or composition comprising a Page 178 of 378 12753881v1Attorney Docket No.: 2013405-0034 compound of the present disclosure or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides, in a method of reducing CITK activity in a subject, the improvement that comprises reducing the activity by reducing the level of CITK in a subject. In some embodiments, an anti- proliferative effect is observed when CITK is contacted with a bifunction CITK degrader. In some embodiments, proliferation of cancer is reduced in a subject. In some embodiments, reducing the level of CITK in a subject comprises degrading CITK protein. In some embodiments, reducing the level of CITK in a subject comprises administering a compound or a pharmaceutical composition comprising a compound of the present disclosure.

[0250] In some embodiments, the present disclosure provides, in a method of treating cancer by reducing CITK activity the improvement that comprises administering or delivering a compound or a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides, in a method of treating a disease, disorder, or condition by reducing CITK activity, the improvement that comprises administering or delivering a compound or a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides, in a method of reducing CITK activity in a subject, the improvement that comprises administering or delivering a compound or a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides, in a method of reducing levels of CITK in a subject, the improvement that comprises administering or delivering a compound or a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides, in a method of treating a disease, disorder, or condition by reducing CITK activity, the improvement that comprises administering or delivering a compound or a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutical composition thereof.

[0251] Without being bound to a particular theory, the present disclosure provides for the rationale that inhibition of the catalytic activity of CITK with small molecule inhibitors, e.g., ATP-competitive small molecule inhibitors, under many circumstances is insufficient, e.g., to phenocopy impaired cycle progression, increased multi-nucleation, and anti-proliferative effects reported with genetic knock down studies. Among other things, the present disclosure demonstrates that reduction of CITK levels, e.g., using small molecules like compounds described herein, can mimic or reproduce various useful phenotypes observed with genetic knock down of CIT.

[0252] In some embodiments, the present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, Page 179 of 378 12753881v1Attorney Docket No.: 2013405-0034 for example, analytical tools and / or control compounds in biological assays.

[0253] In some embodiments, provided compounds are useful as CITK degraders and / or inhibitors. In some embodiments, the present disclosure provides methods of degrading and / or inhibiting CITK, comprising contacting a provided compound with CITK. In some embodiments, contacting occurs in a cell. In some embodiments, contacting occurs in a subject (e.g., a human subject).

[0254] In some embodiments, the present disclosure provides a method for inhibiting a CITK activity, e.g., a kinase activity, in a system comprising CITK, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, the present disclosure provides a method for reducing level of a CITK polypeptide in a system, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, the present disclosure provides a method for inhibiting a PKN2 activity, e.g., a kinase activity, in a system comprising PKN2, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, the present disclosure provides a method for reducing level of a PKN2 polypeptide in a system, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, the present disclosure provides a method for inhibiting an AAK1 activity, e.g., a kinase activity, in a system comprising AAK1, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, the present disclosure provides a method for reducing level of an AAK1 polypeptide in a system, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, a system is or comprises a cell. In some embodiments, a system is or comprises a cancer cell. In some embodiments, a system is or comprises a medulloblastoma cell. In some embodiments, a system is or comprises a breast cancer cell. In some embodiments, a system is or comprises a small cell lung cancer cell. In some embodiments, a system is or comprises a non-small cell lung cancer cell. In some embodiments, a system is or comprises a neuroblastoma cell. In some embodiments, a system is or comprises a neuroendocrine cell. In some embodiments, a system is or comprises a colorectal cancer cell. In some embodiments, a cell is a SW48 cell. In some embodiments, a cell is a HCT116 cell. In some embodiments, a system is or comprises a population of cells. In some embodiments, a system is or comprises a tissue. In some embodiments, a system is or comprises an organ. In some embodiments, a system is or comprises an organism. In some embodiments, a system is or comprises a subject. In some embodiments, a system is a human. In some embodiments, CITK polypeptide levels are selectively reduced over PKN2 polypeptide levels. In some embodiments, CITK polypeptide levels are selectively reduced over AAK1 polypeptide levels. In some embodiments, CITK polypeptide levels are selectively reduced over PKN2 polypeptide levels and AAK1 polypeptide levels. In some embodiments, CITK polypeptide levels and PKN2 polypeptide levels are reduced. In some embodiments, CITK polypeptide levels and AAK1 polypeptide levels are reduced. In Page 180 of 378 12753881v1Attorney Docket No.: 2013405-0034 some embodiments, CITK polypeptide levels, AAK1 polypeptide levels, and PKN2 polypeptide levels are reduced. In some embodiments, CITK activity is selectively inhibited over PKN2 activity. In some embodiments, CITK activity is selectively inhibited over AAK1 activity. In some embodiments, CITK activity is selectively inhibited over AAK1 activity and PKN2 activity. In some embodiments, CITK activity and PKN2 activity are inhibited. In some embodiments, CITK activity and AAK1 activity are inhibited. In some embodiments, CITK activity, AAK1 activity, and PKN2 activity are inhibited. In some embodiments, a CITK polypeptide is described at www.uniprot.org / uniprotkb / O14578 / entry. In some embodiments, a PKN2 polypeptide is described at www.uniprot.org / uniprotkb / Q16513 / entry. In some embodiments, an AAK1 polypeptide is described at www.uniprot.org / uniprotkb / Q2M2I8 / entry. In some embodiments, a polypeptide is a full-length protein. In some embodiments, a provided compound binds to a polypeptide. Various functions of CITK, PKN2, and AAK1, including those related to various conditions, diseases or disorders, have been reported; for example, for PKN2, see, e.g., Murray et al., Cell Rep.2022 Jan 25;38(4):110227; Schmidt et al., EMBO J.2007 Mar 21;26(6):1624-36; Killarney et al., Cancer Discov. 2025 Mar 3;15(3):595-615; etc.

[0255] In some embodiments, a compound is administered or delivered as a salt, e.g., a pharmaceutically acceptable salt. In some embodiments, a compound in a compositions, e.g., a pharmaceutical composition, is a pharmaceutically acceptable salt.

[0256] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with CITK.

[0257] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with CITK, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, provided methods are for treating cancer. In some embodiments, a cancer is a solid tumor. In some embodiments, a cancer is characterized by a hematologic tumor. In some embodiments, a cancer is selected from hematopoietic cancers, including leukemias, lymphomas (e.g., Hodgkin’s and non-Hodgkin’s), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, carcinomas of solid tissue, squamous cell carcinomas of the mouth, throat, larynx, and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterine, and endometrial cancer and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, head and neck cancers, breast cancer, gastro-intestinal cancers and nervous system cancers, benign lesions such as Page 181 of 378 12753881v1Attorney Docket No.: 2013405-0034 papillomas, and the like. In some embodiments, a cancer is selected from medulloblastoma, multiple myeloma, prostate, bladder, breast, ovarian, cervical, brain, head and neck, lung, gastrointestinal, colorectal, sarcoma, liver malignancies, small cell lung, neuroblastoma, and neuroendocrine tumors, non-small cell lung, breast, and colorectal cancer. In some embodiments, provided methods are for treating a leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.) In some embodiments, provided methods are for treating a disease, disorder, or condition selected from acute myeloid leukemia (AML), neuroblastoma, non-small cell lung cancer (NCSLC), small cell lung cancer (SCLC), colorectal cancer, melanoma, and prostate cancer.

[0258] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.

[0259] For example, in some embodiments, a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and / or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care).

[0260] In some embodiments, the present disclosure provides methods of degrading CITK in a subject, comprising administering to the subject a provided compound or composition of the present disclosure. In some embodiments, a method of reducing levels of CITK in a subject comprises administering or delivering a provided compound or composition of the present disclosure. In some embodiments, a method of reducing CITK activity in a subject, comprising reducing the activity by reducing the level of CITK in a subject, is provided. In some embodiments, when CITK is contacted with a bifunctional CITK degrader, an anti-proliferative effect is observed. In some embodiments, proliferation of cancer is reduced in a subject. In some embodiments, reducing the level of CITK in a subject comprises degrading CITK protein. In some embodiments, reducing the level of CITK comprises administering a compound or composition of the present disclosure. Page 182 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0261] In some embodiments, the present disclosure provides methods of treating cancer by reducing CITK activity, comprising administering or delivering a compound or composition of the present disclosure. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition by reducing CITK activity, comprising administering or delivering a compound or composition of the present disclosure. In some embodiments, a method of treating a disease, disorder, or condition by reducing CITK activity, comprising administering a composition that comprises or delivers a CITK degrader. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with CITK, comprising administering to a subject in need thereof a compound or composition of the present disclosure.

[0262] As demonstrated herein, certain provided technologies can reduce PKN2 polypeptide levels. In some embodiments, provided technologies can reduce PKN2 activity. In some embodiments, provided technologies can reduce AAK1 polypeptide levels. In some embodiments, provided technologies can reduce AAK1 activity. In some embodiments, a method or an improvement comprises reduction of PKN2 and / or AAK1 polypeptide level, and / or inhibition of PKN2 and / or AAK1 activity, optionally in addition to reduction of CITK polypeptide level, and / or inhibition of CITK activity. In some embodiments, a provided technology reduces a PKN2 polypeptide level. In some embodiments, a provided technology reduces an AAK1 polypeptide level. In some embodiments, a condition, disease or disorder is associated with CITK. In some embodiments, a condition, disease or disorder is associated with PNK2. In some embodiments, a condition, disease or disorder is associated with AAK1. In some embodiments, a condition, disease or disorder is more responsive to reduction of CITK polypeptide level and reduction of PNK2 and / or AAK1 polypeptide level relative to reduction of CITK, PNK2 or AAK1 polypeptide level only.

[0263] Among other things, the present disclosure provides the following example Embodiments: 1. A compound according to formula I’: CIM—LCL—LBM I’ or a pharmaceutically acceptable salt thereof, wherein: CIM is a CITK binding moiety; LCLis an optional linking moiety; and LBM is an E3 ubiquitin ligase binding moiety. 2. A compound having the structure of formula I: CIM—LCL—LBM, I or a pharmaceutically acceptable salt thereof, wherein: Page 183 of 378 12753881v1Attorney Docket No.: 2013405-0034 ;,each of Ring A, Ring B, Ring C and Ring D is independently an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; each of a, b, c and d is independently 0, 1, 2, 3, or 4; each Rsais independently −Rsa1, −ORsa1, or −Lsa1−Lsa2−Lsa3−N(Rsa1)(Rsa2); Lsa1is a covalent bond, optionally substituted −CH2−, −O−, or −N(R’)−; Lsa2is a covalent bond, or optionally substituted −CH2−; Page 184 of 378 12753881v1Attorney Docket No.: 2013405-0034 Lsa3is a covalent bond, −R’, or −CH2−C(Rsa3)2−, wherein the −CH2− is optionally substituted; each of Rsa1, Rsa2and Rsa3is independently −R’, or Rsa2and one Rsa3are taken together with their intervening atoms to form an optionally substituted 3-14 membered ring having 1-6 heteroatoms independently selected from N, O, and S; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; each of Rsb, Rscand Rsdis independently halogen, −CN, −R’, −OR’, or −N(R’)2; each of Lband Lcis independently a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; Ring P is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Lpis a covalent bond or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −O−, −S−, −N(R’)−, −N=N−, −C(O)−, −C(S)−, −C(NR’)−, −C(NOR’)−, −C(NN(R’)2)−, −C(O)O−, −C(O)N(R’)−, −C(NR’)O−, −C(NR’)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −N(R’)C(O)S−, −N(R’)C(NR’)N(R’)−, −SC(O)−, −S(O)2−, −SO2N(R’)−, or −Cy−; each −Cy− is independently an optionally substituted, mono- or bicyclic, 3- to 11-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-4 heteroatoms independently selected from N, O, and S; Ring Q is optionally substituted ; each of Ring R and Ring S is istituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rspis independently halogen, −CN, −R’ or −OR; each Rsqis independently halogen, −CN, −R’ or −OR’, or two Rsqare taken together with their intervening atom(s) to form an optionally substituted 3-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; each of p and q is independently 0, 1, 2, 3, or 4; Rais −N(Ra1)2, −Ra1, −C(Ra1)3, or −Cy−Ra1;Rcis −R’; Page 185 of 378 12753881v1Attorney Docket No.: 2013405-0034 each Rdis independently halogen, −CN, −R’ or −OR’; r is 0, 1, 2, or 3; each Reis independently halogen, −R’, or −C(O)N(R’)2; m is 1, 2, 3, 4, or 5; t is 1 or 2; Rfis −R, or one Reand one Rfare taken together with their intervening atoms to form an optionally substituted 5-10 membered ring having 1-2 heteroatoms independently selected from N, O, and S; each of Rg, Rhand Rh’is independently −R’; each of Rj, Rk, Rmand Rm’is independently −R’; each of Rn, Rp, Rq, Rr, Rs, Rtand Ruis independently halogen, −CN, −R’ or −OR’; each of n, s, u, u’, v and w is independently 0, 1, 2, 3, 4, or 5; each Rvis independently halogen, −CN, −R’ or −OR’, or one Ruand one Rvare taken together with their intervening atoms to form an optionally substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, −CN, −R or −OR, or one Ruand one Rware taken together with their intervening atoms to form an optionally substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; each R’ is independently −R, −C(O)R, or −S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to 16-membered ring having 0-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen, or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1−C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. 3. The compound of any one of any one of the preceding Embodiments, wherein CIM is ors s a cova ent on or an opt ona y su st tute valent C1-C20hydrocarbon chain, wherein Page 186 of 378 12753881v1Attorney Docket No.: 2013405-0034 one or more methylene units are optionally and independently replaced by −O−, −S−, −N(R’)−, −N=N−, −C(O)−, −C(S)−, −C(NR’)−, −C(NOR’)−, −C(NN(R’)2)−, −C(O)O−, −C(O)N(R’)−, −C(NR’)O−, −C(NR’)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −N(R’)C(O)S−, −N(R’)C(NR’)N(R’)−, −SC(O)−,substituted 6-14 membered aromatic ring having no heteroatoms. 5. The compound of any one of the preceding Embodiments, wherein Ring A is an optionally substituted phenyl ring. 6. The compound of any one of Embodiments 1-2, wherein Ring A is an optionally substituted 5-14 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. 7. The compound of any one of Embodiments 1-2, wherein Ring A is an optionally substituted 3-14 membered heterocycle having 1-4 heteroatoms independently selected from N, O, and S 8. The compound of any one of Embodiments 1-2, wherei isPage 187 of 378 12753881v1Attorney Docket No.: 2013405-0034 , wherein A is C(R’), N or optionally substituted CH. ound of Embodiment 8, wherein A is CH, N or C(CH3).10. The compound of any one of Embodiments 1-2, wherei an optionallys and11. The compound of any one of Embodiments 1-0, wherei is,,Page 188 of 378 12753881v1Attorney Docket No.: 2013405-0034 12. The compound of any one of the preceding Embodiments, wherein a is 1, 2, 3 or 4. 13. The compound of any one of the preceding Embodiments, wherein an occurrence of Rsais −Lsa1−Lsa2−Lsa3−N(Rsa1)(Rsa2). 14. The compound of any one of the preceding Embodiments, wherein Lsa1is −O−. 15. The compound of any one of Embodiments 1-13, wherein Lsa1is −N(R’)−. 16. The compound of any one of Embodiments 1-13, wherein Lsa1is −NH−. 17. The compound of any one of the preceding Embodiments, wherein Lsa2is optionally substituted −CH2−. 18. The compound of any one of Embodiments 1-16, wherein Lsa2is −CH2−. 19. The compound of any one of Embodiments 1-16, wherein Lsa2is −C(O)−. 20. The compound of any one of the preceding Embodiments, wherein Lsa3is −CH2−C(Rsa3)2−, wherein the −CH2− is optionally substituted. 21. The compound of any one of the preceding Embodiments, wherein Rsa2and one Rsa3are taken together with their intervening atoms to form an optionally substituted 3-14 membered ring having 1-6 heteroatoms independently selected from N, O, and S. 22. The compound of Embodiment 21, wherein the formed ring is an optionally substituted 5-6 membered saturated ring having no additional heteroatoms in addition to the nitrogen atom to which Rsa2is attached. 23. The compound of any one of Embodiments 1-19, wherein Lsa3is −CH2−CHRsa3−. 24. The compound of any one of Embodiments 1-13, wherein an occurrence of Rsais −NHC(O)CH(Rsa3)NH2. 25. The compound of any one of Embodiments 1-13, wherein an occurrence of Rsais −OCH2CH(Rsa3)NH2. 26. The compound of any one of the preceding Embodiments, wherein an occurrence of Rsa3is optionally substituted C1-8aliphatic. 27. The compound of Embodiment 26, wherein an occurrence of Rsa3is isopropyl, t-butyl, or methylcyclopropyl. 28. The compound of any one of Embodiments 1-13, wherein Rsais optionally substituted and selected from -NH2, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, -NHC(O)R’’’, or =O; wherein R’’’is optionally substituted and selected from C1-6alkyl, C1-6cycloalkyl, 4- to 6- membered heterocycle, and 6-membered aryl. 29. The compound of any one of Embodiments 1-13, wherein -Rsai ,Page 189 of 378 12753881v1Attorney Docket No.: 2013405-0034 , or31. The compound of any one of Embodiments 1-27, wherein Lais optionally substituted C1-3alkylene. 32. The compound of any one of Embodiments 1-27, wherein Lais −(CH2)1-3−. 33. The compound of any one of Embodiments 1-27, wherein Lais −N(R’)−. 34. The compound of any one of Embodiments 1-27, wherein Lais −NH−. 35. The compound of any one of Embodiments 1-34, wherein Lbis a covalent bond. 36. The compound of any one of Embodiments 1-34, wherein Lbis −C(O)N(R’)−. 37. The compound of any one of Embodiments 1-34, wherein Lbis −NHC(O)− or −C(O)NH−. 38. The compound of any one of Embodiments 1-34, wherein Lbis −N(R’)C(O)N(R’)−. 39. The compound of any one of Embodiments 1-34, wherein Lbis −N(R’)−. 40. The compound of any one of Embodiments 1-34, wherein Lbis −NH−. 41. The compound of any one of Embodiments 1-40, wherein RingB is an optionally substituted 6- 10 membered aromatic ring having no heteroatoms. 42. The compound of any one of Embodiments 1-40, wherein Ring B is an optionally substituted phenyl ring. 43. The compound of any one of Embodiments 1-40, wherein Ring B is an optionally substituted 5- 12 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. 44. The compound of any one of Embodiments 1-40, wherein Ring B is an optionally substituted 5-9 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. 45. The compound of any one of Embodiments 1-40, wherein Ring B is optionally substituted , wherein A is C(R’), N or optionally substituted CH, * denotes the attachment point toLb, and denotes the attachment point to La. 46. The compound of any one of Embodiments 1-40, wherein Ring , wherein A isPage 190 of 378 12753881v1Attorney Docket No.: 2013405-0034 C(R’), N or optionally substituted CH, * denotes the attachment point to Lb, and ** denotes the attachment point to La. 47. The compound of any one of Embodiments 45-46, wherein A is CH, N or C(CH3). 48. The compound of any one of Embodiments 45-46, wherein A is CH. 49. The compound of any one of Embodiments 45-46, wherein A is N. 50. The compound of any one of Embodiments 1-40, wherein Ring B is an optionally substituted ,, ,to La. Page 191 of 378 12753881v1Attorney Docket No.: 2013405-0034 52. The compound of any one of Embodiments 1-40, wherein Ring B , wherein A is C(R’), N or optionally substituted CH, * denotes the attachment point totes the attachment point to La. 53. The compound of Embodiment 50, wherein each A is independently selected from CH, N or C(CH3). 54. The compound of any one of Embodiments 1-51, wherein Ring C is an optionally substituted 6- 10 membered aromatic ring having no heteroatoms. 55. The compound of any one of Embodiments 1-51, wherein Ring C is an optionally substituted phenyl ring. 56. The compound of any one of Embodiments 1-51, wherein Ring C is an optionally substituted 5- 12 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. 57. The compound of any one of Embodiments 1-51, wherein Ring C is an optionally substituted 5-9 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S. 58. The compound of any one of Embodiments 1-51, wherein Ring C is optionally substituted and ,n Apoint to Lb. Page 192 of 378 12753881v1Attorney Docket No.: 2013405-0034 61. The compound of any one of Embodiments 1-56, wherein Lcis a covalent bond. 62. The compound of any one of Embodiments 1-56, wherein Lcis −C(O)N(R’)−. 63. The compound of any one of Embodiments 1-56, wherein Lcis −NHC(O)− or −C(O)NH−. 64. The compound of any one of Embodiments 1-56, wherein Lcis−N(R’)C(O)N(R’)−. 65. The compound of any one of Embodiments 1-56, wherein Lcis −N(R’)−. 66. The compound of any one of Embodiments 1-56, wherein Lcis −NH−. 67. The compound of any one of Embodiments 1-64, wherein Ring D is an optionally substituted phenyl ring. 68. The compound of any one of Embodiments 1-64, wherein Ring D is an optionally substituted 5- 12 membered heterocyclic ring having 1-6 heteroatoms independently selected from N, O, and S. 69. The compound of any one of Embodiments 1-64, wherein Ring D is an optionally substituted 5-9 membered heterocyclic ring having 1-6 heteroatoms independently selected from N, O, and S. 70. The compound of any one of Embodiments 1-64, wherein Rin wherein A is N or optionally substituted CH, * denotes the attachment point to L e attachmentpoint to Lc. 71. The compound of any one of Embodiments 1-64, wherein Ring D wherein * denotes the attachment point to LCL, and ** denotes the attachment point t. 72. The compound of any one of Embodiments 1-71, wherein -Rsais optionally substituted and selected from −NH2, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, −NHC(O)R’’’, or =O; wherein R’’’is optionally substituted and selected from C1-6alkyl, C1-6cycloalkyl, 4- to 6- membered heterocycle, and 6-membered aryl. 73. The compound of any one of Embodiments 1-72, wherein -Rsai or.. e compound of any one of the preceding Embodiments, wherein LCLis less than 14 atoms in length. 75. The compound of any one of the preceding Embodiments, wherein LCLis less than 11 atoms in Page 193 of 378 12753881v1Attorney Docket No.: 2013405-0034 length. 76. The compound of any one of the preceding Embodiments, wherein LCLis less than 9 atoms in length. 77. The compound of any one of the preceding Embodiments, wherein the shortest-path length of LCLis about or no more than 14 atoms. 78. The compound of any one of the preceding Embodiments, wherein the shortest-path length of LCLis about or no more than 10 atoms. 79. The compound of any one of the preceding Embodiments, wherein the number of non-ring consecutive sp3atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1. 80. The compound of any one of the preceding Embodiments, wherein the number of non-ring consecutive sp3atoms in the shortest path chain of LCLis about or no more than about 2. 81. The compound of any one of the preceding Embodiments, wherein the number of bonds between two non-ring sp3atoms in the shortest path chain of LCLis about or no more than 5, 4, 3, 2 or 1. 82. The compound of any one of the preceding Embodiments, wherein the number of bonds between two non-ring sp3atoms in the shortest path chain of LCLis about or no more than 1. 83. The compound of any one of the preceding Embodiments, wherein the number of non-ring sp3C, O, and S atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1. 84. The compound of any one of the preceding Embodiments, wherein the number of non-ring sp3C, O, and S atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1. 85. The compound of any one of the preceding Embodiments, wherein the number of non-ring sp3atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1. 86. The compound of any one of the preceding Embodiments, wherein the number of non-ring sp3atoms in the shortest path chain of LCLis about or no more than about 1. 87. The compound of any one of the preceding Embodiments, wherein the number of non-ring atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1. 88. The compound of any one of the preceding Embodiments, wherein the number of non-ring atoms in the shortest path chain of LCLis about or no more than about 1. 89. The compound of any one of the preceding Embodiments, wherein LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1−C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O−, −S−, −N(R)−, −N=N−, −C(O)−, −C(S)−, −C(NR)−, −C(NOR)−, −C(NN(R)2)−, −OC(O)−, −C(O)O−, −C(O)N(R)−, −N(R)C(O)−, −C(NR)O−, −OC(NR)−, −C(NR)NR−, −N(R)C(NR)−, −N(R)C(O)N(R)−, −N(R)C(O)O−, −OC(O)N(R)−, −N(R)C(O)S−, −SC(O)N(R)−, −N(R)C(NR)N(R)−, −S(O)2−, −SO2N(R)−, −N(R)S(O)2−, or –Cy−. Page 194 of 378 12753881v1Attorney Docket No.: 2013405-0034 90. The compound of any one of the preceding Embodiments, wherein LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1−C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O−, −S−, −N(R)−, −N=N−, −C(O)−, −C(S)−, −C(NR)−, −C(NOR)−, −C(NN(R)2)−, −OC(O)−, −C(O)O−, −C(O)N(R)−, −N(R)C(O)−, −C(NR)O−, −OC(NR)−, −C(NR)NR−, −N(R)C(NR)−, −N(R)C(O)N(R)−, −N(R)C(O)O−, −OC(O)N(R)−, −N(R)C(O)S−, −SC(O)N(R)−, −N(R)C(NR)N(R)−, −S(O)2−, −SO2N(R)−, −N(R)S(O)2−, or –Cy−. 91. The compound of any one of the preceding Embodiments, wherein LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1−C20hydrocarbon chain, wherein at least one methylene unit is replaced by –O−, −N(R)−, −C(O)−, −OC(O)−, −C(O)O−, −C(O)N(R)−, −N(R)C(O)−, or –Cy−. 92. The compound of any one of the preceding Embodiments, wherein LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1−C20hydrocarbon chain, wherein at least two methylene units are replaced by –O−, −N(R)−, −C(O)−, −OC(O)−, −C(O)O−, −C(O)N(R)−, −N(R)C(O)−, or –Cy−. 93. The compound of any one of the preceding Embodiments, wherein a methylene unit is replaced by −C(O)−. 94. The compound of any one of the preceding Embodiments, wherein a methylene unit is replaced by −Cy−. 95. The compound of Embodiment 94, wherein −Cy− is in a shortest path chain. 96. The compound of any one of the preceding Embodiments, wherein LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1−C20hydrocarbon chain, wherein at least one methylene unit is replaced by −C(O)N(R)−. 97. The compound of any one of the preceding Embodiments, wherein LCLcomprises at least one triple bond. 98. The compound of any one of the preceding Embodiments, wherein LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1−C20hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy−. 99. The compound of any one of the preceding Embodiments, wherein LCLis: , wherein:M1and M2are each independently absent, –CH2-, –O−, −N(R)−, −C(O)−, −OC(O)−, −C(O)O−, −C(O)N(R)−, or −N(R)C(O)−; and Page 195 of 378 12753881v1Attorney Docket No.: 2013405-0034 L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1−C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O−, −S−, −N(R)−, −N=N−, −C(O)−, −C(S)−, −C(NR)−, −C(NOR)−, −C(NN(R)2)−, −OC(O)−, −C(O)O−, −C(O)N(R)−, −N(R)C(O)−, −C(NR)O−, −OC(NR)−, −C(NR)NR−, −N(R)C(NR)−, −N(R)C(O)N(R)−, −N(R)C(O)O−, −OC(O)N(R)−, −N(R)C(O)S−, −SC(O)N(R)−, −N(R)C(NR)N(R)−, −S(O)2−, −SO2N(R)−, −N(R)S(O)2−, or –Cy−. 100. The compound of any one of the preceding Embodiments, wherein LCLis selected from102. The compound of Embodiment 101, wherein −Cy− is 3-10 membered. 103. The compound of any one of Embodiments 101-102, wherein −Cy− is 4-, 5- or 6-membered. 104. The compound of any one of Embodiments 101-103, wherein −Cy− is saturated. 105. The compound of any one of Embodiments 101-103, wherein −Cy− is partially unsaturated. 106. The compound of any one of Embodiments 101-105, wherein −Cy− has 1-2 heteroatoms independently selected from N, O, and S. 107. The compound of any one of Embodiments 101-106, wherein −Cy− has at least one nitrogen atom. 108. The compound of any one of Embodiments 1-100, wherein −Cy− is polycyclic. Page 196 of 378 12753881v1Attorney Docket No.: 2013405-0034 109. The compound of any one of Embodiments 1-108, wherein −Cy− is bicyclic. 110. The compound of any one of Embodiments 108-109, wherein −Cy− is 6-16 membered. 111. The compound of any one of Embodiments 108-110, wherein −Cy− is 7-12 membered. 112. The compound of any one of Embodiments 108-111, wherein −Cy− is 7-, 8-, 9-, 10- or 11- membered. 113. The compound of any one of Embodiments 108-112, wherein −Cy− is 11-membered. 114. The compound of any one of Embodiments 108-113, wherein each monocyclic ring unit is independently 4-7 membered. 115. The compound of any one of Embodiments 108-114, wherein each monocyclic ring unit is independently 4-6 membered. 116. The compound of any one of Embodiments 108-115, wherein a monocyclic ring unit is saturated. 117. The compound of any one of Embodiments 108-116, wherein a monocyclic ring unit has 1-2 heteroatoms independently selected from N, O, and S. 118. The compound of any one of Embodiments 108-117, wherein each monocyclic ring unit independently has 1-2 heteroatoms independently selected from N, O, and S. 119. The compound of any one of Embodiments 108-118, wherein each monocyclic ring unit independently has at least one nitrogen atom. 120. The compound of any one of Embodiments 108-119, wherein −Cy− is saturated. 121. The compound of any one of Embodiments 108-119, wherein a monocyclic ring unit is partially unsaturated. 122. The compound of any one of Embodiments 108-121, wherein −Cy− is spiro. 123. The compound of any one of the preceding Embodiments, wherein LCLcomprises one or more basic nitrogen. 124. The compound of any one of the preceding Embodiments, wherein −Cy− comprises one or more basic nitrogen. 125. The compound of any one of the preceding Embodiments, wherein −Cy− is a diamine ring. 126. The compound of any one of Embodiments 2-100, wherein Cy is optionally substituted phenyl or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 127. The compound of any one of Embodiments 2-100, wherein Cy is optionally substituted monocyclic 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 128. The compound of any one of Embodiments 2-100, wherein Cy is optionally substituted bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. 129. The compound of any one of Embodiments 2-100, wherein Cy is a spirocyclic 6- to 7-membered Page 197 of 378 12753881v1Attorney Docket No.: 2013405-0034 heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. 130. The compound of any one of the preceding Embodiments, wherein −Cy− is substituted. 131. The compound of any one of the preceding Embodiments, wherein −Cy− is unsubstituted. 132. The compound of any one of Embodiments 1-98, wherein LCLis −M1−L6−L7−M2−. 133. The compound of any one of Embodiments 101-132, wherein M1is a covalent bond. 134. The compound of any one of Embodiments 101-132, wherein Mis optionally substituted −CH2-. 135. The compound of any one of Embodiments 101-132, wherein M1is −CH2-. 136. The compound of any one of Embodiments 101-132, wherein M1is −C(O)−. 137. The compound of any one of Embodiments 101-136, wherein M1is bonded to PBM. 138. The compound of any one of Embodiments 101-137, wherein L6is a covalent bond. 139. The compound of any one of Embodiments 101-137, wherein L6is optionally substituted −CH2-. 140. The compound of any one of Embodiments 101-139, wherein L7is a covalent bond. 141. The compound of any one of Embodiments 101-139, wherein L7is −O−. 142. The compound of any one of Embodiments 101-141, wherein M2is a covalent bond. 143. The compound of any one of Embodiments 101-141, wherein M2is −O−. 144. The compound of any one of the preceding Embodiments, wherein each R is independently hydrogen or optionally substituted C1-6alkyl. 145. The compound of any one of Embodiments 1-73, wherein LCLis selected from: ,Page 198 of 378 12753881v1Attorney Docket No.: 2013405-0034 , ,Page 199 of 378 12753881v1Attorney Docket No.: 2013405-0034 ,Page 200 of 378 12753881v1Attorney Docket No.: 2013405-0034 , ,146. The compound of any one of Embodiments 1-145, wherein LBM is an E3 ubiquitin ligase binding moiety. 147. The compound of any one of Embodiments 1-73, wherein LCLis absent. Page 201 of 378 12753881v1Attorney Docket No.: 2013405-0034 148. The compound of Embodiment 1, wherein the compound is represented by formula II: wherein: Lais a covalent bond, C1-3alkyl, C1-3haloalkyl, or −NH-; Lbis a covalent bond, C1-3alkyl, C1-3haloalkyl, −NHC(O)−, −C(O)NH-, −NHC(O)NH-, or −NH-; Ring C is an optionally substituted 6-membered aryl or heteroaryl; each A1is independently CH or N; A2is NH or O; each Rzis independently H, C1-6alkyl, or C1-6haloalkyl; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); and Ryis H, C1-6alkyl, C1-6haloalkyl; or C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form a 4-6 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N, O, and S. 149. The compound of Embodiment 148, wherein the compound is represented by formula IIa:or a pharmaceutically acceptable salt thereof. 150. The compound of Embodiment 1, wherein the compound is represented by formula III:or a pharmaceutically acceptable salt thereof, wherein: Ring P is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; Page 202 of 378 12753881v1Attorney Docket No.: 2013405-0034 each Rsqis independently hydrogen or an optionally substituted C1-6aliphatic, or two Rsqgroups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; Lpis a covalent bond or a straight or branched C1-3hydrocarbon chain wherein one methylene is optionally replaced with –O−, −S−, −N(R)−, −S(O)2−, −C(O)N(R)−, or −N(R)C(O)−; and Y is N or CH. 151. The compound of Embodiment 150, wherein Ring P is optionally substituted phenyl, C5-6cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, or 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 152. The compound of Embodiment 150, wherein Ring P is optionally substituted phenyl or 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 153. The compound of Embodiment 150, wherein Rin , wherein: each B is independently selected from N, C, and t no more than two B are N;each Rspis independently selected from halogen, −OR, −N(R)2, −CN, and optionally substituted C1-6aliphatic; and p is 0, 1, 2, or 3. 154. The compound of Embodiment 150, wherein Rin . 155. The compound of Embodiment 150, wherein Rinubstituted C3−C7cycloaliphatic or 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 156. The compound of Embodiment 150, wherein Ring P is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 157. The compound of Embodiment 150, wherein Ring P is: wherein:Page 203 of 378 12753881v1Attorney Docket No.: 2013405-0034 each A is independently N, C, or CH, provided that no more than two A groups are N; each Rsp’is hydrogen, or two Rsp’groups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rspis independently selected from halogen, −OR, −N(R)2, −CN, and optionally substituted C1-6aliphatic; and p is 0, 1, 2, or 3. 158. The compound of Embodiment 157, wherein Ring P is: . 159. The compound of any one of Em wherein Lpis a covalent bond.160. The compound of any one of Embodiments 2-158, wherein Lpis optionally substituted −CH2-. 161. The compound of any one of Embodiments 2-158, wherein Lpis –CH2-. 162. The compound of any one of Embodiments 2-158, wherein Lpis −O−. 163. The compound of any one of Embodiments 2-158, wherein Lpis −S−. 164. The compound of any one of Embodiments 2-158, wherein Lpis −C(O)N(R)−, or −N(R)C(O)−. 165. The compound of any one of Embodiments 2-158, wherein Lpis −C(O)NH-, or −NHC(O)−. 166. The compound of any one of Embodiments 2-158, wherein Lpis –N(R)−. 167. The compound of any one of Embodiments 2-158, wherein Lpis −NH-. 168. The compound of any one of Embodiments 2-158, wherein Lpis −Cy−. 169. The compound of any one of Embodiments 2-158, wherein Lpis −Cy−, wherein −Cy− is aromatic. 170. The compound of any one of Embodiments 150-169, wherein Y is N. 171. The compound of any one of Embodiments 150-169, wherein Y is CH. 172. The compound of any one of Embodiments 150-171, wherein each Rspis independently selected from halogen, −O(C1-6alkyl), C1-6alkyl, and C1-6haloalkyl. 173. The compound of any one of the preceding Embodiments, wherein LBM or ,Page 204 of 378 12753881v1Attorney Docket No.: 2013405-0034 , ormula III-A:or a pharmaceutically acceptable salt thereof, wherein: each Rsp’is independently hydrogen, or two Rsp’groups on the same carbon are taken together to form =O or together with the carbon atom to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected frm N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; Page 205 of 378 12753881v1Attorney Docket No.: 2013405-0034 A3is C(Rsa) or N; Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S. 175. The compound of Embodiment 174, wherein LCLis , wherein each of Cy1and Cy2is independently selected from 12-memberedmonocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.176. The compound of Embodiment 174, wherein LCL ,whereineach of Cy1and Cy2is independently selected from an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; andeach Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. 177. The compound of Embodiment 1, wherein the compound is represented by formula III-B: Page 206 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein: each Rsp’is independently hydrogen, or two Rsp’groups on the same carbon are taken together to form =O or together with the carbon atom to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring; each Rsais independently −R’or −OR’; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl;and Ryis H, optionally substituted C1-6alkyl, or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C-Rsaor N; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and Lcis a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. 178. The compound of Embodiment 1, wherein the compound is represented by formula III-C: Page 207 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein each Rsp’is independently hydrogen, or two Rsp’groups on the same carbon are taken together to form =O or together with the carbon atom to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring; each of Rsa, Rsband Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; each of a, b, and c is independently 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; each of Ring A and Ring B is independently an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S.179. The compound of Embodiment 178, wherein LCL , whereineach of Cy1and Cy2is independently selected froman op ona y su s ue - o 12-membered Page 208 of 378 12753881v1Attorney Docket No.: 2013405-0034 monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.180. The compound of Embodiment 178, wherein LCL i ,whereineach of Cy1and Cy2is independently selected from an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. 181. The compound of Embodiment 1, wherein the compound is represented by formula IV:or a pharmaceutically acceptable salt thereof, wherein: LCLis attached to the bracketed moiety at one of Ra, Rb, Rc, or Rd, or LCLis attached to a point on one Rd; Page 209 of 378 12753881v1Attorney Docket No.: 2013405-0034 Ring R is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Rais −N(Ra1)2, −Ra1, −C(Ra1)3, or −Cy−Ra1; Rbis −Rb1, or −C(Rb1)3; each of Ra1and Rb1is independently −R’; Rcis −R’; each Rdis independently halogen, −CN, −R’ or −OR’; r is 0, 1, 2, or 3; each R’ is independently −R, −C(O)R, or −S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 0-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen, N(R’)2, or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1−C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. 182. The compound of Embodiment 181, wherein Ring R is optionally substituted phenyl, C5-6cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, or 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 183. The compound of Embodiment 181, wherein Ring R is optionally substituted phenyl or 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 184. The compound of Embodiment 181, wherein Rin , wherein: each B is independently selected from N, C, andthat no more than two B are N; each Rdis independently selected from halogen, −CN, −R’ or −OR’; and r is 0, 1, 2, or 3. 185. The compound of Embodiment 181, wherein Ring R . 186. The compound of Embodiment 181, wherein Ring Rs op onally substituted C3−C7cycloaliphatic or 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, Page 210 of 378 12753881v1Attorney Docket No.: 2013405-0034 O, and S. 187. The compound of Embodiment 181, wherein Ring R is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 188. The compound of any one of Embodiments 181-186, wherein Rdis a point of attachment for LCL. 189. The compound of any one of Embodiments 181-186, wherein Rdis halogen. 190. The compound of any one of Embodiments 181-186, wherein Rdis −CN. 191. The compound of any one of Embodiments 181-186, wherein Rdis −R’ or −OR’. 192. The compound of Embodiment 1, wherein the compound is represented by formula IV-A’:or a pharmaceutically acceptable salt thereof, wherein Rbis −R’ or −C(R’)3; Rcis −R’; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each of Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken Page 211 of 378 12753881v1Attorney Docket No.: 2013405-0034 together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; A4is C(Ra1) or N; H−, tlyselected from N, O, and S. 193. The compound of Embodiment 1, wherein the compound is represented by formula IV-A:or a pharmaceutically acceptable salt thereof, wherein: Rbis −R’ or −C(R’)3; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each of Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Page 212 of 378 12753881v1Attorney Docket No.: 2013405-0034 Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; A4is C(Ra1) or N; bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; andRing C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S.194. The compound of Embodiment 192 or 193, wherein LCL ,whereineach of Cy1and Cy2is independently selected from an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.195. The compound of Embodiment 192 or 193, wherein LCL ,whereineach of Cy1and Cy2is independently selected from an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene Page 213 of 378 12753881v1Attorney Docket No.: 2013405-0034 units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. 196. The compound of Embodiment 1, wherein the compound is represented by formula IV-B:or a pharmaceutically acceptable salt thereof, wherein: Rbis −R’ or −C(R’)3; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; Page 214 of 378 12753881v1Attorney Docket No.: 2013405-0034 A4is C(Ra1) or N; Ra1is −R’; Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms indepenent y selected from N, O, and S. 197. The compound of Embodiment 196, wherein LCL is , whereineach of Cy1and Cy2is independently selected fro o 12-memberedmonocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. 198. The compound of Embodiment 196, wherein LCL ,whereineach of Cy1and Cy2is independently selected from an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.rein the compound is represented by formula IV-C: Page 215 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein: Rbis −R’ or −C(R’)3; Rcis −R’; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6 alkyl or optionally substituted C1-6 heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S. Page 216 of 378 12753881v1Attorney Docket No.: 2013405-0034200. The compound of Embodiment 199, wherein LCL is , whereineach of Cy1and Cy2is independently selected fro bered monocyclic, bicyclic, or spirocyclic carbocycle, an optionay su sttute - to -mem ere monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.201. The compound of Embodiment 199, wherein LCL i ,whereineach of Cy1and Cy2is independently selected from an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. 202. The compound of Embodiment 1, wherein the compound is represented by formula IV-D: Page 217 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein: Rbis −R’ or −C(R’)3; Rcis −R’; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S.203. The compound of Embodiment 202, wherein LC einPage 218 of 378 12753881v1Attorney Docket No.: 2013405-0034 each of Cy1and Cy2is independently selected from an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.204. The compound of Embodiment 202, wherein LCL i ,wherein 12each of Cy and Cy is independently selected from an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. 205. The compound of Embodiment 1, wherein the compound is represented by formula IV-E:or a pharmaceutically acceptable salt thereof, wherein: Page 219 of 378 12753881v1Attorney Docket No.: 2013405-0034 Rbis −R’ or −C(R’)3; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; A4is C(Ra1) or N; bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−;Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and Lcis a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. 206. The compound of Embodiment 1, wherein the compound is represented by formula IV-F:or a pharmaceutically acceptable salt thereof, wherein Rbis −R’ or −C(R’)3; Rdis halogen, −CN, −R’ or −OR’; Page 220 of 378 12753881v1Attorney Docket No.: 2013405-0034 each of Rsa, Rsband Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; each of a, b, and c is independently 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A4is C(Ra1) or N; Ra1is −R’; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; each of Ring A and Ring B is independently an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S.207. The compound of Embodiment 206, wherein LCL , whereineach of Cy1and Cy2is independently selected froo 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.208. The compound of Embodiment 206, wherein LCL ,whereineach of Cy1and Cy2is independently selected from an optionally substituted 4- to 12-membered Page 221 of 378 12753881v1Attorney Docket No.: 2013405-0034 monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−. 209. The compound of any one of the preceding Embodiments, wherein the compound can reduce a CITK polypeptide level. 210. The compound of any one of the preceding Embodiments, wherein the compound can reduce a PKN2 polypeptide level. 211. The compound of any one of the preceding Embodiments, wherein the compound can reduce an AAK1 polypeptide level. 212. The compound of any one of the preceding Embodiments, wherein the compound can selectively reduce a CITK polypeptide level over a PKN2 polypeptide level. 213. The compound of Embodiment 212, wherein DC50 for the PKN2 polypeptide is about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100-fold or more of that for the CITK polypeptide. 214. The compound of any one of the preceding Embodiments, wherein the compound can selectively reduce a CITK polypeptide level over an AAK1 polypeptide level. 215. The compound of Embodiment 214, wherein DC50for the AAK1 polypeptide is about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100-fold or more of that for the CITK polypeptide. 216. The compound of any one of Embodiments 1-211, wherein DC50for the PKN2 polypeptide is about or no more than about 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold of that for the CITK polypeptide. 217. The compound of any one of Embodiments 1-211 and 216, wherein DC50for the AAK1 polypeptide is about or no more than about 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold of that for the CITK polypeptide. 218. The compound of any one of the preceding Embodiments, wherein the compound can inhibit CITK activity. 219. The compound of any one of the preceding Embodiments, wherein the compound can inhibit Page 222 of 378 12753881v1Attorney Docket No.: 2013405-0034 PKN2 activity. 220. The compound of any one of the preceding Embodiments, wherein the compound can inhibit AAK1 activity. 221. The compound of any one of the preceding Embodiments, wherein the compound can selectively inhibit CITK activity over PKN2 activity. 222. The compound of Embodiment 221, wherein IC50for inhibiting PKN2 activity is about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100-fold or more of that for inhibiting CITK activity. 223. The compound of any one of the preceding Embodiments, wherein the compound can selectively inhibit CITK activity over AAK1 activity. 224. The compound of Embodiment 223, wherein IC50for inhibiting AAK1 activity is about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100-fold or more of that for inhibiting AAK1 activity. 225. The compound of any one of Embodiments 1-220, wherein IC50for inhibiting PKN2 activity is about or no more than about 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold of that for inhibiting CITK activity. 226. The compound of any one of Embodiments 1-220 and 225, wherein IC50for inhibiting AAK1 activity is about or no more than about 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold of that for inhibiting CITK activity. 227. A compound, wherein the compound is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof. 228. A compound, wherein the compound is: ,Page 223 of 378 12753881v1Attorney Docket No.: 2013405-0034 or229. A compound, wherein the compound is: ,Page 224 of 378 12753881v1Attorney Docket No.: 2013405-0034 , , ,Page 225 of 378 12753881v1Attorney Docket No.: 2013405-0034 , , ,Page 226 of 378 12753881v1Attorney Docket No.: 2013405-0034 , , ,Page 227 of 378 12753881v1Attorney Docket No.: 2013405-0034 , , ,Page 228 of 378 12753881v1Attorney Docket No.: 2013405-0034 , or , or a pharma230. A pharmaceutical composition comprising a compound of any one of Embodiments 1-229, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 231. A method of degrading CITK in a subject, comprising administering to the subject the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 232. A method of reducing level of CITK in a subject, comprising administering or delivering the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 233. A method of reducing CITK activity in a subject, comprising reducing the activity by reducing the level of CITK in a subject. 234. A method of degrading CITK in a system, comprising administering to the system the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 235. A method of reducing level of CITK in a system, comprising administering or delivering to the Page 229 of 378 12753881v1Attorney Docket No.: 2013405-0034 system the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 236. A method of reducing CITK activity in a system, comprising reducing the activity by reducing the level of CITK in a system. 237. The method of any one of the preceding Embodiments, wherein level of PKN2 is reduced. 238. The method of any one of the preceding Embodiments, wherein level of AAK1 is reduced. 239. A method of degrading PKN2 in a system, comprising administering to the system the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 240. A method of reducing level of PKN2 in a system, comprising administering or delivering the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 241. A method of reducing PKN2 activity in a system, comprising reducing the activity by reducing the level of PKN2 in a system. 242. A method of degrading AAK1 in a system, comprising administering to the system the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 243. A method of reducing level of AAK1 in a system, comprising administering or delivering to the system the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 244. A method of reducing AAK1 activity in a system, comprising reducing the activity by reducing the level of AAK1 in a system. 245. The method of any one of the preceding Embodiments, wherein, when CITK is contacted with a bifunctional CITK degrader, an anti-proliferative effect is observed. 246. The method of Embodiment 245, wherein proliferation of cancer is reduced in a subject. 247. The method of Embodiment 236, wherein the step of reducing the level of CITK in a system comprises degrading CITK protein. 248. A method of treating cancer by reducing CITK activity, comprising administering or delivering the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 249. A method of treating a disease, disorder, or condition by reducing CITK activity, comprising administering or delivering the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 250. A method of treating a disease, disorder, or condition by reducing CITK activity, comprising administering a composition that comprises or delivers a CITK degrader. 251. A method of treating a disease, disorder, or condition associated with CITK, comprising administering to a subject in need thereof the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. Page 230 of 378 12753881v1Attorney Docket No.: 2013405-0034 252. The method of Embodiment 251, wherein the disease, disorder, or condition is a cancer. 253. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 254. The method of Embodiment 253, wherein the cancer is selected from medulloblastoma, multiple myeloma, prostate, bladder, breast, ovarian, cervical, brain, head and neck, lung, gastrointestinal, colorectal, sarcoma, liver malignancies, small cell lung, neuroblastoma, neuroendocrine tumors, non-small cell lung, breast, and colorectal cancer. 255. A method of treating a disease, disorder, or condition, comprising administering to a subject in need thereof the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 256. The method of Embodiment 255, wherein the condition, disease or disorder is associated with CITK. 257. The method of any one of Embodiments 255-256, wherein the condition, disease or disorder is associated with PKN2. 258. The method of any one of Embodiments 255-257, wherein the condition, disease or disorder is associated with AAK1. 259. In a method of reducing level of CITK in a subject, the improvement that comprises administering or delivering the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 260. In a method of reducing level of CITK in a system, the improvement that comprises administering or delivering the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 261. In a method of reducing CITK activity in a subject, the improvement that comprises reducing the activity by reducing the level of CITK in a subject. 262. The method of Embodiment 261, wherein, when CITK is contacted with a bifunctional CITK degrader, an anti-proliferative effect is observed. 263. The method of Embodiment 262, wherein proliferation of cancer is reduced in a subject. 264. The method of Embodiment 261, wherein the step of reducing the level of CITK in a subject comprises degrading CITK protein. 265. The method of Embodiment 264, wherein the step of reducing the level of CITK comprises administering the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 266. In a method of treating cancer by reducing CITK activity, the improvement that comprises administering or delivering the compound of any one of Embodiments 1-229 or the Page 231 of 378 12753881v1Attorney Docket No.: 2013405-0034 pharmaceutical composition of Embodiment 230. 267. In a method of treating a disease, disorder, or condition by reducing CITK activity, the improvement that comprises: administering or delivering the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 268. In a method of reducing CITK activity in a subject, the improvement that comprises: administering or delivering the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 269. In a method of reducing level of CITK in a subject, the improvement that comprises: administering or delivering the compound of any one of Embodiments 1-229 or the pharmaceutical composition of Embodiment 230. 270. In a method of treating a disease, disorder, or condition by reducing CITK activity, the improvement that comprises: administering a composition that comprises or delivers a CITK degrader. 271. The method or improvement of any one of the preceding Embodiments, wherein level of PKN2 is reduced. 272. The method or improvement of any one of the preceding Embodiments, wherein level of AAK1 is reduced. 273. A compound or composition of any one of the preceding Embodiments, for preventing or treating a condition, disease or disorder. 274. A compound or composition of any one of the preceding Embodiments, for a method or improvement of any one of the preceding Embodiments. 275. A compound or composition of any one of the preceding Embodiments, for manufacturing a medicament for preventing or treating a condition, disease or disorder. 276. A compound or composition of any one of the preceding Embodiments, for manufacturing a medicament for a method or improvement of any one of the preceding Embodiments. 277. Use of a compound or composition of any one of the preceding Embodiments, for preventing or treating a condition, disease or disorder. 278. Use of a compound or composition of any one of the preceding Embodiments, for a method or improvement of any one of the preceding Embodiments. 279. Use of a compound or composition of any one of the preceding Embodiments, for manufacturing a medicament for preventing or treating a condition, disease or disorder. 280. Use of a compound or composition of any one of the preceding Embodiments, for manufacturing a medicament for a method or improvement of any one of the preceding Embodiments. Page 232 of 378 12753881v1Attorney Docket No.: 2013405-0034 EXEMPLIFICATION

[0264] As described in the Examples below, in certain embodiments, compounds are prepared according to the following procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, such general methods can be applied to prepare various subclasses and species of present disclosure. Additionally or alternatively, various technologies known to those skilled in the art can be utilized to prepare, assess and use provided technologies including provided compounds in accordance with the present disclosure.

[0265] Example 1. Preparation of various compounds.

[0266] Various synthetic technologies may be utilized in accordance with the present disclosure. For example, in some embodiments, evaporations are carried out in vacuo with a rotary evaporator. In some embodiments, analytical samples are dried in vacuo (e.g., 1-5 mmHg) at room temperature. In some embodiments, thin layer chromatography (TLC) is performed on silica gel plates, and spots are visualized using suitable technologies, e.g., UV light (214 and 254 nm). In some embodiments, compounds are purified by column and flash chromatography, e.g., carried out using silica gel (200-300 mesh). Typically, solvent systems are reported as mixtures by volume. In some embodiments, compounds are characterized by NMR. In some embodiments, NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer.1H chemical shifts are typically reported in δ values in ppm with the deuterated solvent as the internal standard. Data are reported as follows (if reported): chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), integration. List of Abbreviations

[0267] The following abbreviations may be used and have the following meanings: Abbreviations DetailsPage 233 of 378 12753881v1Attorney Docket No.: 2013405-0034 MeOH methanol Pd2(dba)3tris(dibenzylideneacetone)dipalladiumPage 234 of 378 12753881v1Attorney Docket No.: 2013405-0034 HPLC high performance liquid chromatography NMR neclear magnetic resonance

[0268] Various analytical technologies can be utilized in accordance with the present disclosure. In some embodiments, the following analytical methods are used to purify and / or characterize the compounds described herein: Certain LCMS / HPLC Methods A: Method Name; B: Solvent System; C: Column; D: Gradient; E: UV range; F: Mass Range; G: Column Temp. (°C); H: Flow Rate (mL / min) A B C D E F G H A (3min A) water + 10 Waters X- From 95:5 to 5:95 inPage 235 of 378 12753881v1Attorney Docket No.: 2013405-0034 0.05% TFA H (3min A) water + Waters From 95:5 to 2:98 in 005% TFA Snfir 16 min 298 f r 14 100-reparaton o ertan nterme ates Intermediate 1: (R)-tert-butyl (1-((4-(2-chloropyridin-4-yl)-3-methylphenyl)amino)-4,4-dimethyl-1- oxopentan -2-yl)carbamate Step 1. The synthesis of (R)-temino)-4,4-dimethyl-1-oxopentan-2- yl)carbamatePage 236 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0269] To a mixture of (R)-2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanoic acid (5.00 g, 20.41 mmol), 4-bromo-3-methylaniline (4.18 g, 22.45 mmol) and NMI (6.69 g, 81.63 mmol) in CH3CN (50 mL), was added TCFH (14.28 g, 51.02 mmol) in portions under ice-water bath. The mixture was allowed to warm to room temperature and stirred for 2 hours. After the consumption of starting material (monitored by LCMS), the mixture was quenched with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate / petroleum ether = 0% to 20%) to give the desired product (R)-tert-butyl (1-((4-bromo-3- methylphenyl)amino)-4,4-dimethyl-1-oxopentan-2 -yl)carbamate (8.00 g, 95% yield) as a yellow solid. LC- MS m / z: 357.0 [M-56+H]+. LCMS: Rt = 2.197 min (LCMS Method A). Step 2. (R)-tert-butyl (1-((4-(2-chloropyridin-4-yl)-3-methylphenyl)amino)-4,4-dimethyl-1-oxopentan-2- yl)carbamate an-2-yl)carbamate (7.70 g, 18.69 mmol, from step 1), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2- yl)pyridine (4.24 g, 17.75 mmol), Pd(dppf)Cl2(1.37 g, 1.87 mmol) and K2CO3(5.16 g, 37.38 mmol) in 1,4- dioxane / H2O(v / v = 40 mL / 10 mL) was stirred at 80oC for 2 hours under nitrogen atmosphere. After the consumption of starting material (monitored by LCMS), the mixture was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate / petroleum ether = 0% to 30%;) to give (R)-tert-butyl (1-((4-(2-chloropyridin-4-yl)-3-methylphenyl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamate (5.30 g, 37% yield) as a white solid. LC-MS m / z: 446.0 [M+H]+. LCMS: Rt = 2.144 min (LCMS Method A). 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.44 (d, J = 4.8 Hz, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 7.42 (d, J = 5.2 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 4.21-4.16 (m, 1H), 2.26 (s, 3H), 1.58-1.55 (m, 2H), 1.39 (s, 9H), 0.93 (s, 9H). Intermediate 2: (R)-tert-butyl (4,4-dimethyl-1-((3-methyl-4-(2-((6-(piperazin-1-yl)pyridin-3- yl)amino)pyridin-4-yl)phenyl)amino)-1-oxopentan-2-yl)carbamate Page 237 of 378 12753881v1Attorney Docket No.: 2013405-0034 Step 1. The synthesis of b te

[0271] -1-carboxylate(10.00 g, 45.45 mmol) and TEA (9.18 g, 45.45 mmol) in DCM (50 mL) was stirred at room temperature overnight. After the consumption of starting material (monitored by LCMS), the mixture was quenched with water (200 mL), and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate / petroleum ether = 0% to 20%) to give the desired product benzyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (15.00 g, 96% yield) as a yellow solid. LC-MS m / z: 343.2 [M+H]+. LCMS: Rt = 1.957 min (LCMS Method A). Step 2. The synthesis of benzyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate [0mmol, from step 1) and SnCl2·H2O (90.79 g, 438.60 mmol) in EtOH (200 mL) was refluxed overnight. After the consumption of starting material (monitored by LCMS), the mixture was quenched with saturated aqueous Na2CO3(200 mL) and filtered via a pad of celite. The cake was washed with DCM / MeOH (v / v = 5:1, 2000 mL). The filtrate was separated and the organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product benzyl 4-(5- aminopyridin-2-yl)piperazine-1-carboxylate (13.10 g, 96% yield) as a brown solid. LC-MS m / z: 313.2 [M+H]+. LCMS: Rt = 1.641 min (LCMS Method A). Step 3. The synthesis of (R)-benzyl 4-(5-((4-(4-(2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanamido)- 2-methylphenyl)pyridin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate Page 238 of 378 12753881v1Attorney Docket No.: 2013405-0034

[0273] mino)-4,4- dimethyl-1-oxopentan-2-yl)carbamate (1.00 g, 2.25 mmol, intermediate 1), benzyl 4-(5-aminopyridin-2- yl)piperazine-1-carboxylate (700 mg, 2.25 mmol, from step 2), Pd2(dba)3(206 mg, 0.22 mmol), X-Phos (107 mg, 0.22 mmol) and Cs2CO3(1.50 g, 4.49 mmol) in 1,4-dioxane (10 mL) was stirred at 100oC for 5 hours under nitrogen atmosphere. After the consumption of starting material (monitored by LCMS), the mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (MeOH / DCM = 0% to 10%) to give (R)-benzyl 4-(5-((4-(4-(2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanamido)-2- methylphenyl)pyridin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (1.50 g, 92% yield) as a black solid. LC-MS m / z: 722.4 [M+H]+. LCMS: Rt = 2.079 min (LCMS Method B). Step 4. The synthesis of (R)-tert-butyl (4,4-dimethyl-1-((3-methyl-4-(2-((6-(piperazin-1-yl)pyridin-3- yl)amino)pyridin-4-yl)phenyl)amino)-1-oxopentan-2-yl)carbamateino)-4,4- dimethylpentanamido)-2-methylphenyl)pyridin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (1.00 g, 1.39 mmol, from step 3) in MeOH (10 mL) was stirred under hydrogen atmosphere at room temperature for 6 hours. After the consumption of starting material (monitored by LCMS), the mixture was filtered via a pad of celite. The cake was washed with MeOH (100 mL). The filtrate was concentrated in vacuo to give the desired product (R)-tert-butyl (4,4-dimethyl-1-((3-methyl-4-(2-((6-(piperazin-1-yl)pyridin-3- yl)amino)pyridin-4-yl)phenyl)amino)-1-oxopentan-2-yl)carbamate (620 mg, 76% yield) as a brown solid. LC-MS m / z: 588.1 [M+H]+. LCMS: Rt = 2.064 min (LCMS Method A).1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.78 (s, 1H), 8.33 (d, J = 2.8 Hz, 1H), 8.08 (d, J = 5.2 Hz, 1H), 7.88 (dd, J = 8.8, 5.6 Hz, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.17 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.63 (dd, J = 5.2, 0.8 Hz, 1H), 6.60 (s, 1H), 4.21-4.10 (m, 1H), 3.30 (t, J = 4.8 Hz, 4H), 2.79 (t, J = 4.8 Hz, 4H), 2.25 (s, 3H), 1.58 (s, 1H), 1.56 (d, J = 2.4 Hz, 1H), 1.39 (s, 9H), 0.93 (s, 9H). Page 239 of 378 12753881v1Attorney Docket No.: 2013405-0034 Intermediate 3: (2S,4R)-1-((S)-2-(6-bromohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (S)--(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (500 mg, 1.13 mmol), 6-bromohexanoic acid (218 mg, 1.13 mmol) and NMI (370 mg, 4.50 mmol) in ACN (5 mL) was added TCFH (788 mg, 2.81 mmol) in portions at room temperature under Argon. The mixture was stirred at room temperature for 2 hours. After the consumption of starting material (monitored by LCMS), the mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (0%-50% acetonitrile, 0.05% TFA / H2O) to give the desired product (2S,4R)-1-((S)-2-(6-bromohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (600 mg, 86% yield) as a white solid. LC-MS m / z: 620.9 [M+H]+. LCMS: Rt = 1.787 min (LCMS Method A).1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 4.95-4.88 (m, 2H), 4.52 (d, J = 9.6 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.60 (s, 2H), 3.51 (t J = 6.8 Hz, 2H), 2.46 (s, 3H), 2.28-2.23 (m, 1H), 2.17-2.11 (m, 1H), 2.04-1.99 (m, 1H), 1.81-1.76 (m, 3H), 1.53-1.46 (m, 2H), 1.38-1.34 (m, 5H), 0.94 (s, 9H). Intermediate 4: (2S,4R)-1-((S)-2-(2-chloroacetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- Page 240 of 378 12753881v1Attorney Docket No.: 2013405-0034 methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide )-1- -(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.50 g, 3.38 mmol) and TEA (1.02 g, 10.13 mmol) in DCM (15 mL), was added slowly a solution of 2-chloroacetyl chloride (381 mg, 3.38 mmol) in DCM (5 mL) at 0 °C under Argon. The resulting reaction mixture was stirred at 0 °C for 3 h. After the consumption of starting material (monitored by LCMS), the mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse chromatography (from 95% [water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] to 5% [water + 0.1% TFA] and 95% [CH3CN + 0.1% TFA]) to give the desired product (2S,4R)-1-((S)-2-(2-chloroacetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.69 g, 96% yield) as an off-white solid. LC-MS m / z: 521.2 [M+H]+. LCMS: Rt = 0.567 min (LCMS Method G).1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.24 (d, J = 9.2 Hz, 1H), 7.46-7.34 (m, 4H), 4.96-4.89 (m, 1H), 4.75-4.63 (m, 1H), 4.52 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 8.4 Hz, 1H), 4.29 (s, 1H), 4.24-4.15 (m, 2H), 3.64-3.45 (m, 2H), 2.46 (s, 3H), 2.06-2.01 (m, 1H), 1.82-1.76 (m, 1H), 1.38 (d, J = 7.2 Hz, 3H), 0.95 (s, 9H). Intermediate 5: (S)-tert-butyl (1-(4-(2-chloropyridin-4-yl)-2-(difluoromethyl)phenoxy)-4,4- dimethylpentan-2-yl)carbamate (3797-3) and (S)-tert-butyl (1-(2-(difluoromethyl)-4-(2-((6-(piperazin-1- yl)pyridin-3-yl)amino)pyridin-4-yl)phenoxy)-4,4-dimethylpentan-2-yl)carbamate Page 241 of 378 12753881v1Attorney Docket No.: 2013405-0034 Step 1. The synthesis of (S)-tert- 2-yl)carbamate

[0277] (6.00 g, 24.50mmol) and N-methylmorpholine (2.47 g, 24.50 mmol) in anhydrous DME (150 mL) was added a solution of isobutyl carbonochloridate (3.50 g, 25.70 mmol) dropwise at -78oC under nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for an additional 1 hour. The precipitate was quickly filtered off and the solution was cooled to -78oC, sodium borohydride (1.58 g, 41.70 mmol) and a few drops of water were added. The resulting mixture was warmed to room temperature and stirred at room temperature for 16 h. After the consumption of starting material (monitored by LCMS), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate:petroleum ether = 1:10 to 1:5) to give (S)-tert-butyl (1-hydroxy-4,4-dimethylpentan-2-yl)carbamate (3.30 g, 58% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 6.46 (d, J = 8.8 Hz, 1H), 4.60 (t, J = 5.6 Hz, 1H), 3.47-3.45 (m, 1H), 3.22-3.18 (m, 1H), 3.09-3.04 (m, 1H), 1.40-1.36 (m, 10H), 1.23-1.17 (m, 1H), 0.87 (s, 9H). Step 2. The synthesis of 4-bromo-2-(difluoromethyl)phenol

[0278] To a solution o 5- romo- - y roxy enza e y e ( 0.00 g, 50.00 mmol) in anhydrous DCM (150 mL) was added DAST (9.66 g, 60.00 mmol) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. After the consumption of starting material (monitored by TLC), the reaction mixture was added into saturated NaHCO3(300 mL) and extracted with Page 242 of 378 12753881v1Attorney Docket No.: 2013405-0034 dichloromethane (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate:petroleum ether = 1:20 to 1:15) to give the desired product 4-bromo-2-(difluoromethyl)phenol (6.50 g, 58% yield)as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.52-7.49 (m, 2H), 7.16-6.89 (m, 2H). Step 3. The synthesis of (S)-tert-butyl (1-(4-bromo-2-(difluoromethyl)phenoxy)-4,4-dimethylpentan-2- yl)carbamate

[0279] To a solution of 4-bromo-2-(difluoromethyl)phenol (3.10 g, 14.00 mmol, from step 2), (S)- tert-butyl (1-hydroxy-4,4-dimethylpentan-2-yl)carbamate (3.22 g, 14.00 mmol, from step 1) and PPh3(5.50 g, 21.00 mmol) in anhydrous THF (40 mL) was added a solution of DIAD (4.24 g, 21.00 mmol) in anhydrous THF (40 mL) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours. After the consumption of starting material (monitored by LCMS), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate:petroleum ether = 1:100 to 1:25) to give (S)-tert-butyl (1-(4-bromo-2-(difluoromethyl)phenoxy)- 4,4-dimethylpentan-2-yl)carbamate (3.40 g, 56% yield) as a white solid. LC-MS m / z: 335.9 [M-100]+. LCMS: Rt = 1.193 min (LCMS Method D). Step 4. The synthesis of (S)-tert-butyl (1-(2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)-4,4-dimethylpentan-2-yl)carbamate.99 mmol), (S)-tert-butyl (1-(4-bromo-2-(difluoromethyl)phenoxy)-4,4-dimethylpentan-2-yl)carbamate (1.70 g, 3.91 mmol, from step 3), KOAc (1.92 g, 19.55 mmol) and Pd(dppf)Cl2 (286 mg, 0.39 mmol) in anhydrous 1,4- dioxane (50 mL) was stirred at 100oC for 30 hours under nitrogen atmosphere. After the consumption of Page 243 of 378 12753881v1Attorney Docket No.: 2013405-0034 starting material (monitored by LCMS), the reaction mixture was used to next step directly. LC-MS m / z: 364.3 [M-100-19]+. LCMS: Rt = 2.417 min (LCMS Method A). Step 5. The synthesis of (S)-tert-butyl (1-(4-(2-chloropyridin-4-yl)-2-(difluoromethyl)phenoxy)-4,4- dimethylpentan-2-yl)carbamate

[0281] ethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4,4-dimethylpentan-2-yl)carbamate (crude, 3.91 mmol, from step 4) was added water (5 mL), 2-chloro-4-iodopyridine (939 mg, 3.91 mmol ), K2CO3(1.62 g, 11.73 mmol) and Pd(dppf)Cl2(286 mg, 0.39 mmol). The resulting reaction mixture was stirred at 80oC for 3 hours under nitrogen atmosphere. After the consumption of starting material (monitored by LCMS), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate:petroleum ether = 1:10 to 1:5) to give (S)-tert-butyl (1-(4-(2-chloropyridin-4-yl)-2-(difluoromethyl)phenoxy)-4,4- dimethylpentan-2-yl)carbamate (1.20 g, 66% yield) as a yellow solid. LC-MS m / z: 469.1 [M+H]+. LCMS: Rt = 2.286 min (LCMS Method A).1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 5.2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.79 (dd, J = 5.6, 1.6 Hz, 1H), 7.31-7.02 (m, 2H), 6.93 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 1.49-1.36 (m, 11H), 0.92 (s, 9H). Step 6. The synthesis of (S)-benzyl 4-(5-((4-(4-((2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentyl)oxy)- 3-(difluoromethyl)phenyl)pyridin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate69 mmol, from step 2 of intermediate 1), (S)-tert-butyl (1-(4-(2-chloropyridin-4-yl)-2-(difluoromethyl)phenoxy)-4,4- dimethylpentan-2-yl)carbamate (2.00 g, 4.27 mmol, from step 5), Cs2CO3(4.18 g, 12.81 mmol), X-Phos (410 mg, 0.86 mmol) and Pd2(dba)3(393 mg, 0.43 mmol) in anhydrous 1,4-dioxane (50 mL) was stirred at Page 244 of 378 12753881v1Attorney Docket No.: 2013405-0034 110oC for 20 hours under nitrogen atmosphere. After the consumption of starting material (monitored by LCMS), the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate:dichloromethane = 1:10 to 1:2) to give (S)-benzyl 4-(5-((4-(4-((2-((tert- butoxycarbonyl)amino)-4,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)amino)pyridin-2- yl)piperazine-1-carboxylate (2.44 g, 77% yield) as a brown solid. LC-MS m / z: 745.3 [M+H]+. LCMS: Rt = 2.327 min (LCMS Method A). Step 7. The synthesis of (S)-tert-butyl (1-(2-(difluoromethyl)-4-(2-((6-(piperazin-1-yl)pyridin-3- yl)amino)pyridin-4-yl)phenoxy)-4,4-dimethylpentan-2-yl)carbamate mino)-4,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (780 mg, 1.05 mmol, from step 6), Pd / C (200 mg, 10% palladium on activated carbon) and 10% Pd(OH)2 / C (200 mg) in M...

Claims

Attorney Docket No.: 2013405-0034 CLAIMS 1. A compound according to formula I: CIM—LCL—LBM, I or a pharmaceutically acceptable salt thereo , w ere n: ;LBM is an E3 ubiquitin ligase binding moiety ,;each of Ring A, Ring B, Ring C and Ring D is independently an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Page 347 of 378 12753881v1Attorney Docket No.: 2013405-0034 each of a, b, c and d is independently 0, 1, 2, 3, or 4; each Rsais independently −Rsa1, −ORsa1, or −Lsa1−Lsa2−Lsa3−N(Rsa1)(Rsa2); Lsa1is a covalent bond, optionally substituted −CH2−, −O−, or −N(R’)−; Lsa2is a covalent bond, or optionally substituted −CH2−; Lsa3is a covalent bond, −R’, or −CH2−C(Rsa3)2−, wherein the −CH2− is optionally substituted; each of Rsa1, Rsa2and Rsa3is independently −R’, or Rsa2and one Rsa3are taken together with their intervening atoms to form an optionally substituted 3-14 membered ring having 1-6 heteroatoms independently selected from N, O, and S; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; each of Rsb, Rscand Rsdis independently halogen, −CN, −R’, −OR’, or −N(R’)2; each of Lband Lcis independently a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; Ring P is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Lpis a covalent bond or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −O−, −S−, −N(R’)−, −N=N−, −C(O)−, −C(S)−, −C(NR’)−, −C(NOR’)−, −C(NN(R’)2)−, −C(O)O−, −C(O)N(R’)−, −C(NR’)O−, −C(NR’)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −N(R’)C(O)S−, −N(R’)C(NR’)N(R’)−, −SC(O)−, −S(O)2−, −SO2N(R’)−, or −Cy−; each −Cy− is independently an optionally substituted, mono- or bicyclic, 3- to 11-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-4 heteroatoms independently selected from N, O, and S; Ring Q is optionally substituted ; each of Ring R and Ring S is ibstituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rspis independently halogen, −CN, −R’ or −OR; each Rsqis independently halogen, −CN, −R’ or −OR’, or two Rsqare taken together with their intervening atom(s) to form an optionally substituted 3-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; each of p and q is independently 0, 1, 2, 3, or 4; Page 348 of 378 12753881v1Attorney Docket No.: 2013405-0034 Rais −N(Ra1)2, −Ra1, −C(Ra1)3, or −Cy−Ra1; Rbis −Rb1, or −C(Rb1)3;; each Rdis independently halogen, −CN, −R’ or −OR’; r is 0, 1, 2, or 3; each Reis independently halogen, −R’, or −C(O)N(R’)2; m is 1, 2, 3, 4, or 5; t is 1 or 2; Rfis −R, or one Reand one Rfare taken together with their intervening atoms to form an optionally substituted 5-10 membered ring having 1-2 heteroatoms independently selected from N, O, and S; each of Rg, Rhand Rh’is independently −R’; each of Rj, Rk, Rmand Rm’is independently −R’; each of Rn, Rp, Rq, Rr, Rs, Rtand Ruis independently halogen, −CN, −R’ or −OR’; each of n, s, u, u’, v and w is independently 0, 1, 2, 3, 4, or 5; each Rvis independently halogen, −CN, −R’ or −OR’, or one Ruand one Rvare taken together with their intervening atoms to form an optionally substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, −CN, −R or −OR, or one Ruand one Rware taken together with their intervening atoms to form an optionally substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; each R’ is independently −R, −C(O)R, or −S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to 16-membered ring having 0-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen, or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1−C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

2. The compound of any one of any one of the preceding claims, wherein CIM is orPage 349 of 378 12753881v1Attorney Docket No.: 2013405-0034 ; ubstituted bivalent C1-C20hydrocarbon chain, whereinone or more methylene units are optionally and independently replaced by −O−, −S−, −N(R’)−, −N=N−, −C(O)−, −C(S)−, −C(NR’)−, −C(NOR’)−, −C(NN(R’)2)−, −C(O)O−, −C(O)N(R’)−, −C(NR’)O−, O)−,d 6- 14 membered aromatic ring having no heteroatoms.

4. The compound of any one of the preceding claims, wherein Ring A is an optionally substituted phenyl ring.

5. The compound of claim 1, whereinPage 350 of 378 12753881v1Attorney Docket No.: 2013405-0034 ,7. The compound of any one of the preceding claims, wherein an occurrence of Rsais −Lsa1−Lsa2−Lsa3−N(Rsa1)(Rsa2).

8. The compound of any one of the preceding claims, wherein Lsa1is −O−.

9. The compound of any one of claims 1-7, wherein Lsa1is −N(R’)−.

10. The compound of any one of claims 1-7, wherein Lsa1is −NH−.

11. The compound of any one of the preceding claims, wherein Lsa2is optionally substituted −CH2−.

12. The compound of any one of claims 1-10, wherein Lsa2is −CH2−.

13. The compound of any one of claims 1-10, wherein Lsa2is −C(O)−.

14. The compound of any one of the preceding claims, wherein Lsa3is −CH2−C(Rsa3)2−, wherein the −CH2− is optionally substituted.

15. The compound of any one of claims 1-7, wherein an occurrence of Rsais −NHC(O)CH(Rsa3)NH2.

16. The compound of any one of claims 1-7, wherein an occurrence of Rsais −OCH2CH(Rsa3)NH2. Page 351 of 378 12753881v1Attorney Docket No.: 2013405-0034 17. The compound of any one of claims 1-7, wherein an occurrence of Rsa,, or19. The compound of any one of claims 1-17, wherein Lais optionally substituted C1-3alkylene or −N(R’)−.

20. The compound of any one of claims 1-19, wherein Lbis a covalent bond.

21. The compound of any one of claims 1-19, wherein Lbis −C(O)N(R’)−, −N(R’)C(O)N(R’)− or −N(R’)−.

22. The compound of any one of claims 1-21, wherein Ring B is an optionally substituted 6-10 membered aromatic ring having no heteroatoms or an optionally substituted 5-12 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S.

23. The compound of any one of claims 1-21, wherein Ring B is optionally substituted , wherein A is C(R’), N or optionally substituted CH, * denotes the attachment point to, otes the attachment point to La.

24. The compound of any one of claims 1-21, wherein Ring , wherein A is C(R’), N or optionally substituted CH, * denotes the attachment point to, an enotes the attachment point to La.

25. The compound of any one of claims 23-24, wherein A is CH.

26. The compound of any one of claims 23-24, wherein A is N.

27. The compound of any one of claims 1-26, wherein Ring C is an optionally substituted 6-10 membered aromatic ring having no heteroatoms, or an optionally substituted 5-12 membered heteroaryl ring having 1-6 heteroatoms independently selected from N, O, and S.

28. The compound of any one of claims 1-26, wherein Ring C is optionally substituted and selected Page 352 of 378 12753881v1Attorney Docket No.: 2013405-0034f d .is a covalent bond.

30. T e compound o any one o c a ms 1-28, w ere n L is −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

31. The compound of any one of claims 1-30, wherein Ring D is an optionally substituted phenyl ring, or an optionally substituted 5-12 membered heterocyclic ring having 1-6 heteroatoms independently selected from N, O, and S.

32. The compound of any one of the preceding claims, wherein the shortest-path length of LCLis about or no more than 14 atoms, the number of non-ring consecutive sp3atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1, the number of bonds between two non-ring sp3atoms in the shortest path chain of LCLis about or no more than 5, 4, 3, 2 or 1, the number of non-ring sp3C, O, and S atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1, the number of non-ring sp3atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1, and / or the number of non-ring atoms in the shortest path chain of LCLis about or no more than about 5, 4, 3, 2 or 1.

33. The compound of any one of the preceding claims, wherein LCLis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1−C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O−, −S−, −N(R)−, −N=N−, −C(O)−, −C(S)−, −C(NR)−, −C(NOR)−, −C(NN(R)2)−, −OC(O)−, −C(O)O−, −C(O)N(R)−, −N(R)C(O)−, −C(NR)O−, −OC(NR)−, −C(NR)NR−, −N(R)C(NR)−, −N(R)C(O)N(R)−, −N(R)C(O)O−, −OC(O)N(R)−, −N(R)C(O)S−, −SC(O)N(R)−, −N(R)C(NR)N(R)−, −S(O)2−, −SO2N(R)−, −N(R)S(O)2−, or –Cy−.

34. The compound of any one of claims 1-31, wherein LCLis selected from: ,Page 353 of 378 12753881v1Attorney Docket No.: 2013405-0034 , ,Page 354 of 378 12753881v1Attorney Docket No.: 2013405-0034 ,Page 355 of 378 12753881v1Attorney Docket No.: 2013405-0034 , ,Page 356 of 378 12753881v1Attorney Docket No.: 2013405-0034 .. e compoun o any one o e prece ng c a ms, w ere n s an u qu n gase binding moiety.

37. The compound of claim 1, wherein the compound is represented by formula II: wherein:Lais a covalent bond, C1-3alkyl, C1-3haloalkyl, or −NH-; Lbis a covalent bond, C1-3alkyl, C1-3haloalkyl, −NHC(O)−, −C(O)NH-, −NHC(O)NH-, or −NH-; Ring C is an optionally substituted 6-membered aryl or heteroaryl; each A1is independently CH or N; A2is NH or O; each Rzis independently H, C1-6alkyl, or C1-6haloalkyl; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); and Ryis H, C1-6alkyl, C1-6haloalkyl; or C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form a 4-6 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N, O, and S.

38. The compound of claim 1, wherein the compound is represented by formula III:or a pharmaceutically acceptable salt thereof, wherein: Ring P is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; Page 357 of 378 12753881v1Attorney Docket No.: 2013405-0034 each Rsqis independently hydrogen or an optionally substituted C1-6aliphatic, or two Rsqgroups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; Lpis a covalent bond or a straight or branched C1-3hydrocarbon chain wherein one methylene is optionally replaced with –O−, −S−, −N(R)−, −S(O)2−, −C(O)N(R)−, or −N(R)C(O)−; and Y is N or CH.

39. The compound of any one of the preceding claims, wherei, ,rmula III-A:or a pharmaceutically acceptable salt thereof, wherein: Page 358 of 378 12753881v1Attorney Docket No.: 2013405-0034 each Rsp’is independently hydrogen, or two Rsp’groups on the same carbon are taken together to form =O or together with the carbon atom to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S.

41. The compound of claim 40, wherein LCL, wherein each of Cy1and Cy2is independently seleted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; orwherein , whereincted from an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, Page 359 of 378 12753881v1Attorney Docket No.: 2013405-0034 bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

42. The compound of claim 1, wherein the compound is represented by formula III-B:or a pharmaceutically acceptable salt thereof, wherein: each Rsp’is independently hydrogen, or two Rsp’groups on the same carbon are taken together to form =O or together with the carbon atom to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring; each Rsais independently −R’or −OR’; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl;and Ryis H, optionally substituted C1-6alkyl, or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C-Rsaor N; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; Page 360 of 378 12753881v1Attorney Docket No.: 2013405-0034 Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and c is a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

43. The compound of claim 1, wherein the compound is represented by formula III-C: or a pharmaceuticaeach Rsp’is independently hydrogen, or two Rsp’groups on the same carbon are taken together to form =O or together with the carbon atom to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring; each of Rsa, Rsband Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; each of a, b, and c is independently 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; each of Ring A and Ring B is independently an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and Page 361 of 378 12753881v1Attorney Docket No.: 2013405-0034 Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S.

44. The compound of claim 43, wherein LCL is , whereineach of Cy1and Cy2is independently sele uted 4- to 12-memberedmonocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; or inan optionally substituted 4- to 12-memberedmonocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

45. The compound of claim 1, wherein the compound is represented by formula IV:Page 362 of 378 12753881v1Attorney Docket No.: 2013405-0034 IV or a pharmaceutically acceptable salt thereof, wherein: LCLis attached to the bracketed moiety at one of Ra, Rb, Rc, or Rd, or LCLis attached to a point on one Rd; Ring R is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Rais −N(Ra1)2, −Ra1, −C(Ra1)3, or −Cy−Ra1; Rbis −Rb1, or −C(Rb1)3; each of Ra1and Rb1is independently −R’; Rcis −R’; each Rdis independently halogen, −CN, −R’ or −OR’; r is 0, 1, 2, or 3; each R’ is independently −R, −C(O)R, or −S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 0-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen, N(R’)2, or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1−C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

46. The compound of claim 1, wherein the compound is represented by formula IV-A’:Page 363 of 378 12753881v1Attorney Docket No.: 2013405-0034 IV-A’ or a pharmaceutically acceptable salt thereof, wherein Rbis −R’ or −C(R’)3; Rcis −R’; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each of Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O (i.e., −C(Rx)2− is −C(O)−); each Rzis independently H or optionally substituted C1-6alkyl (e.g., C1-6haloalkyl); Ryis H, optionally substituted C1-6alkyl (e.g., C1-6haloalkyl) or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; A4i C(Ra1) r N;Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S.

47. The compound of claim 1, wherein the compound is represented by formula IV-A: Page 364 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein: Rbis −R’ or −C(R’)3; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each of Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; A4is C(Ra1) or N; Ra1is −R’; Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently Page 365 of 378 12753881v1Attorney Docket No.: 2013405-0034 selected from N, O, and S.

48. The compound of claim 46 or 47, wherein LCL is , whereineach of Cy1and Cy2is independently selected f - to 12-memberedmonocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; or inan optionally substituted 4- to 12-memberedmonocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

49. The compound of claim 1, wherein the compound is represented by formula IV-B: Page 366 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein: Rbis −R’ or −C(R’)3; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; A4is C(Ra1) or N; Ra1is −R’; Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S. Page 367 of 378 12753881v1Attorney Docket No.: 2013405-0034 50. The compound of claim 49, wherein LCL is , whereineach of Cy1and Cy2is independently sel uted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optona y su sttute - to 2-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; or inan optionally substituted 4- to 12-memberedmonocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6 aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

51. The compound of claim 1, wherein the compound is represented by formula IV-C: Page 368 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein: Rbis −R’ or −C(R’)3; Rcis −R’; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6 alkyl or optionally substituted C1-6 heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S. Page 369 of 378 12753881v1Attorney Docket No.: 2013405-0034 52. The compound of claim 51, wherein LCL is , whereineach of Cy1and Cy2is independently sel uted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optona y su sttute - to 2-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; or inan optionally substituted 4- to 12-memberedmonocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6 aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

53. The compound of claim 1, wherein the compound is represented by formula IV-D: Page 370 of 378 12753881v1Attorney Docket No.: 2013405-0034or a pharmaceutically acceptable salt thereof, wherein: Rbis −R’ or −C(R’)3; Rcis −R’; Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; c is 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S.

54. The compound of claim 53, wherein LCL , whereinPage 371 of 378 12753881v1Attorney Docket No.: 2013405-0034 each of Cy1and Cy2is independently selected from an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; OR inan optionally substituted 4- to 12-memberedmonocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

55. The compound of claim 1, wherein the compound is represented by formula IV-E:or a pharmaceutically acceptable salt thereof, wherein: Rbis −R’ or −C(R’)3; Page 372 of 378 12753881v1Attorney Docket No.: 2013405-0034 Rdis halogen, −CN, −R’ or −OR’; each Rsais independently −R’or −OR’; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A3is C(Rsa) or N; A4is C(Ra1) or N; bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−;Lbis a covalent bond, optionally substituted C1-3alkylene, −C(O)NH−, −NHC(O)NH−, or −NH−; and Lcis a covalent bond, or an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

56. The compound of claim 1, wherein the compound is represented by formula IV-F:or a pharmaceutically acceptable salt thereof, wherein Rbis −R’ or −C(R’)3; Rdis halogen, −CN, −R’ or −OR’; each of Rsa, Rsband Rscis independently halogen, −CN, −R’, −OR’, or −N(R’)2; Page 373 of 378 12753881v1Attorney Docket No.: 2013405-0034 each of a, b, and c is independently 0, 1, 2, 3, or 4; each Rxis independently hydrogen, or the two Rxare taken together to form =O; each Rzis independently H or optionally substituted C1-6alkyl; Ryis H, optionally substituted C1-6alkyl or optionally substituted C1-6heteroalkyl having 1-3 heteroatoms independently selected from N, O and S; or Ryand one Rzare taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated ring having 1-3 heteroatoms independently selected from N, O, and S; each A1is independently optionally substituted CH or N; A2is optionally substituted NH or O; A4is C(Ra1) or N; Ra1is −R’; Lais a covalent bond, an optionally substituted bivalent C1-3hydrocarbon chain, or −N(R’)−; Lbis a covalent bond, optionally substituted C1-3alkylene (e.g., C1-3haloalkylene), −C(O)NH−, −NHC(O)NH−, or −NH−; each of Ring A and Ring B is independently an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S; and Ring C is an optionally substituted 3-14 membered ring having 0-6 heteroatoms independently selected from N, O, and S.

57. The compound of claim 56, wherein LCL , whereineach of Cy1and Cy2is independently seleuted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−; or inan optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic carbocycle, an optionally substituted 4- to 12-membered monocyclic, bicyclic, or spirocyclic heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S, Page 374 of 378 12753881v1Attorney Docket No.: 2013405-0034 an optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and an optionally substituted C6aryl; LCyis an optionally substituted bivalent C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −S(O)−, −N(R’)−, −C(R’)2−, −S−, or −O−; and each Lcis independently a covalent bond, or an optionally substituted bivalent C1-10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by −C(O)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, or −N(R’)−.

58. The compound of any one of the preceding claims, wherein the compound can reduce polypeptide level and / or inhibit activity of CITK.

59. The compound of any one of the preceding claims, wherein the compound can reduce polypeptide level and / or inhibit activity of PKN2.

60. The compound of any one of the preceding claims, wherein the compound can reduce polypeptide level and / or inhibit activity of AAK1.

61. The compound of any one of the preceding claims, wherein the compound can selectively reduce polypeptide level and / or inhibit activity of CITK over PKN2 and / or AAK1.

62. A pharmaceutical composition comprising a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

63. A method of degrading CITK in a system, comprising administering to the system the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or a method of reducing level of CITK in a system, comprising administering or delivering to the system the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or a method of reducing CITK activity in a system, comprising reducing the activity by reducing the level of CITK in a system.

64. The method of any one of the preceding claims, wherein level of PKN2 is reduced.

65. The method of any one of the preceding claims, wherein level of AAK1 is reduced.

66. A method of degrading PKN2 in a system, comprising administering to the system the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; a method of reducing level of PKN2 in a system, comprising administering or delivering to the system the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or a method of reducing PKN2 activity in a system, comprising reducing the activity by reducing the level of PKN2 in a system; or a method of degrading AAK1 in a system, comprising administering to the system the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or Page 375 of 378 12753881v1Attorney Docket No.: 2013405-0034 a method of reducing level of AAK1 in a system, comprising administering or delivering the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or a method of reducing level of AAK1 in a system, comprising administering or delivering to the system the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or a method of reducing AAK1 activity in a system, comprising reducing the activity by reducing the level of AAK1 in a system.

67. A method of treating cancer by reducing CITK activity, comprising administering or delivering the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or a method of treating a disease, disorder, or condition by reducing CITK activity, comprising administering or delivering the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or a method of treating a disease, disorder, or condition by reducing CITK activity, comprising administering a composition that comprises or delivers a CITK degrader; or a method of treating a disease, disorder, or condition associated with CITK, comprising administering to a subject in need thereof the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or a method of treating cancer, comprising administering to a subject in need thereof the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62.

68. The method of claim 67, wherein the cancer is selected from medulloblastoma, multiple myeloma, prostate, bladder, breast, ovarian, cervical, brain, head and neck, lung, gastrointestinal, colorectal, sarcoma, liver malignancies, small cell lung, neuroblastoma, neuroendocrine tumors, non-small cell lung, breast, and colorectal cancer.

69. A method of treating a disease, disorder, or condition, comprising administering to a subject in need thereof the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62.

70. The method of claim 69, wherein the condition, disease or disorder is associated with CITK.

71. The method of any one of claims 69-70, wherein the condition, disease or disorder is associated with PKN2.

72. The method of any one of claims 69-71, wherein the condition, disease or disorder is associated with AAK1.

73. In a method of reducing level of CITK in a subject, the improvement that comprises administering or delivering the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or in a method of reducing level of CITK in a system, the improvement that comprises administering or delivering the compound of any one of claims 1-61 or the pharmaceutical Page 376 of 378 12753881v1Attorney Docket No.: 2013405-0034 composition of claim 62; or in a method of reducing CITK activity in a subject, the improvement that comprises reducing the activity by reducing the level of CITK in a subject; or in a method of treating cancer by reducing CITK activity, the improvement that comprises administering or delivering the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or n a method of treating a disease, disorder, or condition by reducing CITK activity, the improvement that comprises: administering or delivering the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or in a method of reducing CITK activity in a subject, the improvement that comprises: administering or delivering the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or n a method of reducing level of CITK in a subject, the improvement that comprises: administering or delivering the compound of any one of claims 1-61 or the pharmaceutical composition of claim 62; or in a method of treating a disease, disorder, or condition by reducing CITK activity, the improvement that comprises: administering a composition that comprises or delivers a CITK degrader.

74. A compound or composition of any one of the preceding claims, for preventing or treating a condition, disease or disorder, for a method or improvement of any one of the preceding claims, for manufacturing a medicament for preventing or treating a condition, disease or disorder, or for manufacturing a medicament for a method or improvement of any one of the preceding claims.

75. Use of a compound or composition of any one of the preceding claims, for preventing or treating a condition, disease or disorder, for a method or improvement of any one of the preceding claims, for manufacturing a medicament for preventing or treating a condition, disease or disorder, or for manufacturing a medicament for a method or improvement of any one of the preceding claims.

76. A compound, composition, method, improvement or use of any one of Embodiments 1-280. Page 377 of 378 12753881v1

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