Chimeric degraders of cyclin-dependent kinase 9 and uses thereof

Abstract

Provided herein are bifunctional compounds that bind cyclin-dependent kinase 9 (CDK9) and / or promote targeted ubiquitination for the degradation of CDK9, a protein whose dysregulation is implicated in certain cancers. Also provided are pharmaceutical compositions comprising the bifunctional compounds, methods of treating cancer, methods of promoting the degradation of CDK9 and / or IKZF1, and methods of promoting the selective degradation of CDK9 (e.g., over IKZF1) by a compound or composition described herein.

Description

CHIMERIC DEGRADERS OF CYCLIN-DEPENDENT KINASE 9 AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N. 63 / 486,360, filed February 22, 2023, the contents of which are incorporated herein by reference in their entirety.STATEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under CHE- 1845464 awarded by the National Science Foundation. The government has certain rights in the invention.BACKGROUND

[0003] The serine / threonine kinase cyclin-dependent kinase 9 (CDK9) facilitates the phosphorylation of specific protein substrates and thereby modulates their stability and / or activation state. CDK9 and its regulatory cyclin T1 assemble the functional positive transcription elongation factor b (P-TEFb) complex, which phosphorylates the C-terminal domain (CTD) of the largest domain of the multiprotein complex RNA polymerase II (Pol II) RPB1 / POLR2A. In turn, Pol II transitions from abortive to productive elongation. Therefore, CDK9 is heavily involved in the regulation of transcription. Other CDK9 / cyclin T1 phosphorylation targets include EP300, MYODI, RPB1 / POLR2A, and AR as well as the negative elongation factors DSIF and NELF.

[0004] Due to its central role transcriptional regulation, which is frequently dysregulated in cancer, CDK9 has become the target of several drug development efforts. Dysregulation of CDK9 has been observed in a number of solid tumors, including prostate cancer, neuroblastoma, hepatocellular carcinoma, and lymphoma. Moreover, osteosarcoma patients with high CDK9 tumor-expression levels have significantly shorter survival than patients with low CDK9 expression. CDK9 pathway dysregulation has likewise been observed in liquid tumors, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Even though several CDK9 inhibitors are available, CDK9 is difficult to therapeutically inhibit with small molecules since the structure of its catalytic ATP-binding cleft is similar to many other kinases. Therefore, selective inhibition of CDK9 is challenging.

[0005] MYC gene expression is an important hallmark of stimulated signaling pathways that promote cell proliferation. Deregulation of MYC expression resulting from genomicamplification or increased copy number of the gene, among a host of other genomic alterations, is a key driver in cancer development and progression. Thus, the suppression of MYC transcription and downstream programs has been a long-standing goal in therapeutics discovery for cancer.

[0006] CDK9 is crucial for the upstream and downstream regulation of MYC. Moreover, CDK9’s influence on MYC dynamics extends to the protein level as well. CDK9 phosphorylation of MYC at serine 62 protects the oncoprotein from degradation. Thus, MYC genomic amplifications induce an increased dependence on CDK9 which then becomes critical for the maintenance of MYC addicted tumor state. There have been more than 20 CDK9 inhibitors tested in clinical trials against both hematologic and solid tumors. However, a combination of off- and on-target toxicity and the lack of objective response has restricted progress to FDA approval for these agents. Sustained inhibition of CDK9 can induce a compensatory increase in MYC level. This mechanism of resistance is driven by the bromodomain protein BRD4 mediated activation of inactive cellular CDK9 and channeling of available CDK9 to the MYC promoter.

[0007] Recently, a new therapeutic strategy to reduce and / or eliminate proteins associated with certain pathological states, PROTAC (proteolysis targeting chimeras; e.g., see U.S. Patent Application, U.S.S.N. 14 / 792,414, filed July 6, 2015), was developed. PROTACs are heterobifunctional molecules containing two small molecule binding moieties, joined together by a linker. One of the small molecule ligands is designed to bind with high affinity to a target protein in the cell while the other ligand is able to bind with high affinity to an E3 ligase. In the cell, the PROTAC selectively binds to the target protein of interest.The PROTAC then recruits a specific E3 ligase to the target protein to form a ternary complex with both the target protein and the E3 ligase held in close proximity. The E3 ligase then recruits an E2 conjugating enzyme to the ternary complex. The E2 is then able to ubiquitinate the target protein, labelling an available lysine residue on the protein, and then the E2 dissociates from the ternary complex. The E3 ligase can then recruit additional E2 molecules resulting in poly-ubiquitination of the target protein, labelling the target protein for degradation by the cell’s proteasome machinery. The PROTAC can then dissociate from the target protein and initiate another catalytic cycle. The poly-ubiquitinated target protein is recognized and degraded by the proteasome.SUMMARY

[0008] Because kinases such as CDK9 are difficult to target via traditional small molecule inhibition, compounds that can take advantage of cellular machinery involved in protein homeostasis (e.g., ubiquitination and proteasome degradation via PROTAC) may be advantageous therapeutic agents in targeting CDK9.

[0009] In addition, an acute and potent degradation of CDK9 would circumvent the resistance mechanism described above and lead to a more robust attenuation of MYC activity. While the pharmacodynamics of inhibitors are driven by drug concentration, those of PROTACs appear to be driven by the target resynthesis rate. Moreover, PROTACs can act sub-stoichiometrically with rapid kinetics. These attributes confer PROTACs an advantage in preventing the emergence of drug resistance induced by long-term exposure to high concentration of small molecule inhibitors.

[0010] Moreover, targeted protein degradation offers unique advantages over other modalities to study the transient / temporal changes in cellular signaling networks resulting from the acute depletion of proteins.

[0011] As such, the present disclosure describes the conjugation of a CDK9 binding moiety with an E3 ubiquitin ligase binding moiety (e.g., pomalidomide) to provide compounds that can induce the ubiquitination of CDK9 and promote its degradation in cells. The compounds exhibit surprisingly advantageous properties over existing PROTACs, including selective degradation of CDK9 over one or more Ikaros Family Zinc Finger proteins (e.g., IKZF1), effective degradation of CDK9 at low concentrations of compound, extended target engagement and degradation of CDK9, and potent cytotoxicity against cancer cells.

[0012] The compounds also rapidly downregulate MYC levels. Thus, the present disclosure demonstrates that the selective degradation of CDK9 presents an attractive strategy for a robust attenuation of deregulated transcription that may provide a therapeutic relief for patients with aggressive and metastatic cancers, particularly MYC-driven cancers.

[0013] Accordingly, the present disclosure provides new compounds, compositions, kits, uses, and methods for the treatment of cancer.

[0014] In one aspect, provided herein are compounds of Formula (I):(I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: each of R1, R2, R3, and R4is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, -NRAC(=O)RA, -C(=O)RA, -NRAC(=O)ORA, -NRAC(=O)N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)N(RA)2, -S(O)2N(RA)2, or -NRAS(O)2RA; each of R5and R6is independently hydrogen, substituted or unsubstituted alkyl, -C(=O)RA, or a nitrogen protecting group;A is substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene;L1is -C(=O)- or -S(O)2-;L2is a bond, -NRA-, -O-, -S-, substituted or unsubstituted methylene, or substituted or unsubstituted ethylene;L3is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or -C=C-;X is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;Y is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;E is an E3 ligase binding moiety; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring; provided that the compound is not of formula:

[0015] In certain embodiments, the compound of Formula (I) is of Formula (I-a), (I-b) , (I- c), (I-d), (I-e), (I-f), or (I-g):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0016] Exemplary compounds of Formula (I) include, but are not limited to:and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0017] In another aspect, provided are pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0018] In another aspect, provided are methods of treating cancer in a subject in need thereof, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising acompound of Formula (I), to the subject. In certain embodiments, the cancer is a solid tumor or a hematological cancer.

[0019] In another aspect, provided are methods of promoting the degradation of cyclin- dependent kinase 9 (CDK9), the method comprising contacting CDK9 with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I).

[0020] In another aspect, provided are methods of promoting the degradation of cyclin- dependent kinase 9 (CDK9) and Ikaros Family Zinc Finger Protein 1 (IKZF1), the method comprising contacting CDK9 and IKZF1 with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I).

[0021] In another aspect, provided are methods of promoting the degradation of cyclin- dependent kinase 9 (CDK9), Ikaros Family Zinc Finger Protein 1 (IKZF1), and Ikaros Family Zinc Finger Protein 3 (IKZF3), the method comprising contacting CDK9, IKZF1, and IKZF3 with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I).

[0022] In another aspect, provided are methods of promoting the selective degradation of cyclin-dependent kinase 9 (CDK9) over Ikaros Family Zinc Finger Protein 1 (IKZF1), the method comprising contacting CDK9 and IKZF1 with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I).

[0023] In another aspect, provided are methods of promoting the selective degradation of cyclin-dependent kinase 9 (CDK9) over Ikaros Family Zinc Finger Protein 3 (IKZF3), the method comprising contacting CDK9 and IKZF3 with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I).

[0024] In another aspect, provided are kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I). In certain embodiments, the kit further comprises instructions for administration (e.g., human administration) and / or use.

[0025] In another aspect, provided are methods of destabilizing, disrupting, and / or degrading nucleolar homeostasis in a cell, the method comprising contacting a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) with the cell.

[0026] In another aspect, provided are methods of destabilizing, disrupting, and / or degrading nucleolar homeostasis in a cell of a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) to the subject.

[0027] The details of certain embodiments of the disclosure are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the disclosure will be apparent from the Definitions, Examples, Figures, and Claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1 is a graph showing dose response curves for the degradation of CDK9 by comparator compound D08 and exemplary compounds D25, D29, and D32.

[0029] FIG. 2 is a graph showing dose response curves for the degradation of CDK9 by exemplary compounds D29 and D32 at various concentrations.

[0030] FIG. 3 is a graph showing the degradation of CDK9 over time at various concentrations of compound D32.

[0031] FIG. 4 is a Western blot assessing the degradation of IKZF1 by exemplary compounds D21, D24, D25, D29, and D31, comparator compound D8, control compounds KI-Arv-03 and pomalidomide, and vehicle (DMSO). In the figure, L is Ladder, 1 is D31, 2 is D29, 3 is D25, 4 is D24, 5 is D21, 6 is D08, 7 is Pomalidomide, 8 is KI-ARv-03, and 9 is DMSO.

[0032] FIG. 5 is a graph showing the results of a selectivity assessment of D32 in a global mass spectrometry experiment. Normalized intensity values for CDK9 and members of the IKZF family of proteins are displayed. The percentages indicate the levels of degradation of each protein relative to the DMSO control, (ns is non-significant, **** means corrected P- value <0.0001, ** means 0.03 <corrected P-value <0.002).

[0033] FIG. 6 is a graph showing LC50 curves upon treatment of MOLT-4 cells with exemplary compounds D29 and D32 and comparator CDK9 inhibitors.

[0034] FIGs. 7A-7D show D32 (KI-ARv-03-D32) is a potent CDK9 degrader with rapid kinetics. FIG. 7A is an illustration showing kinase profiling of KI- ARv-03. FIGs. 7B-7C are graphs showing hibit-based luminescence evaluation of endogenous CDK9 levels in MOLT-4 cells after 4-hours of treatment with D8 (KI-ARv-03-D08) (FIG. 7B) or D32 (KI-ARv-03- D32) (FIG. 7C). FIG. 7D is a graph showing a kinetics evaluation of D32 (KI-ARv-03-D32) at 1, 2, 4, 6 and 12 hours.

[0035] FIGs. 8A-8C show a Qqantitative mass-spectrometry assessment of the protein-level effects of D32 (KI-ARv-03-D32). D32 (KI-ARv-03-D32) has a robust on-target effect on MYC-driven processes based on proteomics assessments in MOLT4 cells. Cells were treated with DMSO or 50nM of D32 (KI-ARv-03-D32) in four biological replicates, and protein harvested after 1 and 4 hours of exposure to the agents. FIG. 8A is a volcano plot representation of the 4 hour time-point. CDK9, MYC, and MYC target genes from one of the molecular signatures database (MSigDB) Hallmark collection are shown. FIG. 8B is a graph showing top 10 up and down regulated proteins from FIG. 8A. FIG. 8C shows an enrichment analysis of the top 10% of genes that were differentially impacted - (top box) enriched MSigDB Hallmark pathways and (bottom box) enriched KEGG pathways.

[0036] FIGs. 9A-9D show D32 (KI-ARv-03-D32) induces a rapid downregulation of MYC transcripts and downstream effectors relative to inhibition. FIG. 9A is a graph showing RT qPCR at the indicated time-points. FIG. 9B shows an RNA sequencing evaluation of transcript levels following 4 (left) and 8 (right) hours of treatment with 1.2 uM of KB-0742 and 15nM of D32 (KI-ARv-03-D32). LFC is the log2 of the ratio of KB-0742 / D32. The transcripts of genes with LFC > 0 are differentially repressed by the degrader. FIG. 9C shows an enrichment analysis of the top 10% of genes that were differentially impacted. Circles marked with correspond to p. adjust values of about 0.02; “°” corresponds to p. adjust values of about 0.02 to about 0.03; “+”corresponds to p. adjust values of about 0.03. Blank circles correspond to p. adjust values of less than about 0.01. FIG. 9D shows a LFC of Hallmark MYC Target V2 genes in all three cell lines (MOLT-4, PSN-1, and RH-4). As in FIG. 9B, LFC is the log2 of the ratio of KB-0742 / D32. The transcripts of genes with LFC > 0 are differentially repressed the degrader.

[0037] FIGs. 10A-10B show D32 (KL ARv-03 -D32) has a potent effect on nucleolar homeostasis. FIG. 10A shows fluorescence imaging of HEK-293 cells following treatment with the inhibition, degrader, and relevant controls. FIG. 10B shows (phosphopeptide abundance) / (protein abundance) following 4 hours of 50nM of D32 (KLARv-03-D32).

[0038] FIGs. 11A-11B show D32 (KL ARv-03 -D32) demonstrates strong sensitivy. FIG. 11A shows Cell Titer-Gio cytotoxicity evaluations of MOLT-4, PSN-1, and RH-4 120 hours post treatment with D32 (KI-ARv-03-D32), D33 (KI-ARv-03-D33), KL ARv-03, KB-0742, and Thal-SNS-32. Cells were treated in triplicates with doses ranging from 50pM to 500nM for the degraders (D32 and Thal-SNS-32) and 158nM to lOpM for the other compounds. The curves were fitted to a four-parameter log-logistic model and the IC50 values for both the 72hours and 120 hours endpoint measurements (FIG. 1 IB) estimated using the drc package inR.

[0039] FIGs. 12A-12D show D32 (KI-ARv-03-D32) has strong cell killing activity in ALL and brain tumors, but activity is limited in cells with high ABCB1 level. FIG. 12A shows distribution of the half-maximal inhibitory concentrations (IC50) resulting from a pooled screen of -800 cell lines through the Broad Institute’s PRISM platform. The PRISM platform offers a high throughput approach for compound screening in cancer cells derived from a variety of lineages. KB-0742 and D32 (KLARv-03-D32) were evaluated in 9-point three-fold dilutions series with top concentrations of 30pM and 1.5pM, respectively. FIGs. 12B-12C are graphs showing linear correlations between AUC values and gene expression (FIG. 12B) and proteomic (FIG. 12C). FIG. 12D is a graph showing AUC values from PRISM pooled screen and a secondary non-pooled screen.

[0040] FIGs. 13A-13C show D32 (KL ARv-03 -D32) downregulates components of the myogenic super enhancer machinery. Differential expression analysis of RNA sequencing data obtained from the RH4 cell line, a rhabdomyosarcoma cellular model that depends on the myogenic super enhancer machinery. FIGs. 13A-13B show volcano plot representations of log2 fold change and corrected Pvalues 8 hours after treatment with 15nM D32 (KLARv- 03-D32) (FIG. 13A) and 1.2pM KB-0742 (FIG. 13B). Genes that are part of the myogenic super enhancer regulatory network are highlighted in black. FIG. 13C is a bar plot highlighting significant genes of the myogenic genes highlighted in figures (FIG. 13 A) and (FIG. 13B).DEFINITIONSChemical definitions

[0041] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’ s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0042] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0043] In a formula, •'vvvis a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, - is absent or a single bond, and = or= is a single or double bond.

[0044] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0045] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, C6, C1-6, Ci-5, C1-4, C1-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5.6alkyl.

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

[0047] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms(“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (Cs), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec -butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., -CF3, Bn).

[0048] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCI2, -CF2CI, and the like.

[0049] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (z.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain(“heteroCi-i8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-i6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-14 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl.

[0050] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In someembodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 oror( )- double bond.

[0051] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-io alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.

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

[0053] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (z.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-io alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parentchain (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2- 8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-io alkynyl.

[0054] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like.Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro [4.5] dec any 1 (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0055] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.

[0056] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carboncarbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0057] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0058] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, andthietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydro thiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro- lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0059] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 147t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce-14 aryl. In certain embodiments, the aryl group is a substituted Ce-14 aryl.

[0060] “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0061] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7t electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0062] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0063] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, pheno thiazinyl, phenoxazinyl, and phenazinyl.

[0064] “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0065] The term “unsaturated bond” refers to a double or triple bond.

[0066] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0067] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0068] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0069] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of theheteroatoms and results in the formation of a stable moiety. The disclosure is not intended to be limited in any manner by the exemplary substituents described herein.

[0070] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN,-P(ORCC)3+X“, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X“, -OP(ORCC)2, -OP(ORCC)3+X“, -OP(RCC)4, -OP(ORCC)4, -B(R33)2, -B(ORCC)2, -BR33(0RCC), Ci-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X- is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S,each instance of R33is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two R33groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -OR33, -N(RCC)2, -CN, -C(=0)R33, -C(=O)N(RCC)2, -CO2R33, -SO2R33, -C(=NRcc)0R33, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -S0R33, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=0)(R33)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, Ci-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-i oalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X- is a counterion; each instance of Rccis, independently, selected from hydrogen, Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X“, -N(ORee)Rff, -SH, -SRee,-OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, Ci-6alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =0 or =S; wherein X- is a counterion; each instance of Reeis, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen,alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X- is a counterion.

[0071] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0072] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -wherein X-, Raa, Rbb, and Rccare as defined herein.

[0073] The term “amino” refers to the group -NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

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

[0075] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NR^SO^, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein R^, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

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

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

[0078] The term “carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (e.g., -C(=O)Raa), carboxylic acids (e.g., -CO2H), aldehydes (-CHO), esters (e.g., -CO2R33, -C(=0)SR33, -C(=S)SRaa), amides (e.g., -imines (e.g., -C(=NRbb)Raa, - wherein Raaand Rbbare as defined herein.

[0079] The term “silyl” refers to the group -Si(Raa)s, wherein Raais as defined herein.

[0080] The term “oxo” refers to the group =0, and the term “thiooxo” refers to the group =S.

[0081] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogenC2-10 alkenyl, C2-10 alkynyl, heteroCi-ioalkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein R33, Rbb, Rcc, and Rddare as defined herein.

[0082] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, -OH, -OR33, -N(RCC)2, -C(=0)R33, -C(=O)N(RCC)2,-CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, Ci-io alkyl (e.g., aralkyl, heteroaralkyl), C2-io alkenyl, C2-10 alkynyl, heteroCi-io alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0083] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxy acetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N- acetylmethionine derivative, o-nitrobenzamide, and o- (benzoyloxymethyl)benzamide.

[0084] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2, 7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l- methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolylcarbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3- dithianyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cy anoethyl carbamate, m- chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4- dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1 , 1 -dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’ -methoxyphenylazo )benzyl carbamate, 1 -methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-l-(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1 -phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4- (trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0085] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0086] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl- (lO)-acyl derivative, N'-p-tol uenesulfony lam i noacyl derivative, N' -phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N- acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl- 1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl- 4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N- 2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fem), N-2- picolylamino N’ -oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl] methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N,N’- isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl] amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiopho sphinamide (Mpt), diphenylthiopho sphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3 -nitropyridinesulf enamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tertbutyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0087] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, -R^, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa,-SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X“, -P(ORCC)2, -P(ORCC)3+X-, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein X-, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0088] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxycyclohexyl, 4- methoxy tetrahydropyranyl (MTHP), 4-methoxy tetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1 - [(2-chloro-4-methyl)phenyl] -4- methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, 1- (2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"- tris(benzoyloxyphenyl)methyl, 3-(imidazol-l-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS),triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4- nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1 , 1 -dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2- trichloroethoxy ethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxy trityl (MMT), dimethoxy trityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0089] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to,and -P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0090] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (z.e., including one formal negative charge). An anionic counterion may also be multivalent (z.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F , Cl", Br , I"), , sulfonate ions (e.g., methansulfonate,trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid- 2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like),and carborane anions (e.g., CB11H12" or (HCB 11 McsBre) ). Exemplary counterions which may be multivalent include CO32, HPO42, PO43-, B4O72-, SO42’, S2O32-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0091] The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’ s Advanced Organic Chemistry 6th ed. (501- 502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, MO-di mcthy I hydroxy lam i no, pixyl, and haloformates. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, - OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf),or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SRaa, -OC(=O)Raa, - OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, - OS(=O)Raa, -OSO^, -OP(RCC)2, -OP(RCC)3, -OP(=O)2Raa, -OP(=O)(Raa)2, - OP(=O)(ORCC)2, -OP(=O)2N(Rbb)2, and -OP(=O)(NRbb)2, wherein R^, Rbb, and Rccare as defined herein).

[0092] As used herein, use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0093] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0094] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.Other definitions

[0095] The following definitions are more general terms used throughout the present disclosure.

[0096] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0097] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceuticallyacceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0098] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0099] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H2O, wherein R is thecompound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R O.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).

[0100] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0101] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0102] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0103] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0104] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-12 arylalkyl esters of the compounds described herein may be preferred.

[0105] The terms “composition” and “formulation” are used interchangeably.

[0106] A “subject” to which administration is contemplated refers to a human (z.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease. The subject may also be a plant. In certain embodiments, the plant is a land plant. In certain embodiments, the plant is a non- vascular land plant. In certain embodiments, the plant is a vascular land plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicot. In certain embodiments, the plant is a monocot. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments,the plant is a legume, e.g., a bean plant, e.g., soybean plant. In some embodiments, the plant is a tree or shrub.

[0107] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0108] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound, particle, and / or composition of the disclosure is delivered. A tissue may be an abnormal or unhealthy tissue, which may need to be treated. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the tissue is the central nervous system. In certain embodiments, the tissue is the brain.

[0109] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0110] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0111] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0112] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses.

[0113] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for CDK binding and / or promoting the degradation of CDK9. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a cancer.

[0114] A “prophylactic ally effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or symptoms associated with the condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0115] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g.. metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (z.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0116] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0117] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor islocated. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0118] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, hematological malignancies. The term “hematological malignancy” refers to tumors that affect blood, bone marrow, and / or lymph nodes. Exemplary hematological malignancies include, but are not limited to, leukemia, such as acute lymphocytic leukemia (ALL) (e.g., B- cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B- cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL (ABC-DLBCL))), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, Waldenstrom’s macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma, central nervous system (CNS) lymphoma (e.g., primary CNS lymphoma and secondary CNS lymphoma); and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); lymphoma of an immune privileged site (e.g., cerebral lymphoma, ocular lymphoma, lymphoma of the placenta, lymphoma of the fetus, testicular lymphoma); a mixture of one or more leukemia / lymphoma as described above; myelodysplasia; and multiple myeloma (MM). Additional exemplary cancers include, but are not limited to, lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); kidney cancer (e.g., nephroblastoma, a.k.a. Wilms’ tumor, renal cell carcinoma); acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma,lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease; hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); softtissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0119] The term “carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas include, for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiennoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher’s carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, naspharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinomaspongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.

[0120] The term “hematological cancer” refers to cancer that begins in blood-forming tissue, such as the bone marrow, or in the cells of the immune system. Examples of hematologic cancer are leukemia, lymphoma, and multiple myeloma. Hematological cancer is also called blood cancer.

[0121] The term “leukemia” refers to broadly progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia diseases include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0122] The term “lymphoma” refers to a group of blood cancers that develop from lymphocytes. Lymphoma disease includes diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virustype 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, or ALK- positive large B-cell lymphoma.

[0123] The term “sarcoma” generally refers to a tumor which arises from transformed cells of mesenchymal origin. Sarcomas are malignant tumors of the connective tissue and are generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas include, for example, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilns’ tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin’s sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphomas (e.g., Non-Hodgkin Lymphoma), immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

[0124] The term “melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma subungal melanoma, and superficial spreading melanoma.

[0125] The terms “biologic,” “biologic drug,” and “biological product” refer to a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biologies may include sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living entities, such as cells and tissues. Biologies may be isolated from a variety of natural sources (e.g., human, animal, microorganism) and may be produced by biotechnological methods and other technologies.

[0126] The term “small molecule” or “small molecule therapeutic” refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g / mol, not more than about 900 g / mol, not more than about 800g / mol, not more than about 700 g / mol, not more than about 600 g / mol, not more than about 500 g / mol, not more than about 400 g / mol, not more than about 300 g / mol, not more than about 200 g / mol, or not more than about 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and not more than about 500 g / mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present disclosure.

[0127] The term “therapeutic agent” refers to any substance having therapeutic properties that produce a desired, usually beneficial, effect. For example, therapeutic agents may treat, ameliorate, and / or prevent disease. Therapeutic agents, as disclosed herein, may be biologies or small molecule therapeutics.

[0128] The term “E3 ubiquitin ligase” or “E3 ligase” refers to any protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 protein to the protein substrate.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0129] CDK9 coordinates signaling events that regulate RNA polymerase II (Pol II) pause-release state. It is an important co-factor for oncogenic transcription factors that drivetranscription in an addictive manner. CDK9 modulation offers an approach for attenuating transcriptional dysregulation driven by amplified or over expressed transcription factors, such as MYC. CDK9 inhibition triggers a compensatory mechanism that dampens its effect on MYC transcriptional programs and herein describe that this resistance mechanism was overcome through a targeted degradation approach. Accordingly, CDK9 degradation offers a more potent approach over inhibition for disrupting the core regulatory circuitry likely through the abrogation of both enzymatic and scaffolding functions of CDK9.

[0130] Provided herein are bifunctional compounds that bind CDK9 and recruit an E3 ligase (e.g., Cereblon) to promote the degradation of CDK9. In one aspect, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. The compounds are useful for the treatment of diseases associated with CDK9 (e.g., cancer) in a subject in need thereof. The compounds exhibit surprisingly advantageous properties over existing PROTACs, including selective degradation of CDK9 over one or more Ikaros Family Zinc Finger proteins (e.g., IKZF1), effective degradation of CDK9 at low concentrations of compound, extended target engagement and degradation of CDK9, and potent cytotoxicity against cancer cells.Compounds

[0131] In one aspect, disclosed is a compound of Formula (I):(I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: each of R1, R2, R3, and R4is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, -NRAC(=O)RA, -C(=O)RA,-NRAC(=O)ORA, -NRAC(=0)N(RA)2, -OC(=O)RA, -OC(=O)ORA, -0C(=0)N(RA)2, -S(O)2N(RA)2, or -NRAS(O)2RA; each of R5and R6is independently hydrogen, substituted or unsubstituted alkyl, -C(=O)RA, or a nitrogen protecting group;A is substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene;L1is -C(=O)- or -S(O)2-;L2is a bond, -NRA-, -O-, -S-, substituted or unsubstituted methylene, or substituted or unsubstituted ethylene;L3is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or -C=C-;X is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;Y is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;E is an E3 ligase binding moiety; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring;provided that the compound is not of formula:R1, R2, R3, andR4

[0132] As described herein, each of R1, R2, R3, and R4is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, - NRAC(=O)RA, -C(=O)RA, -NRAC(=O)ORA, -NRAC(=O)N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)N(RA)2, -S(O)2N(RA)2, or -NRAS(O)2RA

[0133] In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl.

[0134] In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen, halogen, or substituted or unsubstituted C1-5 alkyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen, halogen, or substituted or unsubstituted CM alkyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen, halogen, or unsubstituted alkyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen, halogen, or unsubstituted C1-5 alkyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen, halogen, or unsubstituted C alkyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen or unsubstituted alkyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen or unsubstituted C1-5 alkyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen or unsubstituted CM alkyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen or unsubstituted pentanyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen or unsubstituted 3- pentanyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen or unsubstituted propyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen or unsubstituted n-propyl. In certain embodiments, each of R1, R2, R3, and R4is independently hydrogen, unsubstituted 3-pentanyl, or unsubstituted n-propyl.

[0135] In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl.

[0136] In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or substituted or unsubstituted C1-5 alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or substituted or unsubstituted CM alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or unsubstituted alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or unsubstituted C1-5 alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or unsubstituted CM alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or unsubstituted pentanyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or unsubstituted 3-pentanyl. In certainembodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or unsubstituted propyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or unsubstituted n-propyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, unsubstituted 3-pentanyl, or unsubstituted n- propyl.

[0137] In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is substituted or unsubstituted alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is substituted or unsubstituted C1-5 alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is substituted or unsubstituted C alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is unsubstituted C1-5 alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is unsubstituted CM alkyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is unsubstituted pentanyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is unsubstituted pentanyl or unsubstituted propyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is unsubstituted propyl. In certain embodiments, each of R2, R3, and R4is hydrogen; and R1is n-propyl.

[0138] In certain embodiments, each of R1, R2, R3, and R4is hydrogen.R5and R6

[0139] As described herein, each of R5and R6is independently hydrogen, substituted or unsubstituted alkyl, -C(=O)RA, or a nitrogen protecting group.

[0140] In certain embodiments, each of R5and R6is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, each of R5and R6is independently hydrogen or unsubstituted alkyl. In certain embodiments, each of R5and R6is independently hydrogen or unsubstituted CM alkyl. In certain embodiments, each of R5and R6is independently hydrogen or methyl.

[0141] In certain embodiments, each of R5and R6is hydrogen.A

[0142] As described herein, A is substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene.

[0143] In certain embodiments, A is substituted or unsubstituted heterocyclylene.

[0144] In certain embodiments, A is substituted or unsubstituted C4-6 heterocyclylene. In certain embodiments, A is substituted or unsubstituted C4-5 heterocyclylene. In certain embodiments, A is substituted or unsubstituted C5-6 heterocyclylene. In certain embodiments,A is substituted or unsubstituted C4 heterocyclylene. In certain embodiments, A is substituted or unsubstituted C5 heterocyclylene. In certain embodiments, A is substituted or unsubstituted C<> heterocyclylene.

[0145] In certain embodiments, A is substituted or unsubstituted piperidine. In certain embodiments, A is substituted or unsubstituted morpholine. In certain embodiments, A is substituted or unsubstituted piperazine. In certain embodiments, A is substituted or unsubstituted pyrrolidine. In certain embodiments, A is substituted or unsubstituted pyrazoline. In certain embodiments, A is substituted or unsubstituted oxazolidine. In certain embodiments, A is substituted or unsubstituted thiazolidine. In certain embodiments, A is substituted or unsubstituted azetidine. In certain embodiments, A is substituted or unsubstituted oxetane.

[0146] In certain embodiments, A is substituted or unsubstituted carbocyclylene.

[0147] In certain embodiments, A is substituted or unsubstituted C3-6 cycloalkylene. In certain embodiments, A is substituted or unsubstituted C4-6 cycloalkylene. In certain embodiments, A is substituted or unsubstituted C3-5 cycloalkylene. In certain embodiments, A is substituted or unsubstituted C3-4 cycloalkylene. In certain embodiments, A is substituted or unsubstituted C5-6 cycloalkylene.

[0148] In certain embodiments, A is substituted or unsubstituted cyclopropylene. In certain embodiments, A is substituted or unsubstituted cyclobutylene. In certain embodiments, A is substituted or unsubstituted cyclopentylene. In certain embodiments, A is substituted or unsubstituted cyclohexylene.

[0149] In certain embodiments, A is unsubstituted cyclopropylene. In certain embodiments, A is unsubstituted cyclobutylene. In certain embodiments, A is unsubstituted cyclopentylene. In certain embodiments, A is unsubstituted cyclohexylene.

[0150] In certain embodiments,certain embodiments,In certain embodiments,certain embodiments,certain embodiments,-L3-X-L2-Y-L3-

[0151] As described herein, L1is -C(=O)- or -S(O)2-; L2is a bond, -NRA-, -O-, -S-, substituted or unsubstituted methylene, or substituted or unsubstituted ethylene; L3is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or -C=C-; X is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Y is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0152] In certain embodiments,L1is -C(=O)-. In certain embodiments, L1is -S(O)2-.

[0153] In certain embodiments, X is substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl. In certain embodiments, X is substituted or unsubstituted heterocyclyl or substituted or unsubstituted phenyl. In certain embodiments, X is substituted or unsubstituted 5-6 membered heterocyclyl or substituted or unsubstituted phenyl. In certain embodiments, X is substituted or unsubstituted 6-membered heterocyclyl, or substituted or unsubstituted phenyl. In certain embodiments, X is substituted or unsubstituted 6-membered heterocyclyl having at least one nitrogen, or substituted or unsubstituted phenyl. In certain embodiments, X is substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted phenyl. In certain embodiments, X is substituted or unsubstituted piperidinyl or substituted or unsubstituted phenyl. In certain embodiments, X is substituted or unsubstituted piperidinyl. In certain embodiments, X is unsubstituted piperidinyl. In certain embodiments, X is substituted or unsubstituted phenyl. In certain embodiments, X is unsubstituted phenyl.

[0154] In certain embodiments, L2is a bond, substituted or unsubstituted methylene, or substituted or unsubstituted ethylene. In certain embodiments, L2is a bond, unsubstituted methylene, or unsubstituted ethylene. In certain embodiments, L2is a bond. In certain embodiments, L2is substituted or unsubstituted methylene. In certain embodiments, L2is substituted methylene. In certain embodiments, L2is unsubstituted methylene (-CH2-). In certain embodiments, L2is substituted or unsubstituted ethylene. In certain embodiments, L2is substituted ethylene. In certain embodiments, L2is unsubstituted ethylene (-CH2CH2-).

[0155] In certain embodiments, Y is substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl. In certain embodiments, Y is substituted or unsubstituted heterocyclyl or substituted or unsubstituted phenyl. In certain embodiments, Y is substituted or unsubstituted 5-6 membered heterocyclyl or substituted or unsubstituted phenyl. In certain embodiments, Y is substituted or unsubstituted 6-membered heterocyclyl, or substituted orunsubstituted phenyl. In certain embodiments, Y is substituted or unsubstituted 6-membered heterocyclyl having at least one nitrogen, or substituted or unsubstituted phenyl. In certain embodiments, Y is substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted phenyl. In certain embodiments, Y is unsubstituted piperidinyl, unsubstituted piperazinyl, or unsubstituted phenyl. In certain embodiments, Y is substituted or unsubstituted piperidinyl or substituted or unsubstituted phenyl. In certain embodiments, Y is unsubstituted piperidinyl or unsubstituted phenyl. In certain embodiments, Y is substituted or unsubstituted piperazinyl or substituted or unsubstituted phenyl. In certain embodiments, Y is unsubstituted piperazinyl or unsubstituted phenyl. In certain embodiments, Y is substituted or unsubstituted piperazinyl or substituted or unsubstituted piperidinyl. In certain embodiments, Y is unsubstituted piperazinyl or unsubstituted piperidinyl. In certain embodiments, Y is substituted or unsubstituted piperidinyl. In certain embodiments, Y is unsubstituted piperidinyl. In certain embodiments, Y is substituted or unsubstituted piperazinyl. In certain embodiments, Y is unsubstituted piperazinyl. In certain embodiments, Y is substituted or unsubstituted phenyl. In certain embodiments, Y is unsubstituted phenyl.

[0156] In certain embodiments, X is substituted or unsubstituted phenyl and Y is substituted or unsubstituted piperidinyl. In certain embodiments, X is unsubstituted phenyl and Y is unsubstituted piperidinyl.

[0157] In certain embodiments, X is substituted or unsubstituted phenyl and Y is substituted or unsubstituted phenyl. In certain embodiments, X is unsubstituted phenyl and Y is unsubstituted phenyl. In certain embodiments, X and Y are not both substituted or unsubstituted phenyl. In certain embodiments, X and Y are not both unsubstituted phenyl.

[0158] In certain embodiments, Y is substituted or unsubstituted piperidinyl and X is substituted or unsubstituted phenyl. In certain embodiments, Y is unsubstituted piperidinyl and X is unsubstituted phenyl.

[0159] In certain embodiments, X is substituted or unsubstituted phenyl and Y is substituted or unsubstituted piperazinyl. In certain embodiments, X is unsubstituted phenyl and Y is unsubstituted piperazinyl.

[0160] In certain embodiments, X is substituted or unsubstituted piperidinyl and Y is substituted or unsubstituted piperazinyl. In certain embodiments, X is unsubstituted piperidinyl and Y is unsubstituted piperazinyl.

[0161] In certain embodiments, L3is a bond, unsubstituted methylene, unsubstituted ethylene, or -C=C-.

[0162] In certain embodiments, L3is a bond, substituted or unsubstituted ethylene, or - C=C-. In certain embodiments, L3is a bond, unsubstituted ethylene, or -C=C-. In certain embodiments, L3is a bond, substituted or unsubstituted methylene, or -C=C-. In certain embodiments, L3is a bond, unsubstituted methylene, or -C=C-. In certain embodiments, L3is a bond, substituted or unsubstituted ethylene, or substituted or unsubstituted methylene. In certain embodiments, L3is a bond, unsubstituted ethylene, or unsubstituted methylene. In certain embodiments, L3is substituted or unsubstituted ethylene, substituted or unsubstituted methylene, or -C=C-. In certain embodiments, L3is unsubstituted ethylene, unsubstituted methylene, or -C=C-.

[0163] In certain embodiments, L3is a bond or substituted or unsubstituted ethylene. In certain embodiments, L3is a bond or unsubstituted ethylene. In certain embodiments, L3is a bond or substituted or unsubstituted methylene. In certain embodiments, L3is a bond or unsubstituted methylene. In certain embodiments, L3is a bond or -C=C-. In certain embodiments, L3is substituted or unsubstituted ethylene, or -C=C-. In certain embodiments, L3is unsubstituted ethylene, or -C=C-. In certain embodiments, L3is substituted or unsubstituted methylene, or -C=C-. In certain embodiments, L3is unsubstituted methylene, or -C=C-.

[0164] In certain embodiments, L3is a bond. In certain embodiments, L3is substituted or unsubstituted methylene. In certain embodiments, L3is substituted methylene. In certain embodiments, L3is unsubstituted methylene (-CH2-). In certain embodiments, L3is substituted or unsubstituted ethylene. In certain embodiments, L3is substituted ethylene. In certain embodiments, L3is unsubstituted ethylene (-CH2CH2-). In certain embodiments, L3is -C=C-.

[0165] In certain embodiments, L2is a bond or unsubstituted methylene; X is substituted or unsubstituted aryl; and Y is substituted or unsubstituted heterocyclyl. In certain embodiments, L2is unsubstituted methylene; X is substituted or unsubstituted aryl; and Y is substituted or unsubstituted heterocyclyl. In certain embodiments, L2is a bond; X is substituted or unsubstituted aryl; and Y is substituted or unsubstituted heterocyclyl. In certain embodiments, L2is a bond or unsubstituted methylene; X is unsubstituted phenyl; and Y is substituted or unsubstituted heterocyclyl. In certain embodiments, L2is a bond or unsubstituted methylene; X is unsubstituted phenyl; and Y is substituted or unsubstitutedpiperidine, or substituted or unsubstituted piperazine. In certain embodiments, L2is a bond or unsubstituted methylene; X is unsubstituted phenyl; and Y is unsubstituted piperidine or unsubstituted piperazine.

[0166] In certain embodiments, -X-L2-Y- is of formula:

[0167] In certain embodiments, -X-L2-Y- is of formula:

[0168] In certain embodiments, -X-L2-Y- is of formula:

[0169] In certain embodiments, -X-L2-Y- is of formula:

[0170] In certain embodiments, -X-L2-Y- is of formula:

[0171] In certain embodiments, -X-L2-Y- is of formula:

[0173] In certain embodiments, -X-L2-Y- is of formula:

[0177] In certain embodiments, -X-L2-Y- is of formula:

[0178] In certain embodiments, -X-L2-Y- is of formula:

[0179] In certain embodiments, -X-L2-Y- is of formula:

[0180] In certain embodiments, -X-L2-Y- is of formula:

[0181] In certain embodiments, -X-L2-Y- is of formula:

[0184] In certain embodiments, -X-L2-Y- is of formula:

[0185] In certain embodiments, -X-L2-Y- is of formula:

[0187] In certain embodiments, -X-L2-Y- is of formula:

[0189] In certain embodiments, -X-L2-Y- is of formula:embodiments, -X-L2-Y- is of formula:

[0192] In certain embodiments, -X-L2-Y- is of formula:

[0193] In certain embodiments, -X-L2-Y- is of formula:certain embodiments, -X-L2-Y- is not of formula:

[0194] In certain embodiments, -X-L2-Y- is of formula:

[0195] In certain embodiments, -X-L2-Y- is of formula:

[0196] In certain embodiments, -X-L2-Y- is of formula:

[0197] In certain embodiments, L1is -C(=O)-; L2is a bond or unsubstituted methylene; L3is a bond or unsubstituted methylene; X is substituted or unsubstituted aryl; and Y is substituted or unsubstituted heterocyclyl. In certain embodiments, L1is -C(=O)-; L2is unsubstituted methylene; L3is a bond or unsubstituted methylene; X is substituted or unsubstituted aryl; and Y is substituted or unsubstituted heterocyclyl. In certain embodiments, L1is -C(=O)-; L2is a bond; L3is a bond or unsubstituted methylene; X is substituted or unsubstituted aryl; and Y is substituted or unsubstituted heterocyclyl. In certain embodiments, L1is -C(=O)-; L2is a bond or unsubstituted methylene; L3is a bond or unsubstituted methylene; X is unsubstituted phenyl; and Y is substituted or unsubstituted heterocyclyl. In certain embodiments, L1is -C(=O)-; L2is a bond or unsubstituted methylene; L3is a bond or unsubstituted methylene; X is unsubstituted phenyl; and Y is substituted or unsubstituted piperidine, or substituted or unsubstituted piperazine. In certain embodiments, L1is -C(=O)-; L2is a bond or unsubstituted methylene; L3is a bond or unsubstituted methylene; X is unsubstituted phenyl; and Y is unsubstituted piperidine or unsubstituted piperazine.

[0198] In certain embodiments, -iJ-X-L Y-L3- is of formula:

[0200] In certain embodiments, -LJ-X-LAY-L3- is of formula:

[0201] In certain embodiments, -LJ-X-LAY-L3- is of formula:

[0202] In certain embodiments, -LJ-X-LAY-L3- is of formula:

[0203] In certain embodiments, -iJ-X-LAY-L3- is of formula:

[0204] In certain embodiments, -iJ-X-LAY-L3- is not of formula:

[0205] In certain embodiments, -iJ-X-LAY-L3- is of formula:

[0206] In certain embodiments, -iJ-X-LAY-L3- is of formula:Group RA

[0208] As described herein, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring.

[0209] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring.

[0210] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring.

[0211] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 5-6 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring.

[0212] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C1-30 heteroalkyl, substituted or unsubstituted 5-6 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring.

[0213] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-30 heteroalkyl.

[0214] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-20 heteroalkyl.

[0215] In certain embodiments, each occurrence of RAis, independently, hydrogen, or substituted or unsubstituted C1-6 alkyl.

[0216] In certain embodiments, each occurrence of RAis hydrogen.Group E

[0217] E is an E3 ubiquitin ligase binding moiety. In certain embodiments, E binds to Cereblon. Human Cereblon (CRBN) is a protein of 442 amino acids with an apparent molecular weight of ~51 kDa (GenBank: AAH17419). (For the CRBN protein sequence see: Higgins et al., Neurology. 2004, 63, 1927-31. For additional information related to the CRBN structure see Hartmann et al., PLoS One. 2015, 10, e0128342.) Human CRBN contains the N-terminal part (237-amino acids from 81 to 317) of ATP-dependent Lon protease domain without the conserved Walker A and Walker B motifs, 11 casein kinase II phosphorylation sites, 4 protein kinase C phosphorylation sites, 1 N-linked glycosylation site, and 2 myristoylation sites. CRBN is widely expressed in testis, spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovary, small intestine, peripheral blood leukocyte, colon, brain, and retina. CRBN is located in the cytoplasm, nucleus, and peripheral membrane. (Chang et al., Int. J. Biochem. Mol. Biol. 2011, 2, 287-94.)

[0218] Cereblon is an E3 ubiquitin ligase, and it forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, Cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates a number of developmental processes, such as limb and auditory vesicle formation.

[0219] In certain embodiments, E is of Formula (E-I):(E-I), wherein:B is a substituted or unsubstituted monocyclic, bicyclic, or tricyclic fused ring system;Y is -(CH2)k-, -(CH2)k-O-, -O(CH2)k-, -NRB(CH2)k-, -(CH2)k-NRB-, -(CH2)k- (C=O)NRB-, -O(CH2)k-(C=O)NRB-, -O(CH2)k-NRB(C=O)-, -NRB(C=O)-(CH2)k-O-, - NRB(CH2)k-NRB(C=O)-, or -(CH2)k-NRB(C=O)-; each RBis, independently, hydrogen, or substituted or unsubstituted alkyl; each R1Ais, independently, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy; each R3Ais, independently, hydrogen or C1-C3 alkyl;each R3is, independently, C1-C3 alkyl; each R4Ais, independently, hydrogen or C1-C3 alkyl; or two R4A, together with the carbon atom to which they are attached, form a C(O), C3-C6 carbocycle, or a 4-6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;R5Ais hydrogen, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 0, 1, or 2.

[0220] In certain embodiments, E is of Formula (E-II):(E-II), wherein:A is a substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl ring;Y is -(CH2)k-, -(CH2)k-O-, -O(CH2)k-, -NRB(CH2)k-, -(CH2)k-NRB-, -(CH2)k- (C=O)NRB-, -O(CH2)k-(C=O)NRB-, -O(CH2)k-NRB(C=O)-, -NRB(C=O)-(CH2)k-O-, - NRB(CH2)k-NRB(C=O)-, or -(CH2)k-NRB(C=O)-; each RBis, independently, hydrogen, or substituted or unsubstituted alkyl; each R1Ais, independently, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy;R3Ais hydrogen or C1-C3 alkyl; each R3is, independently, C1-C3 alkyl; each R4Ais, independently, hydrogen or C1-C3 alkyl; or two R4A, together with the carbon atom to which they are attached, form a C(O), C3-C6 carbocycle, or a 4-6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;R5Ais hydrogen, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 0, 1, or 2.

[0221] In certain embodiments, E is of Formula (E-III):(E-III), wherein:Y is -(CH2)k-, -(CH2)k-O-, -O(CH2)k-, -NRB(CH2)k-, -(CH2)k-NRB-, -(CH2)k- (C=O)NRB-, -O(CH2)k-(C=O)NRB-, -O(CH2)k-NRB(C=O)-, -NRB(C=O)-(CH2)k-O-, - NRB(CH2)k-NRB(C=O)-, or -(CH2)k-NRB(C=O)-;XAis C(O) or C(R3A)2; each RBis, independently, hydrogen, or substituted or unsubstituted alkyl; each R1Ais, independently, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy;R3Ais hydrogen, or C1-C3 alkyl; each R3is, independently, C1-C3 alkyl; each R4Ais, independently, hydrogen or C1-C3 alkyl; or two R4A, together with the carbon atom to which they are attached, form a C(O), C3-C6 carbocycle, or a 4-, 5-, or 6- membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;R5Ais hydrogen, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 0, 1, or 2.

[0222] In certain embodiments, E is of Formula (E-IV):(E-IV), wherein: XAis -C(=O)- or -CH2-; Y is a bond, -O-, or -NH-; and R3Ais hydrogen, or Ci- C3alkyl.

[0223] In certain embodiments, E is of Formula (E-IV-a):wherein: XAis -C(=0)- or -CH2-; Y is a bond, -O-, or -NH-; and R3Ais hydrogen, or Ci- C3alkyl.

[0224] In certain embodiments, E is of Formula (E-IV-b):(E-IV-b), wherein: XAis -C(=O)- or -CH2-; Y is a bond, -O-, or -NH-; and R3Ais hydrogen, or Ci- C3alkyl.

[0225] In certain embodiments, E is of Formula (E-V):(E-V), wherein: XAis -C(=O)- or -CH2-; and Y is a bond, -O-, or -NH-.

[0226] In certain embodiments, E is of Formula (E-V-a):(E-V-a), wherein: XAis -C(=O)- or -CH2-; and Y is a bond, -O-, or -NH-.

[0227] In certain embodiments, E is of Formula (E-V-b):wherein: XAis -C(=0)- or -CH2-; and Y is a bond, -O-, or -NH-.

[0228] In certain embodiments, E is of Formula (E-VI):(E-VI), wherein: XAis -C(=O)- or -CH2-; and R3Ais hydrogen, or C1-C3 alkyl.

[0229] In certain embodiments, E is of Formula (E-VI-a):(E-VI-a), wherein: XAis -C(=O)- or -CH2-; and R3Ais hydrogen, or C1-C3 alkyl.

[0230] In certain embodiments, E is of Formula (E-VI-b):(E-VI-b), wherein: XAis -C(=O)- or -CH2-; and R3Ais hydrogen, or C1-C3 alkyl.

[0231] In certain embodiments, E is of Formula (E-VII):(E-VII), wherein: XAis -C(=O)- or -CH2-.

[0232] In certain embodiments, E is of Formula (E-VII-a):(E-VII-a), wherein: XAis -C(=O)- or -CH2-.

[0233] In certain embodiments, E is of Formula (E-VII-b):(E-VII-b), wherein: XAis -C(=O)- or -CH2-.

[0234] In certain embodiments, E is of formula (E-VIII):(E-VIII), wherein: XAis -C(=O)- or -CH2-; and R3Ais hydrogen, or C1-C3 alkyl.

[0235] In certain embodiments, E is of Formula (E-VIII-a):(E-VIII-a), wherein: XAis -C(=O)- or -CH2-; and R3Ais hydrogen, or C1-C3 alkyl.

[0236] In certain embodiments, E is of Formula (E-VIII-b):(E-VIII-b), wherein: XAis -C(=O)- or -CH2-; and R3Ais hydrogen, or C1-C3 alkyl.

[0237] In certain embodiments, E is of formula (E-IX):(E-IX), wherein: XAis -C(=O)- or -CH2-.

[0238] In certain embodiments, E is of Formula (E-IX-a):(E-IX-a), wherein: XAis -C(=O)- or -CH2-.

[0239] In certain embodiments, E is of Formula (E-IX-b):(E-IX-b), wherein: XAis -C(=O)- or -CH2-.

[0240] In certain embodiments, E is of formula (E-X):(E-X), wherein: XAis -C(=O)- or -CH2-; and R3Ais hydrogen, or C1-C3 alkyl.

[0241] In certain embodiments, E is of Formula (E-X-a):(E-X-a),wherein: XAis -C(=0)- or -CH2-; and R3Ais hydrogen, or C1-C3 alkyl.

[0242] In certain embodiments, E is of Formula (E-X-b):(E-X-b), wherein: XAis -C(=O)- or -CH2-; and R3Ais hydrogen, or C1-C3 alkyl.

[0243] In certain embodiments, E is of formula (E-XI):wherein: XAis -C(=O)- or -CH2-.

[0244] In certain embodiments, E is of Formula (E-XI-a):(E-XI-a), wherein: XAis -C(=O)- or -CH2-.

[0245] In certain embodiments, E is of Formula (E-XI-b):wherein:

[0246] In certain embodiments, E is

[0249] In certain embodiments, E is

[0250] In certain embodiments, E is

[0251] In certain embodiments, E is

[0252] In certain embodiments, the E3 ligase binding moiety binds an E3 ubiquitin ligase with a Kd of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0253] In certain embodiments, the E3 ligase binding moiety binds Cereblon with a Kd of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0254] In certain embodiments, the E3 ligase binding moiety selectively binds an E3 ubiquitin ligase as compared to another protein. In some embodiments, the E3 ligase binding moiety selectively binds Cereblon over another protein. In some embodiments, the E3 ligasebinding moiety selectively binds Cereblon over another E3 ubiquitin ligase. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.Further Embodiments of Formula (I)

[0255] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-a):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, R4, R5, and R6are as defined herein.

[0256] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-a-1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, and R4are as defined herein.

[0257] In certain embodiments, the compound of Formula (I) is a compound of Formula(La-2):(La-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E and R1are as defined herein.

[0258] In certain embodiments, the compound of Formula (I) is a compound of Formulaor a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0259] In certain embodiments, the compound of Formula (I) is a compound of Formula(La-4):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0260] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-b):(I-b), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, R4, R5, and R6are as defined herein.

[0261] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-b-1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, and R4are as defined herein.

[0262] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-b-2):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E and R1are as defined herein.

[0263] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-b-3):(I-b-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0264] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-b-4):(I-b-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0265] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-c):(I-c), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, R4, R5, and R6are as defined herein.

[0266] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-c-1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, and R4are as defined herein.

[0267] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-c-2):(I-c-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E and R1are as defined herein.

[0268] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-c-3):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0269] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-c-4):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0270] In certain embodiments, the compound of Formula (I) is a compound of Formula (I d):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, R4, R5, and R6are as defined herein.

[0271] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-d-1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, and R4are as defined herein.

[0272] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-d-2):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E and R1are as defined herein.

[0273] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-d-3):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0274] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-d-4):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0275] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-e):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, R4, R5, and R6are as defined herein.

[0276] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-e-1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, and R4are as defined herein.

[0277] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-e-2):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E and R1are as defined herein.

[0278] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-e-3):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0279] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-e-4):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0280] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-f):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, R4, R5, and R6are as defined herein.

[0281] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-f-1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, and R4are as defined herein.

[0282] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-f-2):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E and R1are as defined herein.

[0283] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-f-3):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0284] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-f-4):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0285] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-g):(I-g), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, R4, R5, and R6are as defined herein.

[0286] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-g-D:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E, R1, R2, R3, and R4are as defined herein.

[0287] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-g-2):(I-g-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E and R1are as defined herein.

[0288] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-g-3):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0289] In certain embodiments, the compound of Formula (I) is a compound of Formula(I-g-4):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein E is as defined herein.

[0290] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0291] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0292] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0293] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0294] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0295] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0296] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0297] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0298] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0299] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0300] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0301] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0302] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0303] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0304] In certain embodiments, the compound of Formula (I) is a compound of the formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0305] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) bind CDK9 with a Kd of less than 100,000 nM, less than 50,000 nM, less than20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0306] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) inhibit CDK9 with an IC50 of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0307] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) bind IKZF1 with a Kd of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0308] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) inhibit IKZF1 with an IC50 of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0309] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) bind IKZF1 with a Kd of greater than 100,000 nM, greater than 50,000 nM, greater than 20,000 nM, greater than 10,000 nM, greater than 5,000 nM, greater than 2,500 nM, greater than 1,000 nM, greater than 900 nM, greater than 800 nM, greater than 700 nM,greater than 600 nM, greater than 500 nM, greater than 400 nM, greater than 300 nM, greater than 200 nM, greater than 100 nM, greater than 90 nM, greater than 80 nM, greater than 70 nM, greater than 60 nM, greater than 50 nM, greater than 40 nM, greater than 30 nM, greater than 20 nM, greater than 10 nM, greater than 5 nM, greater than 4 nM, greater than 3 nM, greater than 2 nM, or greater than 1 nM.

[0310] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) inhibit IKZF1 with an IC50 of greater than 100,000 nM, greater than 50,000 nM, greater than 20,000 nM, greater than 10,000 nM, greater than 5,000 nM, greater than 2,500 nM, greater than 1,000 nM, greater than 900 nM, greater than 800 nM, greater than 700 nM, greater than 600 nM, greater than 500 nM, greater than 400 nM, greater than 300 nM, greater than 200 nM, greater than 100 nM, greater than 90 nM, greater than 80 nM, greater than 70 nM, greater than 60 nM, greater than 50 nM, greater than 40 nM, greater than 30 nM, greater than 20 nM, greater than 10 nM, greater than 5 nM, greater than 4 nM, greater than 3 nM, greater than 2 nM, or greater than 1 nM.

[0311] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) bind IKZF3 with a Kd of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0312] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) inhibit IKZF3 with an IC50 of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0313] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) bind IKZF3 with a Kd of greater than 100,000 nM, greater than 50,000 nM, greater than 20,000 nM, greater than 10,000 nM, greater than 5,000 nM, greater than 2,500 nM, greater than 1,000 nM, greater than 900 nM, greater than 800 nM, greater than 700 nM,greater than 600 nM, greater than 500 nM, greater than 400 nM, greater than 300 nM, greater than 200 nM, greater than 100 nM, greater than 90 nM, greater than 80 nM, greater than 70 nM, greater than 60 nM, greater than 50 nM, greater than 40 nM, greater than 30 nM, greater than 20 nM, greater than 10 nM, greater than 5 nM, greater than 4 nM, greater than 3 nM, greater than 2 nM, or greater than 1 nM.

[0314] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) inhibit IKZF3 with an IC50 of greater than 100,000 nM, greater than 50,000 nM, greater than 20,000 nM, greater than 10,000 nM, greater than 5,000 nM, greater than 2,500 nM, greater than 1,000 nM, greater than 900 nM, greater than 800 nM, greater than 700 nM, greater than 600 nM, greater than 500 nM, greater than 400 nM, greater than 300 nM, greater than 200 nM, greater than 100 nM, greater than 90 nM, greater than 80 nM, greater than 70 nM, greater than 60 nM, greater than 50 nM, greater than 40 nM, greater than 30 nM, greater than 20 nM, greater than 10 nM, greater than 5 nM, greater than 4 nM, greater than 3 nM, greater than 2 nM, or greater than 1 nM.

[0315] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) selectively bind and / or inhibit CDK9 over another protein. In some embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) selectively bind and / or inhibit CDK9 over a different cyclin-dependent kinase (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK10, CDK11, CDK12, CDK13). In some embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) selectively bind and / or inhibit CDK9 over one or more of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK10, CDK11, CDK12, and CDK13. In some embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) selectively bind and / or inhibit CDK9 over a Ikaros Family Zinc Finger Protein (e.g., IKZF1, IKZF2, IKZF3, IKZF4, IKZF5). In some embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) selectively bind and / or inhibit CDK9 over one or more of IKZF1, IKZF2, IKZF3, IKZF4, and IKZF5. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certainembodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.

[0316] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) bind an E3 ubiquitin ligase with a Kd of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0317] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) bind Cereblon with a Kd of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0318] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) selectively bind an E3 ubiquitin ligase as compared to another protein. In some embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) selectively bind Cereblon over another protein. In some embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) selectively bind Cereblon over another E3 ubiquitin ligase. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.

[0319] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) promote the degradation of CDK9. In certain embodiments, the compounds ofthe disclosure (e.g., a compound of Formula (I)) promote the degradation of CDK9 and IKZF1. In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) promote the degradation of CDK9, IKZF1, and IKZF3. In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) promote the degradation of up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% of CDK9 at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less of the compound. In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) promote the degradation of up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% of IKZF1 at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less of the compound. In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) promote the degradation of up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% of IKZF3 at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less of the compound.

[0320] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) selectively promote the degradation of CDK9 over IKZF1. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90. 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000- fold.

[0321] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) selectively promote the degradation of CDK9 over IKZF3. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90. 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000- fold.

[0322] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I)) increase the rate of CDK9 degradation of up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM orIllless, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less of the compound.Pharmaceutical Compositions, Kits, and Administration

[0323] The present disclosure provides pharmaceutical compositions comprising a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0324] In certain embodiments, a compound of the disclosure (e.g., a compound of Formula (I)) is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a cancer associated with CDK9. In certain embodiments, the effective amount is an amount effective for treating a MYC-dependent cancer (e.g., ovarian, lung, and triple-negative breast cancers). In certain embodiments, the effective amount is an amount effective for treating a solid tumor or a hematological cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a leukemia or a lymphoma in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating hepatocellular carcinoma, prostate cancer, glioblastoma or neuroblastoma in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating lung cancer. In certain embodiments, the effective amount is an amount effective for treating triple-negative breast cancer. In certain embodiments, the effective amount is an amount effective for treating AML, Adult T- Cell Leukemia / Lymphoma, Anaplastic Thyroid Cancer, Bladder Urothelial Carcinoma, Breast Invasive Ductal Carcinoma, Breast Invasive Lobular Carcinoma, Embryonal Rhabdomyosarcoma, Endometrial Carcinoma, Endometrial Stromal Sarcoma, Glioblastoma,Hepatocellular Carcinoma, Lung Adenocarcinoma, Lung Squamous Cell Carcinoma, Melanoma, Oral Cavity Squamous Cell Carcinoma, Osteosarcoma, Pancreatic Adenocarcinoma, Plasma Cell Myeloma, Prostate Adenocarcinoma, Small Cell Lung Cancer, T-lymphoblastic Leukemia / Lymphoma, Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor, Acute Monoblastic / Monocytic Leukemia, Atypical Teratoid / Rhabdoid Tumor, B-Cell Prolymphocytic Leukemia, B-Lymphoblastic Leukemia / Lymphoma, Choriocarcinoma, Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Endometrioid Ovarian Cancer, Esophageal Adenocarcinoma, Ewing Sarcoma, Extrahepatic Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Large Cell Lung Carcinoma, Mantle Cell Lymphoma, Mature B-Cell Neoplasms, Meningioma, Neuroblastoma, Non-Small Cell Lung Cancer, Primitive Neuroectodermal Tumor, Renal Cell Carcinoma, Rhabdoid Cancer, Stomach Adenocarcinoma, Urethral Urothelial Carcinoma, Uterine Adenosquamous Carcinoma, or Uterine Clear Cell Carcinoma.

[0325] In certain embodiments, the effective amount is an amount effective for promoting the degradation of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of CDK9. In certain embodiments, the effective amount is an amount effective for promoting the degradation of CDK9 by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0326] In certain embodiments, the effective amount is an amount effective for destabilizing, disrupting, and / or degrading at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the nucleolus of a cell. In certain embodiments, the effective amount is an amount effective for destabilizing, disrupting, and / or degrading of the nucleolus of a cell by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive. In certain embodiments, the cell is a cancer cell.

[0327] The present disclosure provides pharmaceutical compositions comprising a compound that interacts with CDK9 and / or an E3 ubiquitin ligase (e.g., Cereblon) for use in treating cancer in a subject in need thereof. In certain embodiments, the composition is for use in treating a cancer associated with CDK9. In certain embodiments, the composition is for use in treating a solid tumor or a hematological cancer. In certain embodiments, the composition is for use in treating a leukemia or a lymphoma. In certain embodiments, thecomposition is for use in treating acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). In certain embodiments, the composition is for use in treating hepatocellular carcinoma, prostate cancer, glioblastoma, or neuroblastoma.

[0328] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the composition comprising a compound of the disclosure (e.g., a compound of Formula (I)) into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0329] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.

[0330] The compound and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical, mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol.

[0331] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and / or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve their ability to cross the bloodbrain barrier, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent exhibita synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

[0332] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0333] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal.In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0334] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0335] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating cancer (e.g., a solid tumor or a hematological cancer) in a subject in need thereof. In certain embodiments, the kits are useful for preventing cancer (e.g., a solid tumor or a hematological cancer) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing cancer (e.g., a solid tumor or a hematological cancer) in a subject in need thereof. In certain embodiments, the kits are useful for promoting the degradation of CDK9 in a subject or cell. In certain embodiments, the kits are useful for promoting the selective degradation of CDK9 in a subject or cell.

[0336] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.Methods of Treatment

[0337] CDK9 has a central role in transcriptional regulation, which is frequently dysregulated in cancer. CDK9 is dysregulated in a number of solid tumors, including prostate cancer, neuroblastoma, hepatocellular carcinoma, and lymphoma. CDK9 pathway dysregulation has likewise been observed in liquid tumors, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Thus, inhibitions and / or degradation is an attractive target for the treatment of cancer.

[0338] Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults (i.e., MYC-dependent cancers). The MYC family of protooncogenes (MYC, MYCN, and MYCL) includes the most commonly amplified genes in cancer and is associated with greater tumor aggressiveness across tumor types.

[0339] Immunomodulatory agents, including thalidomide, lenalidomide, and pomalidomide bind Cereblon. Accordingly, use of a bifunctional compound that binds and / or inhibits CDK9 and binds an E3 ubiquitin ligase (e.g., Cereblon) provides a method of treating diseases that rely on CDK9 activity.

[0340] Thus, the present disclosure provides methods for treating cancer. In certain embodiments, the present disclosure provides a method for treating a cancer associated with CDK9. In certain embodiments, the present disclosure provides a method of treating a solid tumor or a hematological cancer. In certain embodiments, the present disclosure provides a method of treating a MYC-dependent cancer (e.g., ovarian, lung, and triple-negative breast cancers). In certain embodiments, the present disclosure provides a method of treating a hematological cancer. In certain embodiments, the present disclosure provides a method of treating a leukemia or a lymphoma. In certain embodiments, the present disclosure provides a method of treating acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). In certain embodiments, the present disclosure provides a method of treating acute myeloid leukemia (AML). In certain embodiments, the present disclosure provides a method of treating acute lymphoblastic leukemia (ALL). In certain embodiments, the present disclosure provides a method of treating a solid tumor. In certain embodiments, the present disclosure provides a method of treating ovarian cancer, osteosarcoma, hepatocellular carcinoma, prostate cancer, glioblastoma, or neuroblastoma. In certain embodiments, the present disclosure provides a method of treating osteosarcoma, hepatocellular carcinoma, prostate cancer, or neuroblastoma. In certain embodiments, the present disclosure provides a method of treating hepatocellular carcinoma, prostate cancer, or neuroblastoma. In certain embodiments, the present disclosure provides a method of treating osteosarcoma. In certain embodiments, the present disclosure provides a method of treating hepatocellular carcinoma. In certain embodiments, the present disclosure provides a method of treating prostate cancer. In certain embodiments, the present disclosure provides a method of treating glioblastoma. In certain embodiments, the present disclosure provides a method of treating neuroblastoma. In certain embodiments, the present disclosure provides a method of treating lung cancer, the present disclosure provides a method of treating triple-negative breast cancer, the presentdisclosure provides a method of treating AML, Adult T-Cell Leukemia / Lymphoma, Anaplastic Thyroid Cancer, Bladder Urothelial Carcinoma, Breast Invasive Ductal Carcinoma, Breast Invasive Lobular Carcinoma, Embryonal Rhabdomyosarcoma, Endometrial Carcinoma, Endometrial Stromal Sarcoma, Glioblastoma, Hepatocellular Carcinoma, Lung Adenocarcinoma, Lung Squamous Cell Carcinoma, Melanoma, Oral Cavity Squamous Cell Carcinoma, Osteosarcoma, Pancreatic Adenocarcinoma, Plasma Cell Myeloma, Prostate Adenocarcinoma, Small Cell Lung Cancer, T-Lymphoblastic Leukemia / Lymphoma, Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor, Acute Monoblastic / Monocytic Leukemia, Atypical Teratoid / Rhabdoid Tumor, B-Cell Prolymphocytic Leukemia, B -Lymphoblastic Leukemia / Lymphoma, Choriocarcinoma, Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Endometrioid Ovarian Cancer, Esophageal Adenocarcinoma, Ewing Sarcoma, Extrahepatic Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Large Cell Lung Carcinoma, Mantle Cell Lymphoma, Mature B-Cell Neoplasms, Meningioma, Neuroblastoma, Non-Small Cell Lung Cancer, Primitive Neuroectodermal Tumor, Renal Cell Carcinoma, Rhabdoid Cancer, Stomach Adenocarcinoma, Urethral Urothelial Carcinoma, Uterine Adenosquamous Carcinoma, or Uterine Clear Cell Carcinoma.

[0341] In certain embodiments, the present disclosure provides a method of promoting the degradation of CDK9. In certain embodiments, the present disclosure provides a method of promoting the degradation of CDK9 and IKZFL In certain embodiments, the present disclosure provides a method of promoting the degradation of CDK9, IKZF1, and IKZF3. In certain embodiments, the present disclosure provides a method of promoting the selective degradation of CDK9 over IKZFL In certain embodiments, the present disclosure provides a method of promoting the selective degradation of CDK9 over IKZF3.

[0342] The present disclosure also provides methods of destabilizing, disrupting, and / or degrading nucleolar homeostasis in a cell. In certain embodiments, the present disclosure provides methods for destabilizing, disrupting, and / or degrading the nucleolus of a cell. In certain embodiments, the present disclosure provides methods for destabilizing nucleolar homeostasis in a cell. In certain embodiments, the present disclosure provides methods for destabilizing the nucleolus of a cell. In certain embodiments, the present disclosure provides methods for disrupting nucleolar homeostasis in a cell. In certain embodiments, the present disclosure provides methods for disrupting the nucleolus of a cell. In certain embodiments, the present disclosure provides methods for degrading nucleolar homeostasis in a cell. In certain embodiments, the present disclosure provides methods for degrading the nucleolus ofa cell. In certain embodiments, the cell is in a subject. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is in a mammal. In certain embodiments, the cell is in a human.

[0343] The present disclosure also provides methods for treating cancer by destabilizing, disrupting, and / or degrading nucleolar homeostasis in a cell. In certain embodiments, the present disclosure provides methods for treating cancer by destabilizing, disrupting, and / or degrading the nucleolus of a cell. In certain embodiments, the present disclosure provides methods for treating cancer by destabilizing nucleolar homeostasis in a cell. In certain embodiments, the present disclosure provides methods for treating cancer by destabilizing the nucleolus of a cell. In certain embodiments, the present disclosure provides methods for treating cancer by disrupting nucleolar homeostasis in a cell. In certain embodiments, the present disclosure provides methods for treating cancer by disrupting the nucleolus of a cell. In certain embodiments, the present disclosure provides methods for treating cancer by degrading nucleolar homeostasis in a cell. In certain embodiments, the present disclosure provides methods for treating cancer by degrading the nucleolus of a cell. In certain embodiments, the cell is in a subject. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is in a mammal. In certain embodiments, the cell is in a human.

[0344] In certain embodiments, the cancer is a solid tumor or a hematological cancer. In certain embodiments, the cancer is a MYC-dependent cancer (e.g., ovarian, lung, and triplenegative breast cancers). In certain embodiments, the cancer is a hematological cancer. In certain embodiments, the the cancer is a leukemia or a lymphoma. In certain embodiments, the cancer is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). In certain embodiments, the cancer is acute myeloid leukemia (AML). In certain embodiments, the the cancer is acute lymphoblastic leukemia (ALL). In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is ovarian cancer, osteosarcoma, hepatocellular carcinoma, prostate cancer, glioblastoma, or neuroblastoma. In certain embodiments, the cancer is osteosarcoma, hepatocellular carcinoma, prostate cancer, or neuroblastoma. In certain embodiments, the cancer is hepatocellular carcinoma, prostate cancer, or neuroblastoma. In certain embodiments, the cancer is osteosarcoma. In certain embodiments, the cancer is hepatocellular carcinoma. In certain embodiments, the the cancer is prostate cancer. In certain embodiments, the cancer is glioblastoma. In certain embodiments, the cancer is neuroblastoma. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is triple-negative breast cancer. In certain embodiments, the cancer is AML, Adult T-Cell Leukemia / Lymphoma, Anaplastic Thyroid Cancer, BladderUrothelial Carcinoma, Breast Invasive Ductal Carcinoma, Breast Invasive Lobular Carcinoma, Embryonal Rhabdomyosarcoma, Endometrial Carcinoma, Endometrial Stromal Sarcoma, Glioblastoma, Hepatocellular Carcinoma, Lung Adenocarcinoma, Lung Squamous Cell Carcinoma, Melanoma, Oral Cavity Squamous Cell Carcinoma, Osteosarcoma, Pancreatic Adenocarcinoma, Plasma Cell Myeloma, Prostate Adenocarcinoma, Small Cell Lung Cancer, T-Lymphoblastic Leukemia / Lymphoma, Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor, Acute Monoblastic / Monocytic Leukemia, Atypical Teratoid / Rhabdoid Tumor, B-Cell Prolymphocytic Leukemia, B -Lymphoblastic Leukemia / Lymphoma, Choriocarcinoma, Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Endometrioid Ovarian Cancer, Esophageal Adenocarcinoma, Ewing Sarcoma, Extrahepatic Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Large Cell Lung Carcinoma, Mantle Cell Lymphoma, Mature B-Cell Neoplasms, Meningioma, Neuroblastoma, Non-Small Cell Lung Cancer, Primitive Neuroectodermal Tumor, Renal Cell Carcinoma, Rhabdoid Cancer, Stomach Adenocarcinoma, Urethral Urothelial Carcinoma, Uterine Adenosquamous Carcinoma, or Uterine Clear Cell Carcinoma.

[0345] In certain embodiments, the methods of the disclosure comprise administering to a subject an effective amount of a compound of the disclosure (e.g., a compound of Lormula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0346] In certain embodiments, the present disclosure provides a compound for use in treating a cancer associated with CDK9. In certain embodiments, the present disclosure provides a compound for use in treating a MYC-dependent cancer (e.g., ovarian, lung, and triple-negative breast cancers). In certain embodiments, the present disclosure provides a compound for use in treating a solid tumor or a hematological cancer. In certain embodiments, the present disclosure provides a compound for use in treating a hematological cancer. In certain embodiments, the present disclosure provides a compound for use in treating a leukemia or a lymphoma. In certain embodiments, the present disclosure provides compound for use in treating acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). In certain embodiments, the present disclosure provides a compound for use in treating acute myeloid leukemia (AML). In certain embodiments, the present disclosure provides a compound for use in treating acute lymphoblastic leukemia (ALL). In certainembodiments, the present disclosure provides a compound for use in treating a solid tumor. In certain embodiments, the present disclosure provides a compound for use in treating ovarian cancer, osteosarcoma, hepatocellular carcinoma, prostate cancer, glioblastoma, or neuroblastoma. In certain embodiments, the present disclosure provides a compound for use in treating osteosarcoma, hepatocellular carcinoma, prostate cancer, or neuroblastoma. In certain embodiments, the present disclosure provides a compound for use in treating hepatocellular carcinoma, prostate cancer, or neuroblastoma. In certain embodiments, the present disclosure provides a compound for use in treating osteosarcoma. In certain embodiments, the present disclosure provides a compound for use in treating hepatocellular carcinoma. In certain embodiments, the present disclosure provides a compound for use in treating prostate cancer. In certain embodiments, the present disclosure provides a compound for use in treating glioblastoma. In certain embodiments, the present disclosure provides a compound for use in treating neuroblastoma. In certain embodiments, the present disclosure provides a compound for use in treating lung cancer. In certain embodiments, the present disclosure provides a compound for use in treating triple-negative breast cancer. In certain embodiments, the present disclosure provides a compound for use in treating AML, Adult T- Cell Leukemia / Lymphoma, Anaplastic Thyroid Cancer, Bladder Urothelial Carcinoma, Breast Invasive Ductal Carcinoma, Breast Invasive Lobular Carcinoma, Embryonal Rhabdomyosarcoma, Endometrial Carcinoma, Endometrial Stromal Sarcoma, Glioblastoma, Hepatocellular Carcinoma, Lung Adenocarcinoma, Lung Squamous Cell Carcinoma, Melanoma, Oral Cavity Squamous Cell Carcinoma, Osteosarcoma, Pancreatic Adenocarcinoma, Plasma Cell Myeloma, Prostate Adenocarcinoma, Small Cell Lung Cancer, T-Lymphoblastic Leukemia / Lymphoma, Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor, Acute Monoblastic / Monocytic Leukemia, Atypical Teratoid / Rhabdoid Tumor, B-Cell Prolymphocytic Leukemia, B-Lymphoblastic Leukemia / Lymphoma, Choriocarcinoma, Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Endometrioid Ovarian Cancer, Esophageal Adenocarcinoma, Ewing Sarcoma, Extrahepatic Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Large Cell Lung Carcinoma, Mantle Cell Lymphoma, Mature B-Cell Neoplasms, Meningioma, Neuroblastoma, Non-Small Cell Lung Cancer, Primitive Neuroectodermal Tumor, Renal Cell Carcinoma, Rhabdoid Cancer, Stomach Adenocarcinoma, Urethral Urothelial Carcinoma, Uterine Adenosquamous Carcinoma, or Uterine Clear Cell Carcinoma.

[0347] In certain embodiments, the present disclosure provides a compound for use in promoting the degradation of CDK9. In certain embodiments, the present disclosure providesa compound for use in promoting the degradation of CDK9 and IKZF1. In certain embodiments, the present disclosure provides a compound for use in promoting the degradation of CDK9, IKZF1, and IKZF3. In certain embodiments, the present disclosure provides a compound for use in promoting the selective degradation of CDK9 over IKZF1. In certain embodiments, the present disclosure provides a compound for use in promoting the selective degradation of CDK9 over IKZF3.

[0348] In certain embodiments, embodiments, the present disclosure provides a compound for use in destabilizing, disrupting, and / or degrading nucleolar homeostasis in a cell. In certain embodiments, embodiments, the present disclosure provides a compound for use in destabilizing, disrupting, and / or degrading the nucleolus of a cell. In certain embodiments, the cell is a cancer cell.

[0349] In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating a cancer associated with CDK9. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating a MYC-dependent cancer (e.g., ovarian, lung, and triple-negative breast cancers). In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating a solid tumor or a hematological cancer. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating a hematological cancer. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating a leukemia or a lymphoma. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating acute myeloid leukemia (AML). In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating acute lymphoblastic leukemia (ALL). In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating a solid tumor. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating ovarian cancer, osteosarcoma, hepatocellular carcinoma, prostate cancer, glioblastoma, or neuroblastoma. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating osteosarcoma, hepatocellular carcinoma, prostate cancer, or neuroblastoma. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament fortreating hepatocellular carcinoma, prostate cancer, or neuroblastoma. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating osteosarcoma. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating hepatocellular carcinoma. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating prostate cancer. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating glioblastoma. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating neuroblastoma. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating lung cancer. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating triple-negative breast cancer. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for treating AML, Adult T-Cell Leukemia / Lymphoma, Anaplastic Thyroid Cancer, Bladder Urothelial Carcinoma, Breast Invasive Ductal Carcinoma, Breast Invasive Lobular Carcinoma, Embryonal Rhabdomyosarcoma, Endometrial Carcinoma, Endometrial Stromal Sarcoma, Glioblastoma, Hepatocellular Carcinoma, Lung Adenocarcinoma, Lung Squamous Cell Carcinoma, Melanoma, Oral Cavity Squamous Cell Carcinoma, Osteosarcoma, Pancreatic Adenocarcinoma, Plasma Cell Myeloma, Prostate Adenocarcinoma, Small Cell Lung Cancer, T-Lymphoblastic Leukemia / Lymphoma, Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor, Acute Monoblastic / Monocytic Leukemia, Atypical Teratoid / Rhabdoid Tumor, B-Cell Prolymphocytic Leukemia, B- Lymphoblastic Leukemia / Lymphoma, Choriocarcinoma, Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Endometrioid Ovarian Cancer, Esophageal Adenocarcinoma, Ewing Sarcoma, Extrahepatic Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Large Cell Lung Carcinoma, Mantle Cell Lymphoma, Mature B-Cell Neoplasms, Meningioma, Neuroblastoma, Non-Small Cell Lung Cancer, Primitive Neuroectodermal Tumor, Renal Cell Carcinoma, Rhabdoid Cancer, Stomach Adenocarcinoma, Urethral Urothelial Carcinoma, Uterine Adenosquamous Carcinoma, or Uterine Clear Cell Carcinoma.

[0350] In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for promoting the degradation of CDK9. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for promoting the degradation of CDK9 and IKZF1. In certain embodiments, thepresent disclosure provides a compound for use in the manufacture of a medicament for promoting the degradation of CDK9, IKZF1, and IKZF3. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for promoting the selective degradation of CDK9 over IKZF1. In certain embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for promoting the selective degradation of CDK9 over IKZF3.

[0351] In certain embodiments, embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for destabilizing, disrupting, and / or degrading nucleolar homeostasis in a cell. In certain embodiments, embodiments, the present disclosure provides a compound for use in the manufacture of a medicament for destabilizing, disrupting, and / or degrading the nucleolus of a cell. In certain embodiments, the cell is a cancer cell.

[0352] In certain embodiments, the subject being treated is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

[0353] Certain methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein. The additional pharmaceutical agent(s) may be administered at the same time as a compound of the disclosure (e.g., a compound of Formula (I)), or at different times than a compound of the disclosure (e.g., a compound of Formula (I)). For example, a compound of the disclosure (e.g., a compound of Formula (I)) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules. All or some doses of a compound of the disclosure (e.g., a compound of Formula (I)) may be administered before all or some doses of an additional pharmaceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof. The timing of administration of a compound of the disclosure (e.g., a compound of Formula(I)) and additional pharmaceutical agents may be different for different additional pharmaceutical agents.

[0354] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of cancer. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of a cancer associated with CDK9. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of a MYC-dependent cancer (e.g., ovarian, lung, and triple-negative breast cancers). In certain embodiments, the additional pharmaceutical agent is useful in the treatment of a solid tumor or a hematological cancer. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of a hematological cancer. In certain embodiments, the additional pharmaceutical agent cancer is useful in the treatment of a leukemia or a lymphoma. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). In certain embodiments, the additional pharmaceutical agent is useful in the treatment of a solid tumor. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of hepatocellular carcinoma, prostate cancer, glioblastoma, or neuroblastoma. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of lung cancer. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of triple-negative breast cancer. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of AML, Adult T-Cell Leukemia / Lymphoma, Anaplastic Thyroid Cancer, Bladder Urothelial Carcinoma, Breast Invasive Ductal Carcinoma, Breast Invasive Lobular Carcinoma, Embryonal Rhabdomyosarcoma, Endometrial Carcinoma, Endometrial Stromal Sarcoma, Glioblastoma, Hepatocellular Carcinoma, Lung Adenocarcinoma, Lung Squamous Cell Carcinoma, Melanoma, Oral Cavity Squamous Cell Carcinoma, Osteosarcoma, Pancreatic Adenocarcinoma, Plasma Cell Myeloma, Prostate Adenocarcinoma, Small Cell Lung Cancer, T-Lymphoblastic Leukemia / Lymphoma, Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor, Acute Monoblastic / Monocytic Leukemia, Atypical Teratoid / Rhabdoid Tumor, B-Cell Prolymphocytic Leukemia, B-Lymphoblastic Leukemia / Lymphoma, Choriocarcinoma, Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Endometrioid Ovarian Cancer, Esophageal Adenocarcinoma, Ewing Sarcoma, Extrahepatic Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Large Cell Lung Carcinoma, Mantle Cell Lymphoma, Mature B-Cell Neoplasms, Meningioma, Neuroblastoma, Non-Small Cell Lung Cancer, Primitive Neuroectodermal Tumor, Renal Cell Carcinoma, Rhabdoid Cancer, Stomach Adenocarcinoma, Urethral Urothelial Carcinoma,Uterine Adenosquamous Carcinoma, or Uterine Clear Cell Carcinoma. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is any anti-cancer agent recited herein. In certain embodiments, the additional pharmaceutical agent is an immunotherapy.

[0355] In another aspect, the present disclosure provides methods for promoting the degradation of CDK9, the method comprising contacting CDK9 with a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In certain embodiments, the degradation is in a cell. In certain embodiments, the degradation is in a subject. In certain embodiments, the degradation is in a biological sample.

[0356] In another aspect, the present disclosure provides methods for promoting the degradation of CDK9 and IKZF1, the method comprising contacting CDK9 and IKZF1 with a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In certain embodiments, the degradation is in a cell. In certain embodiments, the degradation is in a subject. In certain embodiments, the degradation is in a biological sample.

[0357] In another aspect, the present disclosure provides methods for promoting the degradation of CDK9, IKZF1, and IKZF3, the method comprising contacting CDK9, IKZF1, and IKZF3 with a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In certain embodiments, the degradation is in a cell. In certain embodiments, the degradation is in a subject. In certain embodiments, the degradation is in a biological sample.

[0358] In another aspect, the present disclosure provides methods for promoting the selective degradation of CDK9 over IKZF1, the method comprising contacting CDK9 and IKZF1 with a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In certain embodiments, the selective degradation is in a cell. In certain embodiments, the selective degradation is in a subject. In certain embodiments, the selective degradation is in a biological sample. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. Incertain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90. 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000- fold.

[0359] In another aspect, the present disclosure provides methods for promoting the selective degradation of CDK9 over IKZF3, the method comprising contacting CDK9 and IKZF3 with a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In certain embodiments, the selective degradation is in a cell. In certain embodiments, the selective degradation is in a subject. In certain embodiments, the selective degradation is in a biological sample. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90. 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000- fold.

[0360] In another aspect, the present disclosure provides methods for promoting the degradation of CDK9 and binding an E3 ubiquitin ligase, the method comprising administering to the subject a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof.

[0361] In certain embodiments, the present disclosure provides a method of promoting the ubiquitination of CDK9 by an E3 ubiquitin ligase, the method comprising administering tothe subject a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof.

[0362] In another aspect, the present disclosure provides methods for destabilizing, disrupting, and / or degrading nucleolar homeostasis in a cell, the method comprising contacting a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof with the cell. In certain embodiments, the cell is in a subject. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is in a mammal. In certain embodiments, the cell is in a human.

[0363] In certain embodiments, administration of a compound of the disclosure is effective to destabilize at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the nucleolus of the cell. In certain embodiments, administration of a compound of the disclosure is effective to disrupt at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the nucleolus of the cell. In certain embodiments, administration of a compound of the disclosure is effective to degrade at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the nucleolus of the cell. In certain embodiments, administration of a compound of the disclosure is effective to destabilize, disrupt, and / or degrade the nucleolus of the cell by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.EXAMPLES

[0364] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples disclosed herein are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.Preparation of KI-ARv-3

[0365] 5-propylpyrazolo[l,5-a]pyrimidin-7-ol (1): A solution of 3-aminopyrazole(14.5 g, 175 mmol) and ethyl 3-oxoethanoate (29.4 mL, 184 mmol) in glacial acetic acid (100 mL) was refluxed for 3 h. After cooling to room temperature, the solvent was removed under reduced pressure and residuals were suspended in EtOAc. The resulting mixture was filtered and the remaining solid was washed with EtOAc (3 x 100 mL) to yield 1 as an off-white solid (25.1 g, 142 mmol, 81%).JH NMR (400 MHz, DMSO-tfc): 8 12.22 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 6.10 (d, J = 2.0 Hz, 1H), 5.58 (s, 1H), 2.55 - 2.49 (m, 2H), 1.66 (h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H).13C NMR (101 MHz, DMSO-tfc): 6 156.53, 153.79, 142.75, 141.71, 94.28, 88.46, 34.21, 21.27, 13.31. LC-MS (ES+): m / z 178.1.

[0366] 7-chloro-5-propylpyrazolo[l,5-a]pyrimidine (2): To a suspension of 5- propylpyrazolo[l,5-a]pyrimidin-7-ol (1, 801 mg, 4.52 mmol) in dry MeCN were added phosphorous oxychloride (1.68 mL, 18.1 mmol, dropwise), pyridine (438 pL, 5.42 mmol), and dimethylaminopyridine (28 mg, 0.23 mmol). The resulting suspension was refluxed for 3 h. After cooling to room temperature, the solvent was removed in vacuo and the remaining residue was treated with ice water and immediately extracted with EtOAc (3 x 100 mL). The combined organic layers were dried with Na2SO4and the crude was purified by silica gel flash column chromatography (0-30% EtOAc / hexane) to yield 2 as yellow / green liquid (611 mg, 3.12 mmol, 69%). The product was used immediately for subsequent reactions. ’ H NMR (500 MHz, DMSO-tfc): 6 8.27 (d, J = 2.3 Hz, 1H), 7.36 (s, 1H), 6.75 (d, J = 2.3 Hz, 1H), 2.77 (t, J = 7.5 Hz, 2H), 1.74 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H).13C NMR (DMSO-d6): 6 162.27, 149.05, 145.14, 137.33, 108.79, 97.04, 39.08, 21.23, 13.58. LC-MS (ES+): m / z 197.1 and 198.0 [M+H]+.

[0367] tert-butyl ((lR,3R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7- yl)amino)cyclopentyl) carbamate (3): To a solution of 7-chloro-5-propylpyrazolo[l,5-a | pyrimidine (2, 400 mg, 2.04 mmol) in MeCN were added tert-butyl ((lR,3R)-3- aminocyclopentyl)carbamate (429 mg, 2.14 mmol) and K2CO3(563 mg, 4.08 mmol). The resulting suspension was stirred at 60°C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with DCM (3 x 100 mb). The combined organic layers were dried over Na2SO4and the crude was purified by flash column chromatography (0-70% EtOAc / hexane) to yield 3 as a light-brown resin (481 mg, 1.34 mmol, 66%).JH NMR (500 MHz, DMSO-< / 6): 8 7.99 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.28 (d, J = 2.3 Hz, 1H), 6.05 (s, 1H), 4.17 (h, J = 7.3 Hz, 1H), 3.97 (h, J = 6.6 Hz, 1H), 2.61 (dd, J = 8.4, 6.7 Hz, 2H), 2.13 (dtd, J = 12.6, 7.9, 4.6 Hz, 1H), 2.08 - 1.94 (m, 1H), 1.96 - 1.84 (m, 2H), 1.76 - 1.64 (m, 3H), 1.52 - 1.41 (m, 1H), 1.38 (s, 9H), 0.92 (t, J = 7.3 Hz, 3H). LC-MS (ES+): m / z 360.5 [M+H]+.

[0368] (lR,3R)-Nl-(5-propylpyrazolo[l,5-a]pyrimidin-7-yl)cydopentane-l,3-diamine (KI-ARv-3): tert-butyl ((lR,3R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7- yl)amino)cyclopentyl) carbamate (3, 481 mg, 1.34 mmol) was treated with a solution of 4 M HC1 in MeOH for 1.5 h at room temperature. The solution was basified with saturated Na2HCO3solution and extracted with DCM. The combined organic layers were dried over Na2SO4and the solvent was removed in vacuo to yield KI-ARv-3 as brown syrup (343 mg, 1.33 mmol, 99%). ’ H NMR (DMSO-tfc): 8 7.99 (d, J = 2.3 Hz, 1H), 7.44 (s, 1H), 6.28 (d, J = 2.2 Hz, 1H), 6.03 (s, 1H), 4.21 (t, J = 7.3 Hz, 1H), 3.43 (p, J = 5.8 Hz, 1H), 2.61 (dd, J = 8.4, 6.7 Hz, 2H), 2.20 (dtd, J= 12.9, 7.9, 4.9 Hz, 1H), 2.00 - 1.83 (m, 3H), 1.83 - 1.58 (m, 5H), 1.30 (dtd, J = 13.2, 8.0, 5.4 Hz, 1H), 0.92 (t, J = 7.4 Hz, 3H).13C NMR 8 (101 MHz, DMSO- d6) 8 162.26, 148.77, 146.00, 142.99, 93.59, 84.91, 51.59, 51.07, 41.97, 39.84 34.19, 30.66, 21.93, 13.76. LC-MS (ES+): m / z 260.4 [M+H]+.Preparation of Intermediates and Comparison Compound D08

[0369] tert-butyl 4'-(hydroxymethyl)-[l,l'-biphenyl]-4-carboxylate (3): A mixture of 4- (tert-butoxycarbonyl)phenylboronic acid, pinacol ester (1, 1.00 g, 3.29 mmol), (4- Bromophenyl)methanol (2, 615 mg, 3.29 mmol), Pd(PPh3)2Ch (115 mg, 0.164 mmol), and CS2CO3 (2.14 g, 6.57 mmol) in 1,4-dioxane (8.00 mL) and H2O (2.00 mL) was stirred at 100 °C. After 3.5 hours, the mixture was filtered through a pad of Celite and rinsed with ethyl acetate. The filtrate was concentrated to give a crude material, which was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 to 60:40) to yield the title compound as a white solid (997 mg, quant).!H NMR (500 MHz, CDCI3) 8 8.05 (d, J= 8.5 Hz, 2H), 7.62 (dd, J= 8.3, 6.6 Hz, 4H), 7.46 (d, J = 8.0 Hz, 2H), 4.76 (s, 2H), 1.62 (s, 9H).13C NMR (126 MHz, CDCh) 8 165.82, 144.87, 140.89, 139.68, 130.96, 130.09, 127.65, 127.58, 126.95, 81.21, 65.13, 28.37. QToL HRMS m / z: calcd for C18H20NaO3+[M+Na+] = 307.1305; Found 307.1311.

[0370] 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-l, 3-dione (6): A mixture of 4- nitroisobenzofuran- 1,3-dione (4, 2.00 g, 10.4 mmol) and 3-aminopiperidine-2, 6-dione hydrochloride (5, 1.88 g, 11.4 mmol) and KO Ac (3.15 g, 32.1 mmol) in AcOH (20.8 mL) was stirred at 90 °C overnight. The mixture was concentrated, and the resulting solid material was washed with methanol. The title compound was obtained as a gray solid (3.32 g, quant). ’ H NMR (500 MHz, DMSO) 8 11.17 (s, 1H), 8.35 (d, 7= 8.0 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.12 (t, J = 7.8 Hz, 1H), 5.20 (dd, 7 = 12.9, 5.3 Hz, 1H), 2.89 (ddd, 7 = 17.2, 13.9, 5.4 Hz, 1H), 2.66 - 2.57 (m, 1H), 2.56 - 2.45 (m, 1H), 2.12 - 2.03 (m, 1H).13C NMR (126 MHz, DMSO) 8 172.74, 169.52, 165.19, 162.54, 144.44, 136.84, 133.02, 128.89, 127.32, 122.57, 49.44, 30.88, 21.74. QToF HRMS m / z: calcd for C13H9KN3O6+[M+K+] = 342.0123; Found 342.0127.

[0371] 2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4- nitroisoindoline-1, 3-dione (7): DBU (2.22 mL, 14.9 mmol) and SEMC1 (1.98 mL, 11.2 mmol) were added to a stirred solution of 6 (2.26 g, 7.45 mmol) in DMF (24.8 mL) at roomtemperature. After 2 hours, the mixture was quenched by adding saturated aq. NH4CI, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4. Filtration and concentration gave the crude material, which was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 to 50:50) to yield the title compound as a white solid (1.31 g, 41%).JH NMR (500 MHz, DMSO) 5 8.36 (d, J= 8.1 Hz, 1H), 8.24 (d, J = 7.4 Hz, 1H), 8.13 (t, J = 7.8 Hz, 1H), 5.34 (dd, J = 13.1, 5.4 Hz, 1H), 5.08 (s, 2H), 3.52 (dtd, J = 30.6, 9.7, 6.4 Hz, 2H), 3.03 (ddd, J= 17.3, 14.0, 5.4 Hz, 1H), 2.85 - 2.77 (m, 1H), 2.60 - 2.51 (m, 1H), 2.15 - 2.07 (m, 1H), 0.91 - 0.77 (m, 2H), -0.02 (s, 9H).13C NMR (126 MHz, DMSO) 5 171.56, 169.47, 165.11, 162.45, 144.46, 136.86, 132.98, 128.91, 127.30, 122.53, 68.35, 65.99, 49.98, 31.09, 20.73, 17.46, -1.38. QToF HRMS m / z: calcd for C19H27N4O7Si+[M+NH4+] = 451.1644; Found 451.1648.

[0372] A^-(2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-l,3- dioxoisoindolin-4-yl)-2-nitrobenzenesulfonamide (9): A mixture of 7 (660 mg, 1.52 mmol) and Pd / C (10%, 81.0 mg, 0.076 mmol) in ethanol (7.60 mL) was stirred under hydrogen atmosphere at room temperature overnight. The mixture was filtered through a pad of Celite, then concentrated. The resulting crude material was used in the next step without further purification. To a stirred solution of the crude material in pyridine (5.10 mL), 2- nitrobenzenesulfonyl chloride (1.01 g, 4.58 mmol) was added, then the mixture was stirred at 40 °C overnight. After cooling to room temperature, the mixture was quenched by adding 10 drops of H2O. Concentration and purification by silica gel column chromatography (hexane:ethyl acetate = 80:20 to 40:60 including 1% EtsN, then 100% ethyl acetate) gave the title compound as a yellow solid (521 mg, 58%, 2 steps).1H NMR (500 MHz, CDCh) 6 9.66 (d, J= 4.1 Hz, 1H), 8.19 (dt, J= 7.3, 1.8 Hz, 1H), 8.09 (dd, J= 8.6, 3.5 Hz, 1H), 7.92 (dt, J = 1.1, 1.9 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.70 (t, 7= 7.9 Hz, 1H), 7.53 (dd, J = 7.3, 2.2 Hz, 1H), 5.24 (s, 2H), 4.99 - 4.91 (m, 1H), 3.67 - 3.53 (m, 2H), 3.05 - 2.92 (m, 1H), 2.85 - 2.72 (m, 2H), 2.16 - 2.05 (m, 1H), 0.98 - 0.88 (m, 2H), -0.01 (s, 9H).13C NMR (126 MHz, CDCh) 6 170.77, 168.64, 168.08, 166.43, 148.18, 136.54, 135.93, 134.86, 133.08, 132.78, 132.23, 131.14, 126.15, 122.68, 119.13, 116.86, 69.38, 67.59, 50.22, 32.08, 21.84, 18.17, -1.32. AccuTOF DART HRMS m / z: calcd for C25H32N5O9SiS [M+NH4+] = 606.1685; Found 606.1721.

[0373] tert-butyl 4'-((( \-(2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-l,3-dioxoisoindolin-4-yl)-2-nitrophenyl)sulfonamido)methyl)-[l,l'-biphenyl]-4- carboxylate (10): Triphenylphosphine (80.2 mg, 0.306 mmol) and diisopropyl azodicarboxylate (60.2 pL, 0.306 mmol) were added to a stirred solution of 9 (150 mg, 0.255mmol) and 3 (87.0 mg, 0.306 mmol) in THF (2.55 mL) at room temperature. After 22 hours, the mixture was quenched with H2O, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude material, which was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 50:50) followed by prep TLC (hexane:ethyl acetate = 50:50) to yield the title compound as a white solid (116 mg, 53%).JH NMR (500 MHz, CDCI3) 6 8.02 (d, J= 8.5 Hz, 2H), 7.85 - 7.80 (m, 1H), 7.72 - 7.61 (m, 5H), 7.56 (d, J= 8.4 Hz, 2H), 7.53 - 7.46 (m, 3H), 7.31 (d, J = 8.2 Hz, 2H), 5.55 - 5.31 (m, 1H), 5.22 (s, 2H), 4.85 - 4.78 (m, 2H), 3.62 (pd, J= 9.4, 7.3 Hz, 2H), 3.00 - 2.92 (m, 1H), 2.79 - 2.46 (m, 2H), 2.03 - 1.94 (m, 1H), 1.60 (s, 9H), 0.95 (t, J = 8.2 Hz, 2H), 0.00 (s, 9H).13C NMR (126 MHz, CDCI3) 6 170.79, 168.21, 166.38, 165.71, 165.26, 148.10, 144.35, 140.07, 135.45, 135.07, 134.78, 134.02, 133.28, 132.31, 131.74, 131.13, 131.02, 130.07, 129.66, 128.31, 127.61, 126.91, 126.88, 124.36, 124.18, 81.23, 69.39, 67.64, 55.27, 50.15, 32.08, 28.35, 21.72, 18.27, -1.26. QToF HRMS m / z: calcd for C43H46N4Na011SSi+[M+Na+] = 877.2545; Found 877.2547.

[0374] tert-butyl 4 ' - (((2- (2,6-dioxo- 1 - ((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl) - l,3-dioxoisoindolin-4-yl)amino)methyl)-[l,l'-biphenyl]-4-carboxylate (11): CS2CO3 (133 mg, 0.407 mmol) and 4-bromothiophenol (51.3 mg, 0.271 mmol) were added to a stirred solution of 10 (116 mg, 0.136 mmol) in DMF (1.36 mL) at room temperature. After 1 hour, the mixture was poured into H2O, and extracted with CH2Q2. The combined organic layer was dried over anhydrous Na2SO4and concentrated. Purification by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 70:30) gave the title compound as a yellow amorphous (81.2 mg, 89%) H NMR (500 MHz, CDCh) 6 8.05 (d, J= 8.4 Hz, 2H), 7.61 (dd, J = 8.2, 6.0 Hz, 4H), 7.49 - 7.41 (m, 3H), 7.13 (d, J = 7.1 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.74 (t, J= 5.9 Hz, 1H), 5.28 (s, 2H), 4.99 - 4.92 (m, 1H), 4.56 (d, J = 5.7 Hz, 2H), 3.63 (dtd, J = 31.5, 9.8, 6.7 Hz, 2H), 3.03 - 2.94 (m, 1H), 2.86 - 2.73 (m, 2H), 2.17 - 2.07 (m, 1H), 1.61 (s, 9H), 0.95 (ddd, J= 9.8, 6.7, 2.7 Hz, 2H), -0.01 (s, 9H).13C NMR (126 MHz, CDCI3) 5 171.11, 169.66, 169.23, 167.70, 165.74, 146.70, 144.61, 139.71, 137.74, 136.28, 132.66, 131.06, 130.12, 127.88, 127.64, 126.90, 117.18, 112.21, 110.86, 81.20, 69.30, 67.53, 49.78, 46.61, 32.20, 28.36, 22.15, 18.22, -1.31. QToF HRMS m / z: calcd for C37H43N3NaO7Si+[M+Na+] = 692.2762; Found 692.2765.

[0375] 4'-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)methyl)- / V- ((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)-[l,l'-biphenyl]- 4-carboxamide (D08): A mixture of 11 (81.2 mg, 0.121 mmol) and 4 N HC1 in 1,4-dioxane (1.21 mL) was stirred at 40 °C overnight. Concentration gave a crude mixture including 4'-(((2-(l-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)methyl)- [l,l'-biphenyl]-4-carboxylic acid (12), which was used in the next step without further purification. To a stirred solution of the crude material and KI-ARv3 hydrochloride. (61.6 mg, 0.208 mmol) in DMF (1.04 mL), zPr2NEt (54.4 |1L, 0.313 mmol) and HATU (79.2 mg, 0.208 mmol) were added at room temperature. After stirring overnight, the mixture was poured into H2O, and extracted with CH2C12. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography (CH2Cl2:MeOH = 99:1 to 95:5) to yield a mixture of the title compound and 4'-(((2-(l-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin- 4-yl)amino)methyl)-A-((lR,3R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7- yl)amino)cyclopentyl)-[l,l'-biphenyl]-4-carboxamide. To a stirred solution of the mixture in DMF (1 mL) was added Nl,N2-Dimethylethane-l,2-diamine (9.20 |lL, 0.0853 mmol) at 0 °C. After 1.5 hours, the mixture was poured into H2O, and extracted with 10% MeOH in CH2C12. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude material, which was purified on HPLC (MeCN:H2O = 10:90 to 90:10, including 0.1% HCO2H) to yield the title compound as a yellow solid (32.2 mg, 52%, 3 steps).JH NMR (500 MHz, DMSO) 5 11.12 (s, 1H), 8.44 (d, J= 7.2 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 7.94 (d, J= 8.5 Hz, 2H), 7.75 (d, J= 8.1 Hz, 2H), 7.71 (d, J= 7.5 Hz, 2H), 7.55 - 7.46 (m, 3H), 7.30 (t, J = 6.3 Hz, 1H), 7.03 (d, J = 7.1 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.30 (d, J = 2.1 Hz, 1H), 6.06 (s, 1H), 5.09 (dd, J = 12.9, 5.2 Hz, 1H), 4.62 (d, J = 6.3 Hz, 2H), 4.51 (q, J = 7.2 Hz, 1H), 4.28 (q, J = 7.1 Hz, 1H), 2.90 (ddd, J = 17.9, 13.8, 5.4 Hz, 1H), 2.65 - 2.52 (m, 5H), 2.30 - 2.21 (m, 1H), 2.20 - 2.01 (m, 3H), 1.85 - 1.59 (m, 4H), 0.92 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, DMSO) 5 172.89, 170.16, 168.81, 167.33, 165.66, 162.20, 148.65, 146.13, 146.06, 143.17, 142.30, 138.98, 137.96, 136.17, 133.47, 132.27, 128.02, 127.68, 127.06, 126.30, 117.71, 110.84, 109.67, 93.64, 85.03, 54.94, 51.54, 49.28, 48.62, 45.13, 38.42, 31.08, 31.03, 30.63, 22.20, 21.96, 13.79. QToF HRMS m / z: calcd for C41H41N8O5+[M+H+] = 725.3194; Found 725.3206.Preparation of Exemplary Compounds4'-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)methyl)-N-((lR,3R)-3-((5- propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)-[l,r-biphenyl]-4-carboxamide (D19)

[0376] tert-butyl 4'-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)methyl)-[l,l'-biphenyl]-4-carboxylate (14): To a stirred mixture of 2-(2,6- dioxopiperidin-3-yl)-4-hydroxyisoindoline- 1,3-dione (13, 100 mg, 0.365 mmol) and tert- butyl 4'-(hydroxymethyl)-[l,T-biphenyl]-4-carboxylate (3, 124 mg, 0.438 mmol) in THF (3.65 mL), triphenylphosphine (115 mg, 0.438 mmol) and diisopropyl azodicarboxylate (86.2 pL, 0.438 mmol) were added at room temperature. After stirring overnight, the reaction was quenched with H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified with silica gel column chromatography (hexane:ethyl acetate = 80:20 to 40:60). The resulting mixture was purified again by silica gel column chromatography (hexane:ethyl acetate = 80:20 to 40:60, including 0.1% triethylamine) to yield the title compound as a white solid (40.3 mg, 20%).JH NMR (500 MHz, DMSO) 5 11.12 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.87 - 7.76 (m, 5H), 7.66 - 7.59 (m, 3H), 7.48 (d, J = 7.3 Hz, 1H), 5.44 (s, 2H), 5.11 (dd, J= 12.8, 5.4 Hz, 1H), 2.89 (ddd, J = 16.9, 13.8, 5.4 Hz, 1H), 2.64 - 2.47 (m, 2H), 2.10 - 2.00 (m, 1H), 1.56 (s, 9H).13C NMR (126 MHz, DMSO) 5 172.82, 169.97, 166.81, 165.36, 164.76, 155.46, 143.86, 138.57, 137.07, 136.37, 133.32, 130.24, 129.69, 127.96, 127.14, 126.79, 120.23, 116.68, 115.64, 80.76, 69.66, 48.80, 30.96, 27.82, 22.02. QToF HRMS m / z: calcd for C31H32N3O7+[M+NH4+] = 558.2235; Found 558.2239.

[0377] 4'-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)methyl)-2V- ((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)-[l,l'-biphenyl]- 4-carboxamide (D19): A mixture of 14 (78.8 mg, 0.146 mmol) and 4 N HC1 in 1,4-dioxane (1.00 mL) was stirred at 40 °C overnight. Concentration gave a crude mixture, which was used in the next step without further purification. To a stirred solution of the crude material and KLARv3 hydrochloride (32.9 mg, 0.208 mmol) in DMF (1.04 mL), z‘Pr2NEt (48.4 pL, 0.278 mmol) and HATU (52.9 mg, 0.139 mmol) were added at room temperature. After stirring for 3.5 hours, the mixture was quenched with ammonium chloride solution, andextracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography (CFhChiMeOH = 100:0 to 95:5) to yield the title compound as a white solid (62.3 mg, 59%, 2 steps).JH NMR (500 MHz, DMSO) 5 11.11 (s, 1H), 8.45 (d, J= 7.3 Hz, 1H), 8.07 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.87 - 7.82 (m, 1H), 7.80 (dd, J = 8.5, 2.3 Hz, 4H), 7.63 (d, J = 7.8 Hz, 3H), 7.49 (d, J = 7.3 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 6.15 (s, 1H), 5.45 (s, 2H), 5.10 (dd, J = 12.8, 5.5 Hz, 1H), 4.52 (q, J = 7.1 Hz, 1H), 4.35 - 4.30 (m, 1H), 2.89 (ddd, J = 16.9, 13.8, 5.1 Hz, 1H), 2.65 (t, J = 7.5 Hz, 2H), 2.62 - 2.52 (m, 2H), 2.30 - 2.21 (m, 1H), 2.21 - 2.01 (m, 3H), 1.86 - 1.61 (m, 4H), 1.30 - 1.22 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H).13C NMR (126 MHz, DMSO) 5 172.83, 169.97, 166.82, 165.62, 165.38, 161.53, 155.49, 151.15, 146.49, 143.51, 142.14, 138.86, 137.08, 136.03, 133.62, 133.32, 128.04, 127.99, 127.03, 126.41, 120.75, 120.25, 116.68, 115.64, 93.25, 85.26, 69.72, 51.72, 49.29, 48.80, 38.35, 31.08, 30.97, 30.58, 22.03, 21.93, 13.71. QToF HRMS m / z: calcd for C41H40N7O6+[M+H+] = 726.3035; Found 726.3047.4'-(((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)methyl)-2V-((1 / R, 3 / R)-3-((5- propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)-[l,r-biphenyl]-4-carboxamide(D20)

[0378] methyl 5-amino-4-(4-((2-nitrophenyl)sulfonamido)-l-oxoisoindolin-2-yl)-5- oxopentanoate (18) and methyl 5-amino-2-(4-((2-nitrophenyl)sulfonamido)-l- oxoisoindolin-2-yl)-5-oxopentanoate (19): To a stirred mixture of 3-(4-amino-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (15, 1.02 g, 3.93 mmol) in methanol (39.3 mL), potassium carbonate (544 mg, 3.93 mmol) was added at 0 °C, then the mixture was warmedto room temperature. After 1.5 hours, the reaction was quenched with 1 N HC1 (7.86 mL) and concentrated. The residue was diluted with brine, and extracted with CHCh-isopropylalcohol (3:1). The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude material containing methyl 5-amino-4-(4-amino-l-oxoisoindolin- 2-yl)-5-oxopentanoate (16) and methyl 5-amino-2-(4-amino-l-oxoisoindolin-2-yl)-5- oxopentanoate (17), which was used in the next step without further purification. To a stirred solution of the crude material in pyridine (9.50 mL) was added 2-nitrobenzenesulfonyl chloride (1.31 g, 5.90 mmol) at room temperature. After 1.5 hours, the reaction was quenched with small amount of H2O, then concentrated. The residue was repeatedly purified by silica gel column chromatography (CThChiMeOH = 99:1 to 92.8, then CH2Ch:MeOH = 99:1 to 95:5) to yield methyl 5-amino-4-(4-((2-nitrophenyl)sulfonamido)-l-oxoisoindolin-2-yl)-5- oxopentanoate as a yellow solid (18, 727 mg, 39% in 2 steps, less polar), and methyl 5- amino-2-(4-((2-nitrophenyl)sulfonamido)-l-oxoisoindolin-2-yl)-5-oxopentanoate as a yellow solid (19, 439 mg, 23% in 2 steps, more polar).

[0379] JH NMR (500 MHz, DMSO) 5 10.68 (s, 1H), 7.99 (dd, J= 8.0, 1.2 Hz, 1H), 7.91 (d, J= 7.9 Hz, 1H), 7.86 (td, J= 7.7, 1.4 Hz, 1H), 7.79 (td, 7= 7.7, 1.3 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J= 7.5 Hz, 1H), 7.46 (t, J= 7.7 Hz, 1H), 7.33 (d, J= 7.9 Hz, 1H), 7.20 (s, 1H), 4.74 - 4.67 (m, 1H), 4.56 (d, J= 18.0 Hz, 1H), 4.21 (d, J = 17.9 Hz, 1H), 3.50 (s, 3H), 2.26 - 2.10 (m, 3H), 1.99 - 1.85 (m, 1H).13C NMR (126 MHz, DMSO) 5 172.39, 171.46, 167.16, 147.54, 136.23, 134.96, 133.44, 132.69, 131.53, 131.32, 130.05, 129.23, 126.35, 124.68, 120.74, 53.19, 51.38, 45.41, 30.23, 24.92. QToF HRMS m / z: calcd for C20H21N4O8S+[M+H+] = 477.1075; Found 477.1087.

[0380] ’ H NMR (500 MHz, CDCh) 6 8.57 (s, 1H), 7.84 (ddd, J= 8.0, 5.2, 1.3 Hz, 2H), 7.72 (td, 7= 7.8, 1.4 Hz, 1H), 7.65 (dd, 7 = 7.1, 1.3 Hz, 1H), 7.60 (td, 7= 7.8, 1.3 Hz, 1H), 7.42 - 7.33 (m, 2H), 5.99 (s, 1H), 5.84 (s, 1H), 5.04 (dd, 7 = 10.5, 4.4 Hz, 1H), 4.63 (d, 7 =17.5 Hz, 1H), 4.50 (d, J = 17.5 Hz, 1H), 3.69 (s, 3H), 2.46 - 2.34 (m, 1H), 2.33 - 2.13 (m, 3H).13C NMR (126 MHz, CDCh) 6 174.35, 170.89, 168.78, 148.13, 137.15, 134.46, 133.61, 132.70, 132.31, 131.70, 131.12, 129.51, 127.22, 125.46, 122.47, 53.69, 52.68, 45.89, 32.34, 25.51. QToF HRMS m / z: calcd for C20H21N4O8S+[M+H+] = 477.1075; Found 477.1077.

[0381] tert-butyl 4'-((( \-(2-( l-amino-5-methoxy-l,5-dioxopentan-2-yl)-l- oxoisoindolin-4-yl)-2-nitrophenyl)sulfonamido)methyl)-[l,l'-biphenyl]-4-carboxylate(20): To a stirred mixture of 5-amino-4-(4-((2-nitrophenyl)sulfonamido)-l-oxoisoindolin-2- yl)-5-oxopentanoate (18, 150 mg, 0.315 mmol) and 3 (107 mg, 0.378 mmol) in THF (3.15 mL), triphenylphosphine (99.1 mg, 0.378 mmol) and diethyl azodicarboxylate (40 wt% in toluene, 190 pL, 0.378 mmol) were added at room temperature. After stirring overnight, the reaction was quenched with H2O, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was then taken up with toluene (3.15 mL) and heated with magnesium chloride (59.9 mg, 0.630 mmol) at 60 °C for 2 hours. The mixture was filtered through a pad of Celite and rinsed with toluene. Concentration and purification by silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) yielded the title compound as a white foam (87.4 mg, 37%). ’ H NMR (500 MHz, CDCh) 6 8.06 - 8.00 (m, 2H), 7.81 (dd, J= 7.6, 0.9 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.65 - 7.58 (m, 2H), 7.58 - 7.49 (m, 4H), 7.41 (t, J= 7.7 Hz, 1H), 7.29 - 7.22 (m, 2H), 7.18 (dd, J= 8.0, 1.0 Hz, 1H), 5.90 (s, 1H), 5.05 - 4.86 (m, 3H), 4.72 (dd, J= 8.5, 6.8 Hz, 1H), 3.59 (s, 3H), 2.23 (dq, J = 13.9, 7.0 Hz, 1H), 2.16 - 2.08 (m, 2H), 1.89 - 1.76 (m, 1H), 1.61 (s, 9H).13C NMR (126 MHz, CDCh) 6 172.71, 170.84, 168.04, 165.65, 148.23, 144.02, 143.47, 140.32, 135.52, 134.40, 134.04, 133.47, 133.46, 132.25, 131.98, 131.54, 131.28, 130.15, 130.11, 129.80, 127.61, 126.90, 124.95, 124.38, 81.28, 57.01, 53.70, 51.90, 46.22, 30.16, 28.35, 23.96. QToF HRMS m / z: calcd for C38H39N4O10S+[M+H+] = 743.2381; Found 743.2402.

[0382] tert-butyl 4'-((( \-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-2- nitrophenyl)sulfonamido)methyl)-[l,l'-biphenyl]-4-carboxylate (21): To a stirred mixture of 20 (96.6 mg, 0.110 mmol) in acetonitrile (1.30 mL), cesium carbonate (127 mg, 0.390 mmol) was added at room temperature. After stirring overnight, the mixture was poured into H2O, and extracted with CH2Q2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude material, which was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 to 0:100) and prepTLC (ethyl acetate) to yield the title compound as a yellow solid (32.9 mg, 36%).1H NMR (500 MHz, CDCh) 68.04 (d, J = 8.4 Hz, 2H), 7.88 - 7.83 (m, 1H), 7.82 - 7.75 (m, 1H), 7.75 - 7.70 (m, 2H), 7.59 (d, 7= 8.5 Hz, 2H), 7.56 - 7.49 (m, 4H), 7.41 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.16 (d, 7= 7.8 Hz, 1H), 5.15 - 4.73 (m, 3H), 4.00 - 3.45 (m, 2H), 2.73 - 2.59 (m, 2H), 2.07 - 1.94 (m, 1H), 1.94 - 1.81 (m, 1H), 1.62 (s, 9H).13C NMR (126 MHz, CDCh) 6 170.80, 168.60, 168.14, 165.60, 148.19, 144.00, 143.80, 140.38, 135.83, 134.35, 133.99, 133.51, 133.21, 132.48, 131.93, 131.67, 131.39, 130.16, 130.12, 129.94, 127.72, 126.84, 125.32, 124.33, 81.37, 57.48, 51.76, 46.09, 31.45, 28.36, 23.18. QToF HRMS m / z: calcd for C37H34N4NaO9S+[M+Na+] = 733.1939; Found 733.1959.

[0383] tert-butyl 4'-(((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)methyl)- [l,l'-biphenyl]-4-carboxylate (22): To a stirred solution of 21 (32.9 mg, 0.0463 mmol) in DMF (1.00 mL), cesium carbonate (45.2 mg, 0.139 mmol) and 4-bromothiophenol (17.5 mg, 0.0926 mmol) were added at room temperature. After 1 hour, the mixture was poured into H2O, and extracted with CH2Q2. The combined organic layer was dried over anhydrous Na2SO4and concentrated. Purification by prepTLC (5% methanol in CH2Q2) gave the title compound as a white solid (20.1 mg, 83%). ’ H NMR (500 MHz, Pyr) 5 12.92 (s, 1H), 8.26 (d, 7= 8.3 Hz, 2H), 7.79 (d, 7= 8.4 Hz, 2H), 7.72 (d, 7= 8.0 Hz, 2H), 7.61 (d, 7= 8.0 Hz, 2H), 7.56 (d, 7 = 7.5 Hz, 1H), 7.37 (t, 7= 7.7 Hz, 1H), 6.91 (d, 7 = 8.0 Hz, 1H), 6.56 (t, 7 = 5.8 Hz, 1H), 5.69 (dd, 7= 13.3, 5.1 Hz, 1H), 4.70 (d, 7= 16.3 Hz, 1H), 4.62 (d, 7= 5.6 Hz, 2H), 4.53 (d, 7 = 16.2 Hz, 1H), 3.00 - 2.89 (m, 1H), 2.89 - 2.80 (m, 1H), 2.49 - 2.37 (m, 1H), 2.21 - 2.12 (m, 1H), 1.61 (s, 9H).13C NMR (126 MHz, Pyr) 5 173.68, 172.39, 170.73, 166.12, 145.57, 144.64, 140.78, 139.36, 133.84, 131.69, 130.94, 130.34, 128.69, 128.26, 128.09, 127.60, 113.75, 112.56, 81.40, 53.14, 47.65, 46.79, 32.63, 28.56, 24.49. QToF HRMS m / z: calcd for C31H32N3O5+[M+H+] = 526.2336; Found 526.2350.

[0384] 4'-(((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)methyl)- / V- ((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)-[l,l'-biphenyl]- 4-carboxamide (D20): A mixture of 22 (20.1 mg, 0.0382 mmol) and 4 N HC1 in 1,4-dioxane (1.00 mL) was stirred at 40 °C overnight. Concentration gave a crude mixture, which was used in the next step without further purification. To a stirred solution of the crude material and KLARv3 hydrochloride (22.6 mg, 0.0764 mmol) in DMF (1.00 mL), z‘Pr2NEt (20.0 pL. 0.115 mmol) and HATU (22.6 mg, 0.0764 mmol) were added at room temperature. After stirring overnight, the mixture was poured into H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography (5% methanol inCH2CI2) and HPLC (MeCN:H2O = 10:90 to 90:10, including 0.1% HCO2H) to yield the title compound as a white solid (11.1 mg, 41%).!H NMR (500 MHz, DMSO) 5 11.03 (s, 1H), 8.48 - 8.43 (m, 1H), 8.16 - 8.03 (m, 2H), 7.94 (d, J= 8.3 Hz, 2H), 7.75 (d, J= 8.2 Hz, 2H), 7.69 (d, J= 8.0 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.21 (t, J= 7.7 Hz, 1H), 6.93 (d, J= 7.4 Hz, 1H), 6.66 (d, J= 8.0 Hz, 1H), 6.46 (t, J= 6.0 Hz, 1H), 6.35 (d, J= 2.2 Hz, 1H), 6.16 (s, 1H), 5.13 (dd, 7 = 13.3, 5.1 Hz, 1H), 4.57 - 4.43 (m, 3H), 4.37 - 4.30 (m, 2H), 4.22 (d, J = 17.3 Hz, 1H), 2.94 (ddd, J= 17.4, 13.6, 5.4 Hz, 1H), 2.70 - 2.59 (m, 3H), 2.39 - 2.21 (m, 2H), 2.21 - 2.02 (m, 4H), 1.86 - 1.61 (m, 4H), 0.93 (t, J= 7.3 Hz, 3H).13C NMR (126 MHz, DMSO) 5 172.96, 171.28, 168.83, 165.64, 163.05, 161.40, 146.56, 143.57, 143.28, 142.41, 139.79, 137.70, 133.37, 132.14, 129.13, 128.01, 127.77, 126.85, 126.77, 126.24, 112.39, 110.38, 93.18, 85.30, 51.76, 51.58, 49.27, 45.83, 45.74, 40.43, 38.33, 31.28, 31.08, 30.56, 22.83, 21.92, 13.70. QToF HRMS m / z: calcd for C41H43N8O4+[M+H+] = 711.3402; Found 711.3412.4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)methyl)piperidin-l- yl)-AN-((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)benzainide(D21)

[0385] tert-butyl 4-(4-(hydroxymethyl)piperidin-l-yl)benzoate (25): A mixture of 4- piperidinemethanol (24, 646 mg, 5.61 mmol), / / ' / 7-butyl 4-fluorobenzoate (23, 909 pL, 5.10 mmol), and K2CO3(2.47 g, 17.8 mmol) in DMSO (5.10 mL) was stirred at 120 °C for 5 hours. The mixture was neutralized with 1 N HC1, and diluted with ethyl acetate. The organic layer was then washed with H2O, brine, and H2O. It was then dried over anhydrous Na2SO4.Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography (hexane:ethyal acetate = 90:10 to 50:50) to yield the title compound as a white solid (613 mg, 41%).JH NMR (500 MHz, CDCh) 67.85 (d, J= 9.0 Hz, 2H), 6.85 (d, J = 9.1 Hz, 2H), 3.88 (dt, J = 12.7, 3.3 Hz, 2H), 3.53 (t, J= 5.6 Hz, 2H), 2.83 (td, J= 12.7, 2.7 Hz, 2H), 1.88 - 1.80 (m, 2H), 1.78 - 1.67 (m, 1H), 1.57 (s, 9H), 1.35 (qd, J= 12.3, 4.1 Hz, 2H).13C NMR (126 MHZ, CDCh) 6 166.18, 154.14, 131.15, 121.26, 114.00, 80.15, 67.74, 48.20, 38.73, 28.45, 28.32. QToF HRMS m / z: calcd for C17H26NO3+[M+H+] = 292.1907; Found 292.1911.

[0386] tert-butyl 4-(4-((( \-(2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin- 3-yl)-l,3-dioxoisoindolin-4-yl)-2-nitrophenyl)sulfonamido)methyl)piperidin-l- yl)benzoate (26): To a stirred solution of 9 (150 mg, 0.255 mmol) and 25 (89.1 mg, 0.306 mmol) in THF (2.55 mL), triphenylphosphine (80.2 mg, 0.306 mmol) and diisopropyl azodicarboxylate (60.2 pL, 0.306 mmol) were added at room temperature. After stirring overnight, the mixture was quenched with H2O, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude material, which was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 50:50) followed by prep TLC (hexane:ethyl acetate = 45:55) to yield the title compound as a yellow solid (125 mg, 57%).1H NMR (500 MHz, CDCh) 6 7.96 - 7.91 (m, 1H), 7.88 - 7.77 (m, 4H), 7.70 - 7.55 (m, 3H), 7.48 (dd, J= 18.8, 7.6 Hz, 1H), 6.81 (d, J = 9.2 Hz, 2H), 5.26 - 5.11 (m, 2H), 4.84 - 4.67 (m, 1H), 4.10 - 3.94 (m, 1H), 3.84 (dd, J = 35.9, 12.8 Hz, 2H), 3.66 - 3.50 (m, 3H), 2.94 (d, J = 17.0 Hz, 1H), 2.85 - 2.46 (m, 3H), 1.96 (s, 2H), 1.83 - 1.64 (m, 2H), 1.56 (s, 9H), 1.49 - 1.34 (m, 1H), 1.34 - 1.19 (m, 2H), 0.98 - 0.90 (m, 2H), 0.01 (s, 9H).13C NMR (126 MHz, CDCh) 6 170.73, 168.22, 166.24, 166.08, 164.92, 153.77, 148.11, 139.28, 135.72, 133.95, 133.72, 131.59, 131.50, 131.17, 130.94, 128.05, 124.50, 124.09, 123.83, 121.43, 113.99, 80.16, 69.41, 67.60, 57.77, 50.11, 47.95, 36.09, 32.06, 29.24, 28.44, 21.62, 18.25, -1.26. QToF HRMS m / z: calcd for C42H52N5011SSi+[M+H+] = 862.3148; Found 862.3163.

[0387] tert-butyl 4-(4-(((2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-l,3-dioxoisoindolin-4-yl)amino)methyl)piperidin-l-yl)benzoate (27): To a stirred solution of 26 (125 mg, 0.145 mmol) in DMF (1.45 mL), cesium carbonate (142 mg, 0.435 mmol) and 4-bromothiophenol (54.8 mg, 0.290 mmol) were added at room temperature. After 1 hour, the mixture was poured into H2O, and extracted with CH2Q2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crudematerial, which was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 70:30) to yield the title compound as a yellow solid (79.3 mg, 81%).!H NMR (500 MHz, CDCh) 67.86 (d, J= 8.9 Hz, 2H), 7.49 (dd, J= 8.5, 7.1 Hz, 1H), 7.10 (d, J= 7.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 9.0 Hz, 2H), 6.36 (t, J= 6.1 Hz, 1H), 5.27 (s, 2H), 4.93 (dd, J = 12.3, 5.5 Hz, 1H), 3.89 (d, J = 13.2 Hz, 1H), 3.70 - 3.55 (m, 2H), 3.22 - 3.18 (m, 2H), 3.03 - 2.93 (m, 1H), 2.88 - 2.72 (m, 4H), 2.16 - 2.05 (m, 1H), 1.94 - 1.79 (m, 3H), 1.57 (s, 9H), 1.47 - 1.36 (m, 2H), 0.95 (ddd, J= 9.6, 6.8, 2.6 Hz, 2H), 0.00 (s, 9H).13C NMR (126 MHz, CDCh) 6 171.10, 169.75, 169.21, 167.70, 166.06, 153.96, 147.09, 136.26, 132.72, 131.17, 121.62, 116.63, 114.14, 111.73, 110.36, 80.20, 69.30, 67.52, 49.74, 48.40, 48.25, 36.29, 32.20, 29.71, 28.44, 22.14, 18.22, -1.29. QToF HRMS m / z: calcd for C36H48N4O7Si+[M+H+] = 677.3365; Found 677.3372.

[0388] 4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)methyl)piperidin-l-yl)-2V-((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyriinidin-7- yl)amino)cyclopentyl)benzamide (D21): A mixture of 27 (79.3 mg, 0.117 mmol) and 4 N HC1 in 1,4-dioxane (1.17 mL) was stirred at 40 °C overnight. Concentration gave a crude mixture, which was used in the next step without further purification. To a stirred solution of the crude material and KI-ARv3 hydrochloride (73.2 mg, 0.124 mmol) in DMF (1.24 mL), z‘Pr2NEt (64.7 pL, 0.371 mmol) and HATU (94.1 mg, 0.247 mmol) were added at room temperature. After stirring overnight, the mixture was poured into H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography (CH2Q2: methanol = 99:1 to 95:5) to provide a mixture containing 377-[l,2,3]triazolo[4,5- Zz]pyridin-3-yl 4-(4-(((2-(2,6-dioxopiperidin-3-yl)- 1 ,3-dioxoisoindolin-4- yl)amino)methyl)piperidin-l-yl)benzoate (29) as the major component. To a stirred solution of the mixture in DMF (1.00 mL), KLARv3 hydrochloride (31.5 mg, 0.106 mmol) and z‘Pr2NEt (46.4 pL, 0.266 mmol) were added, then the mixture was stirred at 40 °C for 3 hours. The mixture was poured into H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography (CH2C12:methanol = 95:5) and HPLC (MeCN:H2O = 10:90 to 90:10, including 0.1% HCO2H) to yield the title compound as a yellow solid (26.0 mg, 38% in 3 steps).XH NMR (500 MHz, DMSO) 5 11.11 (s, 1H), 8.07 (d, J= 7.3 Hz, 1H), 8.02 (d, J= 2.2 Hz, 1H), 7.79 - 7.70 (m, 3H), 7.57 (t, J= 7.8 Hz, 1H), 7.16 (dd, J= 8.7, 2.2 Hz, 1H), 7.03 (d, J= 7.0 Hz, 1H), 6.93 (d, J= 8.6 Hz, 2H), 6.65 (t, J= 6.3Hz, 1H), 6.31 (d, 7= 2.2 Hz, 1H), 6.07 (s, 1H), 5.06 (dd, 7 = 12.7, 5.4 Hz, 1H), 4.46 (q, 7 = 7.2 Hz, 1H), 4.27 (q, 7= 7.1 Hz, 1H), 3.87 (d, 7= 12.5 Hz, 2H), 3.25 (t, 7= 6.6 Hz, 2H), 2.88 (ddd, 7= 16.9, 13.6, 5.4 Hz, 1H), 2.74 (t, 7= 12.0 Hz, 2H), 2.66 - 2.59 (m, 3H), 2.59 - 2.52 (m, 1H), 2.28 - 2.18 (m, 1H), 2.17 - 1.99 (m, 4H), 1.87 - 1.67 (m, 6H), 1.67 - 1.57 (m, 1H), 1.35 - 1.20 (m, 2H), 0.92 (t, 7= 7.4 Hz, 3H).13C NMR (126 MHz, DMSO) 5 172.86, 170.14, 169.03, 167.31, 165.69, 162.01, 152.66, 148.30, 146.65, 146.21, 143.24, 136.28, 132.20, 128.67, 123.31, 117.43, 113.66, 110.49, 109.06, 93.53, 85.07, 54.93, 51.59, 49.01, 48.58, 47.42, 47.18, 38.49, 35.45, 31.17, 31.01, 30.62, 28.86, 22.19, 21.96, 13.77. QToF HRMS m / z: calcd for C40H46N9O5+[M+H+] = 732.3616; Found 732.3628.4'-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)methyl)-2V-((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)-[l,l'-biphenyl]-4- carboxamide (D22)

[0389] 2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline-l, 3-dione (31): A mixture of 5- nitroisobenzofuran- 1,3-dione (30, 1.00 g, 5.18 mmol) and 3-aminopiperidine-2, 6-dione hydrochloride (5, 983 mg, 5.70 mmol) and KOAc (1.58 g, 16.1 mmol) in AcOH (10.4 mL) was stirred at 90 °C overnight. The mixture was concentrated, and the resulting solid material was washed with methanol. The title compound was obtained as a gray solid (1.70 g, quant).JH NMR (500 MHz, DMSO) 5 11.17 (s, 1H), 8.68 (dd, J= 8.2, 2.0 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.19 (d, J= 8.1 Hz, 1H), 5.24 (dd, J = 12.9, 5.3 Hz, 1H), 2.90 (ddd, J= 17.2, 13.9, 5.4 Hz, 1H), 2.67 - 2.51 (m, 2H), 2.14 - 2.05 (m, 1H).13C NMR (126 MHz, DMSO) 5 172.74, 169.54, 165.56, 165.29, 151.73, 135.75, 132.54, 130.11, 125.03, 118.39, 49.49,30.89, 21.83. QToF HRMS m / z: calcd for C13H9N3NaO6+[M+Na+] = 326.0384; Found 326.0389.

[0390] 2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5- nitroisoindoline-1, 3-dione (32): To a stirred solution of 31 (1.64 g, 5.41 mmol) in DMF (18.0 mL), DBU (1.61 mL, 10.8 mmol) and SEMC1 (1.44 mL, 8.11 mmol) were added at room temperature. After stirring overnight, the mixture was quenched with saturated aq. NH4CI, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4. Filtration and concentration gave the crude material, which was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 50:50) to yield the title compound as a white solid (807 mg, 34%).JH NMR (500 MHz, CDCh) 6 8.70 (d, J = 1.9 Hz, 1H), 8.65 (dd, J= 8.2, 2.0 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 5.31 - 5.23 (m, 2H), 5.10 - 5.00 (m, 1H), 3.62 (dtd, J = 26.7, 9.6, 6.8 Hz, 2H), 3.11 - 2.99 (m, 1H), 2.91 - 2.76 (m, 2H), 2.23 - 2.13 (m, 1H), 1.01 - 0.88 (m, 2H), 0.00 (s, 9H).13C NMR (126 MHz, CDCh) 6 170.61, 168.34, 165.37, 165.10, 152.12, 136.23, 133.30, 129.79, 125.16, 119.32, 69.42, 67.64, 50.81, 32.08, 21.81, 18.20, -1.31. QToF HRMS m / z: calcd for C19H23N3NaO7Si+[M+Na+] = 456.1197; Found 456.1207.

[0391] A^-(2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-l,3- dioxoisoindolin-5-yl)-2-nitrobenzenesulfonamide (34): A mixture of 32 (1.13 g, 2.61 mmol) and Pd / C (10%, 139 mg, 0.130 mmol) in ethanol (26.1 mL) was stirred under hydrogen atmosphere at room temperature overnight. The mixture was filtered through a pad of Celite, then concentrated. The resulting crude material was used in the next step without further purification. To a stirred solution of the crude material in pyridine (7.90 mL), 2- nitrobenzenesulfonyl chloride (1.05 g, 4.76 mmol) was added at room temperature. After stirring for 6.5 hours, the mixture was quenched by adding 10 drops of H2O. Concentration and purification by silica gel column chromatography (hexane:ethyl acetate = 80:20 to 40:60) yielded the title compound as a yellow solid (1.33 g, 87%, 2 steps).XH NMR (500 MHz, CDCh) 6 8.02 - 7.97 (m, 1H), 7.92 - 7.86 (m, 1H), 7.81 - 7.73 (m, 4H), 7.74 - 7.66 (m, 1H), 7.60 (dd, J = 8.0, 2.0 Hz, 1H), 5.25 (s, 2H), 5.06 - 4.92 (m, 1H), 3.61 (dtd, J = 25.9, 9.6, 7.0 Hz, 2H), 3.06 - 2.94 (m, 1H), 2.87 - 2.72 (m, 2H), 2.18 - 2.05 (m, 1H), 0.99 - 0.87 (m, 2H), -0.01 (s, 9H).13C NMR (126 MHz, CDCh) 6 170.90, 168.90, 166.47, 166.45, 148.26, 141.96, 134.91, 133.80, 133.33, 131.90, 131.85, 128.51, 126.72, 125.96, 125.39, 116.32, 69.36, 67.57, 50.34, 32.11, 21.89, 18.19, -1.31. AccuTOF DART HRMS m / z: calcd for C25H32N5O9SiS [M+NH4+] = 606.1685; Found 606.1714.

[0392] tert- butyl 4 ' - (((2- (2,6-dioxo- 1 - ((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl) - l,3-dioxoisoindolin-5-yl)amino)methyl)-[l,r-biphenyl]-4-carboxylate (36):Triphenylphosphine (80.2 mg, 0.306 mmol) and diethyl azodicarboxylate (40 wt% in toluene, 154 .L, 0.306 mmol) were added to a stirred solution of 34 (150 mg, 0.255 mmol) and 3 (87.0 mg, 0.306 mmol) in THF (2.55 mL) at room temperature. After stirring overnight, the mixture was quenched with H2O, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude material, which was taken up with toluene (2.55 mL) and heated with magnesium chloride (48.5 mg, 0.510 mmol) at 60 °C for 2 hours. The mixture was filtered through a pad of Celite and rinsed with toluene. Concentration and purification by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 50:50, including 1% triethylamine) yielded a mixture containing tert-butyl 4'-(((A-(2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-l,3-dioxoisoindolin-5-yl)-2-nitrophenyl)sulfonamido)methyl)-[l,l'-biphenyl]-4- carboxylate (35) as the major component. To a stirred solution of that mixture in DMF (1.00 mL) were added cesium carbonate (175 mg, 0.537 mmol) and 4-bromothiophenol (67.7 mg, 0.358 mmol) at room temperature. After 1 hour, the mixture was poured into H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude material, which was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 to 50:50) and prepTLC (CH2CI2: methanol = 97:3) to yield the title compound as a yellow solid (75.9 mg, 63% in 2 steps).!H NMR (500 MHz, CDCL) 6 8.05 (d, J= 8.2 Hz, 2H), 7.65 - 7.58 (m, 5H), 7.42 (d, J= 7.8 Hz, 2H), 7.00 (s, 1H), 6.81 (dt, 7 = 8.2, 1.9 Hz, 1H), 5.25 (s, 1H), 5.04 - 4.98 (m, 1H), 4.96 - 4.90 (m, 1H), 4.52 - 4.48 (m, 2H), 3.62 (dtd, 7= 26.5, 9.7, 6.8 Hz, 2H), 3.03 - 2.91 (m, 1H), 2.85 - 2.71 (m, 2H), 2.14 - 2.03 (m, 1H), 1.61 (s, 9H), 0.94 (ddd, 7= 8.8, 6.9, 1.4 Hz, 2H), -0.01 (d, 7 = 5.0 Hz, 9H).13C NMR (126 MHz, CDCL) 6 171.19, 169.32, 167.93, 167.51, 165.74, 153.33, 144.54, 139.94, 137.34, 134.82, 131.12, 130.13, 127.95, 127.95, 126.94, 125.67, 119.41, 116.85, 106.67, 81.24, 69.27, 67.52, 49.94, 47.51, 32.22, 28.36, 22.10, 18.19, -1.31. QToF HRMS m / z: calcd for C37H47N4O7Si+[M+NH4+] = 687.3209; Found 687.3229.

[0393] 4'-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)methyl)-iV- ((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)-[l,l'-biphenyl]- 4-carboxamide (D22): A mixture of 36 (75.9 mg, 0.113 mmol) and 4 N HC1 in 1,4-dioxane (1.13 mL) was stirred at 40 °C overnight. Concentration gave a crude mixture, which was used in the next step without further purification. z‘Pr2NEt (59.1 p.L, 0.339 mmol) and HATU(85.9 mg, 0.226 mmol) were added to a stirred solution of the crude material and KI-ARv3 hydrochloride (66.9 mg, 0.226 mmol) in DMF (1.13 mL) at room temperature. After stirring overnight, the mixture was poured into H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography (CH2C12:methanol = 95:5) to yield a mixture of the title compound and 4'-(((2-(l-(hydroxymethyl)-2,6-dioxopiperidin- 3-yl)-l,3-dioxoisoindolin-5-yl)amino)methyl)-A-((lR,3R)-3-((5-propylpyrazolo[l,5- a]pyrimidin-7-yl)amino)cyclopentyl)-[l,r-biphenyl]-4-carboxamide. To a stirred solution of the mixture in DMF (1.00 mL) was added Nl,N2-Dimethylethane-l,2-diamine (6.9 pL, 0.0643 mmol) at 0 °C. After 1.5 hours, the mixture was poured into H2O, and extracted with 10% MeOH in CH2Q2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude material, which was purified on HPLC (MeCN:H2O = 10:90 to 90:10, including 0.1% HCO2H) to yield the title compound as a yellow solid (25.6 mg, 31%, 3 steps).JH NMR (500 MHz, DMSO) 5 11.07 (s, 1H), 8.45 (d, J = 7.0 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.80 - 7.74 (m, 3H), 7.72 (d, J = 7.8 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 6.99 (s, 1H), 6.96 - 6.89 (m, 1H), 6.30 (d, J= 2.2 Hz, 1H), 6.05 (s, 1H), 5.06 - 4.98 (m, 1H), 4.52 (d, J = 6.1 Hz, 3H), 4.33 - 4.22 (m, 1H), 2.92 - 2.81 (m, 1H), 2.65 - 2.52 (m, 4H), 2.30 - 2.21 (m, 1H), 2.20 - 2.03 (m, 2H), 2.03 - 1.94 (m, 1H), 1.84 - 1.61 (m, 5H), 0.92 (t, J= 7.4 Hz, 3H).13C NMR (126 MHz, DMSO) 5 172.86, 170.19, 167.66, 167.14, 165.67, 162.31, 154.26, 148.85, 146.07, 143.12, 142.30, 138.64, 138.00, 134.14, 133.48, 128.03, 127.80, 127.06, 126.31, 125.12, 116.63, 116.09, 105.78, 93.71, 85.00, 54.93, 51.52, 49.28, 48.67, 45.56, 38.43, 31.09, 31.01, 30.65, 22.23, 21.98, 13.80. QToF HRMS m / z: calcd for C41H41N8O5+[M+H+] = 725.3194; Found 725.3206.4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)methyl)piperidin-l-yl)- A^-((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)benzainide (D23)

[0394] tert-butyl 4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- y25oxy)methyl)piperidin-l-yl)benzoate (38): Triphenylphosphine (57.4 mg, 0.219 mmol) and diisopropyl azodicarboxylate (43.1 pL, 0.219 mmol) were added to a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline- 1,3-dione (13, 50.0 mg, 0.182 mmol) and 25 (53.1 mg, 0.182 mmol) in THF (1.82 mL) at room temperature. After 4.5 hours, 25 (10.6 mg, 0.0364 mmol), triphenylphosphine (9.6 mg, 0.0364 mmol) and diisopropyl azodicarboxylate (7.2 pL, 0.0364 mmol) were added. After stirring for 1.5 hours, the mixture was quenched with H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude material, which was then taken up with toluene (1.82 mL) and heated with magnesium chloride (34.7 mg, 0.364 mmol) at 60 °C for 3 hours. The mixture was filtered through a pad of Celite and rinsed with CH2CI2. Concentration and purification by silica gel column chromatography(CH2Q2: methanol = 100:0 to 95:5) and HPLC (MeChkFLO = 10:90 to 90:10, including 0.1% TFA) to yield the title compound as a white solid (29.5 mg, 30%).!H NMR (500 MHz, DMSO) 5 11.10 (s, 1H), 7.82 (dd, J = 8.5, 7.3 Hz, 1H), 7.74 - 7.68 (m, 2H), 7.53 (d, J= 8.5 Hz, 1H), 7.45 (d, J= 7.2 Hz, 1H), 7.00 - 6.93 (m, 2H), 5.08 (dd, J = 12.8, 5.5 Hz, 1H), 4.11 (d, J = 6.5 Hz, 2H), 3.96 (d, J = 13.0 Hz, 2H), 2.93 - 2.82 (m, 4H), 2.67 - 2.35 (m, 2H), 2.11- 1.99 (m, 1H), 1.91 (d, J = 12.8 Hz, 2H), 1.51 (s, 9H), 1.46 - 1.36 (m, 2H). LC-MS (ESAFE): m / z 548.2 [M+H]+.

[0395] 4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)methyl)piperidin-l-yl)benzoic acid (39): A mixture of 38 and 4 N HC1 in 1,4- dioxane (1.00 mL) was stirred at room temperature for 3.5 hours. The mixture was then warmed to 40 °C, and stirred overnight. It was then concentrated, and the residue was washed with ethyl acetate. It was dried overnight by vacuum pumping to yield the title compound as a white solid (20.5 mg, 77%). ’ H NMR (500 MHz, DMSO) 5 11.10 (s, 1H), 7.85 - 7.78 (m, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.02 - 6.95 (m, 2H), 5.07 (dd, J = 12.9, 5.5 Hz, 1H), 4.12 (d, J = 6.5 Hz, 2H), 3.96 (d, J = 12.7 Hz, 2H), 2.93 - 2.82 (m, 4H), 2.63 - 2.51 (m, 2H), 2.11 - 1.97 (m, 1H), 1.91 (d, J= 12.9 Hz, 2H), 1.48- 1.34 (m, 2H). LC-MS (ES-API+): m / z 492.1 [M+H]+.

[0396] 4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)methyl)piperidin-l-yl)-2V-((l / R,3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7- yl)amino)cyclopentyl)benzamide (D23): To a stirred solution of 39 (20.5 mg, 0.0417 mmol) and KI-ARv3 hydrochloride (14.8 mg, 0.0501 mmol) in DMF (0.300 mL), z‘Pr2NEt (21.8 pL, 0.125 mmol) and HATU (23.8 mg, 0.0626 mmol) were added at room temperature. After stirring overnight, the mixture was poured into H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by prepTLC (CH2Q2: methanol = 95:5) to yield the title compound as a yellow solid (21.0 mg, 69%).!H NMR (500 MHz, DMSO) 5 11.11 (s, 1H), 8.17 (s, 1H), 8.08 (d, J = 7.3 Hz, 1H), 8.03 (d, J= 2.2 Hz, 1H), 7.83 (dd, J = 8.5, 7.3 Hz, 1H), 7.74 (d, J= 8.8 Hz, 2H), 7.55 (d, J= 8.5 Hz, 1H), 7.46 (d, J= 7.2 Hz, 1H), 6.98 (d, J= 9.0 Hz, 2H), 6.33 - 6.29 (m, 1H), 6.06 (s, 1H), 5.09 (dd, J= 12.8, 5.4 Hz, 1H), 4.47 (q, J= 7.2 Hz, 1H), 4.27 (q, J = 7.1 Hz, 1H), 4.16 - 4.07 (m, 2H), 3.92 (d, J = 12.5 Hz, 2H), 3.68 - 3.58 (m, 2H), 3.20 - 3.11 (m, 3H), 2.91 - 2.78 (m, 2H), 2.67 - 2.55 (m, 3H), 2.31 - 1.97 (m, 3H), 1.92 (d, J = 12.7 Hz, 2H), 1.84 - 1.67 (m, 3H), 1.67 - 1.57 (m, 1H), 1.51 - 1.37 (m, 2H), 0.94 (t, J= 7.3 Hz, 3H). LC-MS (ES-API+): m / z 367.2 [(M+2H) / 2]+and 733.3 [M+H]+.4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)methyl)piperidin-l-yl)-2V- ((! / ?, 3 / ?)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)benzamide (D24)

[0397] tert-butyl 4-(4-((( \-(2-( l-amino-5-methoxy-l,5-dioxopentan-2-yl)-l- oxoisoindolin-4-yl)-2-nitrophenyl)sulfonamido)methyl)piperidin-l-yl)benzoate (40):Triphenylphosphine (99.1 mg, 0.378 mmol) and diethyl azodicarboxylate (40 wt% in toluene,190 pL. 0.378 mmol) were added to a stirred mixture of 5-amino-4-(4-((2- nitrophenyl)sulfonamido)-l-oxoisoindolin-2-yl)-5-oxopentanoate (18, 150 mg, 0.315 mmol) and 25 (110 mg, 0.378 mmol) in THF (3.15 mL) at room temperature. After stirring overnight, the reaction was quenched with H2O, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was then taken up with toluene (3.15 mL) and heated with magnesium chloride (59.9 mg, 0.630 mmol) at 60 °C overnight. The mixture was filtered through a pad of Celite and rinsed with toluene. Concentration and purification by silica gel column chromatography (hexane: ethyl acetate = 50:50 to 0:100) yielded the title compound as a yellow solid (106 mg, 45%).JH NMR (500 MHz, CDCI3) 67.88 - 7.80 (m, 3H), 7.75 - 7.66 (m, 1H), 7.66 - 7.61 (m, 1H), 7.50 - 7.40 (m, 3H), 7.33 (d, 7= 7.8 Hz, 1H), 6.82 (d, J = 9.1 Hz, 2H), 6.30 (s, 1H), 5.43 (s, 1H), 4.92 - 4.82 (m, 1H), 4.62 - 4.38 (m, 1H), 4.32 (d, J = 17.2 Hz, 1H), 3.89 - 3.81 (m, 2H), 3.78 - 3.52 (m, 6H), 2.84 - 2.74 (m, 2H), 2.46 - 2.23 (m, 3H), 2.15 - 2.02 (m, 1H), 1.98 - 1.79 (m, 2H), 1.56 (s, 9H), 1.51 - 1.35 (m, 2H).13C NMR (126 MHz, CDCL) 6 172.87, 171.18, 168.19, 166.12, 153.85, 148.16, 141.99, 134.44, 134.30, 134.24, 133.61, 131.89, 131.42, 131.33, 131.16, 129.96, 124.83, 124.24, 121.47, 114.06, 80.15, 58.04, 54.08, 52.03, 47.86, 46.52, 35.64, 30.51, 29.35, 28.45, 24.36. QToF HRMS m / z: calcd for C37H44N5O10S+[M+H+] = 750.2803; Found 750.2820.

[0398] tert-butyl 4-(4-((( \-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-2- nitrophenyl)sulfonamido)methyl)piperidin-l-yl)benzoate (41): Cesium carbonate (108 mg, 0.330 mmol) was added to a stirred mixture of 40 (82.7 mg, 0.110 mmol) in acetonitrile (1.10 mL) at room temperature. After stirring overnight, the mixture was poured into H2O, and extracted with CH2Q2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude material, which was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) and prepTLC (ethyl acetate) to yield the title compound as a yellow solid (31.6 mg, 40%). ’ H NMR (500 MHz, CDCL) 6 8.14 (s, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.9 Hz, 2H), 7.70 (td, 7= 7.7, 1.5 Hz, 1H), 7.63 (dd, 7= 8.0, 1.3 Hz, 1H), 7.54 - 7.40 (m, 3H), 6.82 (d, 7= 8.6 Hz, 2H), 5.25 - 5.03 (m, 1H), 4.64 - 4.27 (m, 2H), 3.89 - 3.78 (m, 3H), 3.66 - 3.49 (m, 2H), 2.95 - 2.87 (m, 1H), 2.86 - 2.73 (m, 3H), 2.41 - 2.28 (m, 1H), 2.23 - 2.14 (m, 1H), 1.99 - 1.87 (m, 1H), 1.85 - 1.67 (m, 1H), 1.56 (s, 9H), 1.52 - 1.31 (m, 2H).13C NMR (126 MHz, CDCL) 6 170.94, 169.25, 168.23, 166.09, 153.81, 148.20, 134.50, 134.42, 134.17, 132.09, 131.48, 131.30, 131.17, 131.08, 130.07, 125.12, 124.91, 124.12, 121.55, 114.08, 80.20, 52.09, 47.84, 46.56, 35.70,31.59, 29.41, 29.33, 28.44, 23.41. QToF HRMS m / z: calcd for C36H39N5O9S+[M+H+] = 718.2541; Found 718.2560.

[0399] tert-butyl 4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)methyl)piperidin-l-yl)benzoate (42): Cesium carbonate (43.0 mg, 0.132 mmol) and 4-bromothiophenol (16.6 mg, 0.0880 mmol) were added to a stirred solution of 41 (31.6 mg, 0.0440 mmol) in DMF (1.00 mL) at room temperature. After 1 hour, the mixture was poured into H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4and concentrated. Purification by prepTLC (5% methanol in CH2Q2) gave the title compound as a white solid (14.3 mg, 61%).!H NMR (500 MHz, CDCI3) 6 8.32 (s, 1H), 7.86 (d, J = 9.1 Hz, 2H), 7.36 (t, J = 7.7 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 9.0 Hz, 2H), 6.79 (d, J= 8.0 Hz, 1H), 5.21 (dd, J= 13.4, 5.2 Hz, 1H), 4.29 (d, J= 15.6 Hz, 1H), 4.12 (d, J = 15.4 Hz, 1H), 3.87 (d, J = 12.8 Hz, 1H), 3.16 (d, J = 6.4 Hz, 2H), 2.90 - 2.74 (m, 4H), 2.32 - 2.21 (m, 1H), 2.20 - 2.11 (m, 1H), 1.94 - 1.80 (m, 3H), 1.56 (s, 9H), 1.46 - 1.36 (m, 2H).13C NMR (126 MHz, CDCh) 6 171.43, 170.13, 169.99, 166.11, 153.99, 143.15, 132.03, 131.17, 129.93, 126.34, 121.55, 114.11, 113.16, 112.87, 80.24, 51.89, 49.46, 48.29, 45.12, 35.96, 31.65, 29.85, 28.44, 23.57. QToF HRMS m / z: calcd for C30H37N4O5+[M+H+] = 533.2758; Found 533.2770.

[0400] 4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)methyl)piperidin-l-yl)-NV-((l / R,3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7- yl)amino)cyclopentyl)benzamide (D24): A mixture of 42 (14.3 mg, 0.0268 mmol) and 4 N HC1 in 1,4-dioxane (1.00 mL) was stirred at 40 °C overnight. Concentration gave a crude mixture, which was used in the next step without further purification. z‘Pr2NEt (14.0 pL, 0.0804 mmol) and HATU (20.4 mg, 0.0536 mmol) were added to a stirred solution of the crude material and KI-ARv3 hydrochloride (15.9 mg, 0.0536 mmol) in DMF (1.00 mL) at room temperature. After stirring overnight, the mixture was poured into H2O, and extracted with CH2Q2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture containing 377-[l,2,3]triazolo[4,5-Zb]yridine-3-yl 4-(4- (((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)methyl)piperidin-l-yl)benzoate (44) as the major component. KLARv3 hydrochloride (9.5 mg, 0.0321 mmol) and z‘Pr2NEt (14.0 pL. 0.0804 mmol) were added to a stirred solution of the mixture in DMF (1.00 mL), then the mixture was stirred at 40 °C for 3 hours. The mixture was poured into H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4.Filtration and concentration gave a crude mixture, which was purified on HPLC (MeCN:H2O= 10:90 to 90:10, including 0.1% HCO2H) to yield the title compound as a yellow solid (11.5 mg, 60% in 3 steps).JH NMR (500 MHz, DMSO) 5 11.02 (s, 1H), 8.07 (d, J = 7.3 Hz, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.64 (d, 7 = 7.6 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.97 - 6.88 (m, 3H), 6.78 (d, J = 8.1 Hz, 1H), 6.29 (d, J = 2.3 Hz, 1H), 6.04 (s, 1H), 5.71 (t, 7 = 5.8 Hz, 1H), 5.12 (dd, 7 = 13.2, 5.1 Hz, 1H), 4.51 - 4.40 (m, 1H), 4.30 - 4.20 (m, 2H), 4.14 (d, 7 = 17.2 Hz, 1H), 3.87 (d, 7 = 13.0 Hz, 2H), 3.06 (t, 7 = 6.1 Hz, 2H), 2.98 - 2.87 (m, 1H), 2.74 (td, 7 = 12.6, 2.4 Hz, 2H), 2.67 - 2.59 (m, 3H), 2.36 - 2.18 (m, 2H), 2.17 - 1.99 (m, 4H), 1.90 - 1.56 (m, 7H), 1.35 - 1.21 (m, 2H), 0.92 (t, 7 = 7.3 Hz, 3H).13C NMR (126 MHz, DMSO) 5 172.95, 171.30, 168.91, 165.67, 162.26, 152.76, 148.82, 146.05, 143.78, 143.10, 132.10, 129.24, 128.65, 126.38, 123.28, 113.65, 111.79, 109.87, 93.67, 84.97, 69.80, 51.49, 48.98, 48.36, 47.56, 45.80, 40.43, 38.49, 34.89, 31.26, 31.15, 30.63, 29.32, 22.87, 21.95, 13.79. QToF HRMS m / z: calcd for C40H48N9O4+[M+H+] = 718.3824; Found 718.3836.4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)piperazin-l-yl)methyl)-2V-((1 / R, 3 / ?)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)benzamide (D25)

[0401] benzyl 4-( 4-( / e / 7-bu toxycaNwnyl (benzyl) piperazine- 1 -carboxy late (47): K2CO3(1.25 g, 9.08 mmol) was added to a stirred solution of benzyl piperazine- 1 -carboxylate (45, 877 mg, 4.54 mmol) and tert-butyl 4-(bromomethyl)benzoate (46, 1.29 g, 4.77 mmol) in DMF (15.1 mL) at room temperature. After stirring overnight, the mixture was quenched with H2O, and extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 50:50) to yield the title compound as a colorless oil (2.03 g, quant).1H NMR (500 MHz, CDCh) 5 7.94 (d, 7= 8.2 Hz, 2H), 7.39 - 7.27 (m, 7H), 5.13 (s, 2H), 3.55 (s, 2H), 3.51 (t, 7 =5.1 Hz, 4H), 2.40 (s, 4H), 1.59 (s, 9H).13C NMR (126 MHz, CDCh) 6 165.80, 155.37, 142.83, 136.88, 131.18, 129.61, 128.88, 128.63, 128.15, 128.02, 81.07, 67.24, 62.74, 52.92, 43.96, 28.35. QToF HRMS m / z: calcd for C24H31N2O4+[M+H+] = 411.2278; Found 411.2281.

[0402] tert-butyl 4- (piperazin- l-ylmethyl)benzoate (48): A mixture of 47 (2.03 g, 4.95 mmol) and Pd(OH)2 / C (20 wt%, 347 mg, 0.495 mmol) in methanol (16.5 mL) was stirred under hydrogen atmosphere at room temperature for 3 hours. The mixture was filtered through a pad of Celite and rinsed with ethyl acetate. Concentration gave the title compound as a yellow solid (1.33 g, 97%). ’ H NMR (400 MHz, DMSO) 5 7.84 (d, J = 8.0 Hz, 2H), 7.41 (d, J= 7.9 Hz, 2H), 3.49 (s, 2H), 2.73 (t, J = 4.8 Hz, 4H), 2.31 (t, J = 4.7 Hz, 4H), 1.53 (s, 9H).13C NMR (101 MHz, DMSO) 5 164.86, 143.54, 129.99, 128.92, 128.82, 80.49, 62.14, 53.29, 45.13, 27.79. QToF HRMS m / z: calcd for C16H25N2O2+[M+H+] = 277.1911; Found 277.1914.

[0403] tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)piperazin- l-yl)methyl)benzoate (50): A mixture of 48 (506 mg, 1.83 mmol), 2-(2,6-dioxopiperidin-3- yl)-4-fluoroisoindoline- 1,3-dione (49, 556 mg, 2.01 mmol), and z‘Pr2NEt (1.28 mL, 7.32 mmol) in NMP (4.82 mL) was stirred at 90 °C for 6 hours. The mixture was poured into H2O, then the precipitation was collected and washed with H2O. It was dried overnight by vacuum pumping to yield the title compound as a yellow solid (633 mg, 65%).1H NMR (500 MHz, DMSO) 5 11.08 (s, 1H), 7.87 (d, J= 8.1 Hz, 2H), 7.69 (t, J= 7.8 Hz, 1H), 7.46 (d, J= 8.1 Hz, 2H), 7.39 - 7.26 (m, 2H), 5.08 (dd, J = 12.7, 5.4 Hz, 1H), 3.61 (s, 2H), 3.33 - 3.27 (m, 4H), 2.92 - 2.81 (m, 1H), 2.63 - 2.50 (m, 6H), 2.06 - 1.97 (m, 1H), 1.54 (s, 9H).13C NMR (126 MHz, DMSO) 5 172.80, 169.99, 167.04, 166.28, 164.88, 149.68, 143.28, 135.88, 133.65, 130.13, 129.11, 129.01, 123.76, 116.59, 114.88, 80.55, 61.50, 52.44, 50.49, 48.79, 30.95, 27.81, 22.05. QToF HRMS m / z: calcd for C29H33N4O6+[M+H+] = 533.2395; Found 533.2400.

[0404] 4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)piperazin-l- yl)methyl)- / V-((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7- yl)amino)cyclopentyl)benzamide (D25): A mixture of 50 (100 mg, 0.188 mmol) and 4 N HC1 in 1,4-dioxane (1.88 mL) was stirred at 40 °C overnight. Concentration gave a crude mixture, which was used in the next step without further purification. z‘Pr2NEt (98.2 pL, 0.564 mmol) and HATU (143 mg, 0.376 mmol) were added to a stirred solution of the crude material and KLARv3 hydrochloride (111 mg, 0.376 mmol) in DMF (1.88 mL) at roomtemperature. After stirring overnight, the mixture was poured into H2O, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography (5% MeOH in CH2CI2) and HPLC (MeCN:H2O = 10:90 to 90:10, including 0.1% HCO2H) to yield a formic acid salt of the title compound as a yellow solid (24.5 mg, 17% in 2 steps).!H NMR (500 MHz, DMSO) 5 11.09 (s, 1H), 8.37 (d, 7= 7.3 Hz, 1H), 8.14 (s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.72 - 7.64 (m, 2H), 7.43 (d, J = 7.9 Hz, 2H), 7.34 (dd, J = 16.6, 7.8 Hz, 2H), 6.30 (d, J = 2.2 Hz, 1H), 6.05 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 4.54 - 4.44 (m, 1H), 4.32 - 4.22 (m, 1H), 3.63 (s, 2H), 3.34 - 3.28 (m, 4H), 2.92 - 2.82 (m, 1H), 2.65 - 2.55 (m, 7H), 2.55 - 2.52 (m, 1H), 2.29 - 2.19 (m, 1H), 2.19 - 1.97 (m, 4H), 1.83 - 1.59 (m, 4H), 0.92 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, DMSO) 5 172.82, 170.01, 167.06, 166.31, 165.88, 163.09, 162.27, 149.66, 148.80, 146.07, 143.11, 140.84, 135.89, 133.66, 128.82, 127.33, 127.07, 123.78, 116.63, 114.93, 93.68, 84.98, 61.45, 52.37, 51.49, 50.42, 49.22, 48.81, 40.43, 38.41, 31.07, 30.97, 30.62, 22.07, 21.96, 13.79. QToF HRMS m / z: calcd for C39H44N9O5+[M+H+] = 718.3460; Found 718.3468. l-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)piperazin-l-yl)ethyl)-2V- ((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)piperidine-4- carboxamide (D26)

[0405] 4-(4-(2,2-diethoxyethyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1, 3-dione (53): A mixture of l-(2,2-diethoxyethyl)piperazine. (52, 204 mg, 1.01 mmol), 2- (2, 6-dioxopiperidin-3-yl)-4-fluoroisoindoline- 1,3-dione (49, 306 mg, 1.11 mmol), and z‘Pr2NEt (703 pL, 4.03 mmol) in NMP (3.70 mL) was stirred at 90 °C overnight The mixture was diluted with H2O and extracted with 10% methanol in CH2Q2. The combined organiclayer was washed with brine, and dried over anhydrous Na2SO4. Filtration and concentration gave a crude solid, which was washed with diisopropylether to yield the title compound as a yellow solid (402 mg, 87%).JH NMR (500 MHz, DMSO) 5 11.08 (s, 1H), 7.69 (dd, J= 8.4, 7.1 Hz, 1H), 7.37 - 7.30 (m, 2H), 5.08 (dd, J = 12.7, 5.4 Hz, 1H), 4.63 (t, J = 5.1 Hz, 1H), 3.65 - 3.55 (m, 2H), 3.53 - 3.43 (m, 2H), 3.31 - 3.23 (m, 4H), 2.92 - 2.80 (m, 1H), 2.72 - 2.61 (m, 4H), 2.61 - 2.52 (m, 2H), 2.52 - 2.41 (m, 2H), 2.06 - 1.97 (m, 1H), 1.12 (t, J= 7.0 Hz, 6H).13C NMR (126 MHz, DMSO) 5 172.81, 170.00, 167.06, 166.30, 149.74, 135.86, 133.66, 123.72, 116.49, 114.80, 100.58, 61.05, 60.40, 53.18, 50.56, 48.79, 30.96, 22.06, 15.36. QToF HRMS m / z: calcd for C23H31N4O6+[M+H+] = 459.2238; Found 459.2242.

[0406] / ert-butyl l-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)piperazin-l-yl)ethyl)piperidine-4-carboxylate (56): A mixture of 53 (158 mg, 0.345 mmol) and 2.5 N HC1 (2.64 mL) was stirred at 50 °C for 9 hours. The mixture was basified with saturated aqueous NaHCOa, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was used in the next step without further purification. z‘Pr2NEt (111 pL, 0.635 mmol), 1 drop of AcOH, and sodium cyanoborohydride (59.8 mg, 0.952 mmol) were added to a stirred mixture of the crude material and tert-butyl piperidine-4-carboxylate hydrochloride (55, 141 mg, 0.635 mmol) in methanol (1.00 mL) and DMSO (1.00 mL) at 0 °C, then the mixture was warmed to room temperature. After stirring overnight, the mixture was quenched with H2O, and extracted with 10% methanol in CH2CI2. The combined organic layer was washed with H2O and brine, then dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography(CH2CI2: methanol = 100:0 to 90:10) to yield the title compound as a yellow solid (93.5 mg, 49% in 2 steps). ’ H NMR (500 MHz, CDCh) 6 7.94 (s, 1H), 7.59 (dd, J = 8.4, 7.2 Hz, 1H), 7.41 (d, J= 7.1 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.96 (dd, J = 12.4, 5.4 Hz, 1H), 3.45 - 3.31 (m, 4H), 2.93 - 2.67 (m, 9H), 2.65 - 2.46 (m, 4H), 2.27 - 1.95 (m, 4H), 1.96 - 1.79 (m, 2H), 1.79 - 1.66 (m, 2H), 1.44 (s, 9H).13C NMR (126 MHz, DMSO) 5 173.81, 172.80, 170.00, 167.05, 166.29, 149.72, 135.86, 133.67, 123.70, 116.47, 114.79, 79.40, 55.57, 55.28, 52.98, 52.70, 50.50, 48.79, 41.19, 30.96, 28.05, 27.72, 22.06. QToF HRMS m / z: calcd for C29H40N5O6+[M+H+] = 554.2973; Found 554.2979.

[0407] l-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)piperazin-l- yl)ethyl)-A^-((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7- yl)amino)cyclopentyl)piperidine-4-carboxamide (D26): A mixture of 56 (93.5 mg, 0.169mmol) and 4 N HC1 in 1,4-dioxane (1.69 mL) was stirred at 40 °C overnight. Concentration gave a crude mixture, which was used in the next step without further purification. z‘Pr2NEt (88.3 pL, 0.507 mmol) and HATU (129 mg, 0.338 mmol) were added to a stirred solution of the crude material and KI-ARv3 hydrochloride (100 mg, 0.338 mmol) in DMF (1.69 mL) at room temperature. After stirring overnight, the mixture was poured into H2O, and extracted with CH2Q2. The combined organic layer was dried over anhydrous Na2SO4. Filtration and concentration gave a crude mixture, which was purified by silica gel column chromatography (CH2Q2: methanol = 99:1 to 90:10) and HPLC (MeCN:H2O = 10:90 to 90:10, including 0.1% HCO2H) to yield the title compound as a yellow solid (13.9 mg, 11% in 2 steps).!H NMR (500 MHz, DMSO) 5 11.09 (s, 1H), 8.00 (d, J= 2.1 Hz, 1H), 7.88 (d, J= 7.3 Hz, 1H), 7.70 (t, 7 = 7.8 Hz, 1H), 7.62 (d, 7 = 7.7 Hz, 1H), 7.35 (dd, 7 = 11.6, 7.8 Hz, 2H), 6.29 (d, 7= 2.3 Hz, 1H), 6.01 (s, 1H), 5.09 (dd, 7= 12.8, 5.5 Hz, 1H), 4.20 (dq, 7 = 14.1, 6.9 Hz, 2H), 3.33 - 3.27 (m, 4H), 3.14 - 3.07 (m, 2H), 2.93 - 2.82 (m, 1H), 2.77 - 2.45 (m, 12H), 2.37 - 2.09 (m, 4H), 2.09 - 1.96 (m, 3H), 1.92 - 1.82 (m, 1H), 1.78 - 1.63 (m, 7H), 1.49 - 1.39 (m, 1H), 0.92 (t, 7 = 7.3 Hz, 3H).13C NMR (126 MHz, DMSO) 5 173.43, 172.82, 170.01, 167.06, 166.32, 162.24, 149.65, 148.81, 146.02, 143.09, 135.89, 133.67, 123.74, 116.53, 114.87, 93.67, 84.92, 54.55, 54.22, 52.80, 52.62, 51.37, 50.38, 48.80, 48.42, 40.94, 38.55, 31.07, 30.96, 30.37, 29.02, 27.63, 22.06, 21.93, 13.79. QToF HRMS m / z: calcd for C39H51N10O5+[M+H+] = 739.4038; Found 739.4057. l-(4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)methyl)phenyl)-2V-((! / ?, 3 / ?)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7-yl)amino)cyclopentyl)piperidine-4- carboxamide (D27)

[0408] tert- butyl l-(4-(methoxycarbonyl)phenyl)piperidine-4-carboxylate (60): A mixture of tert-butyl piperidine-4-carboxylate (58, 601 mg, 3.24 mmol), methyl 4- fluorobenzoate (59, 382 pL, 2.95 mmol), and K2CO3(1.43 g, 10.3 mmol) in DMSO (2.95 mL) was stirred at 120 °C overnight. The mixture was poured into H2O, then the precipitation was collected and washed with H2O. It was dried overnight by vacuum pumping to yield the title compound as a beige solid (618 mg, 66%).!H NMR (500 MHz, CDCh) 8 7.92 (d, J =8.9 Hz, 2H), 7.00 - 6.83 (m, 2H), 3.86 (s, 3H), 3.79 (dt, J = 13.3, 4.2 Hz, 2H), 2.97 (t, J =11.9 Hz, 2H), 2.48 - 2.38 (m, 1H), 2.06 - 1.99 (m, 2H), 1.88 - 1.76 (m, 2H), 1.46 (s, 9H). LC-MS (ES-API+): m / z 320.2 [M+H]+.

[0409] methyl 4-(4-(((1 / R, 3 / R)-3-((5-propylpyrazolo[l,5-a]pyrimidin-7- yl)amino)cyclopentyl)carbamoyl)piperidin-l-yl)benzoate (62): A mixture of 60 (200 mg, 0.626 mmol) and 4 N HC1 in 1,4-dioxane (6.30 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was washed with ethyl acetate. It was dried by vacuum pumping, then taken up with DMF (2.30 mL). z‘Pr2NEt (353 pL, 2.03 mmol), and HATU (386 mg, 1.01 mmol) were added to the mixture KLARv3 hydrochloride (240 mg, ...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, and R4is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, -NRAC(=O)RA, -C(=O)RA, -NRAC(=O)ORA, -NRAC(=O)N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)N(RA)2, -S(O)2N(RA)2, or -NRAS(O)2RA; each of R5and R6is independently hydrogen, substituted or unsubstituted alkyl, -C(=O)RA, or a nitrogen protecting group;A is substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene;L1is -C(=O)- or -S(O)2-;L2is a bond, -NRA-, -O-, -S-, substituted or unsubstituted methylene, or substituted or unsubstituted ethylene;L3is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or -C=C-;X is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;Y is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;E is an E3 ligase binding moiety; andeach occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring; provided that the compound is not of formula:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, and R4is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, and R4is independently hydrogen, halogen, or substituted or unsubstituted alkyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein: each of R2, R3, and R4is hydrogen; andR1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: each of R2, R3, and R4is hydrogen; and R1is hydrogen, halogen, or substituted or unsubstituted alkyl.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein: each of R2, R3, and R4is hydrogen; and R1is substituted or unsubstituted alkyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein: each of R2, R3, and R4is hydrogen; and R1is n-propyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each of R5and R6is independently hydrogen or substituted or unsubstituted alkyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein each of R5and R6is hydrogen.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein A is substituted or unsubstituted cycloalkylene.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein A is substituted or unsubstituted C3-6 cycloalkylene.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein A is substituted or unsubstituted cyclopentylene.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein L1is -C(=O)-.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein X is substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein X is substituted or unsubstituted piperidinyl or substituted or unsubstituted phenyl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein X is substituted or unsubstituted piperidinyl.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein X is unsubstituted piperidinyl.

21. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein X is substituted or unsubstituted phenyl.

22. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein X is unsubstituted phenyl.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L2is a bond, substituted or unsubstituted methylene, or substituted or unsubstituted ethylene.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein L2is a bond, unsubstituted methylene, or unsubstituted ethylene.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein L2is a bond.

26. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein L2is unsubstituted methylene.

27. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein L2is unsubstituted ethylene.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Y is substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein Y is substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted phenyl.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein X is substituted or unsubstituted piperidinyl.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein X is unsubstituted piperidinyl.

32. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein X is substituted or unsubstituted piperazinyl.

33. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein X is unsubstituted piperazinyl.

34. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein X is substituted or unsubstituted phenyl.

35. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein X is unsubstituted phenyl.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein X and Y are not both unsubstituted phenyl.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein L3is a bond, unsubstituted methylene, unsubstituted ethylene, or -C=C-.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein L3is a bond.

39. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein L3is unsubstituted methylene.

40. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein L3is unsubstituted ethylene.

41. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein L3is -C=C-.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein -X-L2-Y- is of formula:

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein -X-L2-Y- is of formula:

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein -LJ-X-LAY-L3- is of formula:

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein -LJ-X-LAY-L3- is of formula:

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein -X-L2-Y- is not of formula:

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein -L1-X-L2-Y-L3- is not of formula:

48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, wherein E is a cereblon E3 ubiquitin ligase binding moiety.

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, wherein E is of Formula (E-I):(E-I) wherein:B is a substituted or unsubstituted monocyclic, bicyclic, or tricyclic fused ring system;Y is -(CH2)k-, -(CH2)k-O-, -O(CH2)k-, -NRB(CH2)k-, -(CH2)k-NRB-, -(CH2)k- (C=O)NRB-, -O(CH2)k-(C=O)NRB-, -O(CH2)k-NRB(C=O)-, -NRB(C=O)-(CH2)k-O-, - NRB(CH2)k-NRB(C=O)-, or -(CH2)k-NRB(C=O)-; each RBis, independently, hydrogen, or substituted or unsubstituted alkyl; each R1Ais, independently, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy;R3Ais hydrogen or C1-C3 alkyl; each R3is, independently, C1-C3 alkyl; each R4Ais, independently, hydrogen or C1-C3 alkyl; or two R4A, together with the carbon atom to which they are attached, form a C(=O), C3-C6 carbocycle, or a 4-6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;R5Ais hydrogen, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 0, 1, or 2.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, wherein E is of Formula (E-IV):(E-IV), wherein:XAis -C(=O)- or -CH2-;Y is a bond, -O-, or -NH-; and and R3Ais hydrogen, or C1-C3 alkyl.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein E is of Formula (E-IV-a):(E-IV-a), wherein:XAis -C(=O)- or -CH2-;Y is a bond, -O-, or -NH-; and and R3Ais hydrogen, or C1-C3 alkyl.

52. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein E is of Formula (E-IV-b):(E-IV-b), wherein:XAis -C(=O)- or -CH2-;Y is a bond, -O-, or -NH-; and and R3Ais hydrogen, or C1-C3 alkyl.

53. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein E is of Formula (E-VII):(E-VII), wherein:XAis -C(=O)- or -CH2-.

54. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein E is of Formula (E-IX):(E-IX), wherein:XAis -C(=O)- or -CH2-.

55. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein E is of Formula (E-I-d):wherein:XAis -C(=O)- or -CH2-.

56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, wherein E is of formula:

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

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

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein E is of formula:

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, wherein E is of the formula:

61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, wherein E is of the formula:

62. The compound of claim 1, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

63. The compound of claim 1, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

64. The compound of claim 1, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

65. The compound of claim 1, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

66. The compound of claim 1, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

67. The compound of claim 1, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

68. A pharmaceutical composition comprising a compound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

69. A method of treating cancer in a subject in need thereof, the method comprising administering a compound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68 to the subject.

70. The method of claim 69, wherein the cancer is a solid tumor or a hematological cancer.

71. A method of promoting the degradation of cyclin-dependent kinase 9 (CDK9), the method comprising contacting CDK9 with a compound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68.

72. The method of claim 71, wherein the degradation is in a cell.

73. The method of claim 71 or 72, wherein the degradation is in a subject.

74. The method of claim 71 or 72, wherein the degradation is in a biological sample.

75. A method of promoting the degradation of cyclin-dependent kinase 9 (CDK9) and Ikaros Family Zinc Finger Protein 1 (IKZF1), the method comprising contacting CDK9 and IKZF1 with a compound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68.

76. The method of claim 75, wherein the degradation is in a cell.

77. The method of claim 75 or 76, wherein the degradation is in a subject.

78. The method of claim 75 or 76, wherein the degradation is in a biological sample.

79. A method of promoting the selective degradation of cyclin-dependent kinase 9 (CDK9) over Ikaros Family Zinc Finger Protein 1 (IKZF1), the method comprising contacting CDK9 and IKZF1 with a compound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68.

80. The method of claim 79, wherein the selective degradation is in a cell.

81. The method of claim 79 or 80, wherein the selective degradation is in a subject.

82. The method of claim 79 or 80, wherein the selective degradation is in a biological sample.

83. The method of any one of claims 79-82, wherein the selectivity of the degradation ofCDK9 over IKZF1 is at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10,20, 30, 40, 50, 60, 70, 80, 90. 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000-fold.

84. A kit comprising a compound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68; and instructions for administering the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject.

85. A method of destabilizing, disrupting, and / or degrading nucleolar homeostasis in a cell, the method comprising contacting a compound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68 with the cell.

86. The method of claim 85, wherein the cell is a cancer cell.

87. The method of claim 85 or 86, wherein the cell is in a mammal.

88. The method of any one of claims 85-87, wherein the cell is in a human.

89. A method of treating cancer by destabilizing, disrupting, and / or degrading nucleolar homeostasis in a cell of a subject in need thereof, the method comprising administering acompound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68 to the subject.

90. The method of claim 89, wherein the cancer is a solid tumor or a hematological cancer.

91. The method of any one of claims 69, 70, or 85-90, wherein the cancer is a MYC- dependent cancer.

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