Compositions and methods of use thereof for treating MYC-mediated diseases

Abstract

The present invention relates to compounds and methods of use thereof for modulating the activity of a MYC RNA transcript, or an unspliced isoform, splicing intermediate, isoform, mutant, or fragment thereof. The invention also provides methods of preparing such compounds and methods of treating various diseases, disorders, and conditions, comprising administering an effective amount of a disclosed compound to a subject in need thereof.

Description

COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING MYC-MEDIATED DISEASESCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 614,318, filed on December 22, 2023, the entirety of which is hereby incorporated by reference.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to compounds and use thereof for modulating the activity of MYC. The invention also provides methods of treating various diseases, disorders, and conditions, such as MYC-mediated diseases, which include proliferative disorders.SEQUENCE LISTING

[0003] This application contains a Sequence Listing which has been submitted in .xml format via Patent Center and is hereby incorporated by reference. The ST.26 copy, created on December 18, 2024, is named 394457-017WO_215145_SL. xml and is 4,694 bytes in size.BACKGROUND OF THE INVENTION

[0004] The role of MYC in oncogenesis was discovered more than 40 years ago (Duesberg and Vogt 1979; Hu and Vogt 1979; Sheiness and Bishop 1979, Dalla-Favera et al. 1982; Taub et al. 1982). In the intervening decades, it has become clear that MYC is one of the most frequently dysregulated oncogenes across a broad range of cancers (Beroukhim et al. 2010, Dang 2012). Dysregulation occurs via multiple mechanisms, all of which result in the uncoupling of cellular proliferation from physiological growth-factor dependent regulation. MYC constitutes a critical cellular node that governs and coordinates cellular proliferation, metabolism and immune evasion, and as such, is a hallmark of cancer (Conacci-Sorrell et al. 2014; Gabay et al. 2014). Further, in many clinical settings, MYC deregulation is associated with poor outcomes (Gamberi et al. 1998; Nesbit et al. 1999). In addition, there is significant preclinical data highlighting emerging roles for MYC in the promotion of tumor immune evasion (Schors et al. 2006; Soucek et al. 2007; Sodir et al. 2011; Casey, S.C. et al. 2016; Kortlever et al. 2017), suggesting there would be additional, non-cell-autonomous benefits to therapeutic inhibition of MYC.

[0005] Despite the wealth of data demonstrating MYC is a nodal driver of human cancer and significant investment in discovery of a MYC-directed therapeutic, no direct inhibitors of MYC have entered the clinic. MYC is a transcription factor, which have proven to be a notoriously difficult-to-drug class of proteins (reviewed in Darnell 2002). MYC requires heterodimerization to transactivate targets, and the key protein-protein interactions are mediated by large, flat surfaces that are not readily amenable to small molecule intervention at the protein level (Nair and Burley 2003).

[0006] In contrast, MYC mRNA provides options for therapeutic intervention. MYC mRNA is multiply regulated, providing opportunities for intervention by a molecule that modulates MYC mRNA. Of note, the 5’UTR is reported to include translationally repressive structures (Wolfe et al. 2014), providing a structure-function rationale for an RNA-targeted small molecule approach. In addition, MYC mRNA is regulated through interactions with RNA-binding proteins (RBPs), which can be targeted. For instance, start codon usage is regulated by RBP binding to the MYC 5’UTR (Manjunath et al. 2019). The open reading frame (ORF) and 3’UTR also harbor sequences bound by RBPs and miRNAs that determine the half-life of MYC mRNA (Weidensdorfer et al. 2009; Marderosian et al. 2006; Liao et al. 2014; Ogami, K. et al. 2014; Liu et al. 2015).

[0007] There remains a need to develop small -molecule MYC modulators useful as therapeutic agents. The present invention addresses this need and provides other related advantages.SUMMARY OF THE INVENTION

[0008] In one aspect, the present invention provides compounds, such as those described below, that are useful in treating proliferative disorders, such as cancer. In some aspects, the present invention provides compounds that are useful in treating a MYC-mediated disease, disorder, or condition, such as those described herein. In some aspects, the present invention provides compounds and compositions that are generally useful to treat a disease, disorder, or condition, such as a MYC-mediated disease, disorder or condition, and / or for suppression of the aberrant functionality of a Myc protein, lowering of the expression level of a Myc protein, and / or the modulation of a MYC RNA transcript.

[0009] In some aspect, the present invention provides compounds that are modulators of a MYC protein. In some aspect, the present invention provides compounds that are modulators of a MYC mRNA, and in turn impact the abundance or activity of MYC protein. In some aspect, the presentinvention provides compounds that are modulators of a specific isoform of MYC mRNA. In some aspect, the present invention provides compounds that can selectively target cells, such as certain cancer cells, that contain a specific isoform of MYC mRNA and / or are dependent on a specific isoform of MYC mRNA. In some aspects, the present invention provides compounds that are useful in treating a MYC-mediated disease, disorder, or condition that is characterized by the presence of a specific isoform of MYC mRNA.

[0010] In one aspect, the present disclosure provides a compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered tricyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered tricyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring C is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring D is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R1is independently Ci-6 straight or branched alkyl, alkenyl, or alkynyl group optionally substituted with 1, 2, or 3 deuterium or halogen atoms, and optionally substituted with one -OH, -CN, or NH2 group; halogen, -CN, -C(O)RX, -C(O)ORX, -OC(O)RX, - C(O)N(RX)2, -N(RX)C(O)RX, -N(RX)C(O)N(RX)2, -OC(O)N(RX)2, -N(RX)C(O)ORX, -ORX, - N(RX)2, -NO2, -SRX, -S(O)RX, -S(O)2RX, -S(O)2N(RX)2, or -NRXS(O)2RX; each occurrence of R2is independently optionally substituted C1-6 aliphatic, halogen, -CN, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -NHC(NH)N(R)2, - OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or - NRS(O)2R; each occurrence of R3, R4, and R5is independently optionally substituted C1-6 aliphatic, halogen, -CN, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, - NHC(NH)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -SR, -S(O)R, -S(O)2R, - S(O)2N(R)2, or -NRS(O)2R;each occurrence of Rxis independently H or a Ci-6 straight or branched alkyl, alkenyl, or alkynyl group optionally substituted with 1, 2, or 3 deuterium or halogen atoms;-L1- and -L2- are each independently a covalent bond or a Ci-io bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-;-L3- and -L4- are each independently a covalent bond or a CMO bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-; each occurrence of X is independently N or C with a proviso that at most two X are N; each occurrence of R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each -Cy- is independently an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or anoptionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, 4, or 5.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows a schematic of the transcription start sites of MYC mRNA isoform 1 and 2 along with the various domains of the MYC sequence.

[0012] FIG. 2 is a figure showing BONCAT (Bioorthogonal Noncanonical Amino Acid Tagging) labeling assay using 1-1. FIG. 2 shows that addition of compound 1-1 resulted in a lower level of AHA-labeled MYC protein (newly synthesized MYC) as compared to cells exposed to DMSO only.

[0013] FIG. 3 is a figure showing mRNA reporter transfection data for compound 1-1.

[0014] FIG. 4 is a figure showing MYC protein levels for compound 1-1 after 1.5 h treatment in Daudi and CA46.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0015] The MFC oncogene family consists of three members, C-MYC,MYCN, and MYCL, which encode c-Myc, n-Myc, and 1-Myc, respectively. The Myc oncoproteins belong to a family of so- called “super-transcription factors” that can regulate the transcription of at least 15% of the entire genome. In one aspect, the invention provides compounds and methods for the treatment of MYC- mediated diseases, disorders and conditions. In one aspect, the invention provides compounds and methods for the treatment of c- MYC-mediated diseases, disorders and conditions.

[0016] It has now been found that the compounds disclosed herein and pharmaceutically acceptable salts, solvates, and hydrates thereof, are useful in modulating expression and function of one or more MYC RNA transcripts, such as those described herein. In some embodiments, the compounds disclosed herein can also modulate the expression level and functionality of Myc proteins. In some embodiments, the modulation of the expression level and functionality of Mycproteins is mediated through the modulation of expression and function of one or more MYC RNA transcripts. In some embodiments, the modulation of the expression level and functionality of Myc proteins is mediated through the modulation of expression and function of a specific isoform of MYC RNA transcripts. In one aspect, the compounds are useful in treating one or more diseases, disorders, and conditions, such as those mediated by MYC or a Myc protein, as described herein.

[0017] In one aspect the disclosure provides methods of treating a MYC-mediated disease, disorder, or condition in a patient in need thereof, including administering to the patient an effective amount of a compound, e.g. an RNA-modulating small molecule (rSM), to treat the MYC-mediated disease, disorder, or condition. In another aspect, the present invention provides a method of treating a MYC-mediated disease, disorder, or condition in a patient in need thereof, including administering to the patient an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the MYC-mediated disease, disorder, or condition is one treatable by modulation of the expression level, activity, or splicing of a MYC RNA transcript.

[0018] In some embodiments, the MYC-mediated disease, disorder, or condition is associated with aberrant functionality of a Myc protein. In some embodiments, the MYC-mediated disease, disorder, or condition is associated with overexpression of a Myc protein. In some embodiments, the Myc protein is c-Myc. In one aspect, the compounds and compositions provided herein are effective in treating the MYC-mediated disease, disorder, or condition because the compounds and compositions can suppress the aberrant functionality of the Myc protein. In one aspect, the compounds and compositions provided herein are effective in treating the MYC-mediated disease, disorder, or condition because the compounds and compositions can lower the expression level of the Myc protein. In one aspect, the compounds and compositions provided herein are effective in treating the MYC-mediated disease, disorder, or condition because the compounds and compositions can suppress the aberrant functionality of the Myc protein and lower the expression level of the Myc protein.

[0019] In some embodiments, the MYC-mediated disease, disorder, or condition is a proliferative disorder, such as a cancer.

[0020] In some embodiments, the MYC-mediated disease, disorder, or condition is a cancer, such as a cancer with aberrant functionality and / or increased expression levels of MYC protein, or a mutant or homolog thereof. In some embodiments the cancer has a Myc protein, e.g., c-Myc, withaberrant functionality. In some embodiments the cancer is overexpressing the Myc protein. In some embodiments, the MYC protein is c-Myc. In some embodiments, the MYC-mediated disease, disorder, or condition is Burkitt lymphoma, a B cell lymphoma (such as high grade B-cell lymphoma with MYC and / or Bcl2 and / or Bcl6 rearrangement), non-Burkitt lymphoma, a diffuse large B-cell lymphoma (DLBL), ovarian cancer, neuroblastoma, myeloid leukemia, chronic myeloid leukemia (CML), multiple myeloma, gastric cancer, bladder cancer, small cell lung cancer, thyroid carcinoma, retinoblastoma, or alvelolar rhabdomyosarcoma. In some embodiments, the cancer is lymphoma, melanoma, prostate, breast, colorectal, lung, pancreatic, gastric, gastrointestinal, ovarian, or uterine cancer. In some embodiments, a MYC-mediated disease, disorder, or condition is one related to, caused by and / or associated with abnormal or excessive activity and / or expression of, or abnormal tissue or inter- or intracellular distribution of a Myc protein, e.g., c-Myc, or a mutant or homolog thereof. In some embodiments, a MYC- mediated disease, disorder, or condition is one related to, caused by and / or associated with the presence of a specific MYC iso form. In some embodiments, the MYC-mediated disease, disorder, or condition is one treatable by modulation of the expression level, activity, or splicing of a MYC RNA transcript, or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof. In some embodiments, the MYC-mediated disorder is caused by and / or associated with a deleterious mutation in a MYC gene or gene product thereof. In some embodiments, the MYC- mediated disorder is caused by and / or associated with dysregulation of a MYC RNA transcript, or an unspliced isoform, splicing intermediate, iso form, fragment, or mutant thereof, or a MYC gene or a gene product thereof. In some embodiments, the MYC-mediated disease, disorder, or condition is a cancer, such as a cancer with increased expression levels of Myc protein, or a mutant or homolog thereof. In some embodiments, the Myc protein is c-Myc. In some embodiments, the MYC-mediated disease, disorder, or condition, (e.g., cancer) includes a specific isoform of a MYC RNA transcript.

[0021] In some embodiments, the MYC-mediated disease, disorder, or condition is one associated with deregulation of MYC expression, such as a proliferative disorder that is characterized by deregulated activity of c-Myc or other Myc family members including n-Myc or 1-Myc.

[0022] In some embodiments, the deregulated Myc activity comprises overexpression of c-Myc or other Myc family members comprising n-Myc or 1-Myc.

[0023] In some embodiments, the deregulated Myc activity comprises an aberrant functionality of c-Myc or other Myc family members comprising n-Myc or -Myc. In some embodiments, the aberrant functionality is aberrant activity as a transcription factor. In some embodiments, the aberrant functionality is aberrant activation of downstream protein.

[0024] In one aspect the disclosure provides methods of treating a MYC-mediated disease, disorder, or condition in a patient in need thereof, including administering to a subject (e.g., a patient) an effective amount of an RNA-modulating small molecule (rSM) to treat the MYC- mediated disease, disorder, or condition. In some embodiments, the administration of the rSM results in suppression of the aberrant functionality of the Myc protein. In some embodiments, the administration of the rSM modulates the expression level of a Myc protein. In some embodiments, the administration of the rSM results in lowering of the expression level of a Myc protein. In some embodiments, the administration of the rSM results in suppression of the aberrant functionality of the Myc protein and lowering of the expression level of a Myc protein. In some embodiments, the Myc protein is c-Myc.

[0025] The methods of treatment of a MYC-mediated disease, disorder, or condition are not limited to a specific mechanism. In some embodiments, the compounds of the disclosure are effective in the treatment of a MYC-mediated disease, disorder, or condition because the administration of the rSM results in suppression of the aberrant functionality of the Myc protein. In some embodiments, the compounds of the disclosure are effective in the treatment of a MYC- mediated disease, disorder, or condition because the administration of the rSM modulates the expression level of a Myc protein. In some embodiments, the compounds of the disclosure are effective in the treatment of a MYC-mediated disease, disorder, or condition because the administration of the rSM results in lowering of the expression level of a Myc protein. In some embodiments, the compounds of the disclosure are effective in the treatment of a MYC-mediated disease, disorder, or condition because the administration of the rSM results in suppression of the aberrant functionality of the Myc protein and lowering of the expression level of a Myc protein.

[0026] In some embodiments, the rSM is a small molecule. In some embodiments, the small molecule is a selective modulator of the Myc protein, e.g., it suppresses the aberrant functionality or expression level of a Myc protein preferentially (e.g., more effectively) over other proteins. In some embodiments, the small molecule is a selective modulator of the c-Myc protein, e.g., itsuppresses the aberrant functionality or expression level of a c-Myc protein preferentially (e.g., more effectively) over other proteins (e.g. n-Myc or 1-Myc).

[0027] In some embodiments, the compounds provided herein suppress the aberrant functionality or expression level of a Myc protein at least 2-fold more efficiently than a different protein. In some embodiments, the compounds provided herein suppress the aberrant functionality or expression level of a Myc protein at least 5-fold more efficiently than a different protein. In some embodiments, the compounds provided herein suppress the aberrant functionality or expression level of a Myc protein at least 10-, 20-, 50-, 100, 1000-, 10000-, or 100,000-fold more efficiently than a than a different protein. In some embodiments the Myc protein is c-Myc and, the different protein is n-Myc or 1-Myc.

[0028] In one aspect, the disclosure provides methods of treating a MYC-mediated disease, disorder, or condition in a patient in need thereof, including administering to the patient an effective amount of an RNA-modulating small molecule (rSM) to treat the MY C-mediated disease, disorder, or condition. In some embodiments, the administration of the rSM results in modulation of a MYC RNA transcript. In some embodiments, the administration of the rSM results in modulation of a MYC RNA transcript, which results in a reduction in Myc protein expression. In some embodiments, the administration of the rSM results in modulation of a MY C RNA transcript, which results in suppression of the aberrant functionality of the Myc protein. In some embodiments, the Myc protein is c-Myc.

[0029] It should be appreciated that the methods of treatment of a MYC-mediated disease, disorder, or condition are not limited to a specific mechanism. In some embodiments, the compounds of the disclosure are effective in the treatment of a MYC-mediated disease, disorder, or condition because the administration of the rSM modulates a MYC RNA transcript. In some embodiments, the compounds of the disclosure are effective in the treatment of a MYC-mediated disease, disorder, or condition because the administration of the rSM modulates a MYC RNA transcript which results in lowering of the expression level of Myc protein. In some embodiments, the compounds of the disclosure are effective in the treatment of a MYC-mediated disease, disorder, or condition because the administration of the rSM modulates an MYC RNA transcript which results in suppression of the aberrant functionality of the Myc protein. In some embodiments, the compounds of the disclosure are effective in the treatment of a MYC-mediated disease, disorder, or condition because the administration of the rSM modulates an MYC RNAtranscript which results in suppression of the aberrant functionality of the Myc protein and lowering of the expression level of a Myc protein. In some embodiments, the Myc protein is c- Myc. In some embodiments, aberrant functionality, or excessive expression of a Myc protein confers sensitivity of the cell to the compounds provided herein.

[0030] The term “RNA” (ribonucleic acid) as used herein, means a naturally-occurring or synthetic oligo- or polyribonucleotide independent of source (e.g., the RNA may be produced by a human, animal, plant, virus, or bacterium, or may be synthetic in origin), biological context (e.g., the RNA may be in the nucleus, circulating in the blood, in vitro, cell lysate, or isolated or pure form), or physical form (e.g., the RNA may be in single-, double-, or triple-stranded form (including RNA- DNA hybrids), may include epigenetic modifications, native post-transcriptional modifications, artificial modifications (e.g., obtained by chemical or in vitro modification), or other modifications, may be bound to, e.g., metal ions, small molecules, protein chaperones, or cofactors, or may be in a denatured, partially denatured, or folded state including any native or unnatural secondary or tertiary structure such as junctions (e.g., cis or trans three-way junctions (3WJ)), quadruplexes (e.g., G-quadruplexes), hairpins, triplexes, hairpins, bulge loops, pseudoknots, and internal loops, etc., and any transient forms or structures adopted by the RNA). In some embodiments, the target RNA is 100 or more nucleotides in length. In some embodiments, the target RNA is 250 or more nucleotides in length. In some embodiments, the target RNA is 350, 450, 500, 600, 750, or 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000, or more nucleotides in length. In some embodiments, the target RNA is between 250 and 1,000 nucleotides in length. In some embodiments, the RNA is a pre-RNA, pre-miRNA, or pretranscript. In some embodiments, the RNA is a non-coding RNA (ncRNA), messenger RNA (mRNA), micro-RNA (miRNA), a ribozyme, riboswitch, IncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA, ceRNA, pseudo-gene, viral RNA, or bacterial RNA.

[0031] The term “MYC RNA transcript” includes any RNA transcript or portion or mutant thereof that is transcribed from a MYC gene (e.g., NM_002467 and functionally equivalents thereof) The MYC RNA transcript includes both coding and non-coding regions, and includes unspliced isoforms, splicing intermediates, isoforms, fragments, and mutants of RNA transcripts derived from a MYC gene. In some embodiments, the MYC gene is a mammalian MYC gene, such as a human MYC gene; or a mutant of the gene. In some embodiments, the MYC gene is c-MYC. It should be appreciated that more than one isoform of a MYC RNA transcript have been identified(See e,g., Boxer et al., Oncogene 2001, 20: 5595). In one embodiment, the disclosure provides methods and compositions for targeting a specific isoform of a MYC RNA transcript.

[0032] In some embodiments, the transcript is bound to one or more RNA-binding proteins (RBPs). In some embodiments, the MYC RNA transcript is a pre-mRNA. In some embodiments, the MYC RNA transcript is an intron or exon of such pre-mRNA. In some embodiments, the MYC RNA transcript is a partially processed mRNA. In some embodiments, the MYC RNA transcript is a fully processed (mature) mRNA. In some embodiments, the MYC RNA transcript is a fully processed mRNA bound to one or more RNA-binding proteins (RBPs). In some embodiments, the MYC RNA transcript is single stranded.

[0033] In some embodiments, the MYC RNA transcript is an unspliced form or unspliced isoform of any of the foregoing transcripts. In some embodiments, the MYC RNA transcript is a splicing intermediate of any of the foregoing transcripts. In some embodiments, the MYC RNA transcript is an isoform of any of the foregoing transcripts. In some embodiments, the MYC RNA transcript is a fragment of any of the foregoing transcripts. In some embodiments, the MYC RNA transcript is a mutant of any of the foregoing transcripts.

[0034] In one aspect, the present invention provides a method of modulating the activity of a MYC RNA transcript (also referred to herein as a “MYC transcript” or “MYC RNA”) or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof, comprising contacting the MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof with an rSM or a pharmaceutically acceptable salt thereof that modulates the MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof.

[0035] In another aspect, the present invention provides a method of modulating the activity (e.g., expression level) of a Myc protein or mutant thereof, comprising contacting a corresponding MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof with an rSM or a pharmaceutically acceptable salt thereof that modulates the MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof. In some embodiments, the MYC RNA transcript is a MYC pre-mRNA, splicing intermediate, or mature mRNA. In some embodiments, the MYC RNA transcript encodes c-Myc. In some embodiments, the rSM modulates only a specific isoform of a MYC RNA transcript.

[0036] A compound that modulates an RNA transcript as used herein (e.g., an rSM) refers to a compound that changes the abundance or activity of an RNA transcript. In some embodiments,the change in the abundance or activity of an RNA transcript results in the change in the abundance or activity of the protein corresponding to the RNA transcript. In some embodiments, the RNA transcript is a MYC RNA and the corresponding protein is MYC. In some embodiments, the rSM modulates the RNA transcript by binding the RNA transcript. In some embodiments, the rSM modulates the RNA transcript by interaction with a cellular component, such as an RNA Binding protein (RBP), that in turn binds or interacts with the RNA transcript. In some embodiments, the rSM modulates the RNA transcript by modulating the activity of the RNA Binding Protein (RBP). For clarity, as provided herein, RBPs encompass any protein that interacts with RNA either directly (e.g., by binding) or indirectly. In some embodiments, the rSM modulates the RNA transcript by suppressing or inhibiting binding of the RBP to the RNA transcript. In some embodiments, the rSM modulates the RNA transcript by enhancing binding of the RBP to the RNA transcript. In some embodiments, the rSM modulates the RNA transcript by interaction with a cellular component, such as an RBP, and the RNA simultaneously. It should be appreciated that the compounds described herein are not limited to modulation of an RNA transcript and can treat Myc-mediated diseases, disorders and conditions, e.g., by suppressing the aberrant function or overexpression of the Myc protein.

[0037] In some embodiments, excessive translation of a MYC RNA transcript confers sensitivity of the cell to suppression of translation of a MYC RNA transcript (e.g., by the administration of an rSM).

[0038] In another aspect, the present invention provides a method of decreasing the half-life or increasing degradation of a MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof, comprising contacting the MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof with an rSM or a pharmaceutically acceptable salt thereof that interacts with (e.g., by binding or through interaction with in RBP), the MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof.

[0039] In another aspect, the present invention provides a method of suppressing the aberrant functionality of a MYC protein by contacting a MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof with an rSM or a pharmaceutically acceptable salt thereof that interacts with (e.g., by binding or through interaction with in RBP), the MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutantthereof resulting in suppression of the aberrant functionality of a MYC protein.

[0040] In another aspect, the present invention provides a method of decreasing the expression level a MYC protein by contacting a MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof with an rSM or a pharmaceutically acceptable salt thereof that interacts with (e.g., by binding or through interaction with in RBP), the MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof resulting in decreasing the expression level of a MYC protein.

[0041] In some embodiments, a disclosed rSM binds to a target MYC RNA transcript such as a MYC pre-mRNA transcript, splicing intermediate, or mature mRNA and modulates the activity of the transcript and / or modulate splicing rates or splicing pathways of the transcript. Modulation of MYC mRNA in turn modulates expression levels of the protein encoded by the transcript. Accordingly, in some embodiments, a disclosed rSM compound binds to a MYC pre-mRNA transcript, splicing intermediate, or mature mRNA and modulates its function, e.g., by decreasing translation of Myc protein. In some embodiments, the Myc protein is a c-Myc protein or a mutant or homolog thereof.

[0042] In some embodiments, the compounds and rSMs provided herein are a selective modulator of the MYC RNA transcript. In some embodiments, the compound or rSM interacts with a MYC RNA transcript preferentially (e.g., more effectively) over other RNA transcripts. In some embodiments, the compound or rSM interacts with a specific isoform of an MYC RNA transcript preferentially (e.g., more effectively) over other isoforms of a MYC RNA transcript.

[0043] For example, in some embodiments, the selective modulator (e.g., inhibitor or antagonist) has an IC50 for a MYC RNA transcript that is at least 40 percent lower than the IC50 for another RNA transcript, such as another transcript having at least 90% sequence homology, or another MYC RNA transcript that is not the intended target. In some embodiments, the selective modulator (e.g., inhibitor or antagonist) has an IC50 for the MYC RNA transcript that is at least 50 percent lower than the IC50 for the other, non-target RNA transcript. In some embodiments, the selective modulator (e.g., inhibitor or antagonist) has an IC50 for the MYC RNA transcript that is at least 60, 70, 80, 90, or 95 percent lower than the IC50 for the non-target RNA transcript. In some embodiments, the selective modulator (e.g., antagonist or inhibitor) of a MYC RNA transcript exerts essentially no inhibitory effect on the non-target RNA transcript. In some embodiments, the selective modulation of the MYC RNA transcript results in selective modulation of the Mycprotein, e.g., in that it suppresses the aberrant functionality or expression level of a Myc protein preferentially (e.g., more effectively) over other proteins. In some embodiments, the MYC RNA transcript is a specific isoform of MYC RNA and the non-target RNA transcript is a different isoform of MYC RNA.

[0044] In some embodiments, the selective modulator (e.g., inhibitor or antagonist) modulates the activity of a MY C RNA transcript at least 2-fold more efficiently than a non-target RNA transcript. In some embodiments, the selective modulator (e.g., inhibitor or antagonist) modulates the activity of a MYC RNA transcript at least 5-fold more efficiently than a non-target RNA transcript. In some embodiments, the selective modulator (e.g., inhibitor or antagonist) modulates the activity of a MYC RNA transcript at least 10-, 20-, 50-, 100, 1000-, 10000-, or 100000-fold more efficiently than a non-target RNA transcript. In some embodiments, the selective modulation of the MYC RNA transcript results in selective modulation of the Myc protein, e.g., in that it suppresses the aberrant functionality or expression level of a Myc protein preferentially (e.g., more effectively) over other proteins. In some embodiments, the MYC RNA transcript is a specific isoform of MY C RNA and the non-target RNA transcript is a different isoform of MY C RNA.

[0045] In some embodiments of the methods provided herein, the MYC RNA transcript comprises a 5' untranslated region (UTR) of MYC and an open reading frame (ORF) of MYC. Without wishing to be bound by theory, it is understood that the noncoding regions of mRNA such as the 5' untranslated regions (5 'UTR), the 3 'UTR, and introns can play regulatory roles in affecting mRNA expression levels, alternative splicing, translational efficiency, and mRNA and protein subcellular localization. It is furthermore believed that RNA secondary and tertiary structures are associated with these regulatory activities. Accordingly, modulation of the activity of a MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof is possible by interaction of a disclosed compound (rSM) at one or more RNA secondary and tertiary structureson the MY C RNA transcript.

[0046] In some embodiments of the methods provided herein, the administration of the rSM provides that the translation of the MYC RNA transcript is decreased or inhibited. In some embodiments, production of functional Myc protein is decreased or inhibited by the administration of the rSM.

[0047] In some embodiments of the methods provided herein, the administration of the rSM provides that the activity of the MYC RNA transcript or an unspliced iso form, splicingintermediate, isoform, fragment, or mutant thereof is inhibited or decreased. In some embodiments, binding of a regulatory element such as a protein (e.g., RBP) or miRNA to the MYC RNA transcript is inhibited. In some embodiments, processing or splicing of the MYC RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof is inhibited. In some embodiments, inhibition of processing or splicing results in a decrease in levels of mature MYC mRNA and / or protein. In some embodiments, the activity of the Myc protein or a mutant thereof is inhibited or decreased.

[0048] In some embodiments, the MYC RNA transcript comprises a functionally relevant fragment of MYC RNA. A MYC RNA transcript is “functionally relevant” if it includes a portion of a MYC RNA transcript that is essential to producing a functional MYC protein or mutant thereof. In some embodiments, the MYC RNA transcript is a MYC unspliced isoform, splicing intermediate, pre-mRNA, mature mRNA, or partially processed mRNA. In some embodiments, the MYC RNA transcript comprises a 5' untranslated region (UTR) of MYC. In some embodiments, the MYC RNA transcript comprises an open reading frame (ORF) of MYC. In some embodiments, the MYC RNA transcript comprises a 5' cap. In some embodiments, the MYC RNA transcript comprises a 3' polyA tail (polyadenylated tail). In some embodiments, the rSM interacts with (e.g., binds) to a 5' untranslated region (5' UTR), a 3' UTR, an exon, or an intron present in the MYC RNA transcript.

[0049] In some embodiments, the expression of a MYC mRNA and one or more of its translation products is modulated by targeting noncoding sequences and structures in the 5' and 3' UTRs. For instance, RNA structures in the 5' UTR can affect translational efficiency. RNA structures such as hairpins in the 5' UTR have been shown to affect translation. In general, RNA structures are believed to play an important role in translation of mRNA. One example of these are internal ribosome entry sites (IRES), which can affect the level of translation of the main open reading frame (Komar and Hatzoglou, Frontiers Oncol. 5:233, 2015; Weingarten- Gabb ay et al., Science 351 :pii:aad4939, 2016; Calvo et al., Proc. Natl. Acad. Sci. USA 106:7507-7512; Le Quesne et al., J. Pathol. 220:140-151, 2010; Barbosa et al., PLOS Genetics 9:el0035529, 2013). In some embodiments, the rSM interacts with (e.g., binds) an RNA site is a 5' UTR, internal ribosome entry site, or upsteam open reading frame. In some embodiments, the compounds of the present invention bind selectively to one or more sites on a target MYC RNA transcript, or other sites determined by binding interactions between the rSM and the structure of the target MYC RNAtranscript. In some embodiments, the compounds of the present invention bind selectively to one or more sites on a specific isoform of a MYC RNA transcript, or other sites determined by binding interactions between the rSM and the structure of the specific isoform of a MYC RNA transcript.

[0050] In some embodiments, the MYC RNA transcript includes a structure that allows for modulation by a compound (e.g., an rSM). In some embodiments, the RNA structure is a 3-way junction or a G-quadruplex. In some embodiments, the RNA structure is a G-quadruplex. In some embodiments, the structure that allows for modulation by a compound (e.g., an rSM) is in the 5’ UTR. In some embodiments, the 3 -way junction or a G-quadruplex is in the 5’ UTR. In some embodiments, the G-quadruplex is in the 5’ UTR. It should further be appreciated that in some embodiments, the RNA structure (e.g., 3-way junction or a G-quadruplex) is uniquely found in only one specific isoform, allowing for the targeting of that isoform.

[0051] In some embodiments, the RNA transcript includes a structure that allows for modulation by a compound (e.g., an rSM). In some embodiments, the RNA structure is a 3-way junction or a G-quadruplex. In some embodiments, the RNA structure is a G-quadruplex. G-quadruplexes (“G- quads”) are described for instance in Fay et al. J Mol Biol. 2017 Jul 7; 429(14): 2127-2147. In some embodiments, the compounds disclosed herein modulate the RNA structure directly (e.g., by binding the structure), or indirectly, for instance by interacting with a protein, e.g., an RNA binding protein, that can interact with the RNA structure. In some embodiments, the compounds disclosed herein modulate the RNA transcript by binding an RBP that targets a specific RNA structure. In some embodiments, the compounds disclosed herein modulate the RNA transcript by binding an RBP that targets a specific isoform of MYC RNA.

[0052] In another aspect, the present invention provides a method of modulating the splicing of a target MYC pre-mRNA transcript, comprising the step of contacting the target MYC pre-mRNA transcript with an effective amount of a disclosed rSM or a pharmaceutically acceptable salt thereof. It should be appreciated that even in cases in which defective splicing does not cause the disease, alteration of splicing patterns can be used to correct the disease.

[0053] As used herein, the term “inhibitor” is defined as a compound that binds to and / or modulates or inhibits a MYC RNA transcript with measurable affinity. In certain embodiments, an inhibitor has an IC50 and / or binding constant of less than about 100 pM, less than about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0054] The terms “measurable affinity” and “measurably inhibit,” as used herein, mean a measurable change in a downstream biological effect between a sample comprising a compound of the present invention, or composition thereof, and a MYC RNA transcript, and an equivalent sample comprising the MYC RNA transcript, in the absence of said compound, or composition thereof.

[0055] In some embodiments, administration of the compounds provided herein provides that translation of the MYC RNA transcript is reduced. In some embodiments, levels of Myc protein are decreased in a biological sample contacted with a disclosed rSM or decreased in a patient treated with a disclosed rSM. In some embodiments, administration of the compounds provided herein provides that degradation of the MYC RNA transcript is increased. In some embodiments, degradation of the MYC RNA transcript is increased due to interaction with the rSM (e.g, binding).

[0056] In some embodiments, a cell line contacted by an rSM has decreased viability as compared to a cell line that was not contacted by an rSM. In some embodiments, the cell line is a proliferative cell line. In some embodiments, the cell line is a cancer cell line. In some embodiments of a cell line that is contacted by an rSM and has decreased viability as compared to a cell line that was not contacted by an rSM, there is no measurable difference in MYC levels. It should be appreciated that in some aspects the disclosure provides compounds and methods for the treatment of c-MYC mediated diseases that are associated with the presence of a specific isoform or close homologs thereof. Thus, in one aspect, the disclose provides methods of targeting a cancer call line that is characterized by specific MYC isoforms (See e.g., Boxer et al.)

[0057] In one aspect, the present invention provides a method of modulating the activity of a specific isoform of a MYC RNA transcript. In one aspect, the specific isoform of a MYC RNA transcript comprises a first promoter that is located further upstream from a second promoter (See e.g., Boxer et al.). In some embodiments, the specific isoform is transcribed from the first promoter site. In some embodiments, the specific isoform is transcribed from the second promoter site. In one aspect, the specific isoform of a MYC RNA transcript comprises sequence SEQ ID NO: 1. In one aspect, the specific isoform of a MYC RNA transcript comprises sequence SEQ ID NO: 3. (See FIG. 1 and Table 1). It should be appreciated that MYC RNA transcripts that include sequences that are homologues of a specific sequence (e.g., of SEQ ID NO: 1 and SEQ ID NO:3) can be selectively targeted as well.

[0058] In one aspect the disclosure provides methods of treating a MYC-mediated disease, disorder, or condition in a patient in need thereof, including administering to the patient an effective amount of an RNA-modulating small molecule (rSM) to treat the MY C-mediated disease, disorder, or condition, wherein cells associated with the MYC-mediated disease, disorder, or condition include a specific isoform of the MYC RNA transcript. In some embodiments, the administration of the rSM results in modulation of a specific isoform of the MYC RNA transcript. In some embodiments, the administration of the rSM results in modulation of a specific isoform of the MYC RNA transcript, which results in a reduction in Myc protein expression. In some embodiments, the administration of the rSM results in modulation of a specific isoform of the MYC RNA transcript, which results in suppression of the aberrant functionality of the Myc protein. In some embodiments, the Myc protein is c-Myc. In some embodiments, the specific isoform includes SEQ ID NO: 1 or a homologous sequence. In some embodiments, the specific isoform includes SEQ ID NO:3 or a homologous sequence.

[0059] It should be appreciated that by targeting a specific isoform of the RNA target sequence it is possible to selectively target cells that contain that specific isoform of the RNA target sequence. It should further be appreciated that by targeting a specific isoform of the RNA target sequence it is possible to selectively target a MYC-mediated disease, disorder, or condition that is characterized by, or associated with cells that contain that specific isoform of the RNA target sequence. It should further be appreciated that by targeting a specific isoform of the RNA target sequence it is possible to selectively target a MYC-mediated disease, disorder, or condition that is characterized by, or associated with cells that are dependent on expression of MYC protein by that specific isoform of the RNA target sequence for viability. In some embodiments, the specific isoform includes SEQ ID NO:1 or a homologous sequence. In some embodiments, the specific isoform includes SEQ ID NO:3 or a homologous sequence.

[0060] As provided for instance in Boxer et al. (Oncogene 2001, 20, 5595) specific cancers are characterized by, or associated with cells that are dependent on that specific isoform of the RNA target sequence for viability. Thus, the methods and compositions provided herein allow for the targeting of specific MYC-mediated disease, disorder, or conditions, such as cancer. The MYC isoform that includes SEQ ID NO:3 is found, for instance, in Daudi cells, a Burkitt’s lymphoma. Additional cell lines that include the SEQ ID NO: 3 isoform are described in Boxer et al. It should be appreciated that cell lines can have multiple MYC isoforms that may be expressed at differentlevels. In some embodiments, the compositions of the current disclosure can be used to treat cancers that have measurable levels of a MYC RNA transcript that includes SEQ ID NO: 3.

[0061] In some embodiments, the target MYC RNA transcript is selected from one of those in Table 1 below, or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof. In some embodiments, the MYC RNA transcript is an unspliced form or unspliced isoform of any one of the transcripts of Table 1. In some embodiments, the MYC RNA transcript is a splicing intermediate of any one of the transcripts of Table 1. In some embodiments, the MYC RNA transcript is an isoform of any one of the transcripts of Table 1. In some embodiments, the MYC RNA transcript is a fragment of any one of the transcripts of Table 1. In some embodiments, the MYC RNA transcript is a mutant of any one of the transcripts of Table 1. In some embodiments, the MYC RNA transcript has at least 70%, 80%, 90%, 95%, or 99% sequence homology with any one of the transcripts of Table 1. In some embodiments, the MYC RNA transcript comprises at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the contiguous nucleotide sequence of any one of the transcripts of Table 1. In some embodiments, the MYC RNA transcript comprises at least 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, 400, 500, or 600 contiguous nucleotides of the sequence of any one of the transcripts of Table 1. In some embodiments, the MYC RNA transcript comprises at least 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, 400, or 500, contiguous nucleotides of the transcripts of Table 1.

[0062] In some embodiments, the rSMs provided herein selectively target a specific isoform of MYC RNA. In some embodiments, the rSMs provided herein selectively target SEQ ID NO:1 or SEQ ID NO: 3. In some embodiments, the rSMs provided herein selectively target MYC isoforms that include SEQ ID NO: 1 or SEQ ID NO:3. In some embodiment, the rSMs provided herein selectively target MYC isoforms that include SEQ ID NO:1 or SEQ ID NO:3 but do not target SEQ ID NO: 2. It should be appreciated that in some embodiments the rSMs provided herein also specifically target isoform sequences that are closely homologous to SEQ ID NO:1 or SEQ ID NO:3.

[0063] In some embodiments, the rSM selectively modulates (e.g., binds) a specific isoform MYC RNA transcript, fragment, or mutant thereof. In some embodiments, the compound is at least 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, 500, 1,000, or 10,000-fold selective for binding to a specific isoform MYC RNA transcript, fragment, or mutant thereof, versus a different iso form MYC RNA transcript, fragment, or mutant thereof.

[0064] In some embodiments, the rSM binds to a specific isoform MYC RNA transcript, fragment, or mutant thereof, with a Ka of 1 pM, 500 nM, 100 nM, 50 nM, 10 nM, 1 nM, 500 pM, 10 pM, or 1 pM or lower affinity under biological conditions. In some embodiments, the rSM binds to a specific isoform MYC RNA transcript, fragment, or mutant thereof, with a Ka of 0.1 nm to 500 nm, 10 nm to 250 nm, 0.001-25 pM, 0.01-25 pM, 0.1-25 pM, 0.1-15 pM, 0.01-10 pM, 0.001-1 pM, 0.001-0.1 pM, or 0.001-0.01 pM. It should be appreciated that the rSMs of the invention also include rSM that have no measurable binding to one or more MYC RNA transcripts.Table 1: Target MYC RNA TranscriptsSEQ ID NO: 1 AST-380 / isoform 1ACCCCCGAGCUGUGCUGCUCGCGGCCGCCACCGCCGGGCCCCGGCCGUCCCUGGCUCCCCUCCUGCCUCGAGAAGGGCAGGGCUUCUCAGAGGCUUGGCGGGAAAAAGAACGGAGGGAGGGAUCGCGCUGAGUAUAAAAGCCGGUUUUCGGGGCUUUAUCUAACUCGCUGUAGUAAUUCCAGCGAGAGGCAGAGGGAGCGAGCGGGCGGCCGGCUAGGGUGGAAGAGCCGGGCGAGCAGAGCUGCGCUGCGGGCGUCCUGGGAAGGGAGAUCCGGAGCGAAUAGGGGGCUUCGCCUCUGGCCCAGCCCUCCCGCUGAUCCCCCAGCCAGCGGUCCGCAACCCUUGCCGCAUCCACGAAACUUUGCCCAUAGCAGCGGGCGGGCACUUUGCACUGGAACUUACAACACCCGAGCAAGGACGCGACUCUCCCGACGCGGGGAGGCUAUUCUGCCCAUUUGGGGACACUUCCCCGCCGCUGCCAGGACCCGCUUCUCUGAAAGGCUCUCCUUGCAGCUGCUUAGACGCUGGAUUUUUUUCGGGUAGUGGAAAACCAGCAGCCUCCCGCGACGAUGCCCCUCAACGUUAGCUUCACCAACAGGAACUAUGACCUCGACUACGASEQ ID NO:2 AST-381 / isoform 2AACUCGCUGUAGUAAUUCCAGCGAGAGGCAGAGGGAGCGAGCGGGCGGCCGGCUAGGGUGGAAGAGCCGGGCGAGCAGAGCUGCGCUGCGGGCGUCCUGGGAAGGGAGAUCCGGAGCGAAUAGGGGGCUUCGCCUCUGGCCCAGCCCUCCCGCUGAUCCCCCAGCCAGCGGUCCGCAACCCUUGCCGCAUCCACGAAACUUUGCCCAUAGCAGCGGGCGGGCACUUUGCACUGGAACUUACAACACCCGAGCAAGGACGCGACUCUCCCGACGCGGGGAGGCUAUUCUGCCCAUUUGGGGACACUUCCCCGCCGCUGCCAGGACCCGCUUCUCUGAAAGGCUCUCCUUGCAGCUGCUUAGACGCUGGAUUUUUUUCGGGUAGUGGAAAACCAGCAGCCUCCCGCGACGAUGCCCCUCAACGUUAGCUUCACCAACAGGAACUAUGACCUCGACUACGASEQ ID NO: 3 Sequence unique to isoform 1 (not found in isoform 2)ACCCCCGAGCUGUGCUGCUCGCGGCCGCCACCGCCGGGCCCCGGCCGUCCCUGGCUCCCCUCCUGCCUCGAGAAGGGCAGGGCUUCUCAGAGGCUUGGCGGGAAAAAGAACGGAGGGAGGGAUCGCGCUGAGUAUAAAAGCCGGUUUUCGGGGCUUUAUCUCompounds of the invention

[0065] In one aspect, the present disclosure provides a compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered tricyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered tricyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring C is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring D is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R1is independently Ci-6 straight or branched alkyl, alkenyl, or alkynyl group optionally substituted with 1, 2, or 3 deuterium or halogen atoms, and optionally substituted with one -OH, -CN, or NH2 group; halogen, -CN, -C(O)RX, -C(O)ORX, -OC(O)RX, - C(O)N(RX)2, -N(RX)C(O)RX, -N(RX)C(O)N(RX)2, -OC(O)N(RX)2, -N(RX)C(O)ORX, -ORX, - N(RX)2, -NO2, -SRX, -S(O)RX, -S(O)2RX, -S(O)2N(RX)2, or -NRXS(O)2RX; each occurrence of R2is independently optionally substituted C1-6 aliphatic, halogen, -CN, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -NHC(NH)N(R)2, - OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or - NRS(O)2R; each occurrence of R3, R4, and R5is independently optionally substituted C1-6 aliphatic, halogen, -CN, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, - NHC(NH)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -SR, -S(O)R, -S(O)2R, - S(O)2N(R)2, or -NRS(O)2R; each occurrence of Rxis independently H or a C1-6 straight or branched alkyl, alkenyl, or alkynyl group optionally substituted with 1, 2, or 3 deuterium or halogen atoms;-L1- and -L2- are each independently a covalent bond or a C1-10 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently andoptionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-;-L3- and -L4- are each independently a covalent bond or a C1-10 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-; each occurrence of X is independently N or C with a proviso that at most two X are N; each occurrence of R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each -Cy- is independently an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5;p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, 4, or 5.

[0066] As defined generally above, Ring A is selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-12 membered tricyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0067] In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, Ring A is a 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring A is a 4-8 membered saturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic hetero aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an 8- 12 membered tricyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0069] In some embodiments,is selected from

[0070] In some embodiments,some embodiments,

[0071] In some embodiments, Ring A is selected from those depicted in Table 2, below.

[0072] As defined generally above, Ring B is selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-12 membered tricyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0073] In some embodiments, Ring B is phenyl. In some embodiments, Ring B is a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, Ring B is a 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring B is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring B is a 4-8 membered saturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an 8- 12 membered tricyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0077] In some embodiments, Ring B is selected from those depicted in Table 2, below.

[0078] As defined generally above, Ring C is selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-12 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0079] In some embodiments, Ring C is phenyl. In some embodiments, Ring C is a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, Ring C is a 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring C is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring C is a 4-8 membered saturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring C is an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0080] In some embodiments, Ring C is selected from

[0081] In some embodiments, Ring C is selected from those depicted in Table 2, below.

[0082] As defined generally above, Ring D is selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-12 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0083] In some embodiments, Ring D is phenyl. In some embodiments, Ring D is a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, Ring D is a 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring D is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring D is a 4-8 membered saturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 5-6 membered monocyclic hetero aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0084] In some embodiments, Ring D is selected from, wherein Ring D is substituted with r instances of R5.

[0085] In some embodiments, Ring D is selected from those depicted in Table 2, below.

[0086] As defined generally above, each occurrence of R1is independently Ci-6 straight or branched alkyl, alkenyl, or alkynyl group optionally substituted with 1, 2, or 3 deuterium or halogen atoms, and optionally substituted with one -OH, -CN, or NH2 group; halogen, -CN, - C(O)RX, -C(O)ORX, -OC(O)RX, -C(O)N(RX)2, -N(RX)C(O)RX, -N(RX)C(O)N(RX)2, -OC(O)N(RX)2, -N(RX)C(O)ORX, -ORX, -N(RX)2, -NO2, -SRX, -S(O)RX, -S(O)2RX, -S(O)2N(RX)2, or -NRXS(O)2RX.

[0087] In some embodiments, R1is a C1-6 straight alkyl group. In some embodiments, R1is a C1-6 branched alkyl group. In some embodiments, R1is a C1-6 straight alkenyl group. In some embodiments, R1is a C1-6 branched alkenyl group. In some embodiments, R1is a C1-6 straight alkynyl group. In some embodiments, R1is a C1-6 branched alkynyl group. In some embodiments, R1is a C1-6 straight alkyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R1is a C1-6 branched alkyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R1is a C1-6 straight alkenyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R1is a C1-6 branched alkenyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R1is a C1-6 straight alkynyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R1is a C1-6 branched alkynyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R1is a C1-6 straight alkyl group substituted with 1, 2, or 3 deuterium or halogen atoms and substituted with one -OH, -CN, or NH2group. In some embodiments, R1is a C1-6 branched alkyl group substituted with 1, 2, or 3 deuterium or halogen atoms and substituted with one -OH, -CN, or NH2group. In some embodiments, R1is a C1-6 straight alkenyl group substituted with 1, 2, or 3 deuterium or halogen atoms and substituted with one -OH, -CN, or NH2group. In some embodiments, R1is a C1-6 branched alkenyl group substituted with 1, 2, or 3 deuterium orhalogen atoms and substituted with one -OH, -CN, or NH2 group. In some embodiments, R1is a C1-6 straight alkynyl group substituted with 1, 2, or 3 deuterium or halogen atoms and substituted with one -OH, -CN, or NH2 group. In some embodiments, R1is a C1-6 branched alkynyl group substituted with 1, 2, or 3 deuterium or halogen atoms and substituted with one -OH, -CN, or NH2 group. In some embodiments, R1is halogen. In some embodiments, R1is -CN. In some embodiments, R1is -C(O)RX. In some embodiments, R1is -C(O)ORX. In some embodiments, R1is -OC(O)RX. In some embodiments, R1is -C(O)N(RX)2. In some embodiments, R1is -N(RX)C(O)RX. In some embodiments, R1is -N(Rx)C(0)N(Rx)2. In some embodiments, R1is -OC(O)N(RX)2. In some embodiments, R1is -N(RX)C(O)ORX. In some embodiments, R1is -ORX. In some embodiments, R1is -N(RX)2. In some embodiments, R1is -NO2. In some embodiments, R1is -SRX. In some embodiments, R1is -S(O)RX. In some embodiments, R1is -S(O)2RX. In some embodiments, R1is -S(O)2N(RX)2. In some embodiments, R1is -NRXS(O)2RX.

[0088] In some embodiments, each occurrence of R1is independently selected from -OH, -F, -Br, -Cl, -OMe, -NO2, -CH3, -CH2CH3, -CF3, -OCF3, -CMe3, -NMe2, -NHC(O)CH3, -CN, and -SO2Me.

[0089] In some embodiments, R1is selected from those depicted in Table 2, below.

[0090] As defined generally above, each occurrence of R2is independently optionally substituted C1-6 aliphatic, halogen, -CN, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, - N(R)C(O)N(R)2, -NHC(NH)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -SR, - S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R.

[0091] In some embodiments, R2is a C1-6 aliphatic group. In some embodiments, R2is a substituted C1-6 aliphatic group. In some embodiments, R2is halogen. In some embodiments, R2is -CN. In some embodiments, R2is -C(O)R. In some embodiments, R2is -C(O)OR. In some embodiments, R2is -OC(O)R. In some embodiments, R2is -C(O)N(R)2. In some embodiments, R2is -N(R)C(O)R. In some embodiments, R2is -N(R)C(O)N(R)2. In some embodiments, R2is — NHC(NH)N(R)2. In some embodiments, R2is -OC(O)N(R)2. In some embodiments, R2is - N(R)C(O)OR. In some embodiments, R2is -OR. In some embodiments, R2is -N(R)2. In some embodiments, R2is -NO2. In some embodiments, R2is -SR. In some embodiments, R2is -S(O)R. In some embodiments, R2is -S(O)2R. In some embodiments, R2is -S(O)2N(R)2. In some embodiments, R2is -NRS(O)2R.

[0092] In some embodiments, each occurrence of R2is independently selected from

[0093] In some embodiments, each occurrence of R2is independently selected from -OH, -OMe, methyl, vinyl, -CH2OH, -OCH(CH3)2, -NHSO2Me, -NHC(O)CH3, -CN, -CH2OCH3, -SO2Me, and -C(O)NMe2.

[0094] In some embodiments, R2is selected from those depicted in Table 2, below.

[0095] As defined generally above, each occurrence of R3is independently optionally substituted C1-6 aliphatic, halogen, -CN, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, - N(R)C(O)N(R)2, -NHC(NH)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -SR, - S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R.

[0096] In some embodiments, R3is a C1-6 aliphatic group. In some embodiments, R3is a substituted C1-6 aliphatic group. In some embodiments, R3is halogen. In some embodiments, R3is -CN. In some embodiments, R3is -C(O)R. In some embodiments, R3is -C(O)OR. In some embodiments, R3is -OC(O)R. In some embodiments, R3is -C(O)N(R)2. In some embodiments, R3is -N(R)C(O)R. In some embodiments, R3is -N(R)C(O)N(R)2. In some embodiments, R3is - NHC(NH)N(R)2. In some embodiments, R3is -OC(O)N(R)2. In some embodiments, R3is - N(R)C(O)OR. In some embodiments, R3is -OR. In some embodiments, R3is -N(R)2. In some embodiments, R3is -NO2. In some embodiments, R3is -SR. In some embodiments, R3is -S(O)R. In some embodiments, R3is -S(O)2R. In some embodiments, R3is -S(O)2N(R)2. In some embodiments, R3is -NRS(O)2R.

[0097] In some embodiments, each occurrence of R3is independently selected from -OMe, -OEt, O

[0098] In some embodiments, each occurrence of R3is independently selected from -OMe, -OEt, -OH, methyl, ethyl, vinyl, propyl, -Cl, -Br, -F, -SO2NH2, -OCF3, -SO2NHEt, -NEt2, -C(O)NMe2, -NH2, -CF3, -C(O)OCH3, and -NHC(O)CH3.

[0099] In some embodiments, R3is selected from those depicted in Table 2, below.

[0100] As defined generally above, each occurrence of R4is independently optionally substituted Ci-6 aliphatic, halogen, -CN, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, - N(R)C(O)N(R)2, -NHC(NH)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -SR, - S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R.

[0101] In some embodiments, R4is a Ci-6 aliphatic group. In some embodiments, R4is a substituted Ci-6 aliphatic group. In some embodiments, R4is halogen. In some embodiments, R4is -CN. In some embodiments, R4is -C(O)R. In some embodiments, R4is -C(O)OR. In some embodiments, R4is -OC(O)R. In some embodiments, R4is -C(O)N(R)2. In some embodiments, R4is -N(R)C(O)R. In some embodiments, R4is -N(R)C(O)N(R)2. In some embodiments, R4is - NHC(NH)N(R)2. In some embodiments, R4is -OC(O)N(R)2. In some embodiments, R4is - N(R)C(O)OR. In some embodiments, R4is -OR. In some embodiments, R4is -N(R)2. In some embodiments, R4is -NO2. In some embodiments, R4is -SR. In some embodiments, R4is -S(O)R. In some embodiments, R4is -S(O)2R. In some embodiments, R4is -S(O)2N(R)2. In some embodiments, R4is -NRS(O)2R.

[0102] In some embodiments, each occurrence of R4is independently selected from C1-4 alkyl, C2. 4 alkenyl, and C2-4 alkynyl. In some embodiments, each occurrence of R4is independently selected from -Me, -OH, -CH2OMe, and -CH2NMe2.

[0103] In some embodiments, R4is selected from those depicted in Table 2, below.

[0104] As defined generally above, each occurrence of R5is independently optionally substituted Ci-6 aliphatic, halogen, -CN, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, - N(R)C(O)N(R)2, -NHC(NH)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -SR, - S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R.

[0105] In some embodiments, R5is a Ci-6 aliphatic group. In some embodiments, R5is a substituted Ci-6 aliphatic group. In some embodiments, R5is halogen. In some embodiments, R5is -CN. In some embodiments, R5is -C(O)R. In some embodiments, R5is -C(O)OR. In some embodiments, R5is -OC(O)R. In some embodiments, R5is -C(O)N(R)2. In some embodiments, R5is -N(R)C(O)R. In some embodiments, R5is -N(R)C(O)N(R)2. In some embodiments, R5is - NHC(NH)N(R)2. In some embodiments, R5is -OC(O)N(R)2. In some embodiments, R5is - N(R)C(O)OR. In some embodiments, R5is -OR. In some embodiments, R5is -N(R)2. In some embodiments, R5is -NO2. In some embodiments, R5is -SR. In some embodiments, R5is -S(O)R.In some embodiments, R5is -S(O)2R. In some embodiments, R5is -S(O)2N(R)2. In some embodiments, R5is -NRS(O)2R.

[0106] In some embodiments, each occurrence of R5is independently selected from Ci-4 alkyl, C2- 4 alkenyl, and C2-4 alkynyl.

[0107] In some embodiments, each occurrence of R5is independently selected from -Me, -Et, - OMe, -F, and -C(O)CH3.

[0108] In some embodiments, R5is selected from those depicted in Table 2, below.

[0109] As defined generally above, each occurrence of Rxis independently H or a C1-6 straight or branched alkyl, alkenyl, or alkynyl group optionally substituted with 1, 2, or 3 deuterium or halogen atoms.

[0110] In some embodiments, Rxis H. Rxis a C1-6 straight alkyl group. In some embodiments, Rxis a C1-6 branched alkyl group. In some embodiments, Rxis a C1-6 straight alkenyl group. In some embodiments, Rxis a C1-6 branched alkenyl group. In some embodiments, Rxis a C1-6 straight alkynyl group. In some embodiments, Rxis a C1-6 branched alkynyl group. In some embodiments, Rxis a C1-6 straight alkyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, Rxis a C1-6 branched alkyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, Rxis a C1-6 straight alkenyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, Rxis a C1-6 branched alkenyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, Rxis a C1-6 straight alkynyl group substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, Rxis a C1-6 branched alkynyl group substituted with 1, 2, or 3 deuterium or halogen atoms.

[0111] In some embodiments, Rxis selected from those depicted in Table 2, below.

[0112] As defined generally above, -L1- is a covalent bond or a bivalent C1-10 straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, - C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy.

[0113] In some embodiments, -L1- is a covalent bond. In some embodiments, -L1- is a C1-10 straight hydrocarbon chain. In some embodiments, -L1- is a C2-10 branched hydrocarbon chain. In some embodiments, -L1- is a C1-10 straight hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or - Cy. In some embodiments, -L1- is a C2-10 branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, - (R)NC(S)N(R)-, or -Cy.R R O R

[0114] In some embodiments, L1is selected from, ,

[0115] In some embodiments, L1is selected from -CH2-, -(CH2)2-, -( 12)3-, -CH2CH(CH3)-,

[0116] In some embodiments, L1is selected from those depicted in Table 2, below.

[0117] As defined generally above, -L2- is a covalent bond or a bivalent C1-10 straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, - C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy.

[0118] In some embodiments, -L2- is a covalent bond. In some embodiments, -L2- is a C1-10 straight hydrocarbon chain. In some embodiments, -L2- is a C2-10 branched hydrocarbon chain. In some embodiments, -L2- is a C1-10 straight hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, - (R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or - Cy. In some embodiments, -L2- is a C2-10 branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, - (R)NC(S)N(R)-, or -Cy.

[0119] In some embodiments, L2is selected from

[0120] In some embodiments, L2is selected from -CH2-, -(CH2)2-, -(CH2)3-, -CH2CH(CH3)-,

[0121] In some embodiments, L2is selected from those depicted in Table 1, below.

[0122] As defined generally above, -L3- is a covalent bond or a bivalent C1-10 straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, - C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy.

[0123] In some embodiments, -L3- is a covalent bond. In some embodiments, -L3- is a C1-10 straight hydrocarbon chain. In some embodiments, -L3- is a C2-10 branched hydrocarbon chain. In some embodiments, -L3- is a C1-10 straight hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, - (R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or - Cy. In some embodiments, -L3- is a C2-10 branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, - (R)NC(S)N(R)-, or -Cy.

[0124] In some embodiments, L3is selected from a bond, -O-, -O(CH2)I-S-,,

[0125] In some embodiments, L3is selected from a bond, -O-, -O(CH2)2-, -OCH2-, -CH2-, -

[0126] In some embodiments, L3is selected from those depicted in Table 2, below.

[0127] As defined generally above, -L4- is a covalent bond or a bivalent Ci-io straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, - C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy.

[0128] In some embodiments, -L4- is a covalent bond. In some embodiments, -L4- is a Ci-io straight hydrocarbon chain. In some embodiments, -L4- is a C2-10 branched hydrocarbon chain. In some embodiments, -L4- is a Ci-io straight hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, - (R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or - Cy. In some embodiments, -L4- is a C2-10 branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, - (R)NC(S)N(R)-, or -Cy.

[0129] In some embodiments, L4is selected from a bond, -O-, -O(CH2)I-S-,,

[0130] In some embodiments, L4is selected from a bond, -O-, -SO2-, -O(CH2)2-, -O(CH2)3-, -

[0131] In some embodiments, L4is selected from those depicted in Table 2, below.

[0132] As defined generally above, each occurrence of X is N or C, wherein at most two X are N. In some embodiments, all occurrences of X are C. In some embodiments, one occurrence of X is N and three occurrences of X are C. In some embodiments, two occurrences of X are N and two occurrences of X are C.

[0133] As defined generally above, each occurrence of R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0134] In some embodiments, R is hydrogen. In some embodiments, R is a C1-6 aliphatic group. In some embodiments, R is a substituted C1-6 aliphatic group. In some embodiments, R is a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R is a 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, R is a substituted 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R is a substituted 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, R is phenyl. In some embodiments, R is a substituted phenyl. In some embodiments, R is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R is a substituted 8-10 memberedbicyclic aromatic carbocyclic ring. In some embodiments, R is a 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 5-6 membered monocyclic hetero aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0135] In some embodiments, each R is independently H, Ci-4 alkyl, or phenyl wherein each Ci-4 alkyl and phenyl is optionally substituted with 1, 2, or 3 independently selected deuterium or halogen atoms. In some embodiments, each R is independently H, methyl, or ethyl wherein each methyl and ethyl is optionally substituted with 1, 2, or 3 independently selected deuterium or halogen atoms.

[0136] In some embodiments, R is selected from those depicted in Table 2, below.

[0137] As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0138] In some embodiments, m is selected from those depicted in Table 2, below.

[0139] As defined generally above, n is 0, 1, 2, 3, 4 or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0140] In some embodiments, n is selected from those depicted in Table 2, below.

[0141] As defined generally above, p is 0, 1, 2, 3, 4 or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0142] In some embodiments, p is selected from those depicted in Table 2, below.

[0143] As defined generally above, q is 0, 1, 2, 3, 4 or 5. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5.

[0144] In some embodiments, q is selected from those depicted in Table 2, below.

[0145] As defined generally above, r is 0, 1, 2, 3, 4 or 5. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5.

[0146] In some embodiments, r is selected from those depicted in Table 2, below.

[0147] In some embodiments, the present disclosure provides a compound of Formula II:II or a pharmaceutically acceptable salt thereof, wherein: each of ring A, ring B, ring C, ring D, R1, R2, R3, R4, R5, L1, L2, L3, L4, m, n, p, q and r is as defined above and described in embodiments herein, both singly and in combination.

[0148] In some embodiments, the present disclosure provides a compound of Formula III:Ill or a pharmaceutically acceptable salt thereof, wherein: each of ring A, ring B, ring C, ring D, R1, R2, R3, R4, R5, L1, L2, L3, L4, m, n, p, q and r is as defined above and described in embodiments herein, both singly and in combination.

[0149] In some embodiments, the present disclosure provides a compound of Formula IV:or a pharmaceutically acceptable salt thereof, wherein: each of ring A, ring B, ring C, ring D, R1, R2, R3, R4, R5, L1, L2, L3, L4, m, n, p, q and r is as defined above and described in embodiments herein, both singly and in combination.

[0150] In some embodiments, the present disclosure provides a compound of Formula V:or a pharmaceutically acceptable salt thereof, wherein: each of ring A, ring B, ring C, ring D, R1, R2, R3, R4, R5, L1, L2, L3, L4, m, n, p, q and r is as defined above and described in embodiments herein, both singly and in combination.

[0151] In some embodiments, the present disclosure provides a compound of Formula VI:or a pharmaceutically acceptable salt thereof, wherein: each of ring A, ring B, ring C, ring D, R1, R2, R3, R4, R5, L1, L2, L3, L4, m, n, p, q and r is as defined above and described in embodiments herein, both singly and in combination.

[0152] In some embodiments, the present disclosure provides a compound of Formula VII:or a pharmaceutically acceptable salt thereof, wherein: each of ring A, ring B, ring C, ring D, R1, R2, R3, R4, R5, L1, L2, L3, L4, m, n, p, q and r is as defined above and described in embodiments herein, both singly and in combination.

[0153] In some embodiments, the present disclosure provides a compound of Formula VIII:or a pharmaceutically acceptable salt thereof, wherein: each of ring A, ring B, ring C, ring D, R1, R2, R3, R4, R5, L1, L2, L3, L4, m, n, p, q and r is as defined above and described in embodiments herein, both singly and in combination.

[0154] In some embodiments, the present disclosure provides a compound of Formula IX:or a pharmaceutically acceptable salt thereof, wherein: each of ring A, ring B, ring C, ring D, R1, R2, R3, R4, R5, L1, L2, L3, L4, m, n, p, q and r is as defined above and described in embodiments herein, both singly and in combination.

[0155] In some embodiments, the present disclosure provides a compound of Formula X:or a pharmaceutically acceptable salt thereof, wherein: each of ring A, ring B, ring C, ring D, R1, R2, R3, R4, R5, L1, L2, L3, L4, m, n, p, q and r is as defined above and described in embodiments herein, both singly and in combination.

[0156] In some embodiments, the present disclosure provides a compound of Formula XI:or a pharmaceutically acceptable salt thereof, wherein: each of ring A, ring B, ring C, ring D, R1, R2, R3, R4, R5, L1, L2, L3, L4, m, n, p, q and r is as defined above and described in embodiments herein, both singly and in combination.

[0157] In some embodiments, the present disclosure provides a compound of Formula XII:or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, L1, L2, m, n, and p is as defined above and described in embodiments herein, both singly and in combination.

[0158] In some embodiments, the present disclosure provides a compound of Formula Xlla:Xlla or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, L2, m, n, and p is as defined above and described in embodiments herein, both singly and in combination.

[0159] In some embodiments, the present disclosure provides a compound of Formula Xllb:Xllb or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, L1, m, n, and p is as defined above and described in embodiments herein, both singly and in combination.

[0160] In some embodiments, the present disclosure provides a compound of Formula XIIc:XIIc or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, m, n, and p is as defined above and described in embodiments herein, both singly and in combination.

[0161] In some embodiments, the present disclosure provides a compound of Formula XIII:or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, L1, L2, m, n, and p is as defined above and described in embodiments herein, both singly and in combination.

[0162] In some embodiments, the present disclosure provides a compound of Formula XIV:XIV or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, L1, L2, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0163] In some embodiments, the present disclosure provides a compound of Formula XV:XV or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, L1, L2, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0164] In some embodiments, the present disclosure provides a compound of Formula XVI:XVI or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, L1, L2, m, n, and p is as defined above and described in embodiments herein, both singly and in combination.

[0165] In one aspect, the present invention provides an rSM or pharmaceutically acceptable salt thereof. Such compounds bind to a target RNA transcript, such as a target MYC RNA transcript. Exemplary rSM compounds of the invention are set forth in Table 2, below.Table 2: Exemplary Compounds1-23 1-241-185 1-1861-201 1-202

[0166] In some embodiments, the present invention provides a compound set forth in Table 2, above, or a pharmaceutically acceptable salt thereof.

[0167] In one aspect the disclosure provides compounds and compositions thereof. In some embodiments, the compounds are rSMs (RNA modulating small molecules). In one aspect, the rSMs and composition thereof, disclosed herein can be used to practice the methods disclosed herein. In some embodiments, the rSM for treating a MYC-mediated disease, disorder, or condition, and / or for suppression of the aberrant functionality of a Myc protein, lowering of the expression level of a Myc protein, and / or the modulation of a MYC RNA transcript is selected from a compound disclosed herein, such as a compound shown in Table 2 and paragraphs

[0064] to

[0161] ,

[0168] In some embodiments, the rSM is a small molecule or pharmaceutically acceptable salt thereof. In some embodiments, the rSM has a molecular weight (MW) of 1000 or less. In some embodiments, the rSM has a MW of about 750 or less. In some embodiments, the rSM has a MW of about 600 or less. In some embodiments, the rSM has a MW of about 500 or less. In some embodiments, the rSM has a MW of between about 100 and about 1000. In some embodiments, the rSM has a MW of between about 150 and about 800, about 150 and about 600, about 150 and about 400, about 150 and about 350, about 200 and about 350, or between about 200 and about 450.

[0169] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7thEdition, John Wiley & Sons: 2013; the entire contents of each of which are hereby incorporated by reference.

[0170] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units ofunsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0171] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ort / zo-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or moresubstituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:Exemplary bridged bicyclics include:

[0172] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0173] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0174] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2 / f-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0175] The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

[0176] As used herein, the term “bivalent Ci-s (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain,” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0177] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n- wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0178] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0179] The term “halogen” means F, Cl, Br, or I.

[0180] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0181] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- -quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3- / ?]- l ,4-oxazin-3(4 / 7)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted with a hetero aryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0182] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2 / 7 pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in A substituted pyrrolidinyl).

[0183] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3 / 7 indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0184] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0185] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent (“optional substituent”) at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0186] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o 4R0; -(ClUjo 4OR0; -0(CH2)o-4R°, -O- (ClUjo4C(O)OR°; -(ClUjo4CH(ORO)2; -(CH2)O-4SR°; -(CH2)O4Ph, which may be substituted with R°; -(CILjo40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o40(CH2)o i -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O4N(RO)2; -(CH2)O4N(RO)C(O)R°; -N(R°)C(S)R°; -(CH2)O-4N(R°)C(O)NRO2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR°;N(R°)N(R°)C(O)R°; -N(R°)N(RO)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)o-4C(0)R°; - C(S)R°; -(CH2)O4C(O)OR°; -(CH2)O4C(O)SR°; -(CH2)O4C(O)OSIR°3; -(CH2)O4OC(O)RO; - OC(0)(CH2)O -4SR-, SC(S)SR°; -(CH2)o-4SC(0)R°; -(CH2)o4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2)O 4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; - C(NOR°)R°; -(CH2)o4SSR°; -(CH2)o4S(O)2R°; -(CH2)o4S(O)2OR°; -(CH2)o4OS(O)2R°; - S(O)2NR°2; -(CH2)O4S(O)RO; -N(RO)S(O)2NRO2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; - P(O)2R°; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; SiR°3; -(C1-4 straight or branched alkylene)O-N(R°)2; or -(Ci-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0187] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o 2R*, -(haloR*), -(CH2)O 2OH, -(CH2)O-2OR*, -(CH2)O2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)o-2C(O)R’, -(CH2)O2C(O)OH, -(CH2)O2C(O)OR*, -(CH2)O 2SR*, -(CH2)O 2SH, -(CH2)O 2NH2, - (CH2)O-2NHR*, -(CH2)O-2NR*2, -NO2, -SIR*3, -OSIR*3, -C(O)SR’ -(C1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, - CH2PI1, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0188] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*,wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)23O— , wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0189] Suitable substituents on the aliphatic group of R* include halogen, R*, -(haloR"), -OH, - OR", -O(haloR’), -CN, -C(O)OH, -C(O)OR’, -NH2, -NHR’, -NR’2, or -NO2, wherein each R*is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CHzPh, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0190] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include , C(O)CH2wherein each R1' is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R\ taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0191] Suitable substituents on the aliphatic group of R1' are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -0(CH2)o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0192] As used herein, 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, S. M. 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 invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acidor malonic acid or by using other methods used 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, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0193] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0194] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, 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 including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0195] As used herein, the term “inhibitor” is defined as a compound that binds to and / or modulates or inhibits a MYC RNA transcript with measurable affinity. In certain embodiments, an inhibitor has an IC50 and / or binding constant of less than about 100 pM, less than about 50 pM,less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0196] The terms “measurable affinity” and “measurably inhibit,” as used herein, mean a measurable change in a downstream biological effect between a sample comprising a compound of the present invention, or composition thereof, and a MYC RNA transcript, and an equivalent sample comprising the MYC RNA transcript, in the absence of said compound, or composition thereof.

[0197] The term “RNA” (ribonucleic acid) as used herein, means a naturally-occurring or synthetic oligo- or polyribonucleotide independent of source (e.g., the RNA may be produced by a human, animal, plant, virus, or bacterium, or may be synthetic in origin), biological context (e.g., the RNA may be in the nucleus, circulating in the blood, in vitro, cell lysate, or isolated or pure form), or physical form (e.g., the RNA may be in single-, double-, or triple-stranded form (including RNA- DNA hybrids), may include epigenetic modifications, native post-transcriptional modifications, artificial modifications (e.g., obtained by chemical or in vitro modification), or other modifications, may be bound to, e.g., metal ions, small molecules, protein chaperones, or cofactors, or may be in a denatured, partially denatured, or folded state including any native or unnatural secondary or tertiary structure such as junctions (e.g., cis or trans three-way junctions (3WJ)), quadruplexes, hairpins, triplexes, hairpins, bulge loops, pseudoknots, and internal loops, etc., and any transient forms or structures adopted by the RNA). In some embodiments, the RNA is 100 or more nucleotides in length. In some embodiments, the RNA is 250 or more nucleotides in length. In some embodiments, the RNA is 350, 450, 500, 600, 750, or 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000, or more nucleotides in length. In some embodiments, the RNA is between 250 and 1,000 nucleotides in length. In some embodiments, the RNA is a pre-RNA, pre-miRNA, or pretranscript. In some embodiments, the RNA is a noncoding RNA (ncRNA), messenger RNA (mRNA), micro-RNA (miRNA), a ribozyme, riboswitch, IncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA, ceRNA, pseudo-gene, viral RNA, or bacterial RNA. The term “target RNA” or “target MYC RNA transcript” as used herein, means any type of RNA having or capable of adopting a secondary or tertiary structure that is capable of binding a small molecule ligand described herein. The target RNA may be inside a cell, in a cell lysate, or in isolated form prior to contacting the small molecule.3. General Methods of Providing the Present Compounds

[0198] The compounds of this invention may be prepared or isolated in general by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples and Figures, herein.

[0199] In the schemes and chemical reactions depicted in the detailed description, Examples, and Figures, where a particular protecting group (“PG”), leaving group (“LG”), or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7thEdition, John Wiley & Sons, 2013, Comprehensive Organic Transformations, R. C. Larock, 3rdEdition, John Wiley & Sons, 2018, and Protective Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014, the entirety of each of which is hereby incorporated herein by reference.

[0200] As used herein, the phrase “leaving group” (LG) includes, but is not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.

[0201] As used herein, the phrase “oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triph enylmethoxyacetate, p-chlorophenoxyacetate, 3 -phenylpropionate, 4-oxopentanoate, 4,4- (ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p- nitrobenzyl. Examples of such silyl ethers include trimethyl silyl, triethylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkylethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

[0202] Amino protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0203] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See, for example, March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7thEdition, John Wiley & Sons, 2013, Comprehensive Organic Transformations, R. C. Larock, 3rdEdition, John Wiley & Sons, 2018, the entirety of each of which is incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below.

[0204] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. Such groups and transformations are described in detail in March ’s Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, M. B. Smith and J. March, 7thEdition, John Wiley & Sons, 2013, Comprehensive Organic Transformations, R. C. Larock, 3rdEdition, John Wiley & Sons, 2018, and Protective Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014, the entirety of each of which is hereby incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below in the Exemplification and Figures.

[0205] Compounds set forth in Table 2 above were prepared according to the following general approaches or related synthetic strategies.Synthesis of Intermediates

[0206] Synthesis of alkyl amine functionalized arenes: 4 M HCI(1 ,4-dioxane) fl Tj-R PdCI2(dppf), Cs2CO3, CH2CI2, rt, 2 hBr toluene, water100 °C, 16 h

[0207] Synthesis of amino acid derivatives:

[0209] General synthesis II:4. Uses, Formulation and AdministrationPharmaceutically acceptable compositions

[0210] According to another embodiment, the invention provides compositions comprising a compound of this invention (e.g., an rSM) or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably suppress the aberrant functionality of a Myc protein, lower the expression level of a Myc protein, and / or the modulate a MYC RNA transcript to treat a disease, disorder, or condition, such as a MYC-mediated disease or condition.

[0211] In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably suppress the aberrant functionality of a Myc protein, lower the expression level of a Myc protein, and / or the modulate a MYC RNA transcript, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[0212] The term “patient” or “subject,” as used herein, means an animal, such as a mammal, and, for example, a human.

[0213] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non -toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0214] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

[0215] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrah epatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0216] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0217] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0218] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0219] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0220] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0221] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0222] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0223] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0224] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0225] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0226] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particulardisease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.Uses of Compounds and Pharmaceutically Acceptable Compositions

[0227] Compounds and compositions described herein are generally useful to treat a disease, disorder, or condition, such as a MYC-mediated disease, disorder or condition, and / or for suppression of the aberrant functionality of a Myc protein, lowering of the expression level of a Myc protein, and / or the modulation of a MYC RNA transcript.

[0228] The activity of a compound utilized in this invention to treat the MYC-mediated disease disorder or condition, suppress the aberrant functionality of a Myc protein, lower the expression level of a Myc protein, and / or the modulate a MYC RNA transcript may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that quantitate the ability of the compound to modulate, e.g., bind, the MYC RNA transcript. In vivo or cell line assays include those that, for example, measure expression or functionality of a Myc protein, a cell phenotype, or cell apoptosis. Detailed conditions for assaying a compound utilized in this invention to treat a MYC-mediated disease disorder or condition or measurably suppress the aberrant functionality of a Myc protein, lower the expression level of a Myc protein, and / or the modulate a MYC RNA transcript are set forth in the Examples below.

[0229] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0230] In one aspect, the provided compounds are therefore useful for treating MYC-mediated diseases, disorders or conditions. In some embodiments, the provided compounds can suppress the aberrant functionality of a Myc protein, lower the expression level of a Myc protein, and / or modulate a MYC RNA transcript and are therefore useful for treating MYC-mediated diseases, disorders or conditions. In some embodiments, the compounds can suppress the aberrant functionality of a Myc protein, lower the expression level of a Myc protein, and / or the modulate aMYC RNA transcript and are therefore useful for treating one or more disorders associated with or affected by (e.g., downstream of) the translation of the MYC RNA transcript into a protein. Thus, in certain embodiments, the present invention provides a method for treating an MYC- mediated disorder comprising the step of administering to a subject in need thereof a compound of the present invention, or pharmaceutically acceptable salt or composition thereof.

[0231] As described below, the present invention also provides methods for the treatment or prevention of a proliferative disorder (e.g., cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinfl ammatory disease, or autoimmune disease) or an infectious disease (e.g., a viral disease) in a subject. Such methods comprise the step of administering to the subject in need thereof an effective amount of a disclosed compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer, or a pharmaceutical composition thereof.

[0232] In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject 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, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.

[0233] The present disclosure provides treatment modalities, methods, strategies, compositions, combinations, and dosage forms for the treatment of various diseases, disorders, and conditions. In some embodiments, the disease, disorder, or condition is a proliferative disorder, such as one associated with aberrant activity or function of the Myc protein. In some embodiments, the MYc protein is c-Myc.

[0234] In some embodiments, the disease, disorder, or condition is MYC-mediated. As used herein, a “MYC-mediated” disease, disorder, or condition is one in which a MYC RNA transcript, or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof, or its downstream protein, or a mutant or homolog thereof, is associated or plays a causative role. In some embodiments, “MYC-mediated” means that the disease, disorder, or condition is capable of being treated, ameliorated, or prevented by modulating the activity of a MYC RNA transcript, or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof, or itsdownstream protein. In some embodiments, “MYC -mediated” means that the disease, disorder, or condition is affected by (e.g., downstream of) the MY C RNA transcript, or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof, or the protein expressed thereof. It should be appreciated that, in some aspects, the disclosure provides compounds and methods for the treatment of c-MYC mediated diseases that are associated with the presence of a specific isoform or close homologs thereof. Exemplary MYC-mediated diseases, disorders, and conditions include those described herein, such as cancer.

[0235] In some embodiments, a MYC-mediated disease, disorder, or condition is one related to, caused by and / or associated with abnormal or excessive activity and / or expression of, or abnormal tissue or inter- or intracellular distribution of a Myc protein, e.g., c-Myc, or a mutant or homolog thereof. In some embodiments, the MYC-mediated disease, disorder, or condition is one treatable by modulation of the expression level, activity, or splicing of a MYC RNA transcript, or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof. In some embodiments, the MYC-mediated disorder is caused by and / or associated with a deleterious mutation in a MYC gene or gene product thereof. In some embodiments, the MYC-mediated disorder is caused by and / or associated with dysregulation of a MYC RNA transcript, or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof, or a MYC gene or a gene product thereof. In some embodiments, the MYC-mediated disease, disorder, or condition is a cancer, such as a cancer with increased expression levels of Myc protein, or a mutant or homolog thereof. In some embodiments, the Myc protein is c-Myc. In some embodiments, the Myc protein is N-Myc or L-Myc.

[0236] In some embodiments, the MYC-mediated disease, disorder, or condition is one associated with deregulation of MYC expression, such as a proliferative disorder that is characterized by deregulated activity of c-Myc or other Myc family members comprising N-Myc or L-Myc.

[0237] In some embodiments, the deregulated Myc activity comprises overexpression of c-Myc or other Myc family members comprising N-Myc or L-Myc.

[0238] In some embodiments, the deregulated Myc activity comprises an aberrant functionality of c-Myc or other Myc family members comprising N-Myc or L-Myc. In some embodiments, the aberrant functionality is aberrant activity as a transcription factor. In some embodiments, the aberrant functionality is aberrant activation of downstream protein.

[0239] In some embodiments, the proliferative disorder is selected from cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases. In other embodiments, the present invention provides methods for treating and / or preventing an infectious disease (e.g., a viral infection).

[0240] In some embodiments, the proliferative disorder is a cancer comprising breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer.

[0241] In some embodiments, the MYC-mediated disease, disorder, or condition is Burkitt lymphoma, aB cell lymphoma (such as high grade B-cell lymphoma with MYC and / or Bcl2 and / or Bcl6 rearrangement), non-Burkitt lymphoma, a diffuse large B-cell lymphoma (DLBL), ovarian cancer, neuroblastoma, myeloid leukemia, chronic myeloid leukemia (CML), multiple myeloma, gastric cancer, bladder cancer, small cell lung cancer, thyroid carcinoma, retinoblastoma, or alvelolar rhabdomyosarcoma. In some embodiments, the cancer is lymphoma, melanoma, prostate, breast, colorectal, lung, pancreatic, gastric, gastrointestinal, ovarian, or uterine cancer.

[0242] In some embodiments, the MYC-mediated disease, disorder, or condition is lymphoma. In some embodiments, the lymphoma is Burkitt lymphoma, a B cell lymphoma (such as high-grade B-cell lymphoma with MYC and / or Bcl2 and / or Bcl6 rearrangement), non-Burkitt lymphoma, or a diffuse large B-cell lymphoma (DLBL).

[0243] In some embodiments, the cancer is ovarian cancer, neuroblastoma, myeloid leukemia, chronic myeloid leukemia (CML), multiple myeloma, gastric cancer, bladder cancer, small cell lung cancer, thyroid carcinoma, retinoblastoma, or alvelolar rhabdomyosarcoma. In some embodiments, the cancer is lymphoma, melanoma, prostate, breast, colorectal, lung, pancreatic, gastric, gastrointestinal, ovarian, or uterine cancer.

[0244] In some embodiments, the cancer is selected from hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B- cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin’s lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin’s lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuselarge B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T- lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above.

[0245] In some embodiments, the cancer is selected from a hematological cancer, such as: chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), multiple myeloma, acute lymphoid leukemia (ALL), Hodgkin lymphoma, B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), small lymphocytic leukemia (SLL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt’s lymphoma, diffuse large B cell lymphoma (DLBCL), DLBCL associated with chronic inflammation, chronic myeloid leukemia, myeloproliferative neoplasms, follicular lymphoma, pediatric follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma (extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue), Marginal zone lymphoma, myelodysplasia, myelodysplastic syndrome, nonHodgkin’s lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom’s macroglobulinemia, splenic marginal zone lymphoma, splenic lymphoma / leukemia, splenic diffuse red pulp small B-cell lymphoma, hairy cell leukemia-variant, lymphoplasmacytic lymphoma, a heavy chain disease, plasma cell myeloma, solitary plasmocytoma of bone, extraosseous plasmocytoma, nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, primary cutaneous follicle center lymphoma, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, large B-cell lymphoma arising in HHV8-associatedmulticentric Castleman disease, primary effusion lymphoma, B-cell lymphoma, acute myeloid leukemia (AML), or unclassifiable lymphoma.

[0246] In certain embodiments, the cancer is associated with dependence on BCL-2 anti-apoptotic proteins (e.g., MCL-1 and / or XIAP). In certain embodiments, the proliferative disorder is a cancer associated with overexpression of Myc. In certain embodiments, the proliferative disorder is a hematological malignancy. In certain embodiments, the proliferative disorder is a blood cancer.In certain embodiments, the proliferative disorder is leukemia. In certain embodiments, the proliferative disorder is chronic lymphocytic leukemia (CLL). In certain embodiments, the proliferative disorder is acute lymphoblastic leukemia (ALL). In certain embodiments, the proliferative disorder is T-cell acute lymphoblastic leukemia (T-ALL). In certain embodiments, the proliferative disorder is chronic myelogenous leukemia (CML). In certain embodiments, the proliferative disorder is acute myelogenous leukemia (AML). In certain embodiments, the proliferative disorder is lymphoma. In certain embodiments, the proliferative disorder is melanoma. In certain embodiments, the proliferative disorder is multiple myeloma. In certain embodiments, the proliferative disorder is bone cancer. In certain embodiments, the proliferative disorder is osteosarcoma. In some embodiments, the proliferative disorder is Ewing's sarcoma. In some embodiments, the proliferative disorder is triple-negative breast cancer (TNBC). In some embodiments, the proliferative disorder is brain cancer. In some embodiments, the proliferative disorder is neuroblastoma. In some embodiments, the proliferative disorder is lung cancer. In some embodiments, the proliferative disorder is small cell lung cancer (SCLC). In some embodiments, the proliferative disorder is non-small cell lung cancer (NSCLC). In some embodiments, the proliferative disorder is large cell lung cancer. In some embodiments, the proliferative disorder is a benign neoplasm. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the invention.

[0247] In some embodiments, the proliferative disorder is a disorder of angiogenesis. In some embodiments, the proliferative disorder is selected from an ocular disorder, such as edema or neovascularization for any occlusive or inflammatory retinal vascular disease, such as rubeosis irides, neovascular glaucoma, pterygium, vascularized glaucoma fdtering blebs, conjunctival papilloma; choroidal neovascularization, such as neovascular age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema, such as post-surgical macular edema, macular edema secondary to uveitis including retinal and / or choroidal inflammation,macular edema secondary to diabetes, and macular edema secondary to retinovascular occlusive disease (i.e. branch and central retinal vein occlusion); retinal neovascularization due to diabetes, such as retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, or Eale’s Disease; and genetic disorders, such as VonHippel-Lindau syndrome. In some embodiments, the neovascular age-related macular degeneration is wet age-related macular degeneration. In other embodiments, the neovascular age- related macular degeneration is dry age-related macular degeneration and the patient is characterized as being at increased risk of developing wet age-related macular degeneration.

[0248] In another aspect, the present invention provides methods of reducing transcription of a gene upregulated in a proliferative disorder (e.g., cancers such as breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases), comprising administering to a subject in need thereof or contacting a biological sample with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0249] In another aspect, the present invention provides methods of inducing apoptosis of a cell in a biological sample or a subject, comprising administering to the subject or contacting the cell in a biological sample with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the apoptosis is triggered by c-Myc or other Myc family members (e.g., N-Myc or L-Myc).

[0250] In another aspect, the present invention provides a method of inducing terminal differentiation of a cell in a biological sample or subject, comprising administering to the subject or contacting the cell in a biological sample with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the terminal differentiation is triggered by c-Myc or other Myc family members (e.g., N-Myc or L-Myc).

[0251] In another aspect, the present invention provides a method of inducing senescence of a cell in a biological sample or subject, comprising administering to the subject or contacting the cell in a biological sample with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the senescence is triggered by c-Myc or other Myc family members (e.g., N-Myc or L-Myc).

[0252] In some embodiments, the MYC-mediated disease, disorder or condition is a proliferative disease. A “proliferative disorder,” as used herein, 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; hereby incorporated by reference). In some embodiments, a proliferative disorder is associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, autoinfl ammatory diseases, and autoimmune diseases.

[0253] 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 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.

[0254] As used herein, the term “cancer” refers to a malignant neoplasm (Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990; hereby incorporated by reference). Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma,lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endothelio sarcoma (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; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin’s lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin’s lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T- lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixtureof one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma, clear cell renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine 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 adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0255] The term “angiogenesis” refers to the formation and the growth of new blood vessels. Normal angiogenesis occurs in the healthy body of a subject for healing wounds and for restoring blood flow to tissues after injury. The healthy body controls angiogenesis through a number of means, e.g., angiogenesis-stimulating growth factors and angiogenesis inhibitors. Many diseasestates, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal angiogenesis refers to angiogenesis greater than that in a normal body, especially angiogenesis in an adult not related to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels that feed diseased tissues and / or destroy normal tissues, and in the case of cancer, the new vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).

[0256] As used herein, an “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non- infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis,chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.

[0257] As used herein, “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid, arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barre syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0258] The term “ autoinfl ammatory disease” refers to a category of diseases that are similar but different from autoimmune diseases. Autoinflammatory and autoimmune diseases share common characteristics in that both groups of disorders result from the immune system attacking a subject’s own tissues and result in increased inflammation. In autoinflammatory diseases, a subject’s innate immune system causes inflammation for unknown reasons. The innate immune system reacts even though it has never encountered autoantibodies or antigens in the subject. Autoinflammatory disorders are characterized by intense episodes of inflammation that result in such symptoms as fever, rash, or joint swelling. These diseases also carry the risk of amyloidosis, a potentially fatalI l lbuildup of a blood protein in vital organs. Autoinflammatory diseases include, but are not limited to, familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), deficiency of the interleukin-1 receptor antagonist (DIRA), and Behcet’s disease.

[0259] 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, mucus, 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. Biological samples also include those biological samples that are transgenic, such as transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus.

[0260] In some embodiments, a subject in need thereof has refractory or resistant cancer. “Refractory or resistant cancer” means cancer that does not respond to an established line of treatment. In some embodiments, the cancer is resistant at the beginning of treatment or becomes resistant during treatment. In some embodiments, the subject in need thereof has cancer recurrence following remission after the most recent therapy. In some embodiments, the subject in need thereof received and failed all known effective therapies for cancer treatment. In some embodiments, the subject in need thereof received at least one prior therapy. In some embodiments, the prior therapy is monotherapy. In some embodiments, the prior therapy is combination therapy.

[0261] In some embodiments, a subject in need thereof has a secondary cancer as a result of a previous therapy. “Secondary cancer” means cancer that arises due to or as a result from previous carcinogenic therapies, such as chemotherapy.

[0262] As used herein, the term “responsiveness” is interchangeable with terms “responsive,” “sensitive,” and “sensitivity,” and it is meant that a subject is showing a therapeutic response when administered a composition of the disclosure, e.g., tumor cells or tumor tissues of the subject undergo apoptosis and / or necrosis, and / or display reduced growing, dividing, or proliferation. Insome embodiments, a “response” also means that a subject will have or has a higher probability, relative to the population at large, of showing therapeutic responses when administered a disclosed compound, e.g., tumor cells or tumor tissues of the subject undergo apoptosis and / or necrosis, and / or display reduced growing, dividing, or proliferation.

[0263] In some embodiments, the compounds provided herein modulate a Myc protein or a MYC RNA transcript. Modulating refers to stimulating or inhibiting an activity of a target (e.g. aberrant functionality of a protein, or ability to be translated of an RNA). In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate or hydrate thereof, modulates the activity of a target if it stimulates or inhibits the activity of the target by at least 2-fold relative to the activity of the target under the same conditions but lacking only the presence of the compound. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, modulates the activity of a target if it stimulates or inhibits the activity of the target by at least 5 -fold, at least 10-fold, at least 20-fold, at least 50- fold, at least 100-fold relative to the activity of the target under the same conditions but lacking only the presence of the compound. The activity of a target may be measured by any reproducible means. The activity of a target may be measured in vitro or in vivo, by methods such as those described herein.

[0264] In some embodiments, treating cancer or a proliferative disorder results in cell death. In some embodiments, cell death results in a decrease of at least 10% in number of cells in a population. In some embodiments, cell death means a decrease of at least 20%; at least 30%; at least 40%; at least 50%; or at least 75%. Number of cells in a population may be measured by any reproducible means. A number of cells in a population can be measured by fluorescence activated cell sorting (FACS), immunofluorescence microscopy and light microscopy. Methods of measuring cell death are as shown in Li et al., Proc Natl Acad Sci USA, 100(5): 2674-8, 2003. In some embodiments, cell death occurs by apoptosis.

[0265] In some embodiments, an effective amount of a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, is not significantly cytotoxic to normal cells. A therapeutically effective amount of a compound is not significantly cytotoxic to normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells. A therapeutically effective amount of a compound does not significantly affect the viability of normal cells if administration of the compound in a therapeutically effectiveamount does not induce cell death in greater than 10% of normal cells. In some aspects, cell death occurs by apoptosis.

[0266] In some embodiments, contacting a cell with a disclosed compound, or a pharmaceutically acceptable salt or solvate or hydrate thereof, induces or activates cell death selectively in cancer cells.

[0267] In some embodiments, the present invention provides a method of treating or preventing cancer by administering an effective amount of a disclosed compound, or a pharmaceutically acceptable salt or solvate or hydrate thereof, to a subject in need thereof, wherein administration of the compound, or a pharmaceutically acceptable salt or solvate or hydrate thereof, results in one or more of the following: prevention of cancer cell proliferation by accumulation of cells in one or more phases of the cell cycle (e.g. Gl, Gl / S, G2 / M), or induction of cell senescence, or promotion of tumor cell differentiation; promotion of cell death in cancer cells via cytotoxicity, necrosis or apoptosis, without a significant amount of cell death in normal cells, antitumor activity in animals with a therapeutic index of at least 2. As used herein, “therapeutic index” is the maximum tolerated dose divided by the efficacious dose.

[0268] One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al. , Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al. , Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al. , Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), and Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990); each of which is hereby incorporated by reference in its entirety. These texts can, of course, also be referred to in making or using an aspect of the disclosure.Combination Therapies

[0269] The disclosure also provides pharmaceutical compositions comprising a compound of the disclosure or pharmaceutically acceptable salts thereof, and one or more other therapeutic agents disclosed herein, mixed with pharmaceutically suitable carriers or excipient(s) at doses to treat or prevent a disease or condition as described herein. The pharmaceutical compositions of thedisclosure can also be administered in combination with other therapeutic agents or therapeutic modalities simultaneously, sequentially, or in alternation.

[0270] Mixtures of compositions of the disclosure can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. For example, some aspects of the disclosure relate to a pharmaceutical composition comprising a therapeutically effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, enantiomer or stereoisomer thereof; one or more other therapeutic agents, and a pharmaceutically acceptable diluent or carrier.

[0271] A “pharmaceutical composition” is a formulation containing the compounds of the disclosure in a form suitable for administration to a subject. A compound of the disclosure and one or more other therapeutic agents described herein each can be formulated individually or in multiple pharmaceutical compositions in any combinations of the active ingredients.

[0272] Accordingly, one or more administration routes can be properly elected based on the dosage form of each pharmaceutical composition. Alternatively, a compound of the disclosure and one or more other therapeutic agents described herein can be formulated as one pharmaceutical composition.

[0273] In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0274] A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0275] A composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, for treatment of cancers, a compound of the disclosure may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0276] The term “therapeutically effective amount,” as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. In some aspects, the disease or condition to be treated is cancer. In some aspects, the disease or condition to be treated is a proliferative disorder.

[0277] In certain embodiments the therapeutically effective amount of each pharmaceutical agent used in combination will be lower when used in combination in comparison to monotherapy witheach agent alone. Such lower therapeutically effective amount could afford for lower toxicity of the therapeutic regimen.

[0278] For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0279] The additional pharmaceutical agent(s) may synergistically augment suppression of aberrant functionality of c-Myc or other Myc family members (e.g., N-Myc or L-Myc) induced by the inventive compounds or compositions of this invention in the biological sample or subject. In certain embodiments, the additional pharmaceutical agent is flavopiridol, triptolide, SNS-032 (BMS-387032), PHA-767491, PHA-793887, BS-181, (S)-CR8, (R)-CR8, ABT-737, or NU6140. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a mitogen-activated protein kinase (MAPK). In certain embodiments, the additional pharmaceutical agent is an inhibitor of a Bcl-2 protein. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a glycogen synthase kinase 3 (GSK3). In certain embodiments, the additional pharmaceutical agent is an inhibitor of an AGC kinase. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a CaM kinase. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a casein kinase 1. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a STE kinase. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a tyrosine kinase. Thus, the combination of the inventive compounds or compositions and the additional pharmaceutical agent(s) may be useful in treating proliferative disorders resistant to a treatment using the additional pharmaceutical agent(s) without the inventive compounds or compositions.

[0280] In certain embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In certain embodiments, the immune checkpoint inhibitor is selected from nivolumab (anti -PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-Ll antibody, Imfinzi®, AstraZeneca); avelumab (Bavencio®, Pfizer / Merck KGaA), also known as MSB0010718C); pidilizumab (CureTech), also known as CT-011; or atezolizumab (anti-PD-Ll antibody, Tecentriq®, Genentech).

[0281] In certain embodiments, the additional pharmaceutical agent is a targeted therapeutic or an immunomodulatory drug. In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics which may be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

[0282] In certain embodiments, the additional pharmaceutical agent is a a T-cell engineered to express a chimeric antigen receptor, or CAR. The T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells. CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes. Upon antigen binding, such CARs link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex.

[0283] A disclosed compound of the current invention may also be used to advantage in combination with an antiproliferative compound. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting / decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase;gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17- allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17- demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin. The term “aromatase inhibitor” as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[0284] The term “anti estrogen” as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

[0285] The term “anti-androgen” as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to,bicalutamide (Casodex™). The term “gonadorelin agonist” as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0286] The term “topoisomerase I inhibitor” as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark Camptosar™. Topotecan is marketed under the trade name Hy camptin™.

[0287] The term “topoisomerase II inhibitor” as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as Caelyx™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

[0288] The term “microtubule active agent” relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vincristine sulfate is marketed under the trade name Farmistin™.

[0289] The term “alkylating agent” as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[0290] The term “histone deacetylase inhibitors” or “HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0291] The term “antineoplastic antimetabolite” includes, but is not limited to, 5 -fluorouracil or 5- FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[0292] The term “platin compound” as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Eloxatin™.

[0293] The term “compounds targeting / decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds” as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF- IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which targetdecrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine / threonine kinases, members of the MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC family, and / or members of the cyclin- dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Penfosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a PI3K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23 / RG- 50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, El.l, E2.4, E2.5, E6.2, E6.4, E2.l l, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pynmidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing orinhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparhsib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[0294] The term “PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidy linositol-3 -kinase family, including, but not limited to PI3Ka, PI3Ky, PI3K5, PI3K0, PI3K-C2a, PI3K-C20, PI3K-C2y, Vps34, pl 10-a, pl 10-0, pl 10-y, pl 10-5, p85-a, p85-0, p55-y, pl50, p 101 , and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparhsib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0295] The term “Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT- 199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogues thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogues thereof; see W02008118802), navitoclax (and analogues thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogues thereof, see WO 2004 / 106328, hereby incorporated by reference), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ, of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl- 2 inhibitor is a peptidomimetic.

[0296] The term “BTK inhibitor” as used herein includes, but is not limited to, compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL- 292 and ibrutinib.

[0297] The term “SYK inhibitor” as used herein includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0298] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO 2008 / 039218 and WO 2011 / 090760, the entirety of which are incorporated herein by reference.

[0299] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO 2003 / 063794, WO 2005 / 007623, and WO 2006 / 078846, the entirety of which are incorporated herein by reference.

[0300] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO 2004 / 019973, WO 2004 / 089925, WO 2007 / 016176, US 8,138,347, WO 2002 / 088112, WO 2007 / 084786, WO 2007 / 129161, WO 2006 / 122806, WO 2005 / 113554, and WO 2007 / 044729 the entirety of which are incorporated herein by reference.

[0301] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO 2009 / 114512, WO 2008 / 109943, WO 2007 / 053452, WO 2000 / 142246, and WO 2007 / 070514, the entirety of which are incorporated herein by reference.

[0302] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and TNP-470.

[0303] Examples of proteasome inhibitors useful for use in combination with a disclosed compound include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3 -gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0304] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[0305] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, a- y- or 3- tocopherol or a- y- or 3-tocotrienol.

[0306] The term “cyclooxygenase inhibitor” as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl- 2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.

[0307] The term “bisphosphonates” as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the tradename Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term “mTOR inhibitors” relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0308] The term “heparanase inhibitor” as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term “biological response modifier” as used herein refers to a lymphokine or interferons.

[0309] The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a “famesyl transferase inhibitor” such as L-744832, DK8G557 or R115777 (Zamestra™). The term “telomerase inhibitor” as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase enzyme, such as telomestatin.

[0310] The term “methionine aminopeptidase inhibitor” as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[0311] The term “proteasome inhibitor” as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (Velcade™) and MLN 341.

[0312] The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0313] The term “compounds used in the treatment of hematologic malignancies” as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting,decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1- P-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.

[0314] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.

[0315] The term “HSP90 inhibitors” as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HD AC inhibitors.

[0316] The term “antiproliferative antibodies” as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab -DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.

[0317] For the treatment of acute myeloid leukemia (AML), a disclosed compound can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, a disclosed compound can be administered in combination with, for example, famesyl transferase inhibitors and / or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

[0318] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analogue, which is the 2'-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analogue of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HD AC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA,FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl){2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term “ionizing radiation” referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4thEdition, Vol. 1, pp. 248-275 (1993).

[0319] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term “ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogues including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l, 3-dione derivatives.

[0320] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (A vastin™).

[0321] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.

[0322] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol,cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

[0323] In some embodiments, the co-administered therapeutic is selected from an indoleamine (2,3 )-di oxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP) inhibitor, a histone deacetylase (HD AC) inhibitor, a CDK4 / CDK6 inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor.

[0324] In some embodiments, the IDO inhibitor is selected from epacadostat, indoximod, capmanitib, GDC-0919, PF-06840003, BMS:F001287, Phy906 / KD108, or an enzyme that breaks down kynurenine.

[0325] In some embodiments, the PARP inhibitor is selected from olaparib, rucaparib, or niraparib.

[0326] In some embodiments, the HDAC inhibitor is selected from vorinostat, romidepsin, panobinostat, belinostat, entinostat, or chidamide.

[0327] In some embodiments, the CDK 4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib or trilaciclib.

[0328] In some embodiments, the additional therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include bevacizumab (Avastin®, Genentech / Roche) an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors, such as cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib (Sutent®,Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

[0329] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0330] In some embodiments, the additional therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. Approved mTOR inhibitors useful in the present invention include everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0331] Other co-administered chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; or a shRNA or siRNA therapeutic.

[0332] In some embodiments, the co-administered therapy comprises an aurora kinase inhibitor, such as VX-680. In some embodiments, the co-administered aurora kinase inhibitor is selected from VX-680 (MK-0457), Barasertib (AZDI 152), Alisertib (MLN8237), MLN8054, Danusertib (PHA-739358), PHA-680632, AT9283, PF-03814735, AMG 900, ZM 447439, SNS-314 Mesylate, BI-847325, TAK-901, CCT137690, GSK1070916, ENMD-2076, CCT129202, CYC116, MK-5108 (VX-689), SNS-314, KW-2449, JNJ-7706621, or reversine.

[0333] In some embodiments, the co-administered therapy comprises radiotherapy.Formulations and Routes of Administration

[0334] The compounds and compositions, according to a method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer or other disease, disorder, or condition disclosed herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition ofthe subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0335] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0336] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0337] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0338] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0339] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0340] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0341] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert,pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fdlers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0342] Solid compositions of a similar type may also be employed as fillers in soft and hard-fdled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fdlers in soft and hard-fdled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0343] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0344] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.REFERENCES

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[0369] Wolfe AL, Singh K, Zhong Y, Drewe P, Rajasekhar VK, Sanghvi VR, Mavrakis KJ, Jiang M, Roderick JE, derMeulen J, Schatz JH, Rodrigo CM, Zhao C, RondouP, de StanchinaE, Teruya- Feldstein J, Kelliher MA, Speleman F, Porco JA, Pelletier J, Ratsch G & Wendel HG. 2014. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513: 65-70.EXEMPLIFICATION

[0370] As depicted in the Examples below, exemplary compounds are prepared according to the following general procedures and used in biological assays and other procedures described generally herein. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Similarly, assays and other analyses can be adapted according to the knowledge of one of ordinary skill in the art.Example 1: Synthesis of Exemplary rSM CompoundsLCMS and HPLC Methods

[0371] The following LCMS and HPLC methods were used in compound preparation and characterization.

[0372] LCMS Method A: Column: Zorbax Eclipse Plus C18 (50x2.1 mm, 1.8 pm); Column Temperature: 40°C; Detection: UV @ 210-400 nm; Sample Diluent: Acetonitrile; Mobile Phase A: Water (with 0.1% FA); Mobile Phase B: Acetonitrile (with 0.1% FA); Flowrate: 0.8 mL / Min; Gradient Program (time (min) / %B): 0.0 / 5, 0.25 / 5, 2.5 / 95, 3.5 / 95, 3.6 / 5, 4.0 / 5.

[0373] LCMS Method B: Column: XBridge C8 (4.6x50mm, 3.5 gm); Column Temperature: 40°C; Detection: UV @ 210-400 nm; Sample Diluent: Acetonitrile; Mobile Phase A: Water (lOmM Ammonium bicarbonate); Mobile Phase B: Acetonitrile; Flowrate: 0.8 mL / Min; Gradient Program (time (min) / %B): 0.1 / 5, 0.20 / 5, 2.5 / 98, 3.55 / 98, 3.6 / 5, 4.0 / 5.

[0374] LCMS Method C: Column: Zorbax Eclipse Plus C18 (50x2.1 mm, 1.8 pm); Column Temperature: 40°C; Detection: UV @ 210-400 nm; Sample Diluent: Acetonitrile; Mobile Phase A: Water (with 0.1% TFA); Mobile Phase B: Acetonitrile; Flowrate: 0.8 mL / Min; Gradient Program (time (min) / %B): 0.0 / 5, 0.3 / 5, 2.5 / 95, 3.5 / 95, 3.6 / 5, 4.0 / 5.

[0375] HPLC Method A: Column: X-select CSH C18 (150 x 4.6 mm, 5.0 pm); Column Temperature: ambient; Detection: UV @ 210-400 nm; Sample Diluent: Acetonitrile and Water; Mobile Phase A: Water (with 0.1% FA); Mobile Phase B: Acetonitrile; Runtime: 10.0 min; Flowrate: 2 mL / Min; Elution: Gradient Elution; Gradient Program (time (min) / %B): 0.0 / 5, 8 / 100, 8.01 / 5, 10 / 5.

[0376] HPLC Method B: Column: X-select CSH C18 (150 x 4.6 mm, 5.0 pm); Column Temperature: ambient; Detection: UV @ 210-400 nm; Sample Diluent: Acetonitrile and Water; Mobile Phase A: Water (with 0.1% TFA); Mobile Phase B: Acetonitrile; Runtime: 10.0 min; Flowrate: 2 mL / Min; Elution: Gradient Elution; Gradient Program (time (min) / %B): 0.0 / 5, 8 / 100, 8.01 / 5, 10 / 5.

[0377] HPLC Method C: Column: X-Bridge C8 (150 x 4.6 mm, 5.0 pm); Column Temperature: ambient; Detection: UV @ 210-400 nm; Sample Diluent: Acetonitrile and Water; Mobile Phase A: Water (with 10 mM ammonium bicarbonate); Mobile Phase B: Acetonitrile; Runtime: 10.0 min; Flowrate: 2 mL / Min; Elution: Gradient Elution; Gradient Program (time (min) / %B): 0.0 / 5, 8 / 100, 8.01 / 5, 10 / 5.

[0378] HPLC Method D: Column: X-Bridge C8 (150 x 4.6 mm, 5.0 pm); Column Temperature: ambient; Detection: UV @ 210-400 nm; Sample Diluent: Acetonitrile and Water; Mobile Phase A: Water (with 10 mM ammonium actetate); Mobile Phase B: Acetonitrile; Runtime: 10.0 min; Flowrate: 2 mL / Min; Elution: Gradient Elution; Gradient Program (time (min) / %B): 0.0 / 5, 8 / 100, 8.01 / 5, 10 / 5

[0379] Synthesis of 2-(2-(3-(3,4-dimethoxyphenethyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)isoindoline-l, 3-dione (1-1):

[0380] To a stirred solution of 2-aminobenzoic acid (50 mg, 364.1 mmol) in pyridine (2.5 mL) in a sealed vial, 3-(l,3-dioxoisoindolin-2-yl) propanoic acid (79.7 mg, 364.1 mmol), and triphenyl phosphite (124 mg, 400 mmol) were added at 25 °C. The reaction mixture was stirred at 100 °C for 2 h. After checking the formation of benzo[c / ][ l ,3]oxazin-4-one intermediate (by UPLC / LCMS), 2-(3,4-dimethoxyphenyl)ethan-l -amine (98.9 mg, 364.1 mmol) was added and the reaction was continued to stir at the same temperature for 16 h. After completion of the reaction by UPLC, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (Si02 / 100-200 mesh; 0-100% EtOAc / hexanes) to afford 2-(2-(3-(3,4-dimethoxy phenethyl)-4-oxo-3,4-dihydroquinazolin-2-yl) ethyl) iso in doline - 1,3-dione (1-1) (45.0 g, 46 % yield) as a white solid. ' H-NMR (400 MHz, CDCh) 8 8.30 (dd, J = 8.0, 1.5 Hz, 1H), 7.87 (dd, J= 5.5, 3.1 Hz, 2H), 7.79 - 7.69 (m, 3H), 7.62 (d, J= 8.1 Hz, 1H), 7.49 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 6.85 - 6.74 (m, 3H), 4.34 (t, J = 7.5 Hz, 2H), 4.22 (t, J = 7.5 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.09 (t, J= 7.6 Hz, 2H), 3.02 (t, J= 7.5 Hz, 2H).Chemical Formula: C28H25N3O5, Exact Mass: 483.18, Molecular Weight: 483.52. LCMS (APCI) m / z = 484.2 (M+H), tR= 2.117 mm, 99.1% (Method-A), HPLC: 98.8%, tR= 6.612 mm, (Method-A).Table 3. Compound Characterization DataExample 2: Cell Line Viability Screen

[0381] On day 0, cells will be plated at 4.4x10A3 in 96-well plates and will be incubated in humidified incubator at 37°C with 5% CO2 overnight. On day 1, cells will be treated with compound in a 9-point dose response with the highest compound concentration at 10 pM and with 3.16-fold dilutions in triplicate. Cisplatin at 100 pM will be used as positive control. Cells will be incubated in a humidified incubator at 37°C with 5% CO2 for 72 hours. On day 4, plates will be incubated at room temperature for 30 minutes. CellTiter-Glo reagent (Promega) will be added to each well, followed by a 5 minute incubation on an orbital shaker. Plates will then be incubated for 20 minutes at room temperature and the signal will be read using EnVision Multi Label Reader. In order to calculate the absolute IC50, a dose-response curve will be fitted using a nonlinearregression model with a sigmoidal dose response and the absolute IC50 will be calculated according to the dose-response curve.Example 3: Targeted translation via BONCAT (Bioorthogonal Noncanonical Amino Acid Tagging) labeling

[0382] On the day of the experiment, 10A6Daudi cells were washed with IX PBS, resuspended in methionine-free RPMI with 10% tet-free FBS, and incubated for 30 min in a humidified incubator at 37°C. Cells were then incubated with 4mM azido-homoalanine (AHA) with the indicated compounds in DMSO or with a DMSO control in methionine-free RPMI. As a negative control for AHA-labeling, a sample was incubated with 100 mM L-methionine in methionine-free RPMI. Cells were then incubated in a humidified incubator at 37°C for the indicated times, washed with PBS, and the cell pellets were snap frozen on dry ice and stored at -80 °C until lysis.

[0383] Samples were lysed in 30% RIPA buffer + 70% BONCAT lysis buffer (25mM HEPES, lOOmM NaCl, NP-40, 5mM EDTA in water) plus protease and phosphatase inhibitors and incubated on ice for 20 minutes. The cleared lysates were then normalized for total protein content. Normalized lysates were incubated with 2mM biotin-DBCO with shaking at 700 rpm for 1 hour protected from light. Unreacted biotin was removed with biotin removal columns. At this point approximately 10% of the lysate was removed to keep as a total input for normalization. The remaining lysate was incubated with magnetic streptavidin beads at room temperature with endover-end rotation for 30 min. The beads were then washed 5X with IX PBS and 0.01% Tween- 20. For elution, the beads were incubated with 2X Laemmli buffer with BME and boiled at 95 °C for 10 minutes. Pulldown and input lysate were stored at -80 °C until detection.

[0384] To detect total and AHA-labeled MYC, input and pulldown samples were run on a JESS automated western blot machine. Antibodies used for detection were as follows: MYC (Abeam) and actin (Cell Signaling). To quantify newly synthesized MYC, MYC levels for the input samples were normalized to the actin loading control, and then the pulldown (AHA-labeled MYC) was normalized to input MY C levels at respective timepoints and data was plotted in Graphpad PRISM.

[0385] FIG. 2 shows that addition of compound 1-1 resulted in a lower level of AHA-labeled MYC protein (newly synthesized MYC) as compared to cells exposed to DMSO only.Example 4: MYC HiBiT Assay ProtocolHiBiT cell line generation:

[0386] Daudi and CA46 MYC-HiBiT cell lines were generated using CRISPR / Cas9 editing by inserting the HiBiT sequence into the MYC gene coding sequence directly prior to the endogenous stop codon. Briefly, guide RNAs (Synthego) were incubated with Cas9 protein (New England Biolabs) for 20 minutes at room temperature to generate ribonucleoprotein (RNP) complexes. Single stranded DNA repair template containing HiBiT sequence flanked by 80bp homology arms was added to RNP complexes along with 4x105cells resuspended in nucleofection buffer (Lonza) and then gently mixed. Cells plus repair template and RNP mixture were then transferred to 16- well cassettes followed by nucleofection. Cells were then recovered for 10 minutes at room temperature, resuspended in 0.7 mL RPMI+10% FBS at 37°C, transferred to 24-well plates and returned to humidified incubator at 37°C with 5% CO2 for recovery and cell line expansion.Daudi and CA46 MYC-HiBiT treatment and detection:

[0387] On day 0, Daudi MYC-HiBiT or CA46 MYC-HiBiT cells were split to 3x10A5 cells / mL in flasks and incubated at 37°C with 5% CO2 overnight. On day 1 cells were spun down and concentrated in their own conditioned media to 1.2xlOA6 cells / mL. To create assay ready plates, the Echo (Beckman) was used to dose compounds in DMSO into empty 384 well plates to create 11 -point dose responses with 30 or 1 pM high dose and 3 -fold dilutions in duplicate. Concentrated Daudi or CA46 cells were dispensed into assay ready plates at 100,000 cells / well; plates were incubated in humidified incubator at 37°C with 5% CO2 for 3 or 6 hours. To read out plates, 25uL HiBiT reagent (Promega) was added to each well followed by two-minute incubation on an orbital shaker. Plates were then spun down and incubated for 8 minutes at room temperature; signal was read using an EnVision Multi Label Reader. Data was formatted and uploaded to preconfigured protocols within Collaborative Drug Discovery to calculate IC50, IC90, and Emax.72 Hour viability assessment (CellTiter-Glo assay):

[0388] On day 0, Daudi, CA46, HEL, SUDHL5, or THP1 cells were split to 3xl0A5 cells / mL in flasks and incubated at 37°C with 5% CO2 overnight. On day 1, assay ready plates were prepared using an Echo (Beckman) to dose compounds in DMSO into empty 384 well plates to create 11- point dose responses with 30, 10 or 1 pM high dose and 3-fold dilutions in duplicate. Cells were diluted to 1 xl0A5 cells / mL and dispensed into assay ready plates at 40uL / well; plates were incubated in humidified incubator at 37°C with 5% CO2 for 72 hours. On day 4, plates were read out by addition of 40uL Cell Titre Gio reagent (Promega) to each well followed by ten-minuteincubation on an orbital shaker. Plates were then spun down and incubated for 10 minutes at room temperature. Signal was read using an EnVision Multi Label Reader. Data was formatted and uploaded to preconfigured protocols within Collaborative Drug Discovery to calculate IC50, IC90, and Emax. GraphPad PRISM was used to generate dose-response curve graphs.

[0389] The results are reported in Table 4. Compounds with an IC50 less than or equal to 1.0 pM are designated as “+++”. Compounds with an IC50 greater than 1.0 pM and less than or equal to 10 pM are designated as “++”. Compounds with an IC50 greater than 10 pM are designated asTable 4. Bioactivity DataExample 5: mRNA Transfection Assay ProtocolConstruct design:

[0390] Two reporter plasmids were generated by inserting sequences corresponding to the 5’UTR region of AST-380 or AST-381, respectively, in an expression vector followed by firefly luciferase coding sequence, hCLl and hPEST destabilization domain sequences, 3’UTR of RPS2 and a polyA site. mRNA was in vitro transcribed, capped, polyadenylated and stored in aliquots at -80 °C until day of transfection.Cell plating, transfection, compound dosing and signal detection:

[0391] On day 0, H1299 cells were plated at 105cells / well in 50pL in white 96-well plates and incubated in humidified incubator at 37°C with 5% CO2 overnight. On day 1, Lipofectamine MessengerMAX Transfection Reagent (Thermo) and Optimem were brought to room temperature. For a single reaction, 0.3pL of Lipofectamine MessengerMAX Transfection Reagent was incubated with 4.7pL of Optimem and incubated at room temperature for 10 minutes. During incubation, a second tube containing mRNA for final working concentration of 0.19ng was combined with Optimem for a total volume of 5 jiL. Lipofectamine mix and mRNA mix were then combined, mixed by inverting few times and incubated for an additional 5 minutes. The transfection mix was then diluted 1:5 in RPMI media containing 10% FBS and 50jiL was added to 96-well plate containing cells. Plates were then incubated in humidified incubator at 37°C with 5% CO2 for 60 minutes. Following transfection incubation, plates were removed and dosed with compounds or DMSO using Tecan 300e dispenser at concentrations indicated. Plates were then incubated at 37°C with 5% CO2 for either 90 minutes or 120 minutes. For detection, 100 pL of ONE-Glo buffer (Promega) was added per well, cells were lysed on orbital shaker for 5 min at 500 rpm, and luminescence was read using Envision plate reader. Data is plotted as the percent firefly luciferase signal for each reporter in the presence of compound relative to DMSO control. Data was analyzed and graphed using GraphPad PRISM. mRNA reporter transfection data for compound 1-1 is shown in FIG. 3.Example 6: MYC or N-MYC Protein Levels / Automated Western BlotTreatment and lysate collection:

[0392] Cell lines indicated were treated with compound or DMSO at indicated concentrations for 1.5 or 6 hours. Following treatment cell lines were washed lx with PBS and lysed in RIPA lysis buffer with the addition of protease and phosphatase inhibitors. Lysates were then cleared and total protein levels were determined using BCA Protein Assay (Pierce). Lysates were then normalized to equilibrate total protein concentration using RIPA buffer containing protease and phosphatase inhibitors.MYC and N-MYC detection and quantification:Lysates were prepared and run on FESS automated western machine (Protein Simple) for detection of MYC and N-MYC. To quantify the levels of MYC or N-MYC protein, MYC or N-MYC levelswere first normalized to internal loading controls either beta-actin, vinculin, or a combination of both. Normalized MYC or N-MYC values were used to determine MYC or N-MYC levels relative to DMSO controls. Data analysis and plotting was performed in GraphPad PRISM. Antibodies used for detection were as follows: MYC (Abeam), N-MYC (Cell Signaling), actin (loading control, Cell Signaling), and vinculin (loading control, Thermo). FIG. 4 shows MYC protein levels for compound 1-1 after 1.5 h treatment in Daudi and CA46.

[0393] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMSWe claim:

1. A compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered tricyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered tricyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring C is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring D is phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R1is independently Ci-6 straight or branched alkyl, alkenyl, or alkynyl group optionally substituted with 1, 2, or 3 deuterium or halogen atoms, and optionally substituted with one -OH, -CN, or NH2 group;, halogen, -CN, -C(O)RX, -C(O)ORX, -OC(O)RX, - C(O)N(RX)2, -N(RX)C(O)RX, -N(RX)C(O)N(RX)2, -OC(O)N(RX)2, -N(RX)C(O)ORX, -ORX, - N(RX)2, -NO2, -SRX, -S(O)RX, -S(O)2RX, -S(O)2N(RX)2, or -NRXS(O)2RX; each occurrence of R2is independently optionally substituted C1-6 aliphatic, halogen, -CN, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -NHC(NH)N(R)2, - OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or - NRS(O)2R; each occurrence of R3, R4, and R5is independently optionally substituted C1-6 aliphatic, halogen, -CN, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, - NHC(NH)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -SR, -S(O)R, -S(O)2R, - S(O)2N(R)2, or -NRS(O)2R; each occurrence of Rxis independently H or a C1-6 straight or branched alkyl, alkenyl, or alkynyl group optionally substituted with 1, 2, or 3 deuterium or halogen atoms;-L1- and -L2- are each independently a covalent bond or a C1-10 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently andoptionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-;-L3- and -L4- are each independently a covalent bond or a C1-10 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -N(R)C(NR)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-; each occurrence of X is independently N or C with a proviso that at most two X are N; each occurrence of R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each -Cy- is independently an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5;p is 0, 1, 2, 3, 4, or 5; q is 0, 1,2, 3, 4, or 5; and r is 0, 1,2, 3, 4, or 5.The compound of any one of claims 1 to 3, wherein Ring C is selected fromwherein Ring C is substituted with q instances of R4.

6. The compound of any one of claims 1 to 5, wherein R1is selected from -OH, -F, -Br, -Cl,-OMe, -NO2, -CH3, -CH2CH3, -CF3, -OCF3, -CMe3, -NMe2, -NHC(O)CH3, -CN, and -SO2Me.

7. The compound of any one of claims 1 to 6, wherein R2is independently selected from - OH, -OMe, methyl, vinyl, -CH2OH, -OCH(CH3)2, -NHSO2Me, -NHC(O)CH3, -CN, -CH2OCH3, -SO2Me, and -C(O)NMe2.

8. The compound of any one of claims 1 to 7, wherein R3is selected from -OMe, -OEt, - OH, methyl, ethyl, vinyl, propyl, -Cl, -Br, -F, -SO2NH2, -OCF3, -SO2NHEt, -NEt2, -C(O)NMe2, - NH2, -CF3, -C(O)OCH3, and -NHC(O)CH3.

9. The compound of any one of claims 1 to 8, wherein R4is selected from -Me, -OH, - CH2OMe, and -CH2NMe2.

10. The compound of any one of claims 1 to 9, wherein R5is selected from -Me, -Et, -OMe, - F, and -C(O)CH3.

11. The compound of any one of claims 1 to 10, wherein L1is selected from -CH2-, -(CH2)2-,12. The compound of any one of claims 1 to 11, wherein L2is selected from -CH2-, -(CH2)2-,13. The compound of any one of claims 1 to 12, wherein L3is selected from a bond, -O-, -14. The compound of any one of claims 1 to 13, wherein L4is selected from a bond, -O-, -15. The compound of any one of claims 1 to 14, wherein the compound is of Formula II:II or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1 to 14, wherein the compound is of Formula III:or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1 to 14, wherein the compound is of Formula IV:or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 1 to 14, wherein the compound is of Formula V:V or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 1 to 14, wherein the compound is of Formula VI:or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1 to 14, wherein the compound is of Formula VII:or a pharmaceutically acceptable salt thereof.

21. The compound of any one of claims 1 to 14, wherein the compound is of Formula VIII:or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 1 to 14, wherein the compound is of Formula IX:or a pharmaceutically acceptable salt thereof.

23. The compound of any one of claims 1 to 14, wherein the compound is of Formula X:X or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 1 to 14, wherein the compound is of Formula XI:or a pharmaceutically acceptable salt thereof.

25. The compound of any one of claims 1 to 14, wherein the compound is of Formula XII:XII or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1 to 14, wherein the compound is of Formula Xlla:Xlla or a pharmaceutically acceptable salt thereof.

27. The compound of any one of claims 1 to 14, wherein the compound is of Formula Xllb:Xllbor a pharmaceutically acceptable salt thereof.

28. The compound of any one of claims 1 to 14, wherein the compound is of Formula XIIc:XIIc or a pharmaceutically acceptable salt thereof.

29. The compound of any one of claims 1 to 14, wherein the compound is of Formula XIII:or a pharmaceutically acceptable salt thereof.

30. The compound of any one of claims 1 to 14, wherein the compound is of Formula XIV:XIV or a pharmaceutically acceptable salt thereof.

31. The compound of any one of claims 1 to 14, wherein the compound is of Formula XV:XV or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 1 to 14, wherein the compound is of Formula XVI:XVI or a pharmaceutically acceptable salt thereof.

33. A compound selected from one of those shown in Table 2, or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient.

35. A method of treating a MYC-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of an RNA-modulating small molecule (rSM) to treat the MYC-mediated disease, disorder, or condition.

36. A method of treating a MYC-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof.

37. The method of claim 35 or 36, wherein the MYC-mediated disease, disorder, or condition is a cancer comprising breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer.

38. The method of any one of claims 35 to 37, wherein the MYC-mediated disease, disorder, or condition is Burkitt lymphoma, a B cell lymphoma, non-Burkitt lymphoma, a diffuse large B- cell lymphoma (DLBL), ovarian cancer, neuroblastoma, myeloid leukemia, chronic myeloid leukemia (CML), multiple myeloma, gastric cancer, bladder cancer, small cell lung cancer, thyroid carcinoma, retinoblastoma, or alvelolar rhabdomyosarcoma.

39. The method of any one of claims 35 to 38, wherein the MYC-mediated disease, disorder, or condition is selected from acute lymphocytic leukemia (ALL), acute myelocytic leukemia (AML), chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL); Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma,lymphoplasmacytic lymphoma (i.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma, peripheral T-cell lymphoma (PT CL), 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; or a mixture of one or more leukemia / lymphoma as described above.

40. The method of any one of claims 35 to 39, wherein the MYC-mediated disease, disorder, or condition is associated with aberrant functionality of a Myc protein.

41. The method of any one of claims 35 to 40, wherein administration of the rSM results in suppression of the aberrant functionality of the Myc protein.

42. The method of any one of claims 35 to 41, wherein the MYC-mediated disease, disorder, or condition is associated with overexpression of the Myc protein.

43. The method of any one of claims 35 to 42, wherein administration of the rSM modulates the expression level of a Myc protein.

44. The method of any one of claims 35 to 42, wherein administration of the rSM results in lowering of the expression level of a Myc protein.

45. The method of claim 43 or claim 44, wherein administration of the rSM results in suppression of the aberrant functionality of the Myc protein.

46. The method of any one of claims 40 to 45, wherein the Myc protein is c-Myc.

47. The method of any one of claims 35 to 46, wherein the rSM modulates a MYC RNA transcript.

48. The method of claim 47, wherein modulation of the MYC RNA transcript results in a reduction in Myc protein expression.

49. The method of claim 47 or claim 48, wherein the rSM binds the MYC RNA transcript.

50. The method of any one of claims 47 to 49, wherein the MYC RNA transcript comprises a 5' untranslated region (UTR) of MYC and an open reading frame (ORF) of MYC.

51. The method of claim 50, wherein the MYC RNA transcript includes a G-quadruplex sequence.

52. The method of claim 51, wherein the G-quadruplex sequence is in the 5' UTR.

53. The method of any one of claims 47 to 52, wherein the MYC RNA transcript comprises SEQ ID NO: 1 or a homologous sequence.

54. The method of any one of claims 47 to 52, wherein the MYC RNA transcript comprises SEQ ID NO:3 or a homologous sequence.

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