Methods and compounds for modulating huntington's disease

Abstract

The present disclosure relates to transcription modulator molecules having a first terminus, a second terminus, and an oligomeric backbone and methods for treating Huntington's disease (HD).

Description

METHODS AND COMPOUNDS FOR MODULATING HUNTINGTON’S DISEASE CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 587,622 filed on October 3, 2023 which is hereby incorporated by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] Disclosed herein are new chimeric heterocyclic polyamide compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods to modulate the expression of a target gene comprising the CAG trinucleotide repeat sequence in a subject are also provided for the treatment of diseases such as Huntington’s disease (“HD”).BACKGROUND OF THE DISCLOSURE

[0003] Huntington’s disease (“HD”) was first identified in the late 19thcentury as an autosomal dominant, neurodegenerative disorder. The symptoms of HD, which include a range of movement, cognitive and psychiatric disorders, generally appear in adulthood. HD is associated with the presence of the CAG trinucleotide repeat sequence in the huntingtin gene (HIT), which codes for a protein termed huntingtin. Subjects with more than about 36 trinucleotide repeat sequences generally present with symptoms of HD, with a larger number of trinucleotide repeat sequences associated with an earlier onset of symptoms. Pathology stems from a cascade of steps: production of poly-Q huntingtin, followed by fragmentation of the elongated huntingtin into smaller peptides, which bind together and accumulate in neurons. The effects of this cascade are pronounced in the basal ganglia and cortex of the brain.

[0004] Huntington’s disease-like syndrome refers to a group of ailments whose symptoms are similar to those of Huntington’s disease, but which lack the characteristic mutation in the HTT gene. Huntington’s disease-like 2 syndrome (“HDL2”) is associated with a count of about 40 or more CAG trinucleotide repeat sequences in the junctophilin 3 (Jph3) gene. HDL2 is a genetic disorder that has been seen in subjects with African lineage. Age of onset is inversely correlated with the number of trinucleotide repeat sequences. Symptoms of this syndrome include dystonia and chorea (uncontrolled movements), emotional disruptions, dysarthria, bradykinesia, inability to incorporate new learning, and difficulty in making decisions. Life expectancy can range from a few years post diagnosis to over a decade. The current theory holds that a poly- Q protein that is coded by the Jph3 gene forms aggregates in neuronal cells that is responsible for the pathology of the disease. However, evidence suggesting toxic gain-of-function of mRNA has also been uncovered, indicating a possible dual pathway for pathology.

[0005] In some embodiments, the mechanism set forth above provides opportunity for an effective treatment for a disease or disorder which is characterized by the presence of an excessive count of CAG trinucleotide repeat sequences in a target gene. In some embodiments, the pathology of the disease or disorder is due to the presence of mRNA containing an excessive count of CAG trinucleotide repeat sequences. In some embodiments, the pathology of the disease or disorder is due to the presence of a translation product containing an excessive count of glutamine amino acid residues. In some embodiments,the pathology of the disease or disorder is due to a loss of function in the translation product. In some embodiments, the pathology of the disease or disorder is due to a gain of function in the translation product. In some embodiments, the pathology of the disease or disorder can be alleviated by increasing the rate of transcription of the defective gene. In some embodiments, the pathology of the disease or disorder can be alleviated by decreasing the rate of transcription of the defective gene.SUMMARY OF THE DISCLOSURE

[0006] This disclosure utilizes regulatory molecules present in cell nuclei that control gene expression. Eukaryotic cells provide several mechanisms for controlling gene replication, transcription, and / or translation. Regulatory molecules that are produced by various biochemical mechanisms within the cell can modulate the various processes involved in the conversion of genetic information to cellular components. Several regulatory molecules are known to modulate the production of mRNA and, if directed to the target gene (such as, HTT), would modulate the production of the target gene mRNA that causes diseases such as, for example, Huntington’s disease or Huntington’s disease-like syndrome, and thus reverse the progress of these diseases.

[0007] Provided herein are transcription modulator molecules for recruiting a regulatory molecule into close proximity to the target gene. In some embodiments, provided herein is a transcription modulator molecule having a first terminus, a second terminus, and an oligomeric backbone moiety, or a pharmaceutically acceptable salt thereof, wherein: a) the first terminus comprises a DNA-binding moiety having the structure of Formula (A-l):Formula (A-l), wherein:W1is hydrogen, halogen, optionally substituted Ci-Cw alkyl, optionally substituted Ci-Cw haloalkyl -NRleRlf, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, -NRleC(O)ORlf, - N=C(N(Rle)2)2. -ZB-PO(ORle)2, -ZB-(CH2)P3-PO(ORle)2, or -ZB-(CH2)p3-O-PO(ORle)2, wherein each Rleis independently hydrogen or optionally substituted Ci-Cw alkyl;each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, AAP2, or optionally substituted 5-membered heteroaryl, wherein each AA is an amino acid and p2 is an integer from 1-10;ZB is -N- or -O-; ps is 1-10;W2is optionally substituted C1-C20 alkyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, or optionally substituted C1-C20 hydroxyalkyl; or W2is L’-Z-R4; whereinL1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted C1-C20 alkyl; orRwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH; each X1, X2, X3, X4, X5, X6, X7, and X8is independently S, O, or NR2; each R2is independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each R3is independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3together with the atoms to which they are attached form an optionally substituted C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; ji is 0 or 1;no is 0 or 1 ; mi and are each independently an integer from 0-3; and pi is 3 or 4; wherein the linker is attached at one of R2and the others of R2are as described above; b) the second terminus comprises a protein-binding moiety capable of binding to a regulatory molecule that modulates expression of a gene; and c) the oligomeric backbone links the first terminus and the second terminus.

[0008] In some embodiments, the DNA binding moiety can selectively bind a trinucleotide repeat sequence in for example, HTT. The recruiting moiety, linked to the DNA binding moiety, will thus be held in proximity to the target gene; will recruit the regulatory molecule into proximity with the gene; and the regulatory molecule will modulate expression, and therefore counteract the production of defective target gene by direct interaction with the target gene. This mechanism may provide an effective treatment for HD, which is caused by the expression of defective HTT, where correction of the expression of the defective target gene thus represents an effective method for the treatment for these diseases.

[0009] The DNA binding moiety comprises a polyamide segment that will bind selectively to the target CAG sequence. Polyamides designed by for example Dervan (U.S. Patent Nos. 9,630,950 and 8,524,899) and others can selectively bind to selected DNA sequences. These polyamides sit in the minor groove of double helical DNA and form hydrogen bonding interactions with the Watson-Crick base pairs. Polyamides that selectively bind to particular DNA sequences can be designed by linking monoamide building blocks according to established chemical rules. One building block is provided for each DNA base pair, with each building block binding noncovalently and selectively to one of the DNA base pairs: A / T, T / A, G / C, and C / G. Following this guideline, trinucleotides bind to molecules with three amide units, i.e. tri-amides. In general, these polyamides can orient in either direction of a DNA sequence.

[0010] In principle, longer DNA sequences can be targeted with higher specificity and / or higher affinity by combining a larger number of monoamide building blocks into longer polyamide chains. Ideally, the binding affinity for a polyamide would simply be equal to the sum of each individual monoamide / DNA base pair interaction. In practice, however, due to the geometric mismatch between the fairly rigid polyamide and DNA structures, longer polyamide sequences do not bind to longer DNA sequences as tightly as would be expected from a simple additive contribution. The geometric mismatch between longer polyamide sequences and longer DNA sequences induces an unfavorable geometric strain that subtracts from the binding affinity than would be otherwise expected.

[0011] The disclosure provides for transcription modulator molecules that comprise a DNA binding moiety (for example a polyamide comprising multi-amine subunits) that is connected by a spacer (for example a linker moiety or oligomeric backbone) to a protein binding moiety. The spacer can alleviate the geometric strain that would otherwise decrease binding affinity of a larger polyamide sequence.

[0012] It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes andmodifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.INCORPORATION BY REFERENCE

[0013] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.DETAILED DESCRIPTION

[0014] The disclosure provides for transcription modulator molecules that comprise a DNA binding moiety (for example, a polyamide comprising multi-amine subunits) connected by spacers (for example, a linker moiety or oligomeric backbone) to a protein binding moiety. The spacers can alleviate the geometric strain that would otherwise decrease binding affinity of a larger polyamide sequences.

[0015] Treatment of a subject with these compounds will modulate the expression of the defective target gene, and this can reduce the occurrence, severity, or frequency of symptoms associated with genetic disease (such as for example HD). The compounds described herein recruit the regulatory molecule to modulate the expression of the defective target gene and effectively treat and alleviate the symptoms associated with diseases.Compounds - Transcription modulator molecules

[0016] The compounds disclosed herein are transcription modulator molecules. They possess useful activity for modulating the transcription of a target gene (e.g., HTT) and may be used in the treatment or prophylaxis of a disease or condition in which the target gene plays an active role. Thus, in broad aspects, some embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions.

[0017] In an aspect, provided herein is a transcription modulator molecule having a first terminus, a second terminus, and a linker moiety, wherein: a) the first terminus comprises a DNA-binding moiety; b) the second terminus comprises a protein-binding moiety capable of binding to a regulatory molecule that modulates expression of a gene; and c) the oligomeric backbone links the first terminus and the second terminus.First terminus - DNA binding moiety

[0018] The first terminus interacts and binds with the target gene at the targeted DNA-sequence, particularly within the minor groove. In an aspect, the molecules disclosed herein provide a polyamide sequence.

[0019] In some embodiments, the DNA-binding moiety comprises a polyamide of one or more of the following subunits selected fromC(O)-, -NH-phenylene-C(O)-, -NH-pyridinylene-C(O)-, -NH-piperidinylene-C(O)-, -NH-pyrimidinylene-C(O)-, -NH-anthracenylene-C(O)-, -NH-quinolinylene-wherein eachR’ is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 haloalkyl, or optionally substituted C1-C20 alkylamino; and Z is H, NH2, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkyl -NH2.

[0020] In some embodiments, the DNA-binding moiety comprises the structure of Formula (A-T), or a pharmaceutically acceptable salt thereof:Formula (A-T), wherein:Z1is absent, -O-, or -NH-;W1is hydrogen, halogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl - NRleRlf, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, -NRleC(O)ORlf, - N=C(N(Rle)2)2, -ZB-PO(ORle)2, -ZB-(CH2)P3-PO(ORle)2, or -ZB-(CH2)p3-O-PO(ORle)2, wherein each Rleis independently hydrogen or optionally substituted C1-C10 alkyl; each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- Cio heteroalkyl, AAp2, or optionally substituted 5 -membered heteroaryl, wherein each AA is an amino acid and p2is an integer from 1-10;ZBis -N- or -O-; p3is 1-10;W2is optionally substituted Ci-C2o alkyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci- C20haloalkyl, optionally substituted Ci-C2o heteroalkyl, or optionally substituted Ci-C2o hydroxyalkyl; or W2is L'-Z-R4; whereinL1is Ci-C2o alkylene or C2-C2o heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted Ci-C2o alkyl, or optionally substituted Ci-C2o heteroalkyl;R4bis optionally substituted Ci-C2o alkyl, optionally substituted C2-C2o alkenyl, optionally substituted C2-C2o alkynyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci-C2o haloalkyl, optionally substituted Ci-C2o heteroalkyl, optionally substituted Ci-C2o hydroxyalkyl, optionally substituted C’s-Cs cycloalkyl, optionally substituted 4 to 8- membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10- membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted C1-C20 alkyl; orRwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH; each X1, X2, X3, X4, X5, X6, X7, and X8is independently S, O, or NR2; each R2is independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each R3is independently hydrogen, halogen, Ci-Cg alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3together with the atoms to which they are attached form an optionally substituted C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; ji is 0 or 1; no is 0 or 1 ; mi and are each independently an integer from 0-3; and pi is 2, 3, or 4, provided that when Z1is -O- or -NH- then pi is 2, and when Z1is absent then pi is 3 or 4; wherein the linker is attached at one of R2and the others of R2are as described above.

[0021] In some embodiments of Formula (A-l’), Z1is absent. In some embodiments, Z1is absent, -O-. In some embodiments, Z1is -NH-.

[0022] In some embodiments, the DNA-binding moiety comprises the structure of Formula (A-l), or a pharmaceutically acceptable salt thereof:Formula (A-l), wherein:W1is hydrogen, halogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl - NRleRlf, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, -NRleC(O)ORlf, - N=C(N(Rle)2)2, -ZB-PO(ORle)2, -ZB-(CH2)P3-PO(ORle)2, or -ZB-(CH2)p3-O-PO(ORle)2, wherein each Rleis independently hydrogen or optionally substituted C1-C10 alkyl; each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- Cio heteroalkyl, AAp2, or optionally substituted 5 -membered heteroaryl, wherein each AA is an amino acid and p2is an integer from 1-10;ZBis -N- or -O-; p3is 1-10;W2is optionally substituted Ci-C2o alkyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci- C20haloalkyl, optionally substituted Ci-C2o heteroalkyl, or optionally substituted Ci-C2o hydroxyalkyl; or W2is L’-Z-R4; whereinL1is Ci-C2o alkylene or C2-C2o heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted Ci-C2o alkyl, or optionally substituted Ci-C2o heteroalkyl;R4bis optionally substituted Ci-C2o alkyl, optionally substituted C2-C2o alkenyl, optionally substituted C2-C2o alkynyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci-C2o haloalkyl, optionally substituted Ci-C2o heteroalkyl, optionally substituted Ci-C2o hydroxyalkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4 to 8- membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10- membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted Ci-C2o alkyl; orRwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH; each X1, X2, X3, X4, X5, X6, X7, and X8is independently S, O, or NR2; each R2is independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-Cso alkenyl, optionally substituted C2-Cso alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-Cso heteroalkenyl, optionally substituted C2-Cso heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each R3is independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3together with the atoms to which they are attached form an optionally substituted G-C, cycloalkyl or 3 to 6-membered heterocycloalkyl; ji is 0 or 1; n0is 0 or 1 ; mi and are each independently an integer from 0-3; and pi is 3 or 4; wherein the linker is attached at one of R2and the others of R2are as described above.

[0023] In some embodiments of Formula (A-l) or (A-E), the linker is attached at one of R2.

[0024] In some embodiments, the DNA-binding moiety comprises the structure of Formula (A-2), or a pharmaceutically acceptable salt thereof:Formula (A-2), wherein:W1is hydrogen, optionally substituted Ci-Cio haloalkyl, or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl;W2is optionally substituted C1-C20 alkyl, optionally substituted C1-C20 aminoalkyl, optionally substituted Ci- C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, or optionally substituted C1-C20 hydroxyalkyl; or W2is L’-Z-R4; whereinL1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substitutedC1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4 to 8- membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10- membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted C1-C20 alkyl; or Rwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one R3aand one R3btogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6- membered heterocycloalkyl; each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinRZaand Rzbare each independently hydrogen, alkyl, or PEG;RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and ni and mi are each independently 0 or 1; wherein the linker is attached at one of RZa, Rzb, or RZc.

[0025] In some embodiments, the DNA-binding moiety comprises a structure of Formula (A-3), or a pharmaceutically acceptable salt thereof:Formula (A-3), wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl;W2is optionally substituted C1-C20 alkyl, optionally substituted C1-C20 aminoalkyl, optionally substituted Ci- C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, or optionally substituted C1-C20 hydroxyalkyl; or W2is L'-Z-R4; whereinL1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4 to 8- membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10- membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted C1-C20 alkyl; or Rwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl; each Y5and Y6is independently N or CH; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl,optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C, cycloalkyl or 3 to 6-membered heterocycloalkyl; or one R3aand one R3btogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6- membered heterocycloalkyl; each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinRZaand Rzbare each independently hydrogen, alkyl, or PEG;RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and and mi are each independently 0 or 1; wherein the linker is attached at one of RZa, Rzb, or RZc.

[0026] In some embodiments of any of Formulas (A-l) through (A-3), W2is -L’-Z-R4and Rwis hydrogen.

[0027] In some embodiments, the DNA-binding moiety comprises a structure of Formula (A-4), or a pharmaceutically acceptable salt thereof:Formula (A-4), wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl;each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one R3aand one R3btogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6- membered heterocycloalkyl;L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted Ci- C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated; each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinRZaand Rzbare each independently hydrogen, alkyl, or PEG;RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and ni and mi are each independently 0 or 1; wherein the linker is attached at one of RZa, Rzb, or RZc.

[0028] In some embodiments, the DNA-binding moiety comprises a structure of Formula (A-5), or a pharmaceutically acceptable salt thereof:Formula (A-5), wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl; each Y5and Y6is independently N or CH; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a CYC, cycloalkyl or 3 to 6-membered heterocycloalkyl; or one R3aand one R3btogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6- membered heterocycloalkyl;L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted Ci- C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8-memberedheterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated; each Rzis independently -CN, -OH, -ORZa, -Ns, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinRZaand Rzbare each independently hydrogen, alkyl, or PEG;RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and ni and mi are each independently 0 or 1; wherein the linker is attached at one of RZa, Rzb, or RZc.

[0029] In some embodiments of Formula (A-2), (A-3), (A-4), or (A-5), the linker is attached at one ofRZa, Rzb, or RZcon R2a.

[0030] In some embodiments of Formula (A-2), (A-3), (A-4), or (A-5), the linker is attached at one ofRZa, Rzb, or RZcon R2b.

[0031] In some embodiments of Formula (A-2), (A-3), (A-4), or (A-5), the linker is attached at one of RZa, Rzb, or RZcon R2c. In some embodiments, the linker is attached at one of RZa, Rzb, or RZcon R2d.

[0032] In some embodiments of Formula (A-2), (A-3), (A-4), or (A-5), the linker is attached at one ofRZa, Rzb, or RZcon R2e.

[0033] In some embodiments of Formula (A-2), (A-3), (A-4), or (A-5), the linker is attached at one ofRZa, Rzb, or RZcon R2f.

[0034] In some embodiments of Formula (A-2), (A-3), (A-4), or (A-5), the linker is attached at one ofRZa, Rzb, or RZcon R2g.

[0035] In some embodiments of Formula (A-2), (A-3), (A-4), or (A-5), the linker is attached at one ofRZa, Rzb, or RZcon R2h.

[0036] In some embodiments of Formula (A-2), (A-3), (A-4), or (A-5), the linker is attached at one of RZa, Rzb, or RZc. In some embodiments, the linker is attached at RZa. In some embodiments, the linker is attached at Rzb. In some embodiments, the linker is attached at RZc.

[0037] In some embodiments, the DNA-binding moiety comprises the structure of Formula (A-6), or a pharmaceutically acceptable salt thereof:Formula (A -6), wherein:W1is hydrogen, halogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl - NRleRlf, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, -NRleC(O)ORlf, - N=C(N(Rle)2)2. -ZB-PO(ORle)2, -ZB-(CH2)P3-PO(ORle)2, or -ZB-(CH2)p3-O-PO(ORle)2, wherein each Rleis independently hydrogen or optionally substituted C1-C10 alkyl; each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- Cio heteroalkyl, AAp2, or optionally substituted 5 -membered heteroaryl, wherein each AA is an amino acid and p2is an integer from 1-10;ZBis -N- or -O-; p3is 1-10;W2is optionally substituted Ci-C2o alkyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci- C20haloalkyl, optionally substituted Ci-C2o heteroalkyl, or optionally substituted Ci-C2o hydroxyalkyl; or W2is L'-Z-R4; whereinL1is Ci-C2o alkylene or C2-C2o heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted Ci-C2o alkyl, or optionally substituted Ci-C2o heteroalkyl;R4bis optionally substituted Ci-C2o alkyl, optionally substituted C2-C2o alkenyl, optionally substituted C2-C2o alkynyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci-C2o haloalkyl, optionally substituted Ci-C2o heteroalkyl, optionally substituted Ci-C2o hydroxyalkyl, optionally substituted C’s-Cs cycloalkyl, optionally substituted 4 to 8- membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10- membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted C1-C20 alkyl; orRwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH; each X1, X2, X3, X4, X5, X6, X7, and X8is independently S, O, or NR2; each R2is independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each R3is independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3together with the atoms to which they are attached form an optionally substituted C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; each Rxand Ryis independently hydrogen, halogen, -CN, -OH, -NH2, C1-C10 alkyl, or C1-C10 haloalkyl; or two Rxor two Rytogether with the atoms to which they are attached to form a C3-C6 cycloalkyl or 3 to 6- membered heterocycloalkyl; ji is 0 or 1; no is 0 or 1 ; mi and are each independently an integer from 0-3; and pi is 3 or 4; wherein the linker is attached at one of Rxor one of Ryand the others of Rxand Ryare as described above.

[0038] In some embodiments of Formula (A-l’), (A-l), or (A-6), no is 1. In some embodiments, no is 0.

[0039] In some embodiments of Formula (A-l’), (A-l), or (A-6), pi is 4. In some embodiments, pi is 3.

[0040] In some embodiments of Formula (A-l’), (A-l), or (A-6), each X1, X2, X3, X4, X5, X6, and X7is independently -NR2. In some embodiments, each X1, X2, X3, X4, X5, X6, X7, and X8is independently O. In some embodiments, each X1, X2, X3, X4, X5, X6, X7, and X8is independently S.

[0041] In some embodiments of Formula (A-l’), (A-l), or (A-6), each R2is independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50. In some embodiments, each R2is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3 to 8-memberedheterocycloalkyl, or optionally substituted PEG1-20. In some embodiments, each R2is independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 3 to 8-membered heterocycloalkyl, or optionally substituted PEG1-10.

[0042] In some embodiments of Formula (A-E), (A-l), or (A-6), each R2is independently an optionally substituted C1-C20 alkyl. In some embodiments, each R2is independently an optionally substituted C1-C10 alkyl. In some embodiments, each R2is independently methyl, ethyl, isopropyl, isobutyl, sec-butyl, or tertbutyl. In some embodiments, each R2is independently hydrogen or methyl. In some embodiments, each R2is ethyl. In some embodiments, each R2is isopropyl. In some embodiments, each R2is methyl. In some embodiments, each R2is hydrogen.

[0043] In some embodiments of Formula (A-E), (A-l), or (A-6), each R3is independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG; and R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, each R3is independently -NR3cR3d. In some embodiments, each R3is independently - NHC(O)R3e. In some embodiments, each R3is hydrogen.

[0044] In some embodiments of Formula (A-E), (A-l), or (A-6), two R3together with the atoms to which they are attached combine together to form an optionally substituted C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments, two R3together with the atom(s) to which they are attached form a C3-C6 cycloalkyl. In some embodiments, two R3together with the atom(s) to which they are attached form a 4 to 6-membered heterocycloalkyl. In some embodiments, two R3together with the atom(s) to which they are attached form a 4-membered heterocycloalkyl. In some embodiments, two R3together with the atom(s) to which they are attached form a 5 -membered heterocycloalkyl. In some embodiments, two R3together with the atom(s) to which they are attached form a 6-membered heterocycloalkyl. In some embodiments, two R3together with the atom(s) to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl.

[0045] In some embodiments, the DNA-binding moiety comprises the structure of Formula (A-7), or a pharmaceutically acceptable salt thereof:Formula (A-7), wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl;W2is optionally substituted C1-C20 alkyl, optionally substituted C1-C20 aminoalkyl, optionally substituted Ci- C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, or optionally substituted C1-C20 hydroxyalkyl; or W2is L'-Z-R4; whereinL1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4 to 8- membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10- membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted C1-C20 alkyl; orRwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 8-membered heterocycloalkyl; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one R3aand one R3btogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6- membered heterocycloalkyl; each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinRZaand Rzbare each independently hydrogen, alkyl, or PEG;RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; each Rxand Ryis independently hydrogen, halogen, -CN, -OH, -NH2, C1-C10 alkyl, or C1-C10 haloalkyl; or two Rxor two Rytogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6- membered heterocycloalkyl; and mi and are each independently 0 or 1; wherein the linker is attached at one of Rxor one of Ryand the others of Rxand Ryare as described above.

[0046] In some embodiments of Formula (A-l’), (A-l), (A-6), or (A-7), ji is 1. In some embodiments, j 1 is 0.

[0047] In some embodiments of any of Formulas (A-l’), (A-l), (A-2), (A-3), (A-6) or (A-7), W2is optionally substituted C1-C20 alkyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, or optionally substituted C1-C20 hydroxyalkyl. In some embodiments, W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl. In some embodiments, W2is optionally substituted C1-C20 alkyl. In some embodiments, W2is optionally substituted C1-C20 heteroalkyl. In some embodiments, W2is methyl, ethyl, n-propyl, or isopropyl.

[0048] In some embodiments of Formula (A-l’), (A-l), (A-2), (A-3), (A-6), or (A-7), W2is -L’-Z-R4.

[0049] In some embodiments of Formula (A-l’), (A-l), (A-2), (A-3), (A-6), or (A-7), Rwis hydrogen. In some embodiments, Rwis optionally substituted C1-C20 alkyl.

[0050] In some embodiments of Formula (A-l), (A-l), (A-2), (A-3), (A-6), or (A-7), W2and Rwtogether with the nitrogen to which they are attached form an optionally substituted 4 to 10-membered heterocycloalkyl. In some embodiments, W2and Rwtogether with the nitrogen to which they are attached form an optionally substituted 4-membered heterocycloalkyl. In some embodiments, W2and Rwtogether with the nitrogen to which they are attached form an optionally substituted 5 -membered heterocycloalkyl. Insome embodiments, W2and Rwtogether with the nitrogen to which they are attached form an optionally substituted 6-membered heterocycloalkyl. In some embodiments, W2and Rwtogether with the nitrogen to which they are attached form an optionally substituted 7-membered heterocycloalkyl

[0051] In some embodiments, the DNA-binding moiety comprises the structure of Formula (A-8), or a pharmaceutically acceptable salt thereof:Formula (A-8), wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one R3aand one R3btogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6- membered heterocycloalkyl;L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -0R4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted Ci- C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C’s-Cs cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated; each Rzis independently -CN, -OH, -ORZa, -Ns, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinRZaand Rzbare each independently hydrogen, alkyl, or PEG;RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; each Rxand Ryis independently hydrogen, halogen, -CN, -OH, -NH2, C1-C10 alkyl, or C1-C10 haloalkyl; or two Rxor two Rytogether with the atoms to which they are attached form a Cs-C„ cycloalkyl or 3 to 6- membered heterocycloalkyl; and mi and are each independently 0 or 1; wherein the linker is attached at one Rxor one Ryand the others of Rxand Ryare as described above.

[0052] In some embodiments of Formula (A-6), (A-7), or (A-8), each Rxand Ryis independently hydrogen, halogen, -CN, -OH, -NH2, C1-C10 alkyl, or C1-C10 haloalkyl. In some embodiments, each Rxand Ryis independently hydrogen, -OH, -NH2, C1-C10 alkyl, or C1-C10 haloalkyl. In some embodiments, each Rxand Ryis independently hydrogen.

[0053] In some embodiments of Formula (A-6), (A-7), or (A-8), two Rxcombine together to form a Cs-Ce cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments, two Rxcombine together to form a Cs-Ce cycloalkyl. In some embodiments, two Rxcombine together to form a 3 to 6-membered heterocycloalkyl.

[0054] In some embodiments of Formula (A-6), (A-7), or (A-8), two Rycombine together to form a Cs-Ce cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments, two Rycombine together to form a Cs-Ce cycloalkyl. In some embodiments, two Rycombine together to form a 3 to 6-membered heterocycloalkyl

[0055] In some embodiments of Formula (A-l’), (A-l), (A-2), (A-4), (A-6), (A-7), or (A-8), Y2, Y4, and Y7are each independently N; and Y1and Y3are each independently CH.

[0056] In some embodiments of any of Formulas (A-l’) through (A-8), each Y5is independently CH. In some embodiments, each Y5is independently N.

[0057] In some embodiments of any of Formulas (A-l’) through (A-8), each Y6is independently CH. In some embodiments, each Y6is independently N.

[0058] In some embodiments of Formula (A-l’), (A-l), (A-2), (A-4), (A-6), (A-7), or A-8), Y8is CH. In some embodiments, Y8is N.

[0059] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10- membered heterocycloalkyl, or optionally substituted PEG1.50, each of which is optionally substituted with one or more Rz. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 3 to 8-membered heterocycloalkyl, or optionally substituted PEG1.50. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3 to 8-membered heterocycloalkyl, or optionally substituted PEG1.20. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3 to 8-membered heterocycloalkyl, or optionally substituted PEG1.10. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted PEG1.10. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl or optionally substituted C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic, bicyclic or spirocyclic cycloalkyl.

[0060] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently an optionally substituted C1-C20 alkyl. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently an optionally substituted C1-C10 alkyl. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently methyl, ethyl, isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, each R2is independently hydrogen or methyl. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his ethyl. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his isopropyl. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his methyl. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his hydrogen.

[0061] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently an optionally substituted C1-C20 alkyl or optionally substituted G- G cycloalkyl, each of which is optionally substituted with one or more Rz, wherein each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, -NHC(O)RZc, - NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl.

[0062] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8) each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently an optionally substituted G-Go alkyl or optionally substituted G- G cycloalkyl, each of which is optionally substituted with one or more Rz, wherein each Rzis independently -OH, -ORZa, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, -NHC(O)RZc, -NHC(O)ORZc, or - OC(O)NRZaRzb, wherein the linker is attached at one of RZa, Rzbor RZc. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently an optionally substituted G-Go alkyl or optionally substituted G-G cycloalkyl, each of which is optionally substituted with one or more Rz, wherein each Rzis independently -ORZa, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, or -NHC(O)RZc, wherein the linker is attached at one of RZa, Rzbor RZc.

[0063] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently an optionally substituted G-Go alkyl, optionally substituted Ci- C10 haloalkyl, or optionally substituted G-G cycloalkyl, wherein the linker is attached at one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2hthrough RZa, Rzb, or RZcof substituent -C(O)NRZaRzbor -NHC(O)RZc.

[0064] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2his C1-C10 alkyl which is connected to the linker through -ORZa, -CO(O)RZc, - C(O)ORZc, -C(O)NRZaRzb, or -NHC(O)RZc; and the remainder of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare each independently optionally substituted G-C10 alkyl, optionally substituted G-Go haloalkyl, or optionally substituted G-G cycloalkyl.

[0065] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), each R3aand R3bis independently hydrogen, halogen, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG; and R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, each R3aand R3bis independently -NR3cR3d. In some embodiments, each R3aand R3bis independently -NHC(O)R3e. In some embodiments, each R3is independently hydrogen.

[0066] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), two R3atogether with the atoms to which they are attached combine together to form an optionally substituted G-G, cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments, two R3atogether with the atom(s) to which they are attached form a G-G, cycloalkyl. In some embodiments, two R3atogether with the atom(s) to which they are attached form a 4 to 6-membered heterocycloalkyl. In some embodiments, two R3atogether with the atom(s) to which they are attached form a 4-membered heterocycloalkyl. In some embodiments, two R3atogether with the atom(s) to which they are attached form a 5 -membered heterocycloalkyl. In some embodiments, two R3atogether with the atom(s) to which they are attached form a 6-memberedheterocycloalkyl. In some embodiments, two R3atogether with the atom(s) to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl.

[0067] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), two R3btogether with the atoms to which they are attached combine together to form an optionally substituted C3-C, cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments, two R3btogether with the atom(s) to which they are attached form a C’s-C,, cycloalkyl. In some embodiments, two R3btogether with the atom(s) to which they are attached form a 4 to 6-membered heterocycloalkyl. In some embodiments, two R3btogether with the atom(s) to which they are attached form a 4-membered heterocycloalkyl. In some embodiments, two R3btogether with the atom(s) to which they are attached form a 5 -membered heterocycloalkyl. In some embodiments, two R3btogether with the atom(s) to which they are attached form a 6-membered heterocycloalkyl. In some embodiments, two R3btogether with the atom(s) to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl.

[0068] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), one R3aand one R3btogether with the atoms to which they are attached form a C’s-C,, cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments, one R3aand one R3btogether with the atoms to which they are attached form a C’s-C, cycloalkyl. In some embodiments, one R3aand one R3btogether with the atoms to which they are attached form a 3 to 6-membered heterocycloalkyl.

[0069] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), two R3atogether with the atoms to which they are attached combine together to form an optionally substituted C’s-C,, cycloalkyl and each R3bis hydrogen. In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), two R3btogether with the atoms to which they are attached combine together to form an optionally substituted C’s-C,, cycloalkyl and each R3ais hydrogen.

[0070] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), R3cand R3dare each independently hydrogen, alkyl, or PEG. In some embodiments, R3cand R3dare each independently hydrogen, Ci-C2oalkyl, or PEG1.20. In some embodiments, R3cand R3dare each independently Ci-C2oalkyl. In some embodiments, R3cand R3dare each independently hydrogen.

[0071] In some embodiments of any of Formulas (A-2) through (A-5), (A-7), or (A-8), R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, R3eis C1-C20 alkyl, PEG1.20, C3-C, cycloalkyl, 4 to 6-membered heterocycloalkyl, or phenyl. In some embodiments, R3eis C1-C20 alkyl or PEGi. 20. In some embodiments, R3eis C3-C, cycloalkyl, 4 to 6-membered heterocycloalkyl, or phenyl. In some embodiments, R3eis C1-C20 alkyl.

[0072] In some embodiments of any of Formulas (A-E) through (A-8), L1is C1-C10 alkylene or C2-C10 heteroalkylene. In some embodiments, L1is C1-C10 alkylene, Ci-Cs alkylene, Ci-Ce alkylene, C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene, or C1-C2 alkylene. In some embodiments, L1is C1-C4 alkylene. In some embodiments, L1is C1-C3 alkylene. In some embodiments, L1is C1-C2 alkylene. In some embodiments, L1is C2-C10 heteroalkylene, C2-C8 heteroalkylene, C2-C6 heterolkylene, C2-C5 heteroalkylene, or C2-C4 heteroalkylene. In some embodiments, L1is C2-C10 heteroalkylene. In some embodiments, L1is C2-C8heteroalkylene. In some embodiments, L1is C2-C6 heterolkylene. In some embodiments, L1is C2-C5 heteroalkylene. In some embodiments, L1is C2-C4 heteroalkylene.

[0073] In some embodiments of any of Formulas (A-E) through (A-8), the heteroalkylene is polyethylene glycol. In some embodiments, L1is PEG1.10. In some embodiments, L1is PEGi s. In some embodiments, L1is -(CH2CH2-O)y5-, wherein y is an integer in the range of 1-10. In some embodiments, ys is an integer in the range of 1-8. In some embodiments, ys is an integer in the range of 1-6. In some embodiments, ys is an integer in the range of 1-4. In some embodiments, ys is 1-2.

[0074] In some embodiments of any of Formulas (A-E) through (A-8), the heteroalkylene comprises - (CH2)y6N(Ra)(CH2)y7- , wherein Rais hydrogen or an optionally substituted Ci-Ce alkyl; and eachand y7is independently an integer in the range of 1-6.

[0075] In some embodiments of any of Formulas (A-E) through (A-8), Z is -C(O)-; and R4is -OR4b. In some embodiments, Z is -C(O)-; and R4is -NR4aR4b. In some embodiments, Z is -C(=NH)-; and R4is - NR4aR4b. In some embodiments, Z is absent; and R4is -OR4b. In some embodiments, Z is absent; and R4is - NR4aR4b. In some embodiments, Z is -C(O)-; and R4is Ci-Ce alkyl.

[0076] In some embodiments , of any of Formulas (A-E) through (A-8) Z is absent. In some embodiments, Z is -C(O)-. In some embodiments, Z is -C(=NH)-.

[0077] In some embodiments of any of Formulas (A-E) through (A-8), R4is C1-C3 alkyl or -NR4aR4b. In some embodiments, R4is C1-C3 alkyl. In some embodiments, R4is -NR4aR4b. In some embodiments, R4is - OR4b.

[0078] In some embodiments of any of Formulas (A-E) through (A-8), R4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl. In some embodiments, R4ais an optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl. In some embodiments, R4ais an optionally substituted C1-C20 alkyl. In some embodiments, R4ais an optionally substituted C1-C20 heteroalkyl. In some embodiments, R4ais hydrogen.

[0079] In some embodiments of any of Formulas (A-E) through (A-8), R4bis optionally substituted Ci- C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C’s-Cs cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl. In some embodiments, R4bis optionally substituted C1-C20 alkyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl optionally substituted C1-C20 heteroalkyl, or optionally substituted C1-C20 hydroxyalkyl. In some embodiments, R4bis optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl. In some embodiments, R4bis optionally substituted C1-C20 alkyl. In some embodiments, R4bis optionally substituted C1-C10 alkyl. In some embodiments, R4bis optionally substituted C1-C10 haloalkyl. In some embodiments, R4bis optionally substituted C1-C10 heteroalkyl.

[0080] In some embodiments of any of Formulas (A-E) through (A-8), R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 4 to 10-membered heterocycloalkyl whichis partially or fully saturated. In some embodiments, the heterocycloalkyl is a monocyclic, bicyclic or spirocyclic heterocycloalkyl. In some embodiments, R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 4 to 8-membered heterocycloalkyl. In some embodiments, R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 4-membered heterocycloalkyl. In some embodiments, R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 5 -membered heterocycloalkyl. In some embodiments, R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 6-membered heterocycloalkyl. In some embodiments, R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted piperidine, piperazine or morpholine. In some embodiments, R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted piperazine. In some embodiments, R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted piperidine.

[0081] In some embodiments of any of Formulas (A-l’) through (A-8), R4ais hydrogen or optionally substituted Ci-Cw alkyl and R4bis an optionally substituted Ci-Cw alkyl or optionally substituted Ci-Cw haloalkyl; or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 4 to 8-membered heterocycloalkyl. In some embodiments, R4ais hydrogen or optionally substituted Ci-Cio alkyl and R4bis an optionally substituted Ci-Cio alkyl or optionally substituted Ci-Cio haloalkyl. In some embodiments, R4ais hydrogen and R4bis an optionally substituted Ci-Cw alkyl or optionally substituted Ci- Cio haloalkyl. In some embodiments, R4ais hydrogen and R4bis methyl or ethyl. In some embodiments, R4ais optionally substituted Ci-Cw alkyl and R4bis an optionally substituted Ci-Cio alkyl. In some embodiments, R4ais methyl and R4bis methyl.

[0082] In some embodiments of Formulas (A-3) through (A-5), (A-7), or (A-8), each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, -NHC(O)RZc, -NHC(O)ORZc, - OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl. In some embodiments, each Rzis independently -CN, -OH, -ORZa, -Ns, or -NRZaRzb. In some embodiments, each Rzis independently - C(O)NRZaRzb, -NHC(O)RZc, or -OC(O)NRZaRzb. In some embodiments, each Rzis independently - C(O)NRZaRzbor -NHC(O)RZc. In some embodiments, each Rzis independently an optionally substituted 5 to 10-membered heteroaryl.

[0083] In some embodiments of Formulas (A-2) through (A-5), (A-7), or (A-8), each RZaand Rzbis independently hydrogen, alkyl, or PEG. In some embodiments, each RZaand Rzbis independently hydrogen, C1-C20 alkyl, or PEG i-2o. In some embodiments, each RZaand Rzbis independently C1-C20 alkyl. In some embodiments, each RZaand Rzbis independently hydrogen.

[0084] In some embodiments of Formulas (A-2) through (A-5), (A-7), or (A-8), RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, RZcis C1-C20 alkyl, PEG1.20, C3-Ce cycloalkyl, 4 to 6-membered heterocycloalkyl, or phenyl. In some embodiments, RZcis C1-C20 alkyl or PEG1 20. In some embodiments, RZcis C1-C20 alkyl.

[0085] In some embodiments of Formula (A-l’), (A-l), or (A-6), W1is hydrogen, halogen, optionally substituted Ci-Cw alkyl, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, -NRleC(O)ORlf,or AAi-io. In some embodiments, W1is hydrogen or optionally substituted C1-C10 alkyl. In some embodiments, W1is -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, or -NRleC(O)ORlf. In some embodiments, W1is AAMO. In some embodiments, W1is AA1.4. In some embodiments, W1is AAi.3. In some embodiments, W1is AA1.2.

[0086] In some embodiments of Formula (A-T), (A-l), or (A-6), W1is -ZB-PO(OR16)2, -ZB-(CH2)P3- PO(ORle)2 , or -ZB-(CH2)p3-O-PO2(ORle)2, wherein ZB is O or N, and p3 is 1-10.

[0087] In some embodiments of any of Formulas (A-T) through (A-8), W1is hydrogen or - N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl. In some embodiments, W1is hydrogen or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or methyl.

[0088] In some embodiments of any of Formulas (A-T) through (A-8), W1is C1-C10 haloalkyl. In some embodiments, W1is -CF3.

[0089] In some embodiments of any of Formulas (A-T) through (A-8), W1is hydrogen.

[0090] In some embodiments of Formula (A-T), (A-l), or (A-6), each AA is a natural or unnatural amino acid.

[0091] In some embodiments, each Rleis independently hydrogen or C1-C10 alkyl. In some embodiments, each Rleis independently hydrogen or Ci-Cs alkyl. In some embodiments, each Rleis independently hydrogen or Ci-Ce alkyl. In some embodiments, each Rleis independently hydrogen or C1-C3 alkyl. In some embodiments, each Rleis C1-C3 alkyl. In some embodiments, each Rleis independently methyl. In some embodiments, each Rleis independently hydrogen.

[0092] In some embodiments of Formula (A-T), (A-l), or (A-6), each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted 5- membered heteroaryl. In some embodiments, each Rlfis independently hydrogen or optionally substituted C1-C10 alkyl. In some embodiments, each Rlfis independently hydrogen or optionally substituted Ci-Cs alkyl. In some embodiments, each Rlfis independently hydrogen or optionally substituted Ci-Ce alkyl. In some embodiments, each Rlfis independently optionally substituted Ci-Ce alkyl. In some embodiments, each Rlfis independently methyl. In some embodiments, each Rlfis independently hydrogen.

[0093] In some embodiments of any of Formulas (A-T) through (A-8), mi is 0. In some embodiments, mi is 1. In some embodiments, mi is 2. In some embodiments, mi is 3.

[0094] In some embodiments of any of Formulas (A-T) through (A-8), is 0. In some embodiments, is 1. In some embodiments, is 2. In some embodiments, is 3.

[0095] In some embodiments of Formula (A-T), (A-l), or (A-6), p2 is 1-10. In some embodiments, P2 is 1-8. In some embodiments, P2 is 1-6. In some embodiments, P2 is 1-4. In some embodiments, P2 is 1, 2, 3, or4. In some embodiments, P2 is 1. In some embodiments, P2 is 2. In some embodiments, P2 is 3. In some embodiments, P2 is 4.

[0096] In some embodiments of Formulas (A-T), (A-l), or (A-6), p3 is 1-10. In some embodiments, p3 is 1-8. In some embodiments, P3 is 1-6. In some embodiments, p3 is 1-4. In some embodiments, p3 is 1, 2, 3, or4. In some embodiments, ps is 1. In some embodiments, ps is 2. In some embodiments, ps is 3. In some embodiments, ps is 4.

[0097] The binding affinity between the polyamide and the target gene can be adjusted based on the composition of the polyamide. In some embodiments, the polyamide is capable of binding the DNA with an affinity of less than about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, or about 50nM. In some embodiments, the polyamide is capable of binding the DNA with an affinity of less than about 300 nM. In some embodiments, the polyamide is capable of binding the DNA with an affinity of less than about 200 nM. In some embodiments, the polyamide is capable of binding the DNA with an affinity of greater than about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, or about 1 nM. In some embodiments, the polyamide is capable of binding the DNA with an affinity in the range of about 1-600 nM, 10-500 nM, 20-500 nM, 50-400 nM, or 100-300 nM.

[0098] In some embodiments, the first terminus is capable of binding the DNA with an affinity of less than 500 nM.

[0099] The binding affinity between the polyamide and the target DNA can be determined using a quantitative footprint titration experiment. The experiment involves measuring the dissociation constant Kd of the polyamide for the target sequence at either 24 °C or 37 °C, and using either standard polyamide assay solution conditions or approximate intracellular solution conditions.

[0100] The binding affinity between the regulatory protein and the ligand on the second terminus can be determined using an assay suitable for the specific protein. The experiment involves measuring the dissociation constant Kd of the ligand for the protein and using either standard protein assay solution conditions or approximate intracellular solution conditions.

[0101] The polyamide composed of a pre-selected combination of subunits can selectively bind to the DNA in the minor groove. In their hairpin structure, antiparallel side-by-side pairings of two aromatic amino acids bind to DNA sequences, with a polyamide ring packed specifically against each DNA base.Second Terminus -Regulatory Protein Binding Moiety

[0102] In some embodiments, the second terminus comprises a protein-binding moiety capable of binding to a regulatory molecule that modulates expression of a gene having the expanded nucleotide repeat.

[0103] In some embodiments, the second terminus comprises a bromodomain binding moiety.

[0104] In some embodiments, the second terminus comprises a moiety capable of binding to a bromodomain and extra terminal domain (BET) family member.

[0105] In some embodiments, the BET family member is BRD2, BRD3, BRD4, or BRDT. In some embodiments, the BET family member is BRD2. In some embodiments, the BET family member is BRD3. In some embodiments, the BET family member is BRD4. In some embodiments, the BET family member is BRDT.

[0106] In some embodiments, the protein-binding moiety binds to CBP / p300, PCAF (P300 / CBP- Associated Factor), CECR2 (cat eye syndrome chromosome region candidate 2), BRPF (bromodomain andPHD finger-containing protein), ATAD2 / ATAD2B (chromatin remodeling proteins), TRIM24 (Tripartite motif-containing 24), BAZ2 (Bromodomain Adjacent to Zinc finger), TAF1 (TBP associated factors), BRD7 / 9, BPTF (Bromodomain PHD Finger Transcription Factor), SMARCA2 / 4, or PBRM1.

[0107] In some embodiments, the regulatory molecule is CBP / p300.

[0108] In some embodiments, the regulatory molecule is PCAF (P300 / CBP-Associated Factor).

[0109] In some embodiments, the regulatory molecule is CECR2 (cat eye syndrome chromosome region candidate 2).

[0110] In some embodiments, the regulatory molecule is BRPF (bromodomain and PHD fingercontaining protein).

[0111] In some embodiments, the regulatory molecule is a ATAD2 or ATAD2B chromatin remodeling protein.

[0112] In some embodiments, the regulatory molecule is BAZ2 (Bromodomain Adjacent Zinc Finger.

[0113] In some embodiments, the regulatory molecule is TAF1 (TBP associated factor).

[0114] In some embodiments, the regulatory molecule is TRIM24 (tripartite motif-containing 24).

[0115] In some embodiments, the regulatory molecule is BRD7 / 9.

[0116] In some embodiments, the regulatory molecule is BPTF (Bromodomain PHD Finger Transcription Factor).

[0117] In some embodiments, the regulatory molecule is SMARCA2 / 4.

[0118] In some embodiments, the regulatory molecule is PBRM1.

[0119] In some embodiments, the regulatory molecule modulates the rearrangement of histones.

[0120] In some embodiments, the regulatory molecule modulates the glycosylation, phosphorylation, alkylation, or acylation of histones.

[0121] In some embodiments, the regulatory molecule is a transcription factor.

[0122] In some embodiments, the regulatory molecule is an RNA polymerase.

[0123] In some embodiments, the regulatory molecule is a moiety that regulates the activity of RNA polymerase.

[0124] In some embodiments, the recruiting moiety binds to the regulatory molecule but does not inhibit the activity of the regulatory molecule. In some embodiments, the recruiting moiety binds to the regulatory molecule and inhibits the activity of the regulatory molecule. In some embodiments, the recruiting moiety binds to the regulatory molecule and increases the activity of the regulatory molecule.

[0125] In some embodiments, the recruiting moiety binds to the active site of the regulatory molecule. In certain embodiments, the recruiting moiety binds to a regulatory site of the regulatory molecule.

[0126] The binding affinity between the regulatory protein and the second terminus can be adjusted based on the composition of the molecule or type of protein. In some embodiments, the second terminus binds the regulatory molecule with an affinity of less than about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, or about 50nM. In some embodiments, thesecond terminus binds the regulatory molecule with an affinity of less than about 500 nM. In some embodiments, the second terminus binds the regulatory molecule with an affinity of less than about 400 nM. In some embodiments, the second terminus binds the regulatory molecule with an affinity of less than about 300 nM. In some embodiments, the second terminus binds the regulatory molecule with an affinity of less than about 250 nM. In some embodiments, the second terminus binds the regulatory molecule with an affinity of less than about 200 nM. In some embodiments, the second terminus binds the regulatory molecule with an affinity of less than about 150 nM. In some embodiments, the second terminus binds the regulatory molecule with an affinity of less than about 100 nM. In some embodiments, the second terminus binds the regulatory molecule with an affinity of less than about 50 nM.

[0127] In some embodiments, the second terminus comprises a diazine or diazepine ring, wherein the diazine or diazepine ring is fused with a Ce-Cio aryl or a 5 to 10-membered heteroaryl ring comprising one or more heteroatoms selected from S, N and O. In some embodiments, the second terminus comprises an optionally substituted bicyclic or tricyclic structure.

[0128] In some embodiments, the second terminus has a triazolodiazepine structure. In some embodiments, the second terminus has a thiazolodiazepine structure.

[0129] In some embodiments, the second terminus comprises the structure of Formula (2-A), or a pharmaceutically acceptable salt thereof:Formula (2-A), wherein:Ring A is an optionally substituted aryl or optionally substituted 5 to 6-membered heteroaryl;Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;D is C or N;E is O or N;YAis -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl; or R7is -NR7AR7B, whereinR7Aand R7I;are each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; and xi is an integer from 1-6.

[0130] In some embodiments, D is N and E is N. In some embodiments, D is C and E is O.

[0131] In some embodiments, the second terminus comprises the structure of Formula (2-B), or a pharmaceutically acceptable salt thereof:Formula (2-B), wherein:Ring A is an optionally substituted aryl or optionally substituted 5 to 6-membered heteroaryl;Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;YAis -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl; or R7is -NR7AR7B, whereinR7Aand R7I;are each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; and xi is an integer from 1-6.

[0132] In some embodiments, Ring A is an optionally substituted aryl ring. In some embodiments, Ring A is an optionally substituted phenyl. In some embodiments, Ring A is an optionally substituted 5 membered heteroaryl. In some embodiments, Ring A is an optionally substituted oxazolyl. In some embodiments, Ring A is an optionally substituted furanyl. In some embodiments, Ring A is an optionally substituted thiophenyl.

[0133] In some embodiments, the second terminus comprising the structure of Formula (2-C), or a pharmaceutically acceptable salt thereof:Formula (2-C), wherein:Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;YA is -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl; or R7is -NR7AR7B, whereinR7Aand R7I;are each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R8and R9are each independently selected from hydrogen, -C(O)OR8a, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; andR8ais hydrogen, C1-C20 alkyl, or C1-C20 heteroalkyl; and xi is an integer from 1-6.

[0134] In some embodiments, R8and R9are each independently selected from optionally substituted Ci- Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce hydroxyalkyl. In some embodiments, R8and R9are each independently selected from optionally substituted Ci-Ce alkyl. In some embodiments, R8and R9are each independently methyl, ethyl, or propyl. In some embodiments, R8and R9are each independently methyl. In some embodiments, R8and R9are each independently ethyl. In some embodiments, R8and R9are each independently propyl.

[0135] In some embodiments, the second terminus comprising the structure of Formula (2-D), or a pharmaceutically acceptable salt thereof:Formula (2-D), wherein:Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;YAis -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Cg hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl; or R7is -NR7AR7B, whereinR7Aand R7I;are each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R10is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; and xi is an integer from 1-6.

[0136] In some embodiments, R5is Ci-Ce alkyl. In some embodiments, R5is methyl or ethyl. In some embodiments, R5is methyl. In some embodiments, R5is ethyl. In some embodiments, R5is hydrogen.

[0137] In some embodiments, R7is selected from hydrogen, halogen, optionally substituted Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce hydroxyalkyl. In some embodiments, R7is halogen. In some embodiments, R7is Br, Cl, or F. In some embodiments, R7is Cl. In some embodiments, R7is F. In some embodiments, R7is Br.

[0138] In some embodiments, R7is -NR7AR7I;. wherein R7Aand R7I;are each independently hydrogen or optionally substituted Ci-Ce alkyl.

[0139] In some embodiments, R10is selected from optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl. In some embodiments, R10is selected from optionally substituted Ci-Ce alkyl. In some embodiments, R10is methyl, ethyl, or propyl. In some embodiments, R10is methyl. In some embodiments, R10is optionally substituted C1-6 hydroxyalkyl. In some embodiments, R10is -OMe.

[0140] In some embodiments, R6is selected from optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl. In some embodiments, R6is anoptionally substituted Ci-Ce alkyl. In some embodiments, R6is methyl, ethyl, or propyl. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is propyl. In some embodiments, R6is hydrogen.

[0141] In some embodiments, YA is -NH-. In some embodiments, YA is -O-.

[0142] In some embodiments, YA is NH and xi is 1.

[0143] In some embodiments, xi is an integer from 1-5, 1-4, 1-3, or 1-2. In some embodiments, xi is 1. In some embodiments, xi is 2.

[0144] In some embodiments, Ring B is an optionally substituted 6-membered monocyclic aryl or heteroaryl, each of which is optionally substituted with alkyl, amino, halogen, hydroxy, hydroxyalkyl, or PEG. In some embodiments Ring B is phenyl. In some embodiments, Ring B is 6-membered monocyclic heteroaryl. In some embodiments, Ring B is pyridine or pyrimidine. In some embodiments, Ring B is absent.

[0145] In some embodiments, the second terminus comprises the structure of Formula (2-E), or a pharmaceutically acceptable salt thereof:Formula (2-E).

[0146] In some embodiments, the second terminus comprises the structure of Formula (2-F), or a pharmaceutically acceptable salt thereof:

[0147] In some embodiments, the second terminus comprises the structure of Formula (2-G), or a pharmaceutically acceptable salt thereof:Formula (2-G).

[0148] In some embodiments, the second terminus comprises the structure of Formula (3-A), or a pharmaceutically acceptable salt thereof:Formula (3-A), wherein:YB is -CH2NH-, -CH2O-, -NH-, or -O-;R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R12is hydrogen, halogen, -OH, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Cg hydroxyalkyl;R14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; or R14is -NRARB;R16is an optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, - S(O)(=NH)RA, -SO2RA, or -NHSO2RA;RYAis hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted 5-6-membered monocyclic aryl or heteroaryl; each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 4 to 6-membered heteroalkyl; and yi is 1-3; wherein the attachment to the linker is at either R14or at RYA.

[0149] In some embodiments, the second terminus comprises the structure of Formula (3-B), or a pharmaceutically acceptable salt thereof:Formula (3-B), wherein:Ring C is absent, optionally substituted 5 to 6-membered monocyclic aryl or heteroaryl or 4 to 8-membered heterocycle;YB is -NH-, -CH2NH-, -CH2O-, or -O-;R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R12is hydrogen, optionally substituted Ci-Ce alkyl, C(O)RA, or C(O)NRARB; wherein each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;R13is hydrogen, substituted aryl, substituted heteroaryl, or substituted oxydibenzene; and y2is an integer from 0-2.

[0150] In some embodiments, the second terminus comprises the structure of Formula (3-B1), or a pharmaceutically acceptable salt thereof:Formula (3-B1), wherein:R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R13is hydrogen, substituted aryl, substituted heteroaryl, or substituted oxydibenzene; and y2is an integer from 0-2.

[0151] In some embodiments, y2is 0. In some embodiments, y2is 1. In some embodiments, y2is 2.

[0152] In some embodiments, R13is substituted aryl or substituted heteroaryl. In some embodiments, R13is hydrogen.

[0153] In some embodiments, R13is substituted oxydibenzene.

[0154] In some embodiments,, whereinR14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; or R14is -NRARB;R16is an optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, - S(O)(=NH)RA, -SO2RA, or -NHSO2RA; each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; and yi is 1-3.

[0155] In some embodiments, the second terminus comprises the structure of Formula (3-C), or a pharmaceutically acceptable salt thereof:Formula (3-C), wherein:Ring C is absent, optionally substituted 5 to 6-membered monocyclic aryl or heteroaryl or 4 to 8-membered heterocycle;YBis -CH2NH-, -CH2O-, -NH-, or -O-;R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R12is hydrogen, optionally substituted Ci-Ce alkyl, C(O)RA, or C(O)NRARB;R14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; or R14is -NRARB;R16is an optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, - S(O)(=NH)RA, -SO2RA, or -NHSO2RA; each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; and yi is an integer from 1-3.

[0156] In some embodiments, YB is -NH-. In some embodiments, YB is -CH2NH-. In some embodiments, YB is -CH2O-. In some embodiments, YB is -O-.

[0157] In some embodiments, Ring C is an optionally substituted 5 or 6-membered monocyclic aryl or heteroaryl, each of which is optionally substituted with alkyl, amino, halogen, hydroxy, hydroxyalkyl, or PEG.

[0158] . In some embodiments, Ring C is phenyl. In some embodiments, Ring C is a 6-membered heteroaryl. In some embodiments, Ring C is pyridine, pyrazine, or triazine. In some embodiments, Ring C is pyridine. In some embodiments, Ring C is pyrazine. In some embodiments, Ring C is triazine. In some embodiments, Ring C is a 5 -membered heteroaryl. In some embodiments, Ring C is a pyrazole. In some embodiments, Ring C is a triazole, pyrrole, imidazole, oxazole, oxadiazole, thiazole, or thiadiazole. In some embodiments, Ring C is a triazole. In some embodiments, Ring C is an imidazole or pyrrole. In some embodiments, an oxazole or oxadiazole. In some embodiments, Ring C is a thiazole or thiadiazole.

[0159] In some embodiments, Ring C is absent.

[0160] In some embodiments, the second terminus comprises the structure of Formula (3-D), or a pharmaceutically acceptable salt thereof:Formula (3-D), wherein:R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R12is hydrogen or an optionally substituted Ci-Ce alkyl; each R15is independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;R16is an optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, - S(O)(=NH)RA, -SO2RA, or -NHSO2RA;RAis hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C3-C,, cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6- membered heteroaryl; and yi is an integer from 1-3.

[0161] In some embodiments, R11Aand R11Bare each independently optionally substituted Ci-Ce alkyl. In some embodiments, R11Aand R11Bare each independently methyl, ethyl, propyl, or tert-butyl. In some embodiments, R11Aand R11Bare each independently methyl. In some embodiments, R11Aand R11Bare each independently hydrogen.

[0162] In some embodiments, R11Ais Ci-Ce alkyl, optionally substituted with haloalkyl or phosphorous hydroxide. In some embodiments, R11Ais Ci-Ce alkyl substituted with -OP(O)(OH)2. In some embodiments, R11Ais unsubstituted Ci-Ce alkyl. In some embodiments, R11Ais methyl, ethyl, or tert-butyl. In some embodiments, R11Ais methyl. In some embodiments, R11Ais hydrogen.

[0163] In some embodiments, R12is optionally substituted Ci-Ce alkyl. In some embodiments, R12is hydrogen.

[0164] In some embodiments, R12is C(O)RAor C(O)NRARB. In some embodiments, R12is C(O)NRARB, wherein RAand RBare each independently hydrogen or optionally substituted Ci-Ce alkyl.

[0165] In some embodiments, R14and R15are each independently hydrogen, -CN, or -NO2. In some embodiments, R14and R15are each independently halogen or optionally substituted Ci-Ce alkyl. In some embodiments, R14and R15are each independently Br, Cl, F, methyl, or ethyl. In some embodiments, R14and R15are each independently F or methyl.

[0166] In some embodiments, R16is optionally substituted Ci-Cg alkyl, optionally substituted Ci-Cg heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted Ci-Ce hydroxyalkyl, each of which is optionally substituted with amido, alkyl, alkynyl, azido, amino, halogen, haloalkyl, hydroxy, nitro, oxo (=0), phosphorous hydroxide, or PEG.

[0167] In some embodiments, R16is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, or optionally substituted Ci-Ce hydroxyalkyl. In some embodiments, R16is Ci-Ce alkyl or Ci-Ce heteroalkyl, each or which optionally substituted with -CN, -NH2, -N3, -OH, CF3, or -OP(O)(OH)2.

[0168] In some embodiments, R16is -SO2RA, wherein RAis Ci-Ce alkyl. In some embodiments, R16is - S02Et. In some embodiments, R16is -SO2Me.

[0169] In some embodiments, R16is -NHSO2RA, wherein RAis Ci-Ce alkyl. In some embodiments, R16is -NHSO2Et. In some embodiments, R16is -NHSO2Me.

[0170] In some embodiments, yi is 1. In some embodiments, yi is 2. In some embodiments, yi is 3.

[0171] In some embodiments, the second terminus comprises the structure of Formula (3-E), or a pharmaceutically acceptable salt thereof:Formula (3-E).

[0172] In some embodiments, the second terminus comprising the structure of Formula (3-F), or a pharmaceutically acceptable salt thereof:Formula (3-F).

[0173] In some embodiments, the second terminus comprising the structure of Formula (3-G) or Formula(3-H), or a pharmaceutically acceptable salt thereof:Formula (3-H).

[0174] In some embodiments, the second terminus comprising the structure of Formula (3-1), or a pharmaceutically acceptable salt thereof:Formula (3-1).

[0175] In some embodiments, the second terminus comprises the structure of Formula (4-A), or a pharmaceutically acceptable salt thereof:Formula (4-A), wherein;Ring D is absent, phenyl, or 5 to 6-membered heteroaryl;X9and X10are each independently C or N, wherein one of X9or X10is N;L2is absent, optionally substituted alkylene, -O-, or -NRD-, whereinRDis hydrogen or optionally substituted C1-C3 alkyl;R18is an optionally substituted 5 to 6-membered heteroaryl;R19is an optionally substituted C-G cycloalkyl or optionally substituted 4 to 7-membered heteroaryl;each R20is independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;X3 is an integer from 1-3; and y4 is an integer from 1-4; wherein the attachment to the linker is at either R19or at one of R20.

[0176] In some embodiments, attachment to the linker is at R19.

[0177] In some embodiments, attachment to the linker is at one of R20.

[0178] In some embodiments, the second terminus comprises the structure of Formula (4-B), or a pharmaceutically acceptable salt thereof:Formula (4-B), wherein:Ring D is absent, optionally substituted phenyl, or optionally substituted 5 to 6-membered heteroaryl;X9and X10are each independently C or N, wherein one of X9or X10is N;L2is absent, optionally substituted alkylene, -O-, or -NRD-, whereinRDis hydrogen or optionally substituted C1-C3 alkyl;R18is an optionally substituted 5 to 6-membered heteroaryl;R19is an optionally substituted C3-C8 cycloalkyl or optionally substituted 4 to 7-membered heteroaryl; and X3 is an integer from 1-3.

[0179] In some embodiments, X9is N; and X10is C. In some embodiments, X9is C; and X10is N.

[0180] In some embodiments, the second terminus comprises the structure of Formula (4-C), or a pharmaceutically acceptable salt thereof:Formula (4-C), wherein:Ring D is absent, optionally substituted phenyl, or optionally substituted 5 to 6-membered heteroaryl;L2is absent, optionally substituted alkylene, -O-, or -NRD-, whereinRDis hydrogen or optionally substituted C1-C3 alkyl;R18is an optionally substituted 5 to 6-membered heteroaryl;R19is an optionally substituted C3-C8 cycloalkyl or optionally substituted 4 to 7-membered heteroaryl; andX3 is an integer from 1-3.

[0181] In some embodiments, Ring D is an optionally substituted monocyclic 6-membered aryl or 5 to 6- membered heteroaryl. In some embodiments, Ring D is an optionally substituted monocyclic 6-membered aryl. In some embodiments, Ring D is an optionally substituted phenyl.

[0182] In some embodiments, R19is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R19is optionally substituted 4 to 7-membered heteroaryl.

[0183] In some embodiments, the second terminus comprises the structure of Formula (4-D), or a pharmaceutically acceptable salt thereof:Formula (4-D), wherein:L2is an optionally substituted alkylene, -O-, or -NRD-, whereinRDis hydrogen or optionally substituted C1-C3 alkyl;R18is an optionally substituted 5 to 6-membered heteroaryl;R20is hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;X3 is an integer from 1-3; and y4 is an integer from 1-4.

[0184] In some embodiments, L2is an optionally substituted alkylene. In some embodiments, L2is C2-C4 alkylene, optionally substituted with one or more C1-C3 alkyl. In some embodiments, L2is absent.

[0185] In some embodiments, L2is -NRD-. In some embodiments, L2is -NH-.

[0186] In some embodiments, R18is an optionally substituted 5 -membered heteroaryl. In some embodiments, R18is optionally substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole. In some embodiments, R18is optionally substituted oxazole.

[0187] In some embodiments, R20is halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl.

[0188] In some embodiments, X3 is 1. In some embodiments, X3 is 2. In some embodiments, X3 is 3.

[0189] In some embodiments, y4 is 1 or 2. In some embodiments, y4 is 1. In some embodiments, y4 is 2.In some embodiments, y4 is 3. In some embodiments, y4 is 4.

[0190] In some embodiments, the second terminus comprises the structure of Formula (4-E) or Formula (4-F), or a pharmaceutically acceptable salt thereof:Formula (4-E) or Formula (4F).

[0191] In some embodiments, the second terminus comprises the structure of Formula (4-G), or a pharmaceutically acceptable salt thereof:

[0192] In some embodiments, the second terminus comprises the structure of Formula (5-A), or a pharmaceutically acceptable salt thereof:wherein:Ring E is absent or an optionally substituted phenyl or optionally substituted 5 to 6-membered heteroaryl;X11is CH orN;L3is -NRE- or -CRERE-, wherein each REis independently hydrogen or optionally substituted C1-C3 alkyl;R21is Ci-Ce alkyl or Cs-Ce cycloalkyl; andR22is halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl.

[0193] In some embodiments, Ring E is absent. In some embodiments, Ring E is an optionally substituted phenyl. In some embodiments, Ring E is an optionally substituted 5 to 6-membered heteroaryl. In some embodiments, Ring E is a 5 -membered heteroaryl. In some embodiments, Ring E is a 6-membered heteroaryl.

[0194] In some embodiments, X11is CH and L3is -NRE-. In some embodiments, X11is N and L3is - CRERE-.

[0195] In some embodiments, R21is Ci-Ce alkyl. In some embodiments, R21is methyl.

[0196] In some embodiments, R22is halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl. In some embodiments, R22is CN, F, Cl, Br, or methyl.

[0197] In some embodiments, the second terminus comprises the structure of Formula (5-B) or Formula (5-C), or a pharmaceutically acceptable salt thereof:Formula (5-C).

[0198] In some embodiments, the second terminus comprises the structure of Formula (6-A), or a pharmaceutically acceptable salt thereof:Formula (6-A), wherein:Ring G is absent or an optionally substituted CAC, cycloalkyl or optionally substituted 4 to 6-membered heterocycloalkyl;L6is -O-(optionally substituted alkylene);R28is an optionally substituted 5 to 6-membered heteroaryl;R29is optionally substituted Ci-Ce alkyl-(Ce-Cio aryl) or optionally substituted Ci-Ce alkyl-(6 to 10- membered heteroaryl); andR30is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C’s-Ce cycloalkyl, or optionally substituted 4 to 6-membered heterocycloalkyl.

[0199] In some embodiments, the second terminus comprises the structure of Formula (7-A), or a pharmaceutically acceptable salt thereof:Formula (7-A), wherein:A3is -O-, -NH-, or -CH2-;Z2is CH or N;W is O or S; each R31is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted G-G cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; or two R31together with the atoms to which they are attached form an optionally substituted - cycloalkyl or optionally substituted 5 to 8-membered heterocycloalkyl;R32is hydrogen or optionally substituted C1-C10 alkyl;R32ais hydrogen or optionally substituted C1-C10 alkyl;R33is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl; and qe is 0-4; wherein Formula (7-A) is attached to the linker is at R32aor at one of R31.

[0200] In some embodiments, the second terminus comprises the structure of Formula (7-B), or a pharmaceutically acceptable salt thereof:Formula (7-B), wherein:Ring F is an optionally substituted 5 to 6-membered heteroaryl;A3is -O-, -NH-, or -CH2-;Z3is CH or N;W is O or S; each R31is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-C 10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted G-G-cycloalk l. or optionally substituted 3- to 8-membered heterocycloalkyl;or two R31together with the atoms to which they are attached form an optionally substituted Cs-Cs cycloalkyl or optionally substituted 5 to 8-membered heterocycloalkyl;R32is hydrogen or optionally substituted C1-C10 alkyl; and q6is 1-4.

[0201] In some embodiments, A3is -O-. In some embodiments, A3is -NH-. In some embodiments, A3is - CH2-.

[0202] In some embodiments, Z2is CH. In some embodiments, Z2is N.

[0203] In some embodiments, Z3is CH. In some embodiments, Z3is N.

[0204] In some embodiments, W is O. In some embodiments, W is S.

[0205] In some embodiments, Ring F is an optionally substituted 5 -membered heteroaryl. In some embodiments, Ring F is an optionally substituted 6-membered heteroaryl.

[0206] In some embodiments, each R31is independently an optionally substituted Ci-Cw alkyl, optionally substituted Ci-Cw haloalkyl, or optionally substituted Ci-Cio hydroxyalkyl. In some embodiments, each R31is independently an optionally substituted Cs-Cs -cycloalkyl or optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, each R31is independently hydrogen, halogen, -OH, -CN, -NO2, or - NH2. In some embodiments, each R31is hydrogen.

[0207] In some embodiments, R32is an optionally substituted C1-C10 alkyl. In some embodiments, R32is methyl. In some embodiments, R32is hydrogen.

[0208] In some embodiments, R32ais an optionally substituted C1-C10 alkyl. In some embodiments, R32ais hydrogen.

[0209] In some embodiments, R33is hydrogen, halogen, -OH, -CN, -NO2, or -NFF. In some embodiments, R33is an optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl.

[0210] In some embodiments, Formula (7-A) is attached to the linker is at R32a. In some embodiments, Formula (7-A) is attached to the linker at one of R31.

[0211] In some embodiments, the second terminus comprises the structure of Formula (7-C), or a pharmaceutically acceptable salt thereof:Formula (7-C).

[0212] In some embodiments, the second terminus comprise the structure of Formula (7-D), or a pharmaceutically acceptable salt thereof:

[0213] In some embodiments, the second terminus comprises the structure of Formula (7-E), or a pharmaceutically acceptable salt thereof:Formula (7-E).

[0214] In some embodiments, the second terminus comprises the structure of Formula (8-A), or a pharmaceutically acceptable salt thereof:Formula (8-A), wherein:Ring H is an optionally substituted phenyl or optionally substituted 6-membered heteroaryl; or RingZA is absent or an optionally substituted phenyl formamide;X12is CH or N;R34is an optionally substituted phenyl or optionally substituted 6-membered heteroaryl;R34Ais hydrogen, halogen, or optionally substituted C1-C3 alkyl; andR35is independently halogen, optionally substituted C1-C10 alkyl, or optionally substituted 5 to 6-membered heteroaryl; wherein the attachment to the linker is at R35, ZA, or Ring H.

[0215] In some embodiments, Ring H is an optionally substituted phenyl. In some embodiments, Ring H is an optionally substituted 6-membered heteroaryl.

[0216] In some embodiments, Ring

[0217] In some embodiments, ZA is absent. In some embodiments, ZA is an optionally substituted phenyl formamide. In some embodiments, ZA is -C(O)NH-phenyl.

[0218] In some embodiments, X12is CH. In some embodiments, X12is N.

[0219] In some embodiments, R34is an optionally substituted phenyl. In some embodiments, R34is an optionally substituted 6-membered heteroaryl.

[0220] In some embodiments, R34Ais hydrogen or halogen. In some embodiments, R34Ais an optionally substituted C1-C3 alkyl. In some embodiments, R34Ais methyl.

[0221] In some embodiments, Formula (8-A) is attached to the linker at R35. In some embodiments, Formula (8-A) is attached to the linker at ZA. In some embodiments, Formula (8-A) is attached to the linker at Ring H.

[0222] In some embodiments, the second terminus comprises the structure of Formula (8-B) or Formula

[0223] In some embodiments, the second terminus comprises the structure of Formula (8-D), or a pharmaceutically acceptable salt thereof:Formula (8-D).

[0224] In some embodiments, the second terminus comprises the structure of Formula (9-A), or a pharmaceutically acceptable salt thereof:Formula (9-A).

[0225] In some embodiments, the second terminus comprises the structure of Formula (10-A) or Formula (10-B), or a pharmaceutically acceptable salt thereof:Formula (10-B).

[0226] In some embodiments, the second terminus comprises the structure of Formula (11-A), or a pharmaceutically acceptable salt thereof:Formula (11-A).

[0227] In some embodiments, the second terminus comprises the structure of Formula (12-A), or a pharmaceutically acceptable salt thereof:Formula (12-A), wherein:A4is -CR40R40- or -NR40-, wherein each R40is independently hydrogen or optionally substituted Ci-Cw alkyl;R36is an optionally substituted 5 to 6-membered heteroaryl; each R37is independently hydrogen, halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl;R38is optionally substituted Ci-Cw alkyl, optionally substituted Cs-Cs cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl;R39is hydrogen, halogen, -OH, -CN, -NO2, -NH2, oxo (=0), =S, C1-C10 haloalkyl, or C1-C10 hydroxyalkyl; pn is 1-4; andqi and q2are each independently 0-2; wherein the linker is attached to Formula (12-A) at either R38or R40.

[0228] In some embodiments, R36is an optionally substituted 5 -membered heteroaryl. In some embodiments, R36is optionally substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole. In some embodiments, R36is optionally substituted oxazole.

[0229] In some embodiments, each R37is independently halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each R37is independently halogen.

[0230] In some embodiments, R38is an optionally substituted Ci-Cio alkyl. In some embodiments, R38is an optionally substituted Cs-Cs cycloalkyl or optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R38is a 3 to 8-membered heterocycloalkyl.

[0231] In some embodiments, R39is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10 haloalkyl, or Ci- C10 hydroxyalkyl. In some embodiments, R39is oxo or =S. In some embodiments, R39is oxo. In some embodiments, R39is =S.

[0232] In some embodiments, A4is -NR40. In some embodiments, A4is -NH. In some embodiments, A6is -NCH3. In some embodiments, A4is -CR40R40. In some embodiments, A4is -CH2-.

[0233] In some embodiments, each R40is independently optionally substituted C1-C10 alkyl. In some embodiments, each R40is independently hydrogen.

[0234] In some embodiments, pn is 3 or 4. In some embodiments, pn is 2. In some embodiments, pn is 1.

[0235] In some embodiments, qi is 1 and q2 is 1. In some embodiments, qi is 2 and q2 is 0.

[0236] In some embodiments, the linker is attached to Formula (12-A) through R38. In some embodiments, the linker is attached to Formula (12-A) through R40.

[0237] In some embodiments, the second terminus comprises Formula (12-B) or Formula (12-C), or a pharmaceutically acceptable salt thereof:

[0238] In some embodiments, the second terminus comprises Formula (12-D) or Formula (12-E), or a pharmaceutically acceptable salt thereof:

[0239] In some embodiments, the second terminus comprises the structure of Formula (13-A), or a pharmaceutically acceptable salt thereof:Formula (13-A), wherein:Ring J is absent or optionally substituted 5 to 6-membered heteroaryl;R41is optionally substituted Ci-Ce alkyl, optionally substituted G-G cycloalkyl, -C(O)R41a, -C(O)-, or - C(O)NR41aR41b, whereinR41aand R41bare each independently optionally substituted Ci-Cio alkyl or optionally substituted G-G cycloalkyl;R42is an optionally substituted Ci-Cio alkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted G-G cycloalkyl, or optionally substituted 3 to 8 membered heterocycloalkyl;R43is hydrogen or optionally substituted Ci-Cio alkyl; each R44is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted G-Go alkyl, optionally substituted G-Go haloalkyl, G-Go hydroxyalkyl, optionally substituted G-Go alkenyl, optionally substituted C2- o alkynyl, optionally substituted G-G-cycloalkyl. or optionally substituted 3 to 8-membered heterocycloalkyl; orR43and one of R44together with the atoms to which they are attached form an optionally substituted 5 to 8- membered heterocycloalkyl;P12 is 1-4; and qs is 0 or 1 ; wherein Formula (13-A) is connected to the linker at Ring J, R41, or R42.

[0240] In some embodiments, R41is optionally substituted Ci- alkyl or optionally substituted G-G cycloalkyl. In some embodiments, R41is -C(O)R41a. In some embodiments, R41is -C(O)CH3 or - C(O)CH2CH3. In some embodiments, R41is -C(O)-NR41aR41b.

[0241] In some embodiments, R41ais optionally substituted C1-C10 alkyl. In some embodiments, R41ais optionally substituted G-G cycloalkyl.

[0242] In some embodiments, R41bis optionally substituted Ci-Cw alkyl. In some embodiments, R41bis optionally substituted G-G cycloalkyl.

[0243] In some embodiments, R42is optionally substituted Ci-Cio alkyl or optionally substituted Ci-Cio haloalkyl. In some embodiments, R42is optionally substituted G-G cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl. In some embodiments, R42is optionally substituted 3- to 8-membered heterocycloalkyl ring.

[0244] In some embodiments, R43is optionally substituted Ci-Cio alkyl. In some embodiments, R43is hydrogen.

[0245] In some embodiments, each R44is independently halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, C1-C10 hydroxyalkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted G-G-cycloalkyl. or optionally substituted 3 to 8-membered heterocycle. In some embodiments, each R44is independently halogen or Ci- C10 haloalkyl.

[0246] In some embodiments, R43and one of R44together with the atoms to which they are attached form an optionally substituted 5 to 8-membered heterocycloalkyl. In some embodiments, R43and one of R44together with the atoms to which they are attached form a 5, 6, 7, or 8-membered heterocycloalkyl.

[0247] In some embodiments, pn is 3 or 4. In some embodiments, pn is 2. In some embodiments, pn is 1.

[0248] In some embodiments, cp is 1. In some embodiments, qs is 0.

[0249] In some embodiments, Ring J is an optionally substituted 5 -membered heteroaryl. In some embodiments, Ring J is absent.

[0250] In some embodiments, Formula (13-A) is connected to the linker at Ring J. In some embodiments, Formula (13-A) is connected to the linker at R41. In some embodiments, Formula (13-A) is connected to the linker at R42.

[0251] In some embodiments, the second terminus comprises the structure of Formula (13-B), or a pharmaceutically acceptable salt thereof:Formula (13-B).

[0252] In some embodiments, the second terminus comprises the structure of Formula (13-C1) or Formula (13-C2), or a pharmaceutically acceptable salt thereof:.

[0253] In some embodiments, the second terminus comprises the structure of Formula (13-D1) orFormula (13-D2), or a pharmaceutically acceptable salt thereof:.

[0254] In some embodiments, the second terminus comprises the structure of Formula (13-E), or a pharmaceutically acceptable salt thereof:Formula (13-E).

[0255] In some embodiments, the second terminus comprises the structure of Formula (14-A), or a pharmaceutically acceptable salt thereof:Formula (14-A), wherein:Ring K is a 5 to 6-membered heterocycloalkyl;A5is absent, CH2, -NH-, or -O-;L4is alkylene or heteroalkylene; each R45is independently halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, C1-C10 hydroxyalkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-Cioalkynyl, optionally substituted G-G-cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; each R46is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, optionally substituted Ci -Ci 0 hydroxyalkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-Cioalkynyl, optionally substituted G-G cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl;R47is optionally substituted Ci-Cw alkyl, -C(O)R47a, or -C(O)-NR47aR47b, whereinR47aand R47bare each independently optionally substituted C1-C10 alkyl or optionally substituted G-G cycloalkyl; q4 is 2-3; and qs is 0-2; wherein the Formula (14-A) is connected to the linker through Ring K or through one of R45.

[0256] In some embodiments, A5is absent. In some embodiments, A5is -NH- or -O-. In some embodiments, A5is -NH-. In some embodiments, A5is -O-.

[0257] In some embodiments, L4is alkylene. In some embodiments, In some embodiments, L4is C1-C5 alkylene.

[0258] In some embodiments, L4is heteroalkylene. In some embodiments, L4is C1-C4 heteroalkylene-. In some embodiments, L4is -O-CH2- or -O-CH2CH2-.

[0259] In some embodiments, each R45is independently halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Gohaloalkyl, optionally substituted C1-C10 heteroalkyl, Ci -Ci 0 hydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl. In someembodiments, each R45is independently optionally substituted C1-C10 alkyl or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, each R45is independently Ci-Ciohydroxyalkyl. In some embodiments, each R45is independently -OCH3 or -OCH2CH3.

[0260] In some embodiments, each R46is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, each R46is independently -OCH3. In some embodiments, each R46is independently hydrogen.

[0261] In some embodiments, R47is optionally substituted C1-C10 alkyl. In some embodiments, R47is - C(O)R47a. In some embodiments, R47is -C(O)CH3 or -C(O)CH2CH3. In some embodiments, -C(O)-NR47aR47b.

[0262] In some embodiments, R47ais optionally substituted C1-C10 alkyl. In some embodiments, R47ais optionally substituted C3-C8 cycloalkyl.

[0263] In some embodiments, R47bis optionally substituted C1-C10 alkyl. In some embodiments, R47bis an optionally substituted C3-C8 cycloalkyl.

[0264] In some embodiments, Ring K is a 6-membered heterocycloalkyl.

[0265] In some embodiments, q4 is 3. In some embodiments, q4 is 2.

[0266] In some embodiments, qs is 2. In some embodiments, qs is 1. In some embodiments, qs is 0.

[0267] In some embodiments, Formula (14-A) is connected to the linker through Ring K. In some embodiments, Formula (14-A) is connected to the linker through one of R45.

[0268] In some embodiments, the second terminus comprises the structure of Formula (14-B) or Formula (14-C), or a pharmaceutically acceptable salt thereof:Formula (14-C).

[0269] In some embodiments, the second terminus comprises the structure of Formula (15-A), or a pharmaceutically acceptable salt thereof:Formula (15-A), wherein:Ring L is an aryl or heteroaryl; each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10 alkyl, Ci-Ciohaloalkyl, or C1-C10 hydroxyalkyl;R49and R50are each independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- Ciohaloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-Cio alkynyl;R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-Cio alkynyl;R52is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, or optionally substituted C1-C10 hydroxyalkyl; and p7is 1-4.

[0270] In some embodiments, Ring L is an aryl. In some embodiments, the aryl is phenyl. In some embodiments, Ring L is heteroaryl. In some embodiments, Ring L is a bicyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from N and O.

[0271] In some embodiments, wherein the second terminus comprises the structure of Formula (15-B), or a pharmaceutically acceptable salt thereof:Formula (15-B), wherein: each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10 alkyl, Ci-Ciohaloalkyl, or C1-C10 hydroxyalkyl;R49and R50are each independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- Ciohaloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-Cio alkynyl;R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-Cio alkynyl; and p? is 1-4.

[0272] In some embodiments, wherein the second terminus comprises the structure of Formula ( 15-C), or a pharmaceutically acceptable salt thereof:Formula (15-C), wherein:X is CR48or N; each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10 alkyl, Ci-Ciohaloalkyl, or C1-C10 hydroxyalkyl;R49and R50are each independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- Ciohaloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-Cio alkynyl;R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-Cio alkynyl;R53is hydrogen or optionally substituted C1-C10 alkyl; and p? is 1-3.

[0273] In some embodiments, each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10 alkyl, C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl.

[0274] In some embodiments, R49is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-Cio alkynyl. In some embodiments, R49is an optionally substituted C1-C10 alkyl. In some embodiments, R49is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R49is hydrogen.

[0275] In some embodiments, R50is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-Cio alkynyl. In some embodiments, R50is an optionally substituted C1-C10 alkyl or optionally substituted C2-C10 alkenyl. In some embodiments, R50is hydrogen.

[0276] In some embodiments, R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-Cioalkynyl.

[0277] In some embodiments, R52is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, R52is hydrogen.

[0278] In some embodiments, R53is hydrogen or optionally substituted Ci-Cw alkyl. In some embodiments, R53is an optionally substituted Ci-Cw alkyl. In some embodiments, R53is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R53is hydrogen.

[0279] In some embodiments, p? is 4. In some embodiments, p? is 3. In some embodiments, p? is 2. In some embodiments, p? is 1.

[0280] In some embodiments, the second terminus comprises the structure of Formula (15-D1), (15-D2), or (15-D3), or a pharmaceutically acceptable salt thereof:

[0281] In some embodiments, the second terminus comprises the structure of Formula (15-E1), (15-E2), or (15-E3), or a pharmaceutically acceptable salt thereof:Formula (15-E3).

[0282] In some embodiments, the second terminus comprises the structure of Formula (16-A), or a pharmaceutically acceptable salt thereof:Formula (16-A), wherein:B5is -O-, -NH-, or S;B6is N or CH;R54is optionally substituted aryl or optionally substituted heteroaryl; each R55is independently halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl;R56is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, or optionally substituted C1-C10 hydroxyalkyl;R57is halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl; ps is 1-3; and q? is 0-2.

[0283] In some embodiments, B5is -O- or -S-. In some embodiments, B5is -O-. In some embodiments, B5is -S-.

[0284] In some embodiments, B6is N. In some embodiments, B6is CH.

[0285] In some embodiments, R54is an optionally substituted aryl. In some embodiments, R54is phenyl optionally substituted with one or more halogen, -CN, -NH2, -OH, C1-C10 alkyl, C1-C10 haloalkyl, or C1-C10 hydroxyalkyl.

[0286] In some embodiments, each R55is independently halogen, -OH, -CN, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl.

[0287] In some embodiments, R56is optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, R56is optionally substituted C1-C10 alkyl.

[0288] In some embodiments, R57is halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C10 alkyl.

[0289] In some embodiments, pg is 3. In some embodiments, pg is 2. In some embodiments, pg is 1.

[0290] In some embodiments, q? is 2. In some embodiments, q? is 1. In some embodiments, q? is 0.

[0291] In some embodiments, the second terminus comprises the structure of Formula (16-B), or a pharmaceutically acceptable salt thereof:Formula (16-B).

[0292] In some embodiments, the second terminus comprises the structure of Formula (17-A), or a pharmaceutically acceptable salt thereof:Formula (17-A), wherein:Ring M is optionally substituted aryl or optionally substituted heteroaryl;Ring N is absent or 4 to 8-membered heterocycloalkyl;A6is -O-, -NH-, or -CH2-; each R58is independently halogen, -OH, -CN, -NO2, -NH2, C1-C10 alkyl, C1-C10 haloalkyl, or C1-C10 hydroxyalkyl;R59is hydrogen, -OH, -NH2, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, or -NH-C1-C10 alkyl;R60is hydrogen or optionally substituted C1-C10 alkyl; and pio is 1-4;wherein Formula (17-A) is connected to the linker through R59.

[0293] In some embodiments, Ring M is an aryl, optionally substituted with one or more halogen, CN, NH2, OH, C1-C10 alkyl, Ci-Ciohaloalkyl, or C1-C10 hydroxyalkyl. In some embodiments, Ring M is phenyl. In some embodiments, Ring M is an optionally substituted 6-membered heteroaryl, optionally substituted with one or more halogen, CN, NH2, OH, C1-C10 alkyl, Ci-Ciohaloalkyl, or C1-C10 hydroxyalkyl. In some embodiments, Ring M is an optionally substituted pyridine.

[0294] In some embodiments, Ring N is 4 to 8-membered heterocycloalkyl. In some embodiment, Ring N is a 4-membered heterocycloalkyl. In some embodiments, Ring N is a 5 -membered heterocycloalkyl. In some embodiments, Ring N is a 6-membered heterocycloalkyl. In some embodiments, Ring N is absent.

[0295] In some embodiments, A6is -O- or -NH-. In some embodiments, A6is -CH2-.

[0296] In some embodiments, each R58is independently -OH, -NH2, C1-C10 alkyl, Ci-Ciohaloalkyl, or Ci- C10 hydroxyalkyl. In some embodiments, each R58is independently C1-C10 alkyl, or C1-C10 hydroxyalkyl. In some embodiments, each R58is independently C1-C10 hydroxyalkyl.

[0297] In some embodiments, R59is -OH, -NH2, C1-C10 hydroxyalkyl, or -NH-C1-C10 alkyl. In some embodiments, R59is hydrogen.

[0298] In some embodiments, R60is optionally substituted C1-C10 alkyl. In some embodiments, R60is methyl. In some embodiments, R60is hydrogen.

[0299] In some embodiments, pio is 3 or 4. In some embodiments, pio is 2. In some embodiments, pio is 1.

[0300] In some embodiments, the second terminus comprises the structure of Formula (17-B) or Formula (17-C) or a pharmaceutically acceptable salt thereof:

[0301] In some embodiments, the second terminus comprises the structure of Formula (18-A), or a pharmaceutically acceptable salt thereof:Formula (18-A), wherein:B7is N or CH;R67is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl;R68and R69are each independently an optionally substituted 5-membered heteroaryl; and x5and xe are each independently 0-4.

[0302] In some embodiments, B7is N. In some embodiments, B7is CH.

[0303] In some embodiments, R67is halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, Ci-Ciohaloalkyl, or optionally substituted Ci-Ciohydroxyalkyl. In some embodiments, R67is halogen, -OH, -CN, -NO2, -NH2, or -CH3.

[0304] In some embodiments, R68is optionally substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole. In some embodiments, R68is pyrrole or pyrazole. In some embodiments, R68is pyrrole. In some embodiments, R68is pyrazole.

[0305] In some embodiments, R69is optionally substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole. In some embodiments, R69is pyrrole or pyrazole. In some embodiments, R69is pyrrole. In some embodiments, R69is pyrazole.

[0306] In some embodiments, X5 is 2 or 3. In some embodiments, X5 is 1. In some embodiments, X5 is 0.

[0307] In some embodiments, xe is 3. In some embodiments, x„ is 2. In some embodiments, xe is 1. In some embodiments, x6is 0.

[0308] In some embodiments, the second terminus comprise Formula (18-B), or a pharmaceutically acceptable salt thereof:Formula (18-B).

[0309] In some embodiments, the second terminus comprises Formula (19-A), or a pharmaceutically acceptable salt thereof:Formula (19-A).

[0310] In some embodiments, the second terminus comprises the structure of Formula (20-A), or a pharmaceutically acceptable salt thereof:Formula (20-A), wherein:A7is -NHC(O)- or -NHS(O)2-;A8is -O- or -NH-; each R61is independently hydrogen or Ci-Ce alkyl; each R62is independently halogen, -CN, -NO2, -OH, -OR62a, -NR62aR62b, -C(O)R62a, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl; wherein each R62aand R62bis independently hydrogen or C1-C10 alkyl, wherein each R63is independently -OR63a, -NR63aR63b, optionally substituted C1-C10 alkyl, optionally substituted Ci- Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl; wherein each R63aand R63bis independently hydrogen, C1-C10 alkyl, C1-C10 alkylamino, Ci-Ciohaloalkyl, or Ci -C10 hydroxyalkyl; pis is 1-3; andP14 is 1-3; wherein the linker is connected to Formula (20-A) through one of R62or one of R63.

[0311] In some embodiments, A7is -NHC(O)-. In some embodiments, A7is -NHS(O)2-.

[0312] In some embodiments, A8is -O-. In some embodiments, A8is -NH-.

[0313] In some embodiments, each R61is independently Ci-Ce alkyl. In some embodiments, each R61is methyl. In some embodiments, each R61is hydrogen.

[0314] In some embodiments, each R62is independently optionally substituted C1-C10 alkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, each R62is independently optionally substituted C1-C10 alkyl. In some embodiments, each R62is independently optionally substituted Ci-Ciohaloalkyl. In some embodiments, each R62is independently optionally substituted C1-C10 heteroalkyl. In some embodiments, each R62is independently optionally substituted C1-C10 hydroxyalkyl.

[0315] In some embodiments, each R63is independently optionally substituted C1-C10 alkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, each R63is independently optionally substituted C1-C10 alkyl. In some embodiments, each R66is independently optionally substituted Ci-Ciohaloalkyl. In some embodiments, eachR63is independently optionally substituted Ci-Cw heteroalkyl. In some embodiments, each R63is independently optionally substituted Ci-Cio hydroxyalkyl.

[0316] In some embodiments, pis is 1. In some embodiments, pis is 2. In some embodiments, pis is 3.

[0317] In some embodiments, pi4 is 1. In some embodiments, pi4 is 2. In some embodiments, pi4 is 3.

[0318] In some embodiments, the linker is connected to Formula (20-A) through one of R62. In some embodiments, the linker is connected to Formula (20-A) through one of R63.

[0319] In some embodiments, the second terminus comprises the structure of Formula (20-B) or Formula (20-C)., or a pharmaceutically acceptable salt thereof:

[0320] In some embodiments, the second terminus comprises the structure of Formula (21 -A), or a pharmaceutically acceptable salt thereof:wherein:Ring Q is Cs-Cs cycloalkyl or 4 to 8-membered heterocycloalkyl;A9is -O-, -NH-, or -NHC(O)-; each R64is independently hydrogen or Ci-Ce alkyl;each R65is independently halogen, -CN, -NO2, -OH, -OR62a, -NR62aR62b, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl; wherein each R62aand R62bis independently hydrogen or C1-C10 alkyl; each R66is independently halogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl;P15 is 0-3; andPi6 is 1-3; wherein Formula (21 -A) is connected to the linker at one of R65or one of R66.

[0321] In some embodiments, A9is -O-. In some embodiments, A9is -NH-. In some embodiments, A9is - NHC(O)-.

[0322] In some embodiments, Ring Q is Cs-Cs cycloalkyl. In some embodiments, Ring Q is 4 to 8- membered heterocycloalkyl.

[0323] In some embodiments, each R64is independently Ci-Ce alkyl. In some embodiments, each R64is methyl. In some embodiments, each R64is hydrogen.

[0324] In some embodiments, each R65is independently optionally substituted C1-C10 alkyl, optionally substituted Ci-C 10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, each R65is independently optionally substituted C1-C10 alkyl. In some embodiments, each R65is independently optionally substituted C1-C10 haloalkyl. In some embodiments, each R65is independently optionally substituted C1-C10 heteroalkyl. In some embodiments, each R65is independently optionally substituted C1-C10 hydroxyalkyl.

[0325] In some embodiments, each R66is independently optionally substituted C1-C10 alkyl, optionally substituted Ci-C 10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, each R66is independently optionally substituted C1-C10 alkyl. In some embodiments, each R66is independently optionally substituted C1-C10 haloalkyl. In some embodiments, each R66is independently optionally substituted C1-C10 heteroalkyl. In some embodiments, each R66is independently optionally substituted C1-C10 hydroxyalkyl.

[0326] In some embodiments, pis is 0. In some embodiments, pis is 1. In some embodiments, pis is 2. In some embodiments, pis is 3.

[0327] In some embodiments, pie is 1. In some embodiments, pie is 2. In some embodiments, pie is 3.

[0328] In some embodiments, Formula (21-A) is connected to the linker at one of R65. In some embodiments, Formula (21-A) is connected to the linker at one of R66.

[0329] In some embodiments, the second terminus comprises the structure of Formula (21-B), or a pharmaceutically acceptable salt thereof:Formula (21-B).

[0330] In some embodiments, the second terminus comprises the structure of Formula (22-A), or a pharmaceutically acceptable salt thereof:wherein:R67is hydrogen, -NH2, or -NHSO2CH3;R68and R69are each independently halogen, -CN, -NO2, -OH, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl;R70is -S(O)R70aor -S(O)2R70a, wherein R70ais hydrogen or C1-C10 alkyl; andR71is hydrogen or C1-C10 alkyl; wherein Formula (22-A) is attached to the linker at R67or R71.

[0331] In some embodiments, R67is hydrogen. In some embodiments, R67is -NH2, or -NHSO2CH3.

[0332] In some embodiments, R68and R69are each independently optionally substituted C1-C10 alkyl. In some embodiments, R68and R69are each methyl.

[0333] In some embodiments, R70is -S(O)2R70a. In some embodiments, R70is -S(O)2CH3.

[0334] In some embodiments, Formula (22-A) is attached to the linker at R67. In some embodiments,Formula (22-A) is attached to the linker at R71.

[0335] In some embodiments, the second terminus comprises the structure of Formula (22-B) or Formula (22-C), or a pharmaceutically acceptable salt thereof:Formula (22-C).

[0336] In some embodiments, the second terminus comprises the structure of Formula (23-A), or a pharmaceutically acceptable salt thereof:Formula (23 -A) wherein:B9is -CH-CRB9-, -N-, or NRB1°;B10is -N- or NRB1°, whereinRB9is hydrogen or halogen; and RB1° is hydrogen;R72is halogen, -CN, -NO2, -OH, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl; andR73is hydrogen; wherein Formula (23-A) is attached to the linker at RB9, RB1°, or R73.

[0337] In some embodiments, B9is -CH-CRB9- and B10is -N-. In some embodiments, B9is -N- and B10isNRB1°. In some embodiments, B9is NRB1° and B10is -N-.

[0338] In some embodiments, R72is an optionally substituted C1-C10 alkyl. In some embodiments, R72is methyl.

[0339] In some embodiments, Formula (23-A) is attached to the linker at RB9or RB1°. In some embodiments, Formula (23-A) is attached to the linker at R73.

[0340] In some embodiments, the second terminus comprises the structure of Formula (23-B) or Formula (23 -C), or a pharmaceutically acceptable salt thereof:

[0341] In some embodiments, the second terminus comprises the structure of Formula (23-D) or Formula (23 -E), or a pharmaceutically acceptable salt thereof:

[0342] In some embodiments, the second terminus comprises the structure of Formula (24-A), or a pharmaceutically acceptable salt thereof:Formula (24-A), wherein:R74is -CH2-(optionally substituted 5 -membered heteroaryl);R75is -0-(Ci-Cio alkyl)-R75a; wherein R75ais -C(O)O-alkyl;R76is -OR76a, wherein R76ais hydrogen or alkyl;R77is hydrogen or halogen; andR77ais hydrogen or Ci-Cw alkyl; wherein Formula (24-A) is attached to the linker at R75aor R76a.

[0343] In some embodiments, R75is -0-(Ci-Cio alkyl)-C(O)O-alkyl. In some embodiments, R75is -O-(Ci- C4alkyl)-C(O)O-Ci-C4alkyl.

[0344] In some embodiments, R76is -OH. In some embodiments, R76is -OCHs. In some embodiments, R76is -O-CH2CH3.

[0345] In some embodiments, R77is halogen. In some embodiments, R77is hydrogen.

[0346] In some embodiments, R77ais hydrogen or methyl. In some embodiments, R77ais methyl. In some embodiments, R77ais hydrogen.

[0347] In some embodiments, Formula (24-A) is attached to the linker at R75a. In some embodiments, Formula (24-A) is attached to the linker at R76a.

[0348] In some embodiments, the second terminus comprises the structure of Formula (24-B) or Formula(24-C), or a pharmaceutically acceptable salt thereof:.

[0349] In some embodiments, the second terminus comprises the structure of Formula (25-A), or a pharmaceutically acceptable salt thereof:Formula (25-A), wherein:B12is -NR80a- or -C(R80b)2-;R78is halogen, -CN, -NO2, -OH, or optionally substituted C1-C10 alkyl;R79aand R79bare each independently halogen, -CN, -NO2, -NH2, -N(CH3)2, or optionally substituted C1-C10 alkyl; or R79aand R79btogether with the atoms to which they are attached form a 6-membered aryl;each R80is independently hydrogen, -O-C1-C3 alkyl, C1-C10 alkyl, or C1-C10 alkoxy;R80ais Ci-C6alkyl; each R80bis independently hydrogen or Ci-Ce alkyl; and r7is 1, 2, or 3; wherein Formula (25 -A) is attached to the linker at one of R80.

[0350] In some embodiments, B12is -NR80a-. In some embodiments, B12is -C(R80b)2-.

[0351] In some embodiments, R78is -CN, -NO2, or -OH. In some embodiments, R78is -OH. In some embodiments, R78is halogen. In some embodiments, R78is an optionally substituted C1-C10 alkyl.

[0352] In some embodiments, R79aand R79bare each independently halogen, -NH2, or -N(CH3)2.

[0353] In some embodiments, R79aand R79btogether with the atoms to which they are attached form a 6- membered aryl.

[0354] In some embodiments, each R80is independently hydrogen. In some embodiments, each R80is independently C1-C10 alkyl. In some embodiments, each R80is independently C1-C10 alkoxy. In some embodiments, each R80is independently -OCH3.

[0355] In some embodiments, the second terminus comprises the structure of Formula (25-B), or a pharmaceutically acceptable salt thereof:Formula (25-B).

[0356] In some embodiments, the second terminus comprises the structure of Formula (25-C), or a pharmaceutically acceptable salt thereof:Formula (25-C).

[0357] In some embodiments, the second terminus comprises the structure of Formula (26-A), or a pharmaceutically acceptable salt thereof:Formula (26-A), wherein:B11is -O- or -NR82-;A10is -NR84- or -NR84CH2-;R81aand R81bare each independently Ci-Cio alkyl; or R81aand R81bcombine together to form oxo (=0);R82is hydrogen or C1-C3 alkyl; each R83is independently halogen, -CN, -NO2, -OH, -OR83a, or optionally substituted C1-C10 alkyl; whereinR83ais C1-C10 alkyl;R84is hydrogen, C1-C3 alkyl, Cs-Ce cycloalkyl, or phenyl;R85is hydrogen or C1-C10 alkyl; and r4is 1, 2, or 3; wherein Formula (26-A) is attached to the linker at one of R83.

[0358] In some embodiments, B11is -O-. In some embodiments, B11is -NR82-. In some embodiments, B11is NCH3.

[0359] In some embodiments, A10is -NR84-. In some embodiments, A10is -NR84CH2-.

[0360] In some embodiments, R81aand R81bare each methyl. In some embodiments, R81aand R81bcombine together to form oxo (=0).

[0361] In some embodiments, each R83is independently -CN, -OH, -OR83a, or optionally substituted Ci- Cio alkyl. In some embodiments, each R83is independently -OH or -OR83a.

[0362] In some embodiments, R84is Cs-Ce cycloalkyl or phenyl. In some embodiments, R84is phenyl.

[0363] In some embodiments, R85is Ci-Cio alkyl. In some embodiments, R85is methyl. In some embodiments, R85is hydrogen.

[0364] In some embodiments, the second terminus comprises the structure of Formula (26-B) or Formula (26-C), or a pharmaceutically acceptable salt thereof:

[0365] In some embodiments, the second terminus comprises the structure of Formula (26-D) or Formula (26-E), or a pharmaceutically acceptable salt thereof:Formula (26-D) or Formula (26-E).

[0366] In some embodiments, the second terminus comprises the structure of Formula (27-A), or a pharmaceutically acceptable salt thereof:Formula (27-A).

[0367] In some embodiments, the second terminus comprises the structure of Formula (28-A), or a pharmaceutically acceptable salt thereof:Formula (28-A), wherein:A11is Ci-Ce alkylene;B13is N or CR100;R97is Ci-C6alkyl;R98is halogen;R" is hydrogen, halogen, or optionally substituted C1-C10 alkyl; andR100is -OR100aor optionally substituted C1-C10 alkyl; wherein R100ais hydrogen or C1-C10 alkyl; or R" and R100together with the atoms to which they are attached from a heterocycloalkyl.

[0368] In some embodiments, A11is C1-C4 alkylene. In some embodiments, A11is -CH2CH2-.

[0369] In some embodiments, B13is N. In some embodiments, B13is CR100.

[0370] In some embodiments, R97is methyl.

[0371] In some embodiments, R98is -Cl.

[0372] In some embodiments, R100is -OR100a. In some embodiments, R100is an optionally substituted Ci- C10 alkyl.

[0373] In some embodiments, R" and R100together with the atoms to which they are attached from a heterocycloalkyl.

[0374] In some embodiments, the second terminus comprises the structure of Formula (28-B), or a pharmaceutically acceptable salt thereof:Formula (28-B).

[0375] In some embodiments, the second terminus comprises the structure of Formula (28-C), or a pharmaceutically acceptable salt thereof:Formula (28-C).

[0376] In some embodiments, the second terminus comprises the structure of Formula (29-A), or a pharmaceutically acceptable salt thereof:Formula (29-A).

[0377] In some embodiments, the second terminus comprises the structure of Formula (30-A), or a pharmaceutically acceptable salt thereof:Formula (30-A).

[0378] In some embodiments, the second terminus comprises the structure of Formula (31-A), or a pharmaceutically acceptable salt thereof:Formula (31 -A), wherein:R94is halogen;R94a jshydrogen or C1-C3 alkyl; andR95is hydrogen, halogen, -OH, -OCH3, or optionally substituted C1-C10 alkyl.

[0379] In some embodiments, R94is -Cl.

[0380] In some embodiments, R94ais C1-C3 alkyl. In some embodiments, R94ais methyl. In some embodiments, R94ais hydrogen.

[0381] In some embodiments, R95is halogen, -OH, -OCH3, or optionally substituted C1-C10 alkyl. In some embodiments, R95is hydrogen.

[0382] In some embodiments, the second terminus comprises the structure of Formula (31-B) or Formula(31-C), or a pharmaceutically acceptable salt thereof:

[0383] In some embodiments, the second terminus comprises the structure of Formula (32-A), or a pharmaceutically acceptable salt thereof:Formula (32-A).

[0384] In some embodiments, the second terminus comprises the structure of Formula (33-A), or a pharmaceutically acceptable salt thereof:Formula (33-A).

[0385] In some embodiments, the second terminus comprises the structure of Formula (34-A), or a pharmaceutically acceptable salt thereof:Formula (34-A).

[0386] In some embodiments, the second terminus comprises the structure of Formula (35-A), or a pharmaceutically acceptable salt thereof:Formula (35-A).

[0387] In some embodiments, the second terminus comprises the structure of Formula (36-A) or Formula(36-B), or a pharmaceutically acceptable salt thereof:-B).

[0388] In some embodiments, the second terminus comprises the structure of Formula (37-A), or a pharmaceutically acceptable salt thereof:Formula (37-A), wherein:Ring T is a C -C, cycloalkyl, 5 to 6-membered heterocycloalkyl, or phenyl; each R86is independently halogen, -CN, -NO2, -OH, -OR86a, -N(R86b)2, or optionally substituted C1-C10 alkyl; whereineach R86ais independently C1-C10 alkyl; each R86bis independently hydrogen or C1-C10 alkyl;R87is Cs-Ce cycloalkyl or phenyl; each R88is independently halogen, -CN, -NO2, -OH, -OR88a, -NR88bR88b, or optionally substituted C1-C10 alkyl; wherein each R88ais independently C1-C10 alkyl; each R88bis independently hydrogen or C1-C10 alkyl;R89aand R89bare each independently hydrogen or C1-C10 alkyl; or R89aand R89btogether with the atom to which they are attached form a 5 to 6-membered heterocycloalkyl; R96is hydrogen or -CH3; and r5and re are each independently 0, 1, 2, or 3.

[0389] In some embodiments, Ring T is a C -C, cycloalkyl. In some embodiments, Ring T is a 5 to 6- membered heterocycloalkyl. In some embodiments, Ring T is phenyl.

[0390] In some embodiments, each R86is independently halogen, -OH, -OR86a, or -N(R86b)2. In some embodiments, each R86is independently halogen or -N(R86b)2. In some embodiments, each R86is independently -N(R86b)2.

[0391] In some embodiments, R87is Cs-Ce cycloalkyl. In some embodiments, R87is phenyl.

[0392] In some embodiments, R89aand R89bare each independently C1-C10 alkyl. In some embodiments, R89aand R89bare each hydrogen.

[0393] In some embodiments, R89aand R89btogether with the atom to which they are attached form a 5 to 6-membered heterocycloalkyl.

[0394] In some embodiments, R96is -CH3. In some embodiments, R96is hydrogen.

[0395] In some embodiments, rs and re are each independently 0, 1, or 2.

[0396] In some embodiments, the second terminus comprises the structure of Formula (37-B) or Formula (37-C), or a pharmaceutically acceptable salt thereof:Formula (37-B) orFormula (37-C).

[0397] In some embodiments, the second terminus is selected from the group consisting of:or a pharmaceutically acceptable salt thereof,

[0398] In some embodiments, the second terminus is selected from a moiety described in Table 1, or a pharmaceutically acceptable salt thereof.Table 1. Exemplary binding moieties.Oligomeric Backbone - Linker Moiety

[0399] The oligomeric backbone is a linker that connects the first terminus and the second terminus and brings the regulatory molecule in proximity to the target gene to modulate gene expression.

[0400] The length of the linker depends on the type of regulatory protein and also the target gene. In some embodiments, the linker has a length of less than about 50 Angstroms. In some embodiments, the linker has a length of about 20 to 30 Angstroms.

[0401] In some embodiments, the oligomeric backbone comprises between 5 and 50 chain atoms.

[0402] In some embodiments, the oligomeric backbone comprises a multimer having 2 to 50 spacing moieties, wherein each spacing moiety is independently selected from the group consisting of-((CRlbRlb)x-O)y-, - ((CRlbRlb)x-NRla)y-, -((CRlbRlb)x-CH=CH-(CRlbRlb)x-O)y-, optionally substituted C1-C12 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted Ce-C 10 arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 4- to 10-membered heterocycloalkylene, amino acid residue, -O-, -C(O)NRla-, - NRlaC(O)-, -C(O)-, -NRla-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2NRla-, -NRlaS(O)2-, and -P(O)OH-, and any combinations thereof; whereineach x is independently 2-4; each y is independently 1-10; each Rlais independently hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci- C„ haloalkyl; and each Rlbis independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, optionally substituted alkylamide, sulfonyl, optionally substituted thioalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.

[0403] In some embodiments, the oligomeric backbone comprises a multimer having 2 to 50 spacing moieties, wherein each spacing moiety is independently selected from the group consisting of optionally substituted C1-C12 alkyl, -((CH2)X-O)y-, -((CH2)x-NH)y-, -O-, -C(O)NH-, -NH-, and any combinations thereof.

[0404] In some embodiments, the oligomeric backbone comprises -(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d- (T5-V5)e-, wherein a, b, c, d and e are each independently 0 or 1, and where the sum of a, b, c, d and e is 1 to 5;T1, T2, T3, T4and T5are each independently selected from an optionally substituted C1-C12 alkylene, optionally substituted alkenylene, optionally substituted alkynylene, (EA)W, (EDA)m, (PEG)n, (modified PEG)n, (AA)P, -(CR2aOH)h-, optionally substituted Ce-Cio arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 4- to 10- membered heterocycloalkylene, an acetal group, a disulfide, a hydrazine, a carbohydrate, a beta-lactam, and an ester,(a) w is an integer from 1 to 20;(b) m is an integer from 1 to 20;(c) n is an integer from 1 to 30;(d) p is an integer from 1 to 20;(e) h is an integer from 1 to 12;(f) EA has the following structure(g) EDA has the following structure:wherein each q is independently an integer from 1 to 6, each x is independently an integer from 1 to 4, and each r is independently 0 or 1 ;(h) (PEG)n has the structure of-(CRlbRlb-CRlbRlb-O)n-CRlbRlb-;(i) (modified PEG)nhas the structure of replacing at least one -(CRlbRlb-CRlbRlb-O)- in (PEG)n with -(CH2-CRlb=CRlb-CH2-O)- or -(CRlbRlb-CRlbRlb-S)-;(j) AA is an amino acid residue;(k) V1, V2, V3, V4and V5are each independently selected from the group consisting of a bond, C(O)-, -NRla-, -C(O)NRla-, -NRlaC(O)-, -CONRla-Ci-C4alkyl-, -NRlaC(O)-Ci-C4alkyl-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NRla-, -NRlaS(O)2- and -P(O)OH-;(l) each Rlais independently hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce haloalkyl; and(m) each Rlbis independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0405] In some embodiments, the a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 1. In some embodiments, the a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 2. In some embodiments, the a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 3. In some embodiments, the a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 4. In some embodiments, the a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 5.

[0406] In some embodiments, n is 3-9. In some embodiments, n is 4-8. In some embodiments, n is 5 or 6.

[0407] In some embodiments, T1, T2, T3, and T4, and T5are each independently selected from C1-C12 alkyl, substituted C1-C12 alkyl, (EA)W, (EDA)m, (PEG)n, (modified PEG)n, (AA)P, -(CRlbOH)h-, phenyl, substituted phenyl, piperidin-4-amino (P4A), para-amino-benzyloxycarbonyl (PABC), meta-amino- benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), meta-amino-benzyloxy (MABO), paraaminobenzyl, an acetal group, a disulfide, a hydrazine, a carbohydrate, a beta-lactam, an ester, (AA)P- MABC-(AA)p, (AA)p-MABO-(AA)p, (AA)p-PABO-(AA)pand (AA)p-PABC-(AA)p. In some embodiments, r piperidin-4-amino (P4A) is 'Rla. wherein Rlais hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0408] In some embodiments, T1, T2, T3, T4and T5are each independently selected from (Ci-Ci2)alkyl, substituted C1-C12 alkyl, (EA)W, (EDA)m, (PEG)n, (modified PEG)n, (AA)p,-(CRlbOH)h-, optionally substituted Ce-Cio arylene, 4 to 10-membered heterocycloalkene, optionally substituted 5 to 10-membered heteroarylene. In some embodiments, EA has the following structure:EDA has the following structure:

[0409] In some embodiments, x is 2-3 and q is 1-3 for EA and EDA. In some embodiments, Rlais hydrogen or Ci-Ce alkyl.

[0410] In some embodiments, T4or T5is an optionally substituted Ce-Cio arylene.

[0411] In some embodiments, T4or T5is phenylene or substituted phenylene. In some embodiments, T4or T5is phenylene or phenylene substituted with 1-3 substituents selected from Ci-Ce alkyl, halogen, OH or amine. In some embodiments, T4or T5is 5 to 10-membered heteroarylene or substituted heteroarylene. In some embodiments, T4or T5is 4 to 10-membered heterocyclene or substituted heterocylcylene. In some embodiments, T4or T5is heteroarylene or heterocylene optionally substituted with 1-3 substituents selected from Ci-Ce alkyl, halogen, OH or amine.

[0412] In some embodiments, T1, T2, T3, T4and T5and V1, V2, V3, V4and V5are selected from the following Table 2.Table 2. Exemplary linker units.

[0413] In some embodiments, the oligomeric backbone comprises -N(Rla)(CH2)xN(Rla)(CH2)xN-, wherein each Rlais independently selected from hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce haloalkyl; and each x is independently an integer in the range of 1-10.

[0414] In some embodiments, the oligomeric backbone comprises -(CH2-C(O)N(Rla)-(CH2)q-N(Rla)- (CH2)q-N(Rla)C(O)-(CH2)x-C(O)N(Rla)-A-, -(CH2)x-C(O)N(Rla)-(CH2CH2O)y(CH2)x-C(O)N(Rla)-A-, or - C(O)N(Rla)-(CH2)q-N(Rla)-(CH2)q-N(Rla)C(O)-(CH2)x-A-; wherein each q is independently an integer from 2 to 10; each x is independently an integer from 1-10; and each A is independently selected from a bond, an optionally substituted C1-C12 alkyl, an optionally substituted Ce-Cio arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5 to 10-membered heteroarylene, and optionally substituted 4 to 10- membered heterocycloalkylene.

[0415] In some embodiments, the oligomeric backbone comprises -(CH2CH2-O)X7- or -(CH2CH2-O)xs-A- (CH2CH2-O)X9-, wherein A is an optionally substituted 4 to 10-membered heterocycloalkylene or spirocyclene, and each x7, xs, and xg is independently an integer from 1-15.

[0416] In some embodiments, the oligomeric backbone comprises -NRla-(CH2CH2O)y(CH2)x- or -NRla- (CH2)q-C(O)NRla(CH2CH2O)y(CH2)x-, wherein q is 2-10, x is 1-4, y is 1-50, and each Rlais independently hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce haloalkyl. In some embodiments, the oligomeric backbone comprises -NRla-(CH2CH2O)y(CH2)x,. In some embodiments, the oligomeric backbone comprises -NRla-(CH2)q-C(O)NRla(CH2CH2O)y(CH2)x-.

[0417] In some embodiments, the oligomeric backbone comprises -(CH2CH2-O)X-, -(CH2CH2-O)X- (CH2CH2)-NH-, -NH-(CH2CH2-O)X-, -NH-(CH2CH2-O)X-(CH2CH2)-NH-, -(CH2CH2-O)X-(CH2CH2)- NHC(O)-, or -NH-(CH2CH2-O)X-(CH2CH2)-NHC(O)-. In some embodiments, the oligomeric backbone comprises -NH-(CH2CH2-O)X- or -NH-(CH2CH2-O)X-(CH2CH2)-NH-. In some embodiments, the oligomeric backbone comprises -NH-(CH2CH2-O)X-. In some embodiments, the oligomeric backbone comprises -NH- (CH2CH2-O)X-(CH2CH2)-NH-.

[0418] In some embodiments, the oligomeric backbone comprises polyethylene glycol (PEG). In some embodiments, the oligomeric backbone comprises 1-20 PEG units. In some embodiments, the oligomeric backbone comprises 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 PEG units.

[0420] In some embodiments, A comprises a moiety having the structure, or a pharmaceutically acceptable salt thereof:wherein:A2is absent or -C(O)-; andR27is an optionally substituted C1-C50 alkyl or optionally substituted C1-C50 heteroalkyl.

[0421] In some embodiments, A2is -C(O)-. In some embodiments, A2is absent.

[0422] In some embodiments, R27is C1-C50 alkyl. In some embodiments, R27is C1-C40 alkyl. In some embodiments, R27is C1-C30 alkyl. In some embodiments, R27is C1-C20 alkyl. In some embodiments, R27is C1-C10 alkyl. In some embodiments, R27is C1-C50 heteroalkyl. In some embodiments, R26is C1-C40 heteroalkyl. In some embodiments, R27is C1-C30 heteroalkyl. In some embodiments, R27is C1-C20 heteroalkyl. In some embodiments, R27is C1-C10 heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG).

[0423] In some embodiments, the oligomeric backbone comprises a moiety having a structure of Formula (C-l), or a pharmaceutically acceptable salt thereof:Formula (C-l), wherein:Ring P is absent, arylene, or heterocycloalkylene;L5is absent, optionally substituted alkylene, or optionally substituted alkynylene;B1and B2are each independently CH or N;Si and S2 are each independently 0-3; and** denotes attachment to the second terminus.

[0424] In some embodiments, Ring P is absent. In some embodiments, Ring P is C4-C7 heterocycloalkylene .

[0425] In some embodiments, B1is N. In some embodiments, B1is CH.

[0426] In some embodiments, B2is N. In some embodiments, B2is CH.

[0427] In some embodiments, L5is absent.

[0428] In some embodiments, L5is alkylene or alkynylene.

[0429] In some embodiments, L5is -(CR1GR1G)xio-(alkylene)2-(CR1GR1G)yio-; wherein xio and yio are each independently 0 or 1; and each R1Gis hydrogen or C1-C3 alkyl.

[0430] In some embodiments, the oligomeric backbone comprises a moiety having a structure of Formula (C-2), or a pharmaceutically acceptable salt thereof:Formula (C-2), wherein:L5is absent, optionally substituted alkylene, or optionally substituted alkynylene; andB2, B3and B4are each independently N or CH.

[0431] In some embodiments, each of B3and B4is independently N or CH; and B2is N.

[0432] In some embodiments, L5is C1-C3 alkylene or C1-C3 alkynylene. In some embodiments, L5is Ci- C3 alkylene. In some embodiments, L5is C1-C3 alkynylene. In some embodiments, L5is -CH2-, -CH2CH2-,_ — _ Q=Q Q=Q, or - “ . In some embodiments, L5is -CH2- or -CH2CH2-. In some embodiments, L5is C-C jn Some embodiments,

[0433] In some embodiments, L5is -(CR1GR1G)xio-(alkylene)2-(CR1GR1G)yio-; wherein xio and yio are each independently 0 or 1; and each R1Gis hydrogen or C1-C3 alkyl.

[0434] In some embodiments, the oligomeric backbone comprises a moiety having the structure ofFormula (C-3), or a pharmaceutically acceptable salt thereof:Formula (C-3), wherein:Si and S2 are each independently 0-3; n is an integer from 1-3;R26is an optionally substituted C1-C20 alkylene or optionally substituted C2-C20 heteroalkylene; each R1Gis independently hydrogen or C1-C3 alkyl; and** denotes attachment to the second terminus.

[0435] In some embodiments, R26is an optionally substituted C1-C20 heteroalkylene. In some embodiments, R26is PEG.

[0436] In some embodiments, each R1Gis independently hydrogen. In some embodiments, R1Gis independently C1-C3 alkyl. In some embodiments, the C1-C3 alkyl is methyl, ethyl or propyl. In some embodiments, each R1Gis independently methyl.

[0437] In some embodiments, si and S2 are each independently is 0, 1, or 2. In some embodiments, si and S2 are each independently 0. In some embodiments, si and S2 are each independently 1.

[0438] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0439] In some embodiments, the oligomeric backbone comprises:

[0440] In some embodiments, the oligomeric backbone is joined with the first terminus and / or with the second terminus with a group selected from -C(O)-, -NRla-, -C(O)NRla-, -NRlaC(O)-, -C(O)NRlaCi-C4alkyl- , -NRlaC(O)-Ci-C4alkyl-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NRla-, -NRlaS(O)2-, -P(O)OH-, -((CH2)X-O)-, -((CH2)y-NRla)-, optionally substituted C1-C12 alkylene, optionally substituted C2-Cio alkenylene, optionally substituted C2-Cio alkynylene, optionally substituted Ce-Cio arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5 to 10-membered heteroarylene, and optionally substituted 4 to 10-membered heterocycloalkylene, wherein each x is independently 1-4, each y is independently 1-4, and each Rlais independently a hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce haloalkyl.

[0441] In some embodiments, the oligomeric backbone is joined with the first terminus with a group selected from -O-, -C(O)-, -NRla-, C1-C12 alkyl, -C(O)NRla-, and -NRlaC(O)-. In some embodiments, the oligomeric backbone is joined with the first terminus with a group selected from -O- or -NRla-.

[0442] In some embodiments, the oligomeric backbone is joined with the second terminus with a group selected from -C(O)-, -NRla-, -C(O)NRla-, -NRlaC(O)-, -((CH2)X-O)-, -((CH2)y-NRla)-, -O-, optionally substituted C1-C12 alkyl, optionally substituted Ce-Cio arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, and optionally substituted 4- to 10-membered heterocycloalkylene, wherein each x is independently 1-4, each y is independently 1-4, and each Rlais independently hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce haloalkyl.

[0443] In some embodiments, the oligomeric backbone is joined with the second terminus with a group selected from -O-, -C(O)-, -NRla-, C1-C12 alkyl, -C(O)NRla-, and -NRlaC(O)-. In some embodiments, the oligomeric backbone is joined with the second terminus with a group selected from -O- or -NRla-. In some embodiments, the oligomeric backbone is joined with the second terminus with -O-. In some embodiments,the oligomeric backbone is joined with the second terminus with -NRla-. In some embodiments, the oligomeric backbone is joined with the second terminus with -NH-.

[0444] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0445] In some embodiments, non-limiting examples of the transcription modulator compounds described herein are presented below in Table 3 (next page).Table 3. Compounds of the disclosure.Methods of Use

[0446] In another aspect, provided herein is a method of decreasing expression of a gene in a cell, the method comprising contacting the cell with an effective amount of a molecule disclosed herein, or a pharmaceutically acceptable salt thereof.

[0447] In some embodiments, the gene is huntingtin (HIT). In some embodiments, the gene is mutant huntingtin.

[0448] In some embodiments, the expression of the gene is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or more.

[0449] In another aspect, provided herein is a method of treating Huntington’s disease (HD) in a subject in need thereof, the method comprising administering to the subject a molecule described herein, or a pharmaceutically acceptable salt thereof.

[0450] In another aspect, provided herein is a method of treating Huntington’s disease-like syndrome

[0451] in a subject in need thereof, the method comprising administering to the subject a molecule described herein, or a pharmaceutically acceptable salt thereof.

[0452] In another aspect, provided herein is a method of treating Juvenile Huntington’s disease in a subject in need thereof, the method comprising administering to the subject a molecule described herein, or a pharmaceutically acceptable salt thereof.

[0453] In some embodiments, the method reduces one or more symptoms of Huntington’s disease (HD).

[0454] In some embodiments, the one or more symptoms are selected from chorea, cognitive decline, abnormal libido, abnormal eye movement, abnormal sense of smell, aggression, agitation, anxiety, apathy, bradykinesia, bradyphrenia, clumsiness, delusions, depression, difficulty walking, disinhibition, dystonia, gait imbalance, muscle weakness, hallucinations, hostility, hypokinesia, irritability, memory impairment, myoclonus, obsessive-compulsive behavior, poor fine motor coordination, seizure, speech articulation difficulties, staring gaze, weight loss, abnormal cholesterol metabolism, abnormal cerebral white matter, alcoholism, Babinski sign, caudate atrophy, cerebral atrophy, choking, clonus, degeneration of the striatum, excessive daytime sleepiness, impaired visuospatial constructive cognition, inability to walk, insomnia, mutism, oral-pharyngeal dysphagia, rigidity, suicidal ideation, cerebellar atrophy, dementia, gate ataxia, gliosis, hyperreflexia, neuronal loss, or personality changes.Pharmaceutical Compositions and Administration

[0455] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0456] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptableexcipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, (N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0457] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fdling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.

[0458] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg, e.g., between about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 1000 mg / kg, between about 100-500 mg / kg, or between about 500-1000 mg / kg body weight. The optimaldose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.Definitions

[0459] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0460] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0461] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0462] When ranges of values are disclosed, and the notation “from ... to n2” or “between . . . and n2” is used, where and n2are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 pM (micromolar),” which is intended to include 1 pM, 3 pM, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).

[0463] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0464] “oxo” refers to =0.

[0465] “Carboxyl” refers to -COOH.

[0466] “Cyano” refers to -CN.

[0467] “Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2 -propyl, 2-methyl-l -butyl, 3- methyl-1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l- pentyl, 2-methyl-2-pentyl, 3 -methyl -2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3, 3 -dimethyl- 1- butyl, 2 -ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” or “Ci -ealkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cioalkyl. In some embodiments, the alkyl is a Ci-Cealkyl. In some embodiments, the alkyl is a Ci-Csalkyl. In some embodiments, the alkyl is a Ci-C4alkyl. In some embodiments, the alkyl is a Ci-Csalkyl. Unless stated otherwise specifically in the specification, an alkylgroup may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -Ns, -CN, -C(O)OH, -C(O)OMe, -OH, - OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or - OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0468] “Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (- CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CHs)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or - NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0469] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2- ealkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0470] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, thealkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0471] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -Ns, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0472] “Aryl” refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system can contain only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) K-cIcctron system in accordance with the Htickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -N3, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0473] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-Cis fully saturated cycloalkyl or C3-Cis cycloalkenyl), from three to ten carbon atoms (e.g., C3-Cio fully saturated cycloalkyl or C3-Cio cycloalkenyl), from three to eight carbon atoms (e.g., C3-Cs fully saturated cycloalkyl or C3-Cs cycloalkenyl), from three to six carbon atoms (e.g., C3-Ce fully saturated cycloalkyl or C3-Ce cycloalkenyl), from three to five carbon atoms (e.g., C3-C3fully saturated cycloalkyl or C3-C3cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 - to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, cisdecalin, trans-decalin, bicyclo [2. l.l]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -Ns, -CN, -C(0)0H, C(0)0Me, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0474] “Cycloalkenyl” refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0475] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0476] As used herein, the term “haloalkyl” or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl -2 -fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1- haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2- dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1- chloro,2-fluoroethane .

[0477] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.

[0478] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0479] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0480] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or - CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0481] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, theheterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2- C, heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo- 1,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments,the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0482] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5 - to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5- membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2- oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0483] The term “oligonucleotide sequence” refers to a plurality of nucleic acids having a defined sequence and length (e.g., 2, 3, 4, 5, 6, or even more nucleotides). The term “oligonucleotide repeat sequence” refers to a contiguous expansion of oligonucleotide sequences.

[0484] The term “transcription,” well known in the art, refers to the synthesis of RNA (i.e., ribonucleic acid) by DNA-directed RNA polymerase. The term “modulate transcription” refers to a change in transcriptional level which can be measured by methods well known in the art, for example, assay of mRNA, the product of transcription. In certain embodiments, modulation is an increase in transcription. In other embodiments, modulation is a decrease in transcription.

[0485] The term “polyamide” refers to polymers of linkable units chemically bound by amide (i.e., CONH) linkages; optionally, polyamides include chemical probes conjugated therewith. Polyamides may be synthesized by stepwise condensation of carboxylic acids (COOH) with amines (RR’NH) using methods known in the art. Alternatively, polyamides may be formed using enzymatic reactions in vitro, or by employing fermentation with microorganisms.

[0486] The term “linkable unit” refers to methylimidazoles, methylpyrroles, and straight and branched chain aliphatic functionalities (e.g., methylene, ethylene, propylene, butylene, and the like) which optionally contain nitrogen Substituents, and chemical derivatives thereof. The aliphatic functionalities of linkable units can be provided, for example, by condensation of B-alanine or dimethylaminopropylamine during synthesis of the polyamide by methods well known in the art.

[0487] The term “linker” or “oligomeric backbone” refers to a chain of at least 10 contiguous atoms. In certain embodiments, the linker contains no more than 20 non-hydrogen atoms. The terms linker and oligomeric backbone can be used interchangeably. In some embodiments, the linker contains no more than 40 non-hydrogen atoms. In some embodiments, the linker contains no more than 60 non-hydrogen atoms. In certain embodiments, the linker contains atoms chosen from C, H, N, O, and S. In some embodiments, every non-hydrogen atom is chemically bonded either to 2 neighboring atoms in the linker, or one neighboring atom in the linker and a terminus of the linker. In some embodiments, the linker forms an amide bond with at least one of the two other groups to which it is attached. In certain embodiments, the linker forms an ester or ether bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms a thioester or thioether bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms a direct carbon-carbon bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms an amine or amide bond with at least one of the two other groups to which it is attached. In some embodiments, the linker comprises -(CH2OCH2)- units. In some embodiments, the linker comprises -(CH(CH3)OCH2)- units. In some embodiments, the linker comprises -(CH2NRNCH2) units, for RN = Ci-4alkyl. In some embodiments, the linker comprises an arylene, cycloalkylene, or heterocycloalkylene moiety.

[0488] The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[0489] As used herein, “optionally substituted” is a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom orgroup. Unless otherwise indicated, when a group is deemed to be “substituted” or “optionally substituted” it is meant that the group is substituted with one or more substituents independently selected from Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Ci-Ce heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), Cs-Cv-carbocyclyl-Ci-Ce-alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 3-10 membered heterocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 3-10 membered heterocyclyl-Ci-Ce-alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), aryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), aryl(Ci-Ce)alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Cg alkoxy, Ci-Cg haloalkyl, and Ci-Cg haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 5-10 membered heteroaryl(Ci-Ce)alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci- Ce haloalkoxy), halo, cyano, hydroxy, Ci-Cg alkoxy, Ci-Cg alkoxy(Ci-Ce)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(Ci-Ce)alkyl (e.g., -CF3), halo(Ci-Ce)alkoxy (e.g., -OCF3), Ci-Ce alkylthio, arylthio, amino, amino(Ci-Ce)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=0). Wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0490] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0491] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0492] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0493] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0494] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C).Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,160,170,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. In some embodiments, where isotopic variations are illustrated, the remaining atoms of the compound may optionally contain unnatural portions of atomic isotopes.

[0495] In certain embodiments, the compounds disclosed herein have some or all of the ’H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0496] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0497] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0498] In some embodiments of a compound disclosed herein, one or more of the substituent groups comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments of a compound disclosed herein, one or more hydrogens are replaced with one or more deuteriums.

[0499] In some embodiments of a compound disclosed herein, the abundance of deuterium in each of the substituents is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium.

[0500] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0501] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0502] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluene sulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0503] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0504] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0505] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0506] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.

[0507] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0508] The term “contacting” refers to bringing the compound (e.g., a transcription molecular molecule of the present disclosure) into proximity of the desired target gene. The contacting may result in the binding to or result in a conformational change of the target moiety.

[0509] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.EXAMPLES

[0510] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will be known to those skilled in the art.Compound Synthesis

[0511] Compounds of the present disclosure can be prepared using methods illustrated in general synthetic schemes and experimental procedures detailed below. General synthetic schemes and experimental procedures are presented for purposes of illustration and are not intended to be limiting. Starting materials used to prepare compounds of the present disclosure are commercially available or can be prepared using routine methods known in the art.

[0512] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R.Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser ’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).List of Abbreviations

[0513] AC2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; Boc = tert-butyloxy carbonyl; BusSnH = tributyltin hydride; CD3OD = deuterated methanol; CDCE = deuterated chloroform; CDI = 1,1 '-Carbonyldiimidazole; DBU = 1,8- diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = di-iso-butyl aluminium hydride; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4- dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO-de = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EDC.HC1 = EDCI.HC1 = l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = hour; HATU=2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate methanaminium; HMDS = hexamethyldisilazane; HOBT = 1 -hydroxybenzotriazole; i-PrOH = isopropanol; LAH = lithium aluminium hydride; LiHMDS = Lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; Mel = methyl iodide; MeOH = methanol; MP -carbonate resin = macroporous triethylammonium methylpolystyrene carbonate resin; MsCl = mesyl chloride; MTBE = methyl tertiary butyl ether; MW = microwave irradiation ; n-BuLi = n-butyllithium; NaHMDS = Sodium bis(trimethylsilyl)amide; NaOMe = sodium methoxide; NaOtBu = sodium t-butoxide; NBS = N-bromosuccinimide; NCS = N-chloro- succinimide; NMI = 1 -methylimidazole; NMP = N-Methyl -2 -pyrrolidone; OAc = acetoxy; Pd(Ph3)4 = tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; prep-HPLC = preparative high-performance liquid chromatography; PyBop = (benzotriazol- 1-yloxy)- tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; RT = room temperature; RuPhos = 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; sat. = saturated; ss = saturated solution; t-BuOH = tertbutanol; T3P = Propylphosphonic Anhydride; TBS = TBDMS = tert-butyldimethylsilyl; TBSC1 = TBDMSC1 = tert-butyldimethylchlorosilane; TCFH = chloro-N, N, N’, N’-tetramethylformamidium hexafluorophosphate; TEA = EtsN = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; Tol = toluene; TsCl = tosyl chloride; XPhos = 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl.SYNTHESIS OF TARGETING LIGAND

[0514] Example 1. Synthesis of I-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f|[l,2,4]triazolo[4,3-a][l,4] diazepin-6-yl)-N-(4-hvdroxyphenyl)acetamide

[0515] Scheme 1.

[0516] Step 1. To a stirred solution of (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methoxy-4- oxobutanoic acid (5.00 g, 13.54 mmol, 1.00 equiv) in DMF (60.00 mb) was added NMI (3.33 g, 40.61 mmol, 3.00 equiv), TCFH (5.70 g, 20.31 mmol, 1.50 equiv) and 3-(4-chlorobenzoyl)-4,5-dimethylthiophen- 2-amine (3.96 g, 14.90 mmol, 1.10 equiv) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The reaction quenched with water / ice (200 mb) and the precipitated solids were collected by filtration, washed with water (3x30 mb), and dried under vacuum. The solid was purified by silica gel column chromatography, eluted with PE / EA (3: 1) to afford methyl (3R)-3-[[3-(4-chlorobenzoyl)-4,5- dimethylthiophen-2-yl]carbamoyl]-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoate (4.95 g, 56.00%) as a yellow solid. LCMS: mass calcd. For C33H29CIN2O6S: 616.14, found: 617.05 [M+H]+

[0517] Step 2. To a solution of methyl (3R)-3-amino-3-[[3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2- yl] carbamoyl] propanoate (4.95 g) in DCM was treated with EtsN followed by AcOH treatment in DCE to give 2.10 g of methyl 2-[(3R)-5-(4-chlorophenyl)-6,7-dimethyl-2-oxo-lH,3H-thieno[2,3-e][l,4]diazepin-3- yl]acetate as a yellow solid (70.00% yield of two steps). LCMS: mass calcd. For C18H17CIN2O3S: 376.06, found: 377.15 [M+H]+.

[0518] Step 3. To a solution of methyl 2-[(3R)-5-(4-chlorophenyl)-6,7-dimethyl-2-oxo-lH,3H- thieno[2,3-e][l,4]diazepin-3-yl]acetate (1.10 g, 2.92 mmol, 1.00 equiv) in toluene (25.00 ml) was added P2S5 (1.30 g, 0.006 mmol, 2.00 equiv) and ISfeCCE (0.62 g, 5.85 mmol, 2.00 equiv). The reaction was stirred at 110 °C for 17 h. The solid was fdtered and the fdtrate was concentrated. The residue was purified by silica gel column chromatography, eluted with PE: EA = 1: 1 to afford methyl 2-[(3R)-5-(4- chlorophenyl)-6,7-dimethyl-2-sulfanylidene-lH,3H-thieno[2,3-e][l,4]diazepin-3-yl]acetate (2 g, crude) as a yellow solid. LCMS: mass calcd. For C18H17CIN2O2S2: 392.04, found: 393.10 [M+H]+.

[0519] Step 4. To a solution of methyl 2-[(3R)-5-(4-chlorophenyl)-6,7-dimethyl-2-sulfanylidene-lH,3H- thieno[2,3-e][l,4]diazepin-3-yl]acetate (900.00 mg, 2.29 mmol, 1.00 equiv) in THF (6.00 mb) was added NH2NH2.H2O (344.00 mg, 6.87 mmol, 3.00 equiv) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h. AcCl (539.41 mg, 6.87 mmol, 3.00 equiv) and EtsN (695.34 mg, 6.87 mmol, 3.00 equiv) were added and the mixture was stirred at 0 °C for 30 mins. The reaction mixture was then quenched with H2O (15 mb), extracted with EA (3x15 mb), washed with brine (20 mb), and dried over Na2SO4. The solid was filtratedand the filtrate was concentrated to dryness. The crude product was dissolved in AcOH (10.0 mL) and stirred at 40 °C for 4 h. The solvent was removed and the residue was purified by reverse flash chromatography with the following conditions: column, C18 column; mobile phase, MeCN in water (0.05% TFA), 5% to 50% gradient in 40 min; detector, UV 254 nm to afford methyl (R)-2-(4-(4-chlorophenyl)- 2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate(400.00 mg, 42.09%) as a yellow solid. LCMS: mass calcd. For C20H19CIN4O2S: 414.09, found: 415.10 [M+H]+.

[0520] Step 5. A solution of methyl (R)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f] [l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate (400.00 mg, 0.96 mmol, 1.00 equiv) in LiOH (2M, 2.00 mL, 4.00 equiv) and MeOH (2.00 mL) was stirred at 40 °C for 2 h. The mixture was acidified with HC1 (2M) and concentrated. The residue was dissolved in DMF (2 mL) and purified by reverse phase column with the following conditions: column, C18 column; mobile phase, MeCN in water (0.05% TFA),5% to 50% gradient in 40 min; detector, UV 254 nm to afford (R)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl- 6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetic acid (340.00 mg, 87.97% yield) as a white solid. LCMS: mass calcd. For C19H17CIN4O2S: 400.09, found: 401.10 [M+H]+.

[0521] Example 2. Synthesis of 4-[2-(2,4-difluorophenoxy)-5-ethanesulfonamidophenyl]-6-methyl-7- oxo-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid

[0522] Scheme 2.

[0523] Step 1. A solution of 2,4-difluorophenol (2.66 g, 20.45 mmol, 1.50 equiv) and 2-bromo-l-fluoro- 4-nitrobenzene (3.00 g, 13.64 mmol, 1.00 equiv) in DMF (50.00 mL) was stirred at 85 °C for 3.0 h. Thereaction was cooled to room temperature and was then diluted with water (150 mL). The precipitate was filtered and the filter cake was washed with water and dried to afford 2-bromo-l-(2,4-difluorophenoxy)-4- nitrobenzene (4.40 g, 98.21%) as light a yellow solid. 'H NMR (300 MHz, DMSO-t / e) 5: 8.56-8.58 (m, 1H), 8.18-8.22 (m, 1H), 7.48-7.63 (m, 2H), 7.22-7.28(m, 1H), 6.99 (d, J= 9.0 Hz, 1H).

[0524] Step 2. Iron powder (7.78 g, 139.36 mmol, 10.00 equiv) was added in portions to a stirred solution of 2-bromo-l-(2,4-difluorophenoxy)-4-nitrobenzene (4.40 g, 13.37 mmol, 1.00 equiv) in EtOH (20.00 mL) and THF (20.00 mL), NH4CI (7.45 g, 139.36 mmol, 10.00 equiv), and H2O (20.00 mL) at room temperature. The mixture was heated at 70 °C for 2.0 h. The reaction mixture was cooled to room temperature and was then filtered through a pad of Celite. The filtrate was concentrated under vacuum and the resulting residue was diluted with water (20 mL) and extracted with EA (50 mLx3). The combined organic layers were washed with brine (100 mL), dried over ISfeSCh, and concentrated to afford 3-bromo-4- (2,4-difluorophenoxy)aniline (3.77 g, 65.28%) as a brown solid. LC / MS: mass calcd. For Ci2H8BrF2NO: 298.98, found: 299.90, 301.90 [M+H, M+H+2]+.

[0525] Step 3. To a mixture of 3-bromo-4-(2,4-difluorophenoxy)aniline (2.51 g, 8.36 mmol, 1.00 equiv) and EtsN (3.39 g, 33.45 mmol, 4.00 equiv) in DCM (10.00 mL) a solution of ethane sulfonyl chloride (3.23 g, 25.09 mmol, 3.00 equiv) in DCM (10.00 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 3.0 h. The reaction was concentrated under vacuum, diluted with water (20 mL), and extracted with EA (20 mLx3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The resulting crude was suspended in 1,4-dioxane (30.00 mL) and 10% NaOH (6.00 mL) and the mixture was heated at 100 °C for 2.0 h. The reaction was concentrated under vacuum, diluted with water (20 mL), and extracted with EA (20 mLx3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to afford N-[3-bromo-4-(2,4- difluorophenoxy)phenyl] ethane sulfonamide (3.00 g, 92.02% yield) as a brown solid. LC / MS: mass calcd. For Ci4Hi2BrF2NO3S: 390.97, found: 392.21 [M+H]+. ’H NMR (300 MHz, DMSO-tf,) 5: 9.94(s, 1H), 7.46- 7.53 (m, 2H), 7.20-7.24 (m, 1H), 7.07-7.15(m, 2H), 6.88-7.04 (m, 1H), 3.09-3.16(m, 2H), 1.21(t, J= 7.2 Hz, 3H).

[0526] Step 4. A mixture of N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide (1.00 g, 2.55 mmol, 1.00 equiv) and ethyl 6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrrolo[2,3-c]pyridine-2-carboxylate (970.00 mg, 2.80 mmol, 1.10 equiv), Pd(dtbpf)C12 (166.00 mg, 0.25 mmol, 0.10 equiv), and K3PO4 (1.10 g, 5.18 mmol, 2.03 equiv) in toluene (8.00 mL) and H2O (2.00 mL) was stirred for 1.0 h at 75 °C under nitrogen atmosphere. The reaction mixture was cooled to room temperature and was T quenched with water (70.00 mL). The mixture was extracted with EA (50 mLx3) and the combined organic layers were washed with water (40 mLx2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with QLCf / MeOH (15: 1) to afford ethyl 4-[2-(2,4-difluorophenoxy)-5-ethanesulfonamidophenyl]-6- methyl-7-oxo-lH-pyrrolo[2,3-c]pyridine-2-carboxylate (1.20 g, 88.55%) as a brown solid. LC / MS: mass calcd. For C25H23F2N3O6S: 531.13, found: 532.10 [M+H]+.

[0527] Step 5. The procedure was the same as 4-{4-[3-({4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({l- methyl-4-[ 1 -methyl -4-(3 - { [ 1 -methyl -4-( 1 -methylimidazole-2-amido)pyrrol-2- yl]formamido}propanamido)imidazole-2-amido]pyrrol-2-yl}formamido)butanamido]-l-methylimidazol-2- yl}formamido)propanamido]-l-methylpyrrole-2-amido}-l-methylimidazole-2-carboxylic acid (Example 3 Step 2). 1.10 g of ethyl 4-[2-(2,4-difluorophenoxy)-5-ethanesulfonamidophenyl]-6-methyl-7-oxo-lH- pyrrolo[2,3-c]pyridine-2 -carboxylate was used and 1.00 g of the desired product was obtained as a grey solid (95.97% yield). LC / MS: mass calcd. For C23H19F2N3O6S: 503.10, found: 504.10 [M+H]+.

[0528] Example 3. Synthesis of tert-butyl (3R,5R)-3-((5-bromo-2-methyl-3-oxo-2,3- dihvdropyridazin-4-yl)amino)-5-phenylpiperidine-l-carboxylate

[0529] Scheme 3.

[0530] Step 1. To a solution of 4,5-dibromo-2H-pyridazin-3-one (5.00 g, 19.69 mmol, 1.00 equiv.) in DMF (50.00 mL) was added methyl iodide (8.39 g, 59.08 mmol, 3.00 equiv.) and K2CO3 (6.80 g, 49.24 mmol, 2.50 equiv.). The resulting mixture was stirred for 17.0 h at room temperature. The reaction mixture was poured into water (200 mL). The precipitated solids were collected by filtration and washed with water (150.00 mL) and dried to afford 4,5-dibromo-2-methylpyridazin-3-one (3.30 g, 62.54%) as a yellow solid. LC / MS: mass calcd. For CMLB ^O: 265.87, found: 266.85, 268.85 [M+H, M+H+2]+.

[0531] Step 2. To a stirred solution of picolinic acid (10.14 g, 82.38 mmol, 1.10 equiv.) in DCM (100 mL) was added HATU (34.17 g, 89.87 mmol, 1.20 equiv.) and DIEA (10.65 g, 82.38 mmol, 1.10 equiv.). The resulting mixture was stirred at 25 °C for 0.5 h. The tert-butyl (3R)-3-aminopiperidine-l-carboxylate (15.00 g, 74.89 mmol, 1.00 equiv.) and DIEA (19.36 g, 149.79 mmol, 2.00 equiv.) were added in portions and the resulting mixture was stirred at 25 °C for 1.0 h. Then the resulting mixture was concentrated undervacuum and the residue was purified by silica gel column chromatography (30-50% EA / PE) to afford tertbutyl (3R)-3-(pyridine-2-amido)piperidine-l-carboxylate (22.00 g, 96.19%) as a yellow solid. LC / MS: mass calcd. For C16H23N3O3: 305.17, found: 306.10 [M+H]+.

[0532] Step 3. To a stirred solution of tert-butyl (3R)-3-(pyridine-2-amido)piperidine-l-carboxylate (19.00 g, 62.22 mmol, 1.00 equiv.) in 2-methylpropan-2-ol (100 mL) was added iodophenyl (63.47 g, 311.09 mmol, 5.00 equiv.), 2,6-dimethylbenzoic acid (2.34 g, 15.58 mmol, 0.25 equiv.), Pd(OAc)2 (1.40 g, 6.22 mmol, 0.10 equiv.) and Ag2CC>3 (17.16 g, 62.22 mmol, 1.00 equiv.) and the resulting mixture was stirred at 100 °C for 16.0 h. Then the resulting mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (30-50% EA / PE) to afford tert-butyl (3R,5R)-3-phenyl-5- (pyridine-2-amido)piperidine-l -carboxylate (10.70 g, 45.08%) as a yellow solid. LC / MS: mass calcd. For C22H27N3O3: 381.21, found: 326.15 [M+H-56]+.

[0533] Step 4. To a stirred solution of tert-butyl (3R,5R)-3-phenyl-5-(pyridine-2-amido)piperidine-l- carboxylate (10.70 g, 28.05 mmol, 1.00 equiv) in i-PrOH (100 mL) was added NaOH (11.22 g, 280.49 mmol, 10.00 equiv.) and the reaction mixture was stirred for 16.0 h at 85 °C. The reaction was filtered and the filtrate was concentrated. The resulting residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% NH4HCO3), 30% to 50% gradient in 30 min; Detector, UV 254 nm. The fractions were combined and concentrated to afford tertbutyl (3R,5R)-3-amino-5-phenylpiperidine-l-carboxylate (6.50 g, 83.85%) as a white solid. LC / MS: mass calcd. For C16H24N2O2: 276.18, found: 277.10 [M+H]+.

[0534] Step 5. To a stirred solution of tert-butyl (3R,5R)-3-amino-5-phenylpiperidine-l-carboxylate (6.00 g, 21.71 mmol, 1.00 equiv.) in DMF (50 mL) was added 4,5-dibromo-2-methylpyridazin-3-one (5.82 g, 21.71 mmol, 1.00 equiv.) and DIEA (11.22 g, 86.84 mmol, 4.00 equiv.). The reaction mixture was irradiated with microwave radiation for 10.0 h at 120 °C and then 100.00 mL H2O was added. The resulting mixture was extracted with EA (100 mLx3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (30-50% EA / PE) to afford tert-butyl (3R,5R)-3-[(5-bromo-l-methyl-6-oxopyridazin-4-yl)amino]-5- phenylpiperidine-1 -carboxylate (5.02 g, 46.83%) as a yellow solid and tert-butyl (3R,5R)-3-((5-bromo-2- methyl-3-oxo-2,3-dihydropyridazin-4-yl)amino)-5-phenylpiperidine-l-carboxylate (2.00 g, 19.88%) as a yellow solid. LC / MS: mass calcd. For C2iH27BrN4O3: 462.13, found: 463.10, 465.10 [M+H, M+H+2]+.

[0535] Example 4. Synthesis of (S)-2-chloro-4-(2-(5-(3,5-dimethylisoxazol-4-yl)-l-(2- morpholinopropyl)-lH-benzo[d1imidazol-2-yl)ethyl)phenol

[0536] Scheme 4.

[0537] Step 1. Into a 500 ml flask was added 4-bromo-l-fluoro-2-nitorbenzene (15.40 g, 70.00 mmol, 1.00 equiv), 3, 5 -dimethyl- l,2-oxazol-4-ylboronic acid (9.87 g, 70.001 mmol, 1.00 equiv), NaHC’CF (11.76 g, 140.00 mmol, 2.00 equiv), Pd(dppf)C12.CH2C12 (2.86 g, 3.500 mmol, 0.05 equiv), DME (100.00 mb), and H2O (10.00 mL) and the reaction mixture was stirred at 95 °C for 3.0 h under N2 atmosphere. The reaction was concentrated and the residue was purified by silica gel column with PE / A (1 : 1) to yield 4-(4-fluoro-3- nitrophenyl)-3,5-dimethyl-l,2-oxazole (15.7 g , 90.21% yield) as a white solid. LC / MS: mass calcd. For CnH9FN2O3:236.06, found: 237.10[M+H]+.

[0538] Step 2. Into a 500 ml flask was added 4-(4-fluoro-3-nitrophenyl)-3,5-dimethyl-l,2- oxazole (12.70 g, 53.77 mmol, 1.00 equiv), (2S)-propane-I,2-diamine (3.99 g, 53.92 mmol, 1.00 equiv), K2CO3 (14.86 g, 107.54 mmol, 2.00 equiv), and CH3CN (300.00 mL) and the reaction was stirred at 50 °C for 24.0 h. The reaction was filtered and washed with CH3CN. The filtrate was concentrated and the residue was purified by silica gel column with PE / EA (1: 1) to afford (2S)-NI-[4-(3,5-dimethyl-l,2-oxazol-4-yl)-2- nitrophenyl]propane-I,2- diamine (6.10 g, 37.01% yield) as a yellow oil. LC / MS: mass calcd. For CnH9FN2O3:290.14, found: 291.05[M+H]+.

[0539] Step 3. Into a 500 ml flask was added (2S)-NI-[4-(3,5-dimethyl-l,2-oxazol-4-yl)-2- nitrophenyl]propane-I,2-diamine (6.10 g, 21.01 mmol, 1.00 equiv) and CH3CN (200.00 mL). Then 1- bromo-2-(2-bromoethoxy)ethane (5.36 g, 23.11 mmol, 1.10 equiv), K2CO3 (8.71 g, 63.03mmol, 3.00 equiv), and KI (4.19 g, 25.21 mmol, 1.20 equiv) were added and the reaction mixture was stirred at 80 °C for 60.0 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography with PE / EA (1: 1) to afford 4-(3,5-dimethyl-l,2-oxazol-4-yl)-N-[(2S)-2-(morpholin-4-yl)propyl] -2 -nitroaniline (6.00 g, 71.31% yield) as a red solid. LC / MS: mass calcd. For C18H24N4O4: 360.18, found: 361.10[M+H]+.

[0540] Step 4. Into a 500 ml flask was added 4-(3,5-dimethyl-l,2-oxazol-4-yl)-N-[(2S)-2-(morpholin-4- yl)propyl] -2 -nitroaniline (3.00 g, 8.32 mmol, 1.00 equiv), EtOH (50.00 mL), H2O (50.00 mL), and Na2S2C>4 (7.25 g, 41.62 mmol, 5.00 equiv) and the reaction was stirred at 80 °C for 1.0 h. The reaction was then concentrated under the reduced pressure and the residue was extracted with EA (50 mLx3). The combined organic phase was washed with NaCl (100 mL), dried over anhydrous ISfeSCE, and concentrated. The residue (1.70 g, 61.19% yield) was used directly in the next step without further purification. LC / MS: mass calcd. For C18H26N4O2: 330.21, found: 331.15[M+H]+.

[0541] Step 5. Into a 250 ml flask was added 4-(3,5-dimethyl-l,2-oxazol-4-yl)-Nl-[(2S)-2-(morpholin- 4- yl)propyl] benzene- 1,2-diamine (1.70 g, 5.15 mmol, 1.00 equiv), EA (60.00 mL), 3-(3-chloro-4- hydroxyphenyl) propanoic acid (1.03 g, 5.15 mmol, 1.00 equiv), T3P (2.46 g, 7.72 mmol, 1.50 equiv), and DIEA (2.66 g, 20.58 mmol, 4.00 equiv) and the reaction mixture was stirred at 80 °C for 1.0 h. Then the reaction mixture was washed with H2O (20 ml x 3) and the combined organic phase was dried with anhydrous Na2SO4 and concentrated. The residue (1.10 g, 27.92% yield) was used directly in the next step without further purification. LC / MS: mass calcd. For C27H33CIN4O4: 512.22, found: 513.15 [M+H]+.

[0542] 6. Into a 100 ml flask was added 3-(3-chloro-4-hydroxyphenyl)-N-[5-(3,5-dimethyl-l,2-oxazol-4- yl)-2-[[(2S)-2-(morpholin-4-yl)propyl]amino]phenyl]propanamide (1.10 g, 2.14 mmol, 1.00 equiv) and HC1 (20.00 mL) and the reaction mixture was stirred at 65 °C for 40 mins. The reaction was concentrated and the residue was purified by reverse flash chromatography with the following conditions: Column: C18 column; mobile phase: MeCN in water (0.05% NH4HCO3), 10% to 50% gradient in 30 min; Detector: UV 254 nm. The fractions were combined and concentrated to afford 2-chloro-4-[2-[5 -(3,5-dimethyl-l,2- oxazol-4-yl)-l-[(2S)-2-(morpholin-4-yl)propyl]-I,3-benzodiazol-2-yl]ethyl]phenol (490.00 mg, 46.00% yield) as a white oil. LC / MS: mass calcd. For C27H31CIN4O3: 494.21, found: 495.05[M+H]+.

[0543] 'HNMR (400 MHz, Methanol-d4) 5: 7.52 - 7.56 (m, 2H), 7.17 - 7.23 (m, 2H), 6.94 (d, J= 8.3 Hz, 1H), 6.81 (d, J= 8.2 Hz, 1H), 4.16 - 4.21 (m, 1H), 3.92 - 3.97 (m, 1H), 3.58 - 3.66 (m, 4H), 3.21 - 3.25 (m, 2H), 3.12 - 3.16 (m, 2H), 2.82 - 2.90 (m, 1H), 2.66 - 2.72 (m, 2H), 2.39 - 2.59 (m, 5H), 2.29 (s, 3H), 0.99 (d, J= 6.7 Hz, 3H).

[0544] 13C NMR (75 MHz, MeOD) 5: 165.35, 158.86, 155.96, 151.51, 141.90, 134.59, 132.82, 129.54, 127.68, 123.98, 123.50, 120.25, 118.50, 117.01, 116.32, 110.56, 78.27, 77.83, 77.40, 66.86, 59.47, 32.55, 29.25, 10.79, 10.20, 9.51.SYNTHESIS OF REPRESENTATIVE COMPOUNDS

[0545] Example 5. Synthesis of Compound B-l

[0546] Scheme 5.

[0547] Step 1. To a stirred solution of methyl 4-amino-l -methyl- lH-pyrrole-2 -carboxylate hydrochloride (3.50 g, 22.70 mmol, 1.00 equiv) in DMF (20.00 mL) was added lH-imidazole-2 -carboxylic acid (2.54 g, 22.70 mmol, 1.00 equiv), PyBOP (14.18 g, 27.24 mmol, 1.20 equiv) and DIEA (11.86 mL, 68.10 mmol, 3.00 equiv). The resulting mixture was stirred for 1.0 h at room temperature and was then quenched with ice water (60.00 mL). The precipitated solids were collected, washed with water (3x40.00 mL), and dried under vacuum to afford methyl 4-(lH-imidazole-2 -amido)- l-methylpyrrole-2 -carboxylate (5.00 g, 88.72%) as a yellow solid. LC / MS: mass calcd. For C11H12N4O3: 248.09, found: 249.05 [M+H]+.

[0548] Step 2. To a stirred solution of methyl 4-(lH-imidazole-2 -amido)- l-methylpyrrole-2 -carboxylate (4.95 g, 19.94 mmol, 1.00 equiv) in MeOH (20.00 mL) was added KOH (10 M in H2O, 19.94 mL, 199.40 mmol, 10.00 equiv) and the resulting mixture was stirred for 2.0 h at 45 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O (30.00 mL) and the mixture was acidified to pH 3~5 with 2 M HC1. The precipitated solids were collected by filtration, washed with H2O (3x20.00 mL), and dried under vacuum to afford 4-(lH-imidazole-2 -amido)- l-methylpyrrole-2 -carboxylic acid (4.20 g, 89.93%) as a yellow solid. LC / MS: mass calcd. For C10H10N4O3: 234.08, found: 235.05 [M+H]+.

[0549] Step 3. To a solution of ethyl l-methyl-4-nitroimidazole-2-carboxylate (30.00 g, 150.63 mmol, 1.00 equiv) in EtOH (120.00 mL) and EA (120.00 mL) was added Pd / C (8.01 g, 27% w / w) and the reaction was stirred for 17.0 h at room temperature under PF atmosphere. The reaction was filtered and the filtrate was concentrated to afford ethyl 4-amino-l -methylimidazole-2 -carboxylate (22.30 g, 75.20%) as a yellow solid. LC / MS: mass calcd. For C7H11N3O2: 169.09, found: 170.15 [M+H]+.

[0550] Step 4. Into a 500 mL flask was added 3 -[(tert-butoxy carbonyl) amino]propanoic acid (22.45 g, 118.65 mmol, 0.90 equiv), DMF (180.00 mL) and the mixture was cooled to 0 °C. Then HATU (75.18 g, 197.71 mmol, 1.50 equiv) and DIEA (51.11 g, 395.43 mmol, 3.00 equiv) were added and the mixture was stirred for 10 mins. Next ethyl 4-amino-l-methylimidazole-2 -carboxylate (22.30 g, 131.81 mmol, 1.00 equiv) was added in portions and the reaction was stirred at room temperature for 1.0 h. The reaction was quenched with ice water (600 mL). The precipitated solids were collected by fdtration, washed with water (3x50 mL), and dried under vacuum to afford ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]- l-methylimidazole-2 -carboxylate (34.50 g, 76.90%) as a light yellow solid. LC / MS: mass calcd. For C15H24N4O5: 340.17, found: 340.10 [M+H]+.

[0551] Step 5. To a stirred solution of ethyl 4-{3-[(tert-butoxycarbonyl)amino]propanamido}-l- methylimidazole-2 -carboxylate (5.00 g, 14.68 mmol, 1.00 equiv) in DCM (45.00 mL) was added TFA (15.00 mL) and the resulting mixture was stirred for 1.0 h at room temperature. The mixture was then concentrated to afford ethyl 4-(3-aminopropanamido)-l-methylimidazole-2 -carboxylate (5.00 g, crude) as a yellow oil. The crude product was used in the next step without further purification. LC / MS: mass calcd. For C10H16N4O3: 240.12, found: 241.10 [M+H]+.

[0552] Step 6. To a stirred solution of 4-(lH-imidazole-2 -amido)- l-methylpyrrole-2 -carboxylic acid (5.00 g, 21.34 mmol, 1.00 equiv) in DMF (20.00 mL) were added ethyl 4-(3-aminopropanamido)-l- methylimidazole-2-carboxylate (6.15 g, 25.61 mmol, 1.20 equiv), PyBOP (13.33 g, 25.61 mmol, 1.20 equiv) and DIEA (11.16 mL, 64.04 mmol, 3.00 equiv) and the resulting mixture was stirred for 1.0 h at room temperature. The mixture was quenched with ice water (60.00 mL) and the precipitated solids were collected by filtration, washed with water (3x30.00 mL), and dried under vacuum to afford ethyl 4-(3-{[4-(lH- imidazole-2 -amido)- 1 -methylpyrrol-2-yl]formamido}propanamido)- 1 -methylimidazole-2 -carboxylate (8.60 g, 88.25%) as a white solid. LC / MS: mass calcd. For C20H24N8O5: 456.19, found: 457.20 [M+H]+.

[0553] Step 7. To a stirred solution of ethyl 4-(3-{[4-(lH-imidazole-2-amido)-l-methylpyrrol-2- yl]formamido} propanamido)-l -methylimidazole-2 -carboxylate (8.50 g, 18.62 mmol, 1.00 equiv) in MeOH (40.00 mL) was added LiOH (2M in H2O, 74.49 mL, 148.96 mmol, 8.00 equiv) and the resulting mixture was stirred for 1.0 h at room temperature. The mixture was neutralized to pH 7 with 2 M HC1 and concentrated under vacuum. The residue was dissolved in H2O (40 mL) and acidified to pH 3~5 with 2 M HC1. The precipitated solids were collected by filtration, washed with H2O (3x40 mL), and dried under vacuum to afford 4-(3-{[4-(lH-imidazole-2-amido)-l-methylpyrrol-2-yl]formamido}propanamido)-l- methylimidazole-2 -carboxylic acid (7.20 g, 90.25%) as a yellow solid. LC / MS: mass calcd. For Cis^oNsCE: 428.16, found: 429.10 [M+H]+.

[0554] Step 8. To a stirred solution of 4-(3-{[4-(lH-imidazole-2-amido)-l-methylpyrrol-2- yl]formamido} propanamido)-l -methylimidazole-2 -carboxylic acid (1.00 g, 2.33 mmol, 1.00 equiv) in DMF (5.00 mL) was added NMI (574.96 mg, 7.00 mmol, 3.00 equiv), TCFH (785.92 mg, 2.80 mmol, 1.20 equiv) and prop-2-en-l-yl 4-amino- l-methylpyrrole-2 -carboxylate (420.64 mg, 2.33 mmol, 1.00 equiv). The resulting mixture was stirred for 1.0 h at room temperature and was then quenched with ice water (30 mL).The precipitated solids were collected by filtration, washed with water (3x15 mL), and dried under vacuum to afford prop-2-en-l-yl 4-[4-(3-{[4-(lH-imidazole-2-amido)-l-methylpyrrol-2- yl]formamido}propanamido)-l-methylimidazole-2-amido]-l-methylpyrrole-2-carboxylate (1.10 g, 79.79%) as a yellow solid. LC / MS: mass calcd. For C27H29N10O6: 590.23, found: 591.30 [M+H]+.

[0555] Step 9. To a stirred solution of prop-2-en-l-yl 4-[4-(3-{[4-(lH-imidazole-2-amido)-l- methylpyrrol-2-yl] formamido}propanamido)-l-methylimidazole-2-amido]-l-methylpyrrole-2 -carboxylate (1.01 g, 1.71 mmol, 1.00 equiv) in DMF (10.00 mL) was added tert-butyl 6-bromohexanoate (0.47 g, 1.88 mmol, 1.10 equiv) and CS2CO3 (2.23 g, 6.84 mmol, 4.00 equiv) and the resulting mixture was stirred for 17.0 h at 70 °C. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to afford prop-2-en-l-yl 4- (4-{3-[(4-{ l-[6-(tert-butoxy)-6-oxohexyl]imidazole-2-amido}-l-methylpyrrol-2- yl)formamido]propanamido} - 1 -methylimidazole-2 -amido)- 1 -methylpyrrole-2 -carboxylate (990.00 mg, 76.09%) as a white solid. LC / MS: mass calcd. For CsvFLsNioOs: 760.37, found: 761.40 [M+H]+.

[0556] Step 10. To a stirred solution of prop-2-en-l-yl 4-(4-{3-[(4-{l-[6-(tert-butoxy)-6- oxohexyl]imidazole-2 -amido} - 1 -methylpyrrol-2-yl)formamido]propanamido} - 1 -methylimidazole-2 -amido)- 1 -methylpyrrole-2 -carboxylate (970.00 mg, 1.27 mmol, 1.00 equiv) in DMF (4.00 mL) was added phenylsilane (275.92 mg, 2.55 mmol, 2.00 equiv) and Pd(PPh3)4(147.32 mg, 0.12 mmol, 0.10 equiv) and the resulting mixture was stirred for 1.0 h at room temperature. The mixture was quenched with ice water (20 mL). The precipitated solids were collected by filtration, washed with water (2x20 mL), and dried under vacuum to afford 4-(4-{3-[(4-{l-[6-(tert-butoxy)-6-oxohexyl]imidazole-2-amido}-l-methylpyrrol-2- yl)formamido]propanamido}-l -methylimidazole-2 -amido)- 1 -methylpyrrole-2 -carboxylic acid (780.00 mg, 84.88%) as a yellow solid. LC / MS: mass calcd. For C34H44N10O8: 720.33, found: 721.35 [M+H]+.

[0557] Step 11. To a stirred solution of 4-(4-{3-[(4-{ l-[6-(tert-butoxy)-6-oxohexyl]imidazole-2-amido}- 1 -methylpyrrol-2-yl)formamido]propanamido} - 1 -methylimidazole-2 -amido)- 1 -methylpyrrole-2 -carboxylic acid (150.00 mg, 0.21 mmol, 1.00 equiv) in DMF (1.00 mL) was added 4-[4-(3-{[4-(4-aminobutanamido)-l- methylimidazol-2-yl]formamido}propanamido)-l-methylpyrrole-2-amido]-l-methyl-N-[3-oxo-3-(piperidin- l-yl)propyl] imidazole-2-carboxamide (141.67 mg, 0.21 mmol, 1.00 equiv), EDCI (99.73 mg, 0.52 mmol, 2.50 equiv) and DMAP (63.56 mg, 0.52 mmol, 2.50 equiv). The resulting mixture was stirred for 17.0 h at room temperature. The resulting mixture was quenched with ice water (5 mL). The precipitated solids were collected by filtration, washed with water (3x5 mL), and dried under vacuum to afford tert-butyl 6-(2-{[l- methyl-5-({2-[(l-methyl-2-{[l-methyl-5-({3-[(l-methyl-2-{[2-({ l-methyl-5-[(l-methyl-2-{[3-oxo-3- (piperidin- 1 -yl)propyl] carbamoyl } imidazol-4-yl)carbamoyl]pyrrol-3 - yl } carbamoyl)ethyl] carbamoyl } imidazol-4-yl) carbamoyl] propyl } carbamoyl)pyrrol-3 - yl] carbamoyl } imidazol-4-yl)carbamoyl] ethyl } carbamoyl)pyrrol-3 -yl] carbamoyl } imidazol- 1 -yl)hexanoate (100.00 mg, 34.73%) as a white solid. LC / MS: mass calcd. For C65H86N22O13: 1382.67, found: 1383.90 [M+H]+.

[0558] Step 12. To a stirred solution of tert-butyl 6-(2-{[l-methyl-5-({2-[(l-methyl-2-{[l-methyl-5-({3- [(l-methyl-2-{[2-({ l-methyl-5-[(l-methyl-2-{[3-oxo-3-(piperidin-l-yl)propyl]carbamoyl}imidazol-4- yl)carbamoyl] pyrrol-3-yl}carbamoyl)ethyl] carbamoyl }imidazol-4-yl)carbamoyl]propyl}carbamoyl)pyrrol- 3 -yl] carbamoyl } imidazol-4-yl)carbamoyl]ethyl} carbamoyl)pyrrol-3 -yl]carbamoyl } imidazol- 1 -yl)hexanoate (70.00 mg, 0.05 mmol, 1.00 equiv) in DCM (2.00 mb) was added TFA (0.60 mb) and the resulting mixture was stirred for 4.0 h at room temperature. The mixture was concentrated to afford 6-(2-{[l-methyl-5-({2- [(l-methyl-2-{[l-methyl-5-({3-[(l-methyl-2-{[2-({ l-methyl-5-[(l-methyl-2-{[3-oxo-3-(piperidin-l-yl) propyl] carbamoyl }imidazol-4-yl)carbamoyl]pyrrol-3 -yl } carbamoyl)ethyl] carbamoyl } imidazol-4-yl) carbamoyl]propyl}carbamoyl)pyrrol-3-yl]carbamoyl}imidazol-4-yl)carbamoyl]ethyl}carbamoyl)pyrrol-3- yl]carbamoyl}imidazol-l-yl)hexanoic acid (70.00 mg, crude) as a yellow oil. LC / MS: mass calcd. For C61H78N22O13: 1326.61, found: 664.75 [M / 2+H]+.

[0559] Step 13. To a stirred solution of (S)-N-(4-((50-amino- 3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxapentacontyl)oxy)phenyl)-2-(4-(4-chlorophenyl)- 2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo [4,3-a][l,4]diazepin-6-yl)acetamide (70.00 mg, 0.05 mmol, 1.00 equiv) in DMF (2.00 mb) was added 6-(2-{[l-methyl-5-({2-[(l-methyl-2-{[l-methyl-5-({3-[(l-methyl- 2- { [2-( { 1 -methyl-5 -[( 1 -methyl -2- { [3 -oxo-3 -(piperidin- 1 -yl)propyl] carbamoyl }imidazol-4- yl)carbamoyl]pyrrol-3-yl}carbamoyl)ethyl]carbamoyl} imidazol-4-yl)carbamoyl]propyl}carbamoyl)pyrrol- 3 -yl] carbamoyl } imidazol-4-yl)carbamoyl] ethyl } carbamoyl)pyrrol-3 -yl] carbamoyl } imidazol- 1 -yl)hexanoic acid (74.94 mg, 0.05 mmol, 1.00 equiv), EDCI (27.06 mg, 0.14 mmol, 2.50 equiv) and DMAP (17.24 mg, 0.14 mmol, 2.50 equiv). The resulting mixture was stirred for 17.0 h at room temperature and was then quenched with ice water (3 mb). The precipitated solids were collected by filtration, washed with water (3x3 mb), and dried under vacuum. The residue was purified by Perp-HPLC with the following conditions: Column: Xselect CSH Prep Fluoro-Phenyl Column, 19*250, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 30% B to 53% B in 12 min, 53% B to 53% B in 15 min; Wave Length: 254 nm / 220 nm; RTl(min): 14.23. The fractions were combined and lyophilized to afford (S)-4-(3-(4-(l-(l-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)acetamido)phenoxy)-52-oxo-3,6,9, 12,15,18,21,24,27,30,33,36,39,42,45,48- hexadecaoxa-51 -azaheptapentacontan-57 -yl)- lH-imidazole-2-carboxamido)- 1 -methyl- lH-pyrrole-2- carboxamido)propanamido)- 1 -methyl -N-( 1 -methyl-5 -((4-(( 1 -methyl -2-((3 -(( 1 -methyl-5 -(( 1 -methyl -2-((3 - oxo-3-(piperidin-l-yl)propyl)carbamoyl)-lH-imidazol-4-yl)carbamoyl)-lH-pyrrol-3-yl)amino)-3- oxopropyl)carbamoyl)-lH-imidazol-4-yl)amino)-4-oxobutyl)carbamoyl)-lH-pyrrol-3-yl)-lH-imidazole-2- carboxamide formic acid (12.40 mg, 8.18%) as a white solid. HRMS: mass calcd. For C120H167CIN28O30S: 2547.1812, found: 2548.1873 [M+H]+. HPLC: 96.670% purity.

[0560] Example 6. Synthesis of Compound B-44

[0561] Scheme 6.

[0562] Step 1. To a stirred solution of 4-[(tert-butoxycarbonyl)amino]-l-methylpyrrole-2-carboxylic acid (10.00 g, 41.62 mmol, 1.00 equiv) in DMF (100.00 mL) was added DMAP (12.71 g, 104.055 mmol, 2.50 equiv), ethyl 4-amino-l-methylimidazole-2 -carboxylate (7.04 g, 41.62 mmol, 1.00 equiv) and EDCI (19.95 g, 104.06 mmol, 2.50 equiv) at 0 °C. The resulting mixture was stirred for 16.0 h at room temperature andwas then quenched with H2O (3x100 mL). This resulted in ethyl 4-{4-[(tert-butoxycarbonyl)amino]-l- methylpyrrole-2-amido}-l-methylimidazole-2-carboxylate (15.00 g, 92.07%) as a light yellow solid. LC / MS: mass calcd. For Ci^sNsCh: 391.19, found: 392.20 [M+H]+.

[0563] Step 2. To a stirred solution of ethyl 4-{4-[(tert-butoxycarbonyl)amino]-l-methylpyrrole-2- amido}-l-methylimidazole-2 -carboxylate (24.00 g, 61.31 mmol, 1.00 equiv) in DCM (240.00 mL) was added TFA (80.00 mL) and the resulting mixture was stirred for 1.0 h at room temperature. The mixture was concentrated under reduced pressure to afford ethyl 4-(4-amino-l-methylpyrrole-2-amido)-l- methylimidazole-2 -carboxylate (24.00 g, crude) as a brown oil. LC / MS: mass calcd. For C13H17N3O3: 291.13, found: 292.15 [M+H]+.

[0564] Step 3. To a stirred solution of ethyl 4-(4-amino-l-methylpyrrole-2 -amido)- l-methylimidazole-2 - carboxylate (24.00 g, 82.39 mmol, 1.00 equiv) in DMF (240.00 mL) was added PyBOP (64.31 g, 123.58 mmol, 1.50 equiv), DIEA (127.78 g, 988.63 mmol, 12.00 equiv) and 3-[(tert- butoxycarbonyl)amino]propanoic acid (21.82 g, 115.34 mmol, 1.40 equiv) in portions at 0 °C. The resulting mixture was stirred for 1.0 h at room temperature. The reaction was quenched with ice water (1200 mL) and the precipitated solids were collected by fdtration, washed with H2O (3x1000 mL), and dried under vacuum. This resulted in ethyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-l-methylpyrrole-2-amido)-l- methylimidazole-2 -carboxylate (23.00 g, 60.37%) as a white solid. LC / MS: mass calcd. For C21H30N6O6: 462.22, found: 463.30 [M+H]+

[0565] Step 4. To a stirred solution of ethyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-l- methylpyrrole-2 -amido)- l-methylimidazole-2 -carboxylate (12.00 g, 25.95 mmol, 1.00 equiv) in MeOH (150.00 mL) was added LiOH (51.89 mL, 103.78 mmol, 4.00 equiv, 2M in H2O) at room temperature. The resulting mixture was stirred for 2.0 h at 45 °C. The mixture was concentrated under vacuum, was diluted with H2O (100 mg), and was then acidified to pH 6 with HC1 (2 M in H2O). The precipitated solids were collected by filtration, washed with water (3x50 mL), and dried to afford 4-(4-{3-[(tert- butoxycarbonyl)amino]propanamido} - 1 -methylpyrrole -2 -amido)- 1 -methylimidazole -2 -carboxylic acid (10.70 g, 94.94%) as a white solid. LC / MS: mass calcd. For CiTLeNeCL: 434.19, found: 435.20 [M+H]+.

[0566] Step 5. To a stirred solution of 4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-l- methylpyrrole-2 -amido)- l-methylimidazole-2 -carboxylic acid (100.00 mg, 0.23 mmol, 1.00 equiv) 4-(4-{3- [(tert-butoxycarbonyl) amino]propanamido } - 1 -methylpyrrole-2 -amido)- 1 -methylimidazole -2 -carboxylic acid (10.60 g, 24.40 mmol, 1.00 equiv) in DMF (90.00 mL) was added PyBOP (19.05 g, 36.60 mmol, 1.50 equiv), DIEA (18.92 g, 146.39 mmol, 6.00 equiv) and P-alanine ethyl ester (3.14 g, 26.838 mmol, 1.10 equiv) in portions at 0 °C and the resulting mixture was stirred for 1.0 h at room temperature. The reaction mixture was quenched with water (600 mL) and extracted with EA (3x200 mL). The organics were combined and washed by H2O (200 mL) and NaCl (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1: 1) to afford ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-l-methylpyrrole-2-amido)-l-methylimidazol-2-yl]formamido}propanoate (11.50 g, 88.39%) as a light yellow oil. LC / MS: mass calcd. For C24H35N7O7: 533.26, found: 534.35 [M+H]+.

[0567] Step 6. To a stirred solution of ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-l- methylpyrrole-2-amido)-l-methylimidazol-2-yl]formamido}propanoate (600.00 mg, 1.12 mmol, 1.00 equiv) in MeOH (10.00 mb) was added LiOH (0.56 mL, 1.12 mmol, 1.00 equiv, 2M in H2O) at room temperature and the resulting mixture was stirred for 1.0 h at 45 °C. The mixtures were concentrated under vacuum. The 50 mL of H2O was added and the mixture was acidified to pH 6 with HC1 (2 M in H2O). The precipitated solids were collected by filtration, washed with water (3x50 mL), and dried to afford 53-{[4-(4-{3-[(tert- butoxycarbonyl)amino]propanamido } - 1 -methylpyrrole -2 -amido)- 1 -methylimidazol-2- yl]formamido} propanoic acid (480.00 mg, 84.51%) as a white solid. LC / MS: mass calcd. For C23H3IN7O7: 505.23, found: 506.25 [M+H]+.

[0568] Step 7. To a stirred solution of 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-l- methylpyrrole-2-amido)-l-methylimidazol-2-yl]formamido}propanoic acid (460.00 mg, 0.91 mmol, 1.00 equiv) in DMF (2.00 mL) was added piperidine (77.48 mg, 0.91 mmol, 1.00 equiv), TCFH (306.37 mg, 1.09 mmol, 1.20 equiv) and NMI (224.13 pL, 2.73 mmol, 3.00 equiv) and the resulting mixture was stirred for 1.0 h at room temperature. The mixture was quenched with ice water (10 mL) and the precipitated solids were collected by filtration, washed with water (10 mL), and dried to afford tert-butyl N-[2-({ l-methyl-5- [( 1 -methyl -2- { [3 -oxo-3 -(piperidin- 1 -yl)propyl] carbamoyl } imidazol-4-yl)carbamoyl]pyrrol-3 - yl}carbamoyl)ethyl] carbamate (330.00 mg, 63.33%) as a white solid. LC / MS: mass calcd. For C27FLoNs06: 572.31, found: 573.35 [M+H]+.

[0569] Step 8. To a stirred solution of tert-butyl N-[2-({ l-methyl-5-[(l-methyl-2-{[3-oxo-3-(piperidin-l- yl)propyl] carbamoyl}imidazol-4-yl)carbamoyl]pyrrol-3-yl}carbamoyl)ethyl]carbamate (300.00 mg, 0.52 mmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (0.30 mL) and the resulting mixture was stirred for 1.0 h at room temperature. Then the mixture was concentrated under reduced pressure to afford 4-[4-(3- aminopropanamido)- 1 -methylpyrrole-2 -amido] - 1 -methyl -N-[3 -oxo-3 -(piperidin- 1 -yl)propyl] imidazole-2- carboxamide (300.00 mg, crude) as a brown oil. LC / MS: mass calcd. For C22H32NsC>4: 472.25, found: 473.35 [M+H]+.

[0570] Step 9. To a solution of ethyl 4-nitro-lH-imidazole-2 -carboxylate (10.00 g, 54.01 mmol, 1.00 equiv) in EA (100.00 mL) and EtOH (100.00 mL) was added Pd / C (2.00 g, 20% w / w) and the reaction was stirred for 17.0 h at room temperature under H2 atmosphere. The reaction was fdtered and the fdter cake was washed with EA. The fdtrate was concentrated to afford ethyl 4-amino-l-methylimidazole-2 -carboxylate (8.00 g, 95.46%) as a yellow solid. LC / MS: mass calcd. For C7HI3N3O3: 171.10, found: 156.20 [M-15+H]+.

[0571] Step 10. To a stirred solution of ethyl 4-amino-lH-imidazole-2-carboxylate (1.00 g, 5.84 mmol, 1.00 equiv) in DMF (30.00 mL) was added TCFH (2.46. g, 8.761 mmol, 1.50 equiv), NMI (2.88 g, 35.05 mmol, 6.00 equiv) and 4-[(tert-butoxycarbonyl)amino]butanoic acid (1.19 g, 5.84 mmol, 1.00 equiv) at 0 °C. The resulting mixture was stirred for 1.0 h at room temperature. Then the mixture was fdtered and the fdtrate was purified by reverse phase column with the following conditions: C18 column; mobile phase,ACN in water (0.05% TFA), 30% to 60% gradient in 20 min; Detector, UV 254 nm. This resulted in ethyl 4- {4-[(tert-butoxycarbonyl)amino]butanamido}-lH-imidazole-2-carboxylate (1.80 g, 90.53%) as a yellow solid. LC / MS: mass calcd. For C15H24N4O5: 340.17, found: 341.20 [M+H]+.

[0572] Step 11. To a stirred solution of ethyl 4-{4-[(tert-butoxycarbonyl)amino]butanamido}-lH- imidazole-2-carboxylate (300.00 mg, 0.88 mmol, 1.00 equiv) in DCM (3.00 mb) was added TFA (1.00 mb) and the resulting mixture was stirred for 1.0 h at room temperature. Then the mixture was concentrated under reduced pressure to afford ethyl 4-(4-aminobutanamido)-lH-imidazole-2 -carboxylate (300.00 mg, crude) as a brown oil. LC / MS: mass calcd. For C10H16N4O3: 240.12, found: 241.05 [M+H]+.

[0573] Step 12. To a stirred solution of ethyl 4-(4-aminobutanamido)-lH-imidazole-2 -carboxylate (212.79 mg, 0.89 mmol, 1.00 equiv) in DMF (5.00 mb) was added DIEA (686.80 mg, 5.32 mmol, 6.00 equiv), 1 -methyl -4-[ 1 -m ethyl -4-(3 - { [ 1 -methyl -4-( 1 -methylimidazole-2-amido)pyrrol-2- yl]formamido}propanamido)imidazole-2-amido]pyrrole-2 -carboxylic acid (500.00 mg, 0.89 mmol, 1.00 equiv) and PyBOP (599.15 mg, 1.15 mmol, 1.30 equiv) in portions at 0 °C. The resulting mixture was stirred for 1.0 h at room temperature and was then quenched with ice water (50 mb). The precipitated solids were collected by fdtration, washed with water (50 mb), and dried to afford ethyl 4-[4-({ l-methyl-4-[l-methyl-4- (3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2- amido]pyrrol-2-yl}formamido)butanamido]-lH-imidazole-2 -carboxylate (600.00 mg, 86.10% ) as a yellow solid. LC / MS: mass calcd. For C35H42N14O18: 786.33, found: 787.35 [M+H]+.

[0574] Step 13. To a stirred solution of ethyl 4-[4-({l-methyl-4-[l-methyl-4-(3-{[l-methyl-4-(l- methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-amido]pyrrol-2- yl}formamido)butanamido]-lH-imidazole-2-carboxylate (500.00 mg, 0.64 mmol, 1.00 equiv) in DMF (5.00 mb) was added tert-butyl 6-bromohexanoate (159.61 mg, 0.64 mmol, 1.00 equiv) and CS2CO3 (145.14 mg, 1.90 mmol, 3.00 equiv) at and the resulting mixture was stirred for 2.0 h at room temperature. Next the reaction was filtered and the filtrate was purified by reverse phase column with the following conditions: C18 column; mobile phase, ACN in water (0.05% TFA), 30% to 60% gradient in 20 min; Detector, UV 254 nm. The fractions were combined and concentrated to afford ethyl l-[6-(tert-butoxy)-6-oxohexyl]-4-[4-({l- methyl-4-[l-methyl-4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido} propanamido)imidazole-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (400.00 mg, 65.77%) as a yellow solid. LC / MS: mass calcd. For C45H60N14O10: 956.46, found: 479.55 [M / 2+H]+.

[0575] Step 14. To a stirred solution of ethyl l-[6-(tert-butoxy)-6-oxohexyl]-4-[4-({l -methyl -4-[l- methyl-4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2- amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (300.00 mg, 0.31 mmol, 1.00 equiv) in DCM (3.00 mL) was added TFA (1.00 mL) and the resulting mixture was stirred for 1.0 h at room temperature. The mixture was concentrated under reduced pressure to afford 6-[2-(ethoxycarbonyl)-4-[4- ( { 1 -methyl -4-[ 1 -methyl -4-(3 - { [ 1 -methyl -4-( 1 -methylimidazole-2-amido)pyrrol-2- yl]formamido}propanamido)imidazole-2-amido]pyrrol-2-yl}formamido)butanamido]imidazol-l-yl]hexanoic acid (300.00 mg, crude) as a brown oil. LC / MS: mass calcd. For C41H52N14O10: 900.40, found: 901.60 [M+H]+.

[0576] Step 15. To a stirred solution of 6-[2-(ethoxycarbonyl)-4-[4-({ l-methyl-4-[l-methyl-4-(3-{[l- methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-amido]pyrrol-2- yl}formamido) butanamido]imidazol-l-yl]hexanoic acid (300.00 mg, 0.33 mmol, 1.00 equiv) in DMF (5.00 mL) was added (S)-N-(4-((50-amino-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48- hexadecaoxapentacontyl) oxy)phenyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamide (412.87 mg, 0.33 mmol, 1.00 equiv), PyBOP (225.27 mg, 0.43 mmol, 1.30 equiv) and DIEA (258.22 mg, 2.00 mmol, 6.00 equiv) and the resulting mixture was stirred for 1.0 h at room temperature. The mixture was quenched with ice water (20 mL) and the precipitated solids were collected by fdtration, washed with water (20 mL), and dried under vacuum to afford ethyl (S)- l-(l-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)phenoxy)-52-oxo-3,6,9, 12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxa-51- azaheptapentacontan-57 -yl)-4-(4-( 1 -methyl -4-( 1 -methyl -4-(3 -( 1 -methyl -4-( 1 -methyl- lH-imidazole-2- carboxamido)- lH-pyrrole-2-carboxamido) propanamido)- lH-imidazole-2-carboxamido)- lH-pyrrole-2- carboxamido)butanamido)-lH-imidazole-2 -carboxylate (500.00 mg, 70.73%) as a yellow solid. LC / MS: mass calcd. For C100H141CIN20O27S: 2120.97, found: 1062.05 [M / 2+H]+.

[0577] Step 16. To a stirred solution of ethyl (S)-l-(l-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno [3 ,2-f] [ 1 ,2,4]triazolo [4,3 -a] [ 1 ,4] diazepin-6-yl)acetamido)phenoxy)-52-oxo- 3,6,9,12,15,18,21,24,27,30,33,36,39, 42,45,48-hexadecaoxa-51-azaheptapentacontan-57-yl)-4-(4-(l-methyl- 4-( 1 -methyl -4-(3-( 1 -methyl-4-( 1 -methyl- lH-imidazole-2-carboxamido)- lH-pyrrole-2- carboxamido)propanamido)- lH-imidazole-2-carboxamido)- lH-pyrrole-2-carboxamido)butanamido)- 1H- imidazole-2-carboxylate (400.00 mg, 0.19 mmol, 1.00 equiv) in MeOH (5.00 mL) was added LiOH (31.63 mg, 0.75 mmol, 4.00 equiv, 2M in H2O) and the reaction was stirred for 1.0 h at 45 °C. Then the mixture was concentrated under vacuum and 100 mL H2O was added. The residue was acidified to pH 6 with HC1 (2 M in H2O). The precipitated solids were collected by filtration, washed with water (3x20 mL), and dried to afford (S)-l-(l-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)acetamido)phenoxy)-52-oxo-3,6,9,12,15, 18,21,24,27,30,33,36,39,42,45,48- hexadecaoxa-51 -azaheptapentacontan-57 -yl)-4-(4-( 1 -methyl -4-( 1 -methyl -4-(3 -( 1 -methyl -4-( 1 -methyl- 1H- imidazole -2-carboxamido) - 1 H-pyrrole -2-carboxamido)propanamido) - 1 H-imidazole -2-carboxamido)- 1 H- pyrrole-2-carboxamido)butanamido)-lH-imidazole-2 -carboxylic acid (300.00 mg, 76.00%) as a yellow solid. LC / MS: mass calcd. For C98Hi37ClN2o027S: 2092.94, found: 1048.35 [M / 2+H]+.

[0578] Step 17. To a stirred solution of (S)-l-(l-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][l,2,4] triazolo[4,3-a][l,4]diazepin-6-yl)acetamido)phenoxy)-52-oxo- 3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48 -hexadecaoxa-51 -azaheptapentacontan-57-yl)-4-(4-(l -methyl- 4-( 1 -methyl -4-(3-( 1 -methyl-4-( 1 -methyl- lH-imidazole-2-carboxamido)- lH-pyrrole-2- carboxamido)propanamido)- lH-imidazole-2-carboxamido)- lH-pyrrole-2-carboxamido)butanamido)- 1H-imidazole-2-carboxylic acid (100.00 mg, 0.05 mmol, 1.00 equiv) in DMF (1.00 mL) was added 4-[4-(3- aminopropanamido)- 1 -methylpyrrole-2 -amido] - 1 -methyl -N-[3 -oxo-3 -(piperidin- 1 -yl)propyl] imidazole-2- carboxamide (22.39 mg, 0.05 mmol, 1.00 equiv), PyBOP (32.05 mg, 0.06 mmol, 1.30 equiv) and DIEA (36.74 mg, 0.28 mmol, 6.00 equiv) and the resulting mixture was stirred for 1.0 h at room temperature. The mixture was filtered and the filtrate was purified by Perp-HPLC: Column: XSelect CSH Cl 8 Column, 19*250 mm, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 31% B to 56% B in 15min; Wave Length: 254nm nm; RTl(min): 13.29. The fractions were combined and lyophilized to afford (S)-N-(5-((4-((l-(l-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][l,2,4] triazolo[4,3-a][l,4]diazepin-6-yl)acetamido)phenoxy)-52-oxo- 3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48 -hexadecaoxa-51-azaheptapentacontan-57-yl)-2-((3-((l- methyl-5 -(( 1 -methyl -2-((3 -oxo-3 -(piperidin- 1 -yl)propyl)carbamoyl)- lH-imidazol-4-yl)carbamoyl)- 1H- pyrrol-3-yl)amino)-3-oxopropyl)carbamoyl)-lH-imidazol-4-yl)amino)-4-oxobutyl)carbamoyl)-l-methyl- lH-pyrrol-3-yl)- 1 -methyl -4-(3-( 1 -methyl -4-( 1 -methyl- lH-imidazole-2-carboxamido)- lH-pyrrole-2- carboxamido)propanamido)-lH-imidazole-2-carboxamide formic acid (23.20 mg, 17.48%) as an off-white solid. HRMS: mass calcd. For C120H167CIF3N28O30S: 2547.1812, found: 2548.1859 [M+H]+. HPLC: 92.959% purity.

[0579] Example 7. General synthesis and purification of the compounds of the disclosure

[0580] Compounds of the disclosure were made by methods similar to Examples 1-6. The compounds were subsequently purified by HRMS methods A or B.

[0581] Method A: Instrument: Waters Acquity I Class UPLC with Xevo G2-XSQ Tof HRMS; Column: ACQUITY UPLC BEH-C18, 2.1 x 50 mm, 2.7 pm; mobile phase A: H2O (0.1% HCOOH), mobile B, CAN (0. 1% HCOOH); Flow rate:0.4mL / min; Gradient: 10% B to 95% B in 1.5 min, hold 95% for another 0.5 min, then down to 10% B in 0.3 min, hold 10% B for another 0.7 min; detector: 254nm.

[0582] Method B: Instrument: Waters Acquity I Class UPLC with Xevo G2-XS Q Tof HRMS; Column: ACQUITY UPLC BEH-C18, 2.1 x 50 mm, 2.7pm; mobile phase A: H2O (0.1% HCOOH), mobile B, CAN (0.1% HCOOH); Flow rate:0.4 mL / min; Gradient: 5% B to 40% B in 2.0min, to 95% in another 1.5 min, hold 95% for 1.5 min, then down to 5% B in 0.3 min, hold 5% B for another 0.7 min; detector: 254nm.

[0583] Experimental data for the compounds of the disclosure purified by Method A are provided in Table 4.Table 4. LCMS analysis of compounds of the disclosure.BIOLOGICAL EXAMPLES

[0584] Example B-l. Activity

[0585] Fibroblast: a cell type derived from a skin biopsy of a patient. These cells are not altered genetically, so they serve as a primary cell culture model of disease.

[0586] iPSC: induced pluripotent stem cell, a cell type that results as a reprogramming of another cell type (typically skin cells or blood cells) into a more embryonic-like state that enables the development of other cell types to model therapeutic effects of drugs in vitro.

[0587] SNP: Single Nucleotide Polymorphism, a variation in a single base pair in a DNA sequence

[0588] Molecular Biology Toolkit:• qPCR primer probe sets: o RNA input normalization was assessed utilizing human glyceraldehyde 3-phosphate dehydrogenase (hGAPDH) TaqMan assay (ThermoFisher cat# 4351370) or Human Cyclophillin (IAPP) TaqMan assay (ThermoFisher cat# 4351372) o Total HTT detection was assessed utilizing human Htt TaqMan assay (ThermoFisher cat# 4331182) o Allele-specific detection of human HTT expression in HD cells containing the SNP rs362331C / T(Exon 50): for each assay, allele-specific probes to detect the SNP variant contained locked nucleic acid bases to improve allele discrimination, as compared to unmodified DNA probes.■ 362331-F (331 forward primer)■ 362331-R (331 reverse primer)■ 362331 -C probe : TCC CTC ATC + C + AC TGT GT■ 362331-T probe: CTC + A + T + C + T + A + C TGT GT o qPCR was performed using Agpath ID one-step reverse transcriptase polymerase chain reaction (RT-PCR) reagent

[0589] Protein measurements were performed via western blots probing with antibody MW 1 (polyQ specific) to assess reduction of mtHTT alone. D7F7 (a.a surrounding Prol218) was used to visualize both wtHTT and mtHTT. Lysates were standardized by DC prior to separation on a 3-8% Tris-acetate gel and transferred via wet transfer method onto nitrocellulose membranes. Blots were probed with the previously mentioned antibodies and complementary fluorescent secondary antibodies and imaged on the Li-Cor Odyssey® DLx Imaging system.

[0590] Antibody pairing of 2B7 (a.a. 1-17) and MW1 (polyQ specific) will be used to track mtHTT levels while pairing of MAB2166 (a.a. 181-810) and MAB5490 (a.a. 115-129) will be employed to track total full- length HTT.

[0591] Screening of HD molecules methods: GM09197 and / or GM04022 fibroblasts were cultured in T175 flasks incubated at 37 °C and 5% CO2. Once confluency was reached, the media was removed, the cells were washed with IX PBS, and cells were dissociated using TrypLE™ Express Enzyme. Media was added to the enzyme and collected into a 15-mL conical tube and centrifuged at 500xg for 5 minutes to pellet the cells. Media and enzyme were aspirated using a serological pipette. Cells were resuspended in fresh media and counted using a Countess 3 Automated Cell Counter. Cells were plated at a density of 15,000 cells / well in a tissue culture -treated polystyrene 96-well dish and incubated at 37 °C and 5% CO2 overnight. The next day, media was removed using an 8-channel aspirator. 200 pL media / well are added back into the plate. The molecules are formulated to 1 mM and are dispensed using a Multidrop™ Pico 8 Digital Dispenser. After a 48-hour incubation with compounds, media was removed from plates, cells were washed with IX PBS, and cells were lysed in 40 pL per well guanidinium thiocyanate buffer. RNA was isolated and purified in 382-well glass fiber column plates using chaotropic salts. Human mtHTT, wtHTT, and GAPDH mRNA were measured via RT-PCR using the ThermoFisher QuantStudio™ 7 Flex System in 384-well format. Results of HTT levels were normalized to GAPDH mRNA levels. Normalized HTTmRNA levels were expressed relative to vehicle -treated samples to assess fold change after molecule treatment.

[0592] iPSC-Neuron Duration of Action of HD molecules methods: Fibroblasts isolated from HD patients were reprogrammed into iPSCs expanded in the presence of cytokines and transduced with the Sendai virus, a cytoplasmic RNA vector. These iPSCs expressed stem cell markers and have normal karyotypes and express the pluripotent markers Nanog, Tra-1-60, and SSeA-44. iPSC-derived neuron differentiation methodology followed standard protocols for mixed cortical neuron differentiation resulting in immunohistochemical staining of iPS-Neuron of Tuj 1 and Map2. iPSC-neuronal precursor cells were plated at 300,000 cells / well in a PLO / Laminin-521 coated culture-treated polystyrene 96-well dish and incubated at 37 °C and 5% CO2. The next day, media was changed to allow neuron precursor cells to continue maturation into neurons. Four days later, media was refreshed, and cells were treated with mitotic inhibitor to remove any remaining dividing cells, resulting in a pure neuronal culture. Three days later, media was removed. 200 pL media / well were added back into the plate. The molecules were formulated to 1 mM and dispensed using a Multidrop™ Pico 8 Digital Dispenser. After 96-hour incubation with compounds, media was removed and refreshed and the cells were retreated. After 7 days of compound exposure, media was removed from plates, and cells were lysed in 60 pL of Ambion Lysis buffer. RNA is isolated using PureLink™ RNA isolation kits. cDNA is synthesized with Agilent Superscript II kit. Human mtHTT, wtHTT, and GAPDH mRNA were measured via RT-PCR using the ThermoFisher QuantStudio™ 7 Flex System in 384-well format. Results of HTT levels were normalized to GAPDH mRNA levels. Normalized HTT mRNA levels were expressed relative to vehicle-treated samples to assess fold change after treatment with the HD compounds.

[0593] Representative in vitro biochemical data is presented in Table 5, where A < 100 nM, B > 100 nM to < 1 pM, C > 1 pM.Table 5A. Representative biochemical data in GM04022 fibroblasts.Table 5B. Representative biochemical data in GM09197 fibroblasts.

[0594] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A transcription modulator molecule having a first terminus, a second terminus, and an oligomeric backbone moiety, or a pharmaceutically acceptable salt thereof, wherein: a) the first terminus comprises a DNA-binding moiety having the structure of Formula (A-l):Formula (A-l), wherein:W1is hydrogen, halogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, -NRleRlf, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, -NRleC(O)ORlf, - N=C(N(Rle)2)2, -ZB-PO(ORle)2, -ZB-(CH2)P3-PO(ORle)2, or -ZB-(CH2)p3-O-PO(ORle)2, wherein each Rleis independently hydrogen or optionally substituted C1-C10 alkyl; each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, AAp2, or optionally substituted 5-membered heteroaryl, wherein each AA is an amino acid and p2is an integer from 1-10;ZBis -N- or -O-; p3is 1-10; ps is an integer from 1-10;W2is optionally substituted Ci-C2o alkyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci-C2o haloalkyl, optionally substituted Ci-C2o heteroalkyl, or optionally substituted Ci-C2o hydroxyalkyl; or W2is L’-Z-R4;L1is Ci-C2o alkylene or C2-C2o heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted Ci-C2o alkyl, or optionally substituted Ci-C2o heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted C1-C20 alkyl; orRwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH; each X1, X2, X3, X4, X5, X6, X7, and X8is independently S, O, or NR2; each R2is independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each R3is independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3together with the atoms to which they are attached form an optionally substituted C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; ji is 0 or 1; n0is 0 or 1 ; mi and are each independently an integer from 0-3; and pi is 3 or 4; wherein the linker is attached at one of R2and the others of R2are as described above; b) the second terminus comprises a protein-binding moiety capable of binding to a regulatory molecule that modulates expression of a gene; and c) the oligomeric backbone links the first terminus and the second terminus. The molecule of claim 1, or a pharmaceutically acceptable salt thereof, wherein each X1, X2, X3, X4, X5, X6, X7, and X8is independently NR2. The molecule of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein mi and nl are each independently is 2 or 3. The molecule of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein pi is 3.The molecule of claim 1, or a pharmaceutically acceptable salt thereof, wherein the DNA-binding moiety comprises a structure of Formula (A-2):Formula (A-2), wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl;W2is optionally substituted C1-C20 alkyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, or optionally substituted C1-C20 hydroxyalkyl; or W2is L’-Z-R4;L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C’s-Cs cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted C1-C20 alkyl; or Rwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH;each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one R3aand one R3btogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinRZaand Rzbare each independently hydrogen, alkyl, or PEG;RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and and mi are each independently 0 or 1; wherein the linker is attached at one of RZa, Rzb, or RZc. The molecule of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein Y2, Y4, and Y7are each independently N; and Y1and Y3are each independently CH. The molecule of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Y8is N. The molecule of claim 5, wherein the DNA-binding moiety comprises a structure of Formula (A-3), or a pharmaceutically acceptable salt thereof:Formula (A-3), wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl;W2is optionally substituted C1-C20 alkyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, or optionally substituted C1-C20 hydroxyalkyl; or W2is L’-Z-R4;L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C’s-Cs cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted C1-C20 alkyl; or Rwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl; each Y5and Y6is independently N or CH; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionallysubstituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one R3aand one R3btogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinRZaand Rzbare each independently hydrogen, alkyl, or PEG;RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and and mi are each independently 0 or 1; wherein the linker is attached at one of RZa, Rzb, or RZc. The molecule of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein Rwand W2combine together with the atoms to which they are attached to form an optionally substituted 3 to 10-membered heterocycloalkyl. The molecule of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 haloalkyl. The molecule of claim 10, or a pharmaceutically acceptable salt thereof, wherein W2is Ci-Cg alkyl. The molecule of any one of claims 1-8, 10 or 11, or a pharmaceutically acceptable salt thereof, wherein Rwis hydrogen. The molecule of any one of claims 5-12, or a pharmaceutically acceptable salt thereof, wherein each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 haloalkyl; each of which is optionally substituted with one or more Rz. The molecule of claim 13, or a pharmaceutically acceptable salt thereof, wherein one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his C1-C20 alkyl substituted with one or more Rz, and the remaining of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare each independently C1-C20 alkyl. The molecule of claim 14, or a pharmaceutically acceptable salt thereof, wherein the remaining of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare each independently methyl, ethyl, or propyl.

16. The molecule of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Rwis hydrogen and W2is L’-Z-R4.

17. The molecule of claim 1, wherein the DNA-binding moiety comprises a structure of Formula (A-4), or a pharmaceutically acceptable salt thereof:Formula (A-4), wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently N or CH; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one R3aand one R3btogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl;L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4 to 8- membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10- membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated; each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinRZaand Rzbare each independently hydrogen, alkyl, or PEG;RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and and mi are each independently 0 or 1; wherein the linker is attached at one of RZa, Rzb, or RZc.

18. The molecule of claim 17, or a pharmaceutically acceptable salt thereof, wherein Y2, Y4, and Y7are each independently N; and Y1and Y3are each independently CH.

19. The molecule of claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein Y8is N.

20. The molecule of claim 17, or a pharmaceutically acceptable salt thereof, wherein the DNA-binding moiety comprises a structure of Formula (A-5), or a pharmaceutically acceptable salt thereof:Formula (A-5), wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, wherein each Rleis independently hydrogen or C1-C3 alkyl; each Y5and Y6is independently N or CH;each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1.50; each of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one R3aand one R3btogether with the atoms to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl;L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8- membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10- membered heteroaryl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated; each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinRZaand Rzbare each independently hydrogen, alkyl, or PEG;RZcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and ni and mi are each independently 0 or 1; wherein the linker is attached at one of RZa, Rzb, or RZc.

21. The molecule of any one of claims 17-20, or a pharmaceutically acceptable salt thereof, wherein each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 haloalkyl; each of which is optionally substituted with one or more Rz.

22. The molecule of claim 21 , or a pharmaceutically acceptable salt thereof, wherein one of R2a, R2b,alkyl substituted with one or more Rz, and the remaining of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare each independently C1 -C20 alkyl.

23. The molecule of claim 22, or a pharmaceutically acceptable salt thereof, wherein the remaining of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare each independently methyl, ethyl, or propyl.

24. The molecule of any one of claims 17-23, or a pharmaceutically acceptable salt thereof, wherein L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent or -C(O)-; and R4is -NR4aR4b.

25. The molecule of claim 24, or a pharmaceutically acceptable salt thereof, wherein Z is absent.

26. The molecule of claim 24, or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)-.

27. The molecule of any one of claims 24-26, or a pharmaceutically acceptable salt thereof, wherein L1is C1-C10 alkylene.

28. The molecule of any one of claims 17-27, or a pharmaceutically acceptable salt thereof, wherein: R4ais hydrogen, optionally substituted C1 -C20 alkyl, or optionally substituted C1-C20 heteroalkyl; and R4bis optionally substituted C1 -C20 alkyl or optionally substituted C1 -C20 heteroalkyl.

29. The molecule of claim 28, or a pharmaceutically acceptable salt thereof, wherein R4ais optionally substituted Ci-Ce alkyl; and R4bis optionally substituted Ci-Ce alkyl.

30. The molecule of any one of claims 5-29, or a pharmaceutically acceptable salt thereof, wherein each R3bis hydrogen; and each R3ais independently selected from hydrogen, -NR3cR3d, and -NHC(O)R3e.

31. The molecule of any one of claims 5-29, or a pharmaceutically acceptable salt thereof, wherein each R3ais hydrogen; and each R3bis independently selected from hydrogen, -NR3cR3d, and -NHC(O)R3e.

32. The molecule of any one of claims 5-29, or a pharmaceutically acceptable salt thereof, wherein each R3ais hydrogen and each R3bis hydrogen.

33. The molecule of any one of claims 5-29, or a pharmaceutically acceptable salt thereof, wherein two R3atogether with the carbon atom to which they are attached form a C3-C, cycloalkyl or 3 to 6- membered heterocycloalkyl; and each R3bis hydrogen.

34. The molecule of any one of claims 5-29, or a pharmaceutically acceptable salt thereof, wherein two R3btogether with the carbon atom to which they are attached form a C3-C, cycloalkyl or 3 to 6- membered heterocycloalkyl; and each R3ais hydrogen.

35. The molecule of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein ni is 1.

36. The molecule of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein is 0.

37. The molecule of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein each Y6is independently CH.

38. The molecule of any one of claims 1-36 or a pharmaceutically acceptable salt thereof, wherein each Y6is independently N.

39. The molecule of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein mi is 1.

40. The molecule of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein mi is 0.

41. The molecule of any one of claims 1 -39, or a pharmaceutically acceptable salt thereof, wherein each Y5is independently CH.

42. The molecule of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein each Y5is independently N.

43. The molecule of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the first terminus is capable of binding the DNA with an affinity of less than 500 nM.

44. The molecule of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the oligomeric backbone is a linker having a length of less than about 50 Angstroms.

45. The molecule of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the oligomeric backbone is a linker having a length of about 10 to 60 Angstroms.

46. The molecule of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein the oligomeric backbone comprises a multimer having 2 to 50 spacing moieties, wherein each spacing moiety is independently selected from the group consisting of -((CRlbRlb)x- O)y-, -((CRlbRlb)x-NRla)y-, -((CRlbRlb)x-CH=CH-(CRlbRlb)x-O)y-, optionally substituted Ci-Cio alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted Ce-C 10 arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5 to 10- membered heteroarylene, optionally substituted 4 to 10-membered heterocycloalkylene, amino acid residue, -O-, -C(O)NRla-, -NRlaC(O)-, -C(O)-, -NRla-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2NRla-, - NRlaS(O)2-, and -P(O)OH-, and any combinations thereof; wherein each x is independently 2-4; each y is independently 1-10; each Rlais independently a hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce haloalkyl; and each Rlbis independently hydrogen, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce haloalkyl.

47. The molecule of claim 46, or a pharmaceutically acceptable salt thereof, wherein the oligomeric backbone comprises a multimer having 2 to 50 spacing moieties, wherein each spacing moiety is independently selected from the group consisting of -((CH2)X-O)y-, -((CH2)x-NH)y-, -O-, -C(O)NH-, -NH-, and any combinations thereof.

48. The molecule of claim 46, or a pharmaceutically acceptable salt thereof, wherein the oligomeric backbone comprises a multimer having 2 to 50 spacing moieties selected from -NHC(O)((CH2)X- O)y-, -C(O)NH((CH2)X-O)y-.

49. The molecule of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, wherein the second terminus comprises a bromodomain binding moiety.

50. The molecule of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, wherein the second terminus comprises a moiety capable of binding to a bromodomain and extra terminal domain (BET) family member.

51. The molecule of claim 50, or a pharmaceutically acceptable salt thereof, wherein the BET family member is BRD2, BRD3, BRD4, or BRDT.

52. The molecule of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, wherein the second terminus comprises a moiety capable of binding to CBP / p300, PCAF (P300 / CBP-Associated Factor), CECR2 (cat eye syndrome chromosome region candidate 2), BRPF (bromodomain and PHD finger-containing protein), ATAD2 / ATAD2B (chromatin remodeling proteins), TRIM24 (Tripartite motif-containing 24), BAZ2 (Bromodomain Adjacent to Zinc finger), TAF1 (TBP associated factors), BRD7 / 9, BPTF (Bromodomain PHD Finger Transcription Factor), SMARCA2 / 4, or PBRM1.

53. The molecule of claim 52, or a pharmaceutically acceptable salt thereof, wherein the second terminus comprises a CBP / p300 binding moiety.

54. The molecule of claim 52, or a pharmaceutically acceptable salt thereof, wherein the second terminus comprises a PCAF binding moiety.

55. The molecule of any of claims 1-48, wherein the second terminus comprises the structure of Formula (4-A), or a pharmaceutically acceptable salt thereof:Formula (4-A), wherein:Ring D is absent, phenyl, or 5 to 6-membered heteroaryl;X9and X10are each independently C or N, wherein one of X9or X10is N;L2is absent, optionally substituted alkylene, -O-, or -NRD-, whereinRDis hydrogen or optionally substituted C1-C3 alkyl;R18is an optionally substituted 5 to 6-membered heteroaryl;R19is an optionally substituted C-G cycloalkyl or optionally substituted 4 to 7-membered heteroaryl;each R20is independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;X3 is an integer from l-3;and y4 is an integer from 1-4; wherein the attachment to the linker is at either R19or at one of R20.

56. The molecule of claim 55, wherein the second terminus comprises the structure of Formula (4-B), or a pharmaceutically acceptable salt thereof:Formula (4-B), wherein:Ring D is absent, optionally substituted phenyl, or optionally substituted 5 to 6-membered heteroaryl;X9and X10are each independently C or N, wherein one of X9or X10is N;L2is absent, optionally substituted alkylene, -O-, or -NRD-, whereinRDis hydrogen or optionally substituted C1-C3 alkyl;R18is an optionally substituted 5 to 6-membered heteroaryl;R19is an optionally substituted C3-C8 cycloalkyl or optionally substituted 4 to 7-membered heteroaryl; and x3is an integer from 1-3.

57. The molecule of claim 55, wherein the second terminus comprises the structure of Formula (4-D), or a pharmaceutically acceptable salt thereof:Formula (4-D), wherein:L2is an optionally substituted alkylene, -O-, or -NRD-, whereinRDis hydrogen or optionally substituted C1-C3 alkyl;R18is an optionally substituted 5 to 6-membered heteroaryl;R20is hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; x3is an integer from 1-3; andy4 is an integer from 1-4.

58. The molecule of any of claims 1-48, wherein the second terminus comprises the structure ofFormula (7-A), or a pharmaceutically acceptable salt thereof:Formula (7-A), wherein:A3is -O-, -NH-, or -CH2-;Z2is CH or N;W is O or S; each R31is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted Cs-Cs cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; or two R31together with the atoms to which they are attached join together to form an optionally substituted Cs-Cs cycloalkyl or optionally substituted 5 to 8-membered heterocycloalkyl;R32is hydrogen or optionally substituted C1-C10 alkyl;R32ais hydrogen or optionally substituted C1-C10 alkyl;R33is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl; and qe is 0-4; wherein Formula (7-A) is attached to the linker is at R32aor at one of R31.

59. The molecule of any one of claims 1-48, wherein the second terminus comprises the structure of Formula (2 -A), or a pharmaceutically acceptable salt thereof:wherein:Ring A is an optionally substituted aryl or optionally substituted 5 to 6-membered heteroaryl;Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;D is C or N;E is O or N;YA is -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl; or R7is -NR7AR7B, whereinR7Aand R7I;are each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; and xi is an integer from 1-6.

60. The molecule of claim 59, wherein the second terminus comprises the structure of Formula (2-B), or a pharmaceutically acceptable salt thereof:Formula (2-B), wherein:Ring A is an optionally substituted aryl or optionally substituted 5 to 6-membered heteroaryl;Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;YA is -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Cg hydroxyalkyl; or R7is -NR7AR7B, whereinR7Aand R7I;are each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; and xi is an integer from 1-6.

61. The molecule of claim 59, wherein the second terminus comprises the structure of Formula (2-C), or a pharmaceutically acceptable salt thereof:Formula (2-C), wherein:Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;YA is -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl; or R7is -NR7AR7B, whereinR7Aand R7I;are each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R8and R9are each independently selected from hydrogen, -C(O)OR8a, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; andR8ais hydrogen, C1-C20 alkyl, or C1-C20 heteroalkyl; and xi is an integer from 1-6.

62. The molecule of claim 59, wherein the second terminus comprises the structure of Formula (2-D), or a pharmaceutically acceptable salt thereof:Formula (2-D), wherein:Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;YAis -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl; or R7is -NR7AR7B, whereinR7Aand R7I;are each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R10is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Cg hydroxyalkyl; and xi is an integer from 1-6.

63. The molecule of any of claims 1-48, wherein the second terminus comprises the structure ofFormula (3-A), or a pharmaceutically acceptable salt thereof:Formula (3-A), wherein:YBis -CH2NH-, -CH2O-, -NH-, or -O-;R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R12is hydrogen, halogen, -OH, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;R14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; or R14is -NRARB;R16is an optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, -S(O)(=NH)RA, -SC>2RA, or -NHSC>2RA;RYAis hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted 5-6-membered monocyclic aryl or heteroaryl; each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C3-C,, cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; andyi is 1-3; wherein the attachment to the linker is at either R14or at RYA.

64. The molecule of any one of claims 1-48, wherein the second terminus comprises the structure of Formula (3-B), or a pharmaceutically acceptable salt thereof:Formula (3-B), wherein:Ring C is absent, optionally substituted 5 to 6-membered monocyclic aryl or heteroaryl or 4 to 8- membered heterocycle;YB is -NH-, -CH2NH-, -CH2O-, or -O-;R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R12is hydrogen, optionally substituted Ci-Ce alkyl, C(O)RA, or C(O)NRARB; wherein each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;R13is hydrogen, substituted aryl, substituted heteroaryl, or substituted oxydibenzene; and y2is an integer from 0-2.

65. The molecule of claim 63, wherein the second terminus comprises the structure of Formula (3-C), or a pharmaceutically acceptable salt thereof:Formula (3-C), wherein:Ring C is absent, optionally substituted 5 to 6-membered monocyclic aryl or heteroaryl or 4 to 8- membered heterocycle;YB is -CH2NH-, -CH2O-, -NH-, or -O-;R14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; or R14is -NRARB;R16is an optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, -S(O)(=NH)RA, -SC>2RA, or -NHSC>2RA; each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; and yi is an integer from 1-3.

66. The molecule of claim 63, wherein the second terminus comprises the structure of Formula (3-D), or a pharmaceutically acceptable salt thereof:Formula (3-D), wherein:R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R12is hydrogen or an optionally substituted Ci-Ce alkyl; each R15is independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;R16is an substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2- C, alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, - S(O)(=NH)RA, -SO2RA, or -NHSO2RA;RAis hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; and yi is an integer from 1-3.

67. The molecule of any of claims 1-48, wherein the second terminus is selected from the group consisting of, or a pharmaceutically acceptable salt thereof:or a pharmaceutically acceptable salt thereof.

68. A molecule selected from Table 3, or a pharmaceutically acceptable salt thereof.

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

70. A method of decreasing expression of a gene in a cell, the method comprising contacting the cell with an effective amount of a molecule of any one of claims 1-68, or a pharmaceutically acceptable salt thereof.

71. The method of claim 70, wherein the gene is HTT.

72. A method of treating Huntington’s disease (HD) in a subject in need thereof, the method comprising administering to the subject a molecule of any one of claims 1-68, or a pharmaceutically acceptable salt thereof.

73. The method of claim 72, wherein the method reduces one or more symptoms of Huntington’s disease.

74. The method of claim 73, wherein the one or more symptoms are selected from chorea, cognitive decline, abnormal libido, abnormal eye movement, abnormal sense of smell, aggression, agitation, anxiety, apathy, bradykinesia, bradyphrenia, clumsiness, delusions, depression, difficulty walking,disinhibition, dystonia, gait imbalance, muscle weakness, hallucinations, hostility, hypokinesia, irritability, memory impairment, myoclonus, obsessive-compulsive behavior, poor fine motor coordination, seizure, speech articulation difficulties, staring gaze, weight loss, abnormal cholesterol metabolism, abnormal cerebral white matter, alcoholism, Babinski sign, caudate atrophy, cerebral atrophy, choking, clonus, degeneration of the striatum, excessive daytime sleepiness, impaired visuospatial constructive cognition, inability to walk, insomnia, mutism, oral-pharyngeal dysphagia, rigidity, suicidal ideation, cerebellar atrophy, dementia, gate ataxia, gliosis, hyperreflexia, neuronal loss, or personality changes.

Images