Methods of treating haploinsufficiency disorders

Abstract

The present disclosure relates to methods of treating a haploinsufficiency disorder or disease, the method comprising administering to a subject a compound having (i) a first terminus comprising a DNA-binding moiety, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the first terminus and second terminus, or a pharmaceutically acceptable salt thereof.

Description

METHODS OF TREATING HAPLOINSUFFICIENCY DISORDERS CROSS REFERENCE

[0001] This application claims the benefit of U.S. Application No.63 / 670,343, filed July 12, 2024, which is hereby incorporated by reference in its entirety. FIELD OF THE DISCLOSURE

[0002] Disclosed herein are methods of treating a haploinsufficiency disorder or disease comprising administering to a subject in need thereof a therapeutic amount of a chimeric heterocyclic polyamide compound or a composition thereof. BACKGROUND OF THE DISCLOSURE

[0003] Haploinsufficiency disorders are characterized by a model of dominant gene action where a single copy of a wildtype allele at a locus in combination with a variant allele is insufficient to produce a wildtype phenotype. In some cases, haploinsufficiency arises via a de novo or inherited loss-of-function mutation in the variant allele which produces little or gene product (e.g., protein), while the wildtype allele produces a standard amount of the gene product, which is insufficient to result in a wild-type phenotype. Haploinsufficiency is thought to play a role in many human diseases such as Williams syndrome, autosomal dominant retinitis pigmentosa, cancer, 1q21.1 deletion syndrome, 5q syndrome, 22q11.2 deletion syndrome, cleidocranial dysostosis, Ehlers-Danlos syndrome, frontotemporal dementia, DiVivo syndrome, Holt-Oram syndrome, Marfan syndrome, Phelan-McDermid syndrome, Polydactyly, Dravet syndrome, FOXP1 syndrome, NR4A2-related syndrome, and Pitt-Hopkins syndrome.

[0004] For example, Pitt–Hopkins syndrome is a rare genetic disorder characterized by developmental delay, epilepsy, distinctive facial features, and possible intermittent hyperventilation followed by apnea. PTHS can be marked by intellectual disabilities as well as problems with socializing.

[0005] This disorder is due to a haploinsufficiency of the transcription factor 4 (TCF4) gene which is located on the long arm of chromosome 18 (18q21.2). The TCF4 mutational spectrum includes 40% point mutations, 30% small deletions / insertions, and 30% deletions. Most are private mutations and generate premature stop codons. Almost all appear to be de novo mutations. Missense mutations are primarily localized in the bHLH domain, which is a mutational hotspot. There is no apparent genotype / phenotype correlation. A variety of TCF4 de novo translocations, deletions, insertions, nonsense, frame-shift, and splice-site mutations which affect overall TCF4 expression or the functionality of the bHLH domain have been identified in PTHS patients. Defects in TCF4 expression are also linked to Rhett syndrome, schizophrenia and rare intellectual disorders. These findings confirm that TCF4 haploinsufficiency is the molecular mechanism underlying PTHS. The present disclosure is directed in part to methods of treating PTHS.SUMMARY OF THE DISCLOSURE

[0006] Disclosed herein are methods of treating a haploinsufficiency disorder or disease in a subject in need thereof, wherein the subject has a haploinsufficient gene, the method comprising administering to the subject an effective amount of a compound having (i) a first terminus comprising a DNA-binding moiety capable of binding a haploinsufficient gene, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the first terminus and second terminus, or a pharmaceutically acceptable salt thereof, wherein the haploinsufficient gene comprises a repetitive DNA sequence comprising a motif selected from CCCCWG, CCCCWGC, CCCCWWC, CCGGGG, CCWCC, CCWCW, CCWCWW, CCWGC, CCWWC, CCWWWW, CWC, CWCWCCC, CWCWCG, CWCWCWC, CWCWGCW, CWW, CWWCCWC, CWWWW, G, GCC, GCW, GCWC, GGGCCW, GGGGC, GGGGCG, GGGGWG, GGGWCW, GWCCCWG, GWGGGW, GWWW, W, WC, WCCCCW, WCCWW, WCWGC, WCWWC, WCWWCWW, WCWWWC, WCWWWG, WGGCCCC, WGGG, WGGGWGG, WGWC, WGWGWC, WGWGWGW, WGWWGG, WGWWWWG, WWGG, WWGGGW, WWGWWGG, WWWWWC, or WWWWWWC, wherein each W is independently A or T.

[0007] Without being bound by theory, the compounds of the present disclosure may facilitate transcription through the target genetic locus to elevate expression of a haploinsufficient gene.

[0008] Treatment of a subject with these compounds will modulate expression of a haploinsufficient gene, and this can reduce the occurrence, severity, or frequency of symptoms associated with disease. Certain compounds disclosed herein will provide higher binding affinity and selectivity than has been observed previously for this class of compounds.

[0009] The DNA binding moiety comprises a polyamide segment that will bind selectively to a target nucleotide 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 binds 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 that would be otherwise expected.

[0011] 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 and modifications 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

[0012] 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. FIGURES

[0013] Various aspects of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawing below.

[0014] FIG.1A and 1B. demonstrates that Compound A-7 elevates TCF4 transcription. FIG.1A shows RPMI-8226 (B cell lymphoma) treated with A-7 for 48 hrs. TCF4 transcription measured by qPCR. FIG.1B shows GM26038 fibroblast (PTHS patient) treated with A-7 for 96 hrs. TCF4 transcription measure by qPCR.

[0015] FIG.2. illustrates the chimeric heterocyclic polyamide compound restoring function of haploinsufficient TCF4 by increasing transcription of the unmutated copy of TCF4. DETAILED DESCRIPTION

[0016] The disclosure provides for methods of treating a haploinsufficiency disorder or disease in a subject in need thereof, wherein the subject has a haploinsufficient gene, the method comprising administering to the subject an effective amount of a compound having (i) a first terminus comprising a DNA-binding moiety capable of binding a haploinsufficient gene, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the first terminus and second terminus, or a pharmaceutically acceptable salt thereof, wherein the haploinsufficient gene comprises a repetitive DNA sequence comprising a motif selected form: CCCCWG, CCCCWGC, CCCCWWC, CCGGGG, CCWCC, CCWCW, CCWCWW, CCWGC, CCWWC, CCWWWW, CWC, CWCWCCC, CWCWCG, CWCWCWC, CWCWGCW, CWW, CWWCCWC, CWWWW, G, GCC, GCW, GCWC, GGGCCW, GGGGC, GGGGCG, GGGGWG, GGGWCW, GWCCCWG, GWGGGW, GWWW, W, WC, WCCCCW, WCCWW, WCWGC, WCWWC, WCWWCWW, WCWWWC, WCWWWG, WGGCCCC, WGGG, WGGGWGG, WGWC, WGWGWC, WGWGWGW, WGWWGG, WGWWWWG, WWGG, WWGGGW, WWGWWGG, WWWWWC, or WWWWWWC, wherein each W is independently A or T.First terminus – DNA binding moiety

[0017] The first terminus comprises a DNA-binding moiety capable of interacting with and / or binding to a haploinsufficient gene.

[0018] In some embodiments, the DNA-binding moiety is a polyamide selected from a linear polyamide, a hairpin polyamide, a H-pin polyamide, a U-pin polyamide, an overlapped polyamide, a slipped polyamide, a cyclic polyamide, a tandem polyamide, and an extended polyamide.

[0019] In some embodiments, the DNA-binding moiety is a linear polyamide. In some embodiments, the DNA-binding moiety is a hairpin polyamide. In some embodiments, the DNA-binding moiety is an H-pin polyamide. In some embodiments, the DNA-binding moiety is an overlapped polyamide. In some embodiments, the DNA-binding moiety is a U-pin polyamide. In some embodiments, the DNA-binding moiety is a slipped polyamide. In some embodiments, the DNA-binding moiety is a cyclic polyamide. In some embodiments, the DNA-binding moiety is a tandem polyamide. In some embodiments, the DNA- binding moiety is an extended polyamide.

[0020] In some embodiments, the DNA-binding moiety comprises a polyamide having one or more of the following subunits selected from:NH-benzopyrazinylene-C(O)-, -NH-phenylene-C(O)-, -NH-pyridinylene-C(O)-, -NH-piperidinylene-C(O)-,-NH-pyrimidinylene-C(O)-, -NH-anthracenylene-C(O)-, -NH-quinolinylene-C(O)-, andeach R’ is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C1-C20haloalkyl, optionally substituted C1-C20hydroxyalkyl, optionally substituted C3-C10cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each R” is independently hydrogen, halogen, -OH, optionally substituted C1-C20alkyl, or optionally substituted C1-C20 haloalkyl; each R”’ is independently hydrogen, halogen, -CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl; or two R”’ on the same or on adjacent atoms together with the atom(s) to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; and Z is hydrogen, optionally substituted C1-C6 alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, -N(R1D)2, -ZB- P(O)(OR1C)2, -ZB-(CH2)p3-P(O)(OR1C)2, -ZB-(CH2)p3-O-P(O)(OR1C)2, wherein each R1Cis independently hydrogen or optionally substituted C1-C20 alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20 alkyl, optionally substituted C2-C10 heteroalkyl, or (AA)p2; each AA is an amino acid; p2 is an integer from 1-10; ZB is N or O; and p3 is an integer from 1-10.

[0021] In some embodiments, the polyamide comprises a structure of Formula (A-1), or a pharmaceutically acceptable salt thereof:Formula (A-1), wherein: Z1is absent, -O- or -NH-; each X1, X2, X3, X4, X5, X6, X7, and X8is independently -O-, -S-, or -NR2-; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-; W1is hydrogen, optionally substituted C1-C6alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, -N(R1D)2, - ZB-P(O)(OR1C)2,-ZB-(CH2)p3-P(O)(OR1C)2,-ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZB is N or O; p3 is an integer from 1-10; W2is an optionally substituted C1-C6 alkyl or -C(O)NR1CR1D; each R2is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, or -NC(O)R3A, wherein each R3Ais independently C1-C6 alkyl or phenyl; or two R3on the same or on adjacent atoms combine together with the atom(s) to which they are attached to form an optionally substituted C3-C6 cycloalkyl or optionally substituted 3 to 6-membered heterocycloalkyl; each R1Cis independently hydrogen or optionally substituted C1-C20 alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20 alkyl, optionally substituted C2-C10 heteroalkyl, or (AA)p2, wherein each AA is an amino acid; p2 is an integer from 1-10; or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6- membered heterocycloalkyl; j1 is 0 or 1; n0 is 1 or 0; m1and n1are each independently an integer from 0-3; and p1is 2 or 3, provided that when Z1is -O- or -NH-, then p1is 2 and when Z1is absent then p1is 3; wherein the oligomeric backbone is attached at W1, W2, one of R2, or one of R3.

[0022] In some embodiments of Formula (A-1), n0is 1. In some embodiments of Formula (A-1), n0is 0.

[0023] In some embodiments, the polyamide comprises a structure of Formula (A-2), or a pharmaceutically acceptable salt thereof:Formula (A-2), wherein: Z1is absent; each X1, X2, X3, X4, X5, X6, X7, and X8is independently -NR2-; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-; W1is hydrogen, optionally substituted C1-C6 alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, -N(R1D)2, - ZB-P(O)(OR1C)2, -ZB-(CH2)p3-P(O)(OR1C)2, -ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZB is N or O; p3 is an integer from 1-10; W2is optionally substituted C1-C6 alkyl or -C(O)NR1CR1D; each R2is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20haloalkyl, optionally substituted C1-C20hydroxyalkyl, optionally substituted C3-C10cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6alkyl or phenyl; or two R3on the same or on adjacent atoms combine together with the atom(s) to which they are attached to form an optionally substituted C3-C6cycloalkyl or optionally substituted 3 to 6-membered heterocycloalkyl; each R1Cis independently hydrogen or optionally substituted C1-C20alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20alkyl, optionally substituted C2-C10heteroalkyl, or (AA)p2, wherein each AA is an amino acid; p2is an integer from 1-10;or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6- membered heterocycloalkyl; j1is 0 or 1; m1and n1are each independently an integer from 0-3; and p1is 3; wherein the oligomeric backbone is attached at W1, W2, one of R2, or one of R3.

[0024] In some embodiments, the polyamide comprises the structure of Formula (A-3), or a pharmaceutically acceptable salt thereof:Formula (A-3), wherein: Z1is absent; each X1, X2, X3, X4, X5, X7, and X8is independently -NR2-; each Y1, Y2, Y3, Y4, Y5, Y7, and Y8is independently -CH- or -N-; W1is hydrogen, optionally substituted C1-C6 alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, -N(R1D)2, - ZB-P(O)(OR1C)2, -ZB-(CH2)p3-P(O)(OR1C)2, -ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZB is N or O; p3 is an integer from 1-10; W2is optionally substituted C1-C6 alkyl or C(O)NR1CR1D; each R2is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6 alkyl or phenyl;or two R3on the same or on adjacent atoms combine together with the atom(s) to which they are attached to form an optionally substituted C3-C6cycloalkyl or optionally substituted 3 to 6-membered heterocycloalkyl; each R1Cis independently hydrogen or optionally substituted C1-C20alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20alkyl, optionally substituted C2-C10heteroalkyl, or (AA)p2, wherein each AA is an amino acid; p2is an integer from 1-10; or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6- membered heterocycloalkyl; j1 is 0 or 1; m1 and n1 are each independently an integer from 0-3; and p1 is 3; wherein the oligomeric backbone is attached at W1, W2, one of R2, or one of R3.

[0025] In some embodiments of Formula (A-1), (A-2), or (A-3), p1 is 2. In some embodiments of Formula (A-1), (A-2), or (A-3), p1 is 3.

[0026] In some embodiments of Formula (A-1), (A-2), or (A-3), Z1is absent. In some embodiments of Formula (A-1), (A-2), or (A-3), Z1is -O- or -NH-.

[0027] In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-1), (A-2), or (A-3), at W1or W2. In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-1), (A-2), or (A-3), at W1. In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-1), (A-2), or (A-3), at W2.

[0028] In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-1), (A-2), or (A-3), at one of R2.

[0029] In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-1), (A-2), or (A-3), at one of R3.

[0030] In some embodiments of Formula (A-1), (A-2), or (A-3), W2is -C(O)NR1CR1D, wherein W2is attached to the oligomeric backbone. In some embodiments of Formula (A-1), (A-2), or (A-3), R1Cis hydrogen and R1Dis AA, wherein AA is a beta alanine. In some embodiments of Formula (A-1), (A-2), or (A-3) , W2is -C(O)NH-(beta alanine)-. In some embodiments of Formula (A-1), (A-2), or (A-3), W2is - C(O)NR1CR1D, wherein R1Cis hydrogen and R1Dis alkyl optionally substituted with an oxo (=O). In some embodiments of Formula (A-1), (A-2), or (A-3), W2is -C(O)NH(CH2)2C(O)-**, wherein the oligomeric backbone is attached at **. In some embodiments of Formula (A-1), (A-2), or (A-3), W2is -C(O)NH-**, wherein the linker moiety is attached at **.

[0031] In some embodiments, the polyamide comprises the structure of Formula (A-4), or a pharmaceutically acceptable salt thereof:Formula (A-4), wherein: each X1, X2, X3, X4, X5, X6, X7, and X8is independently -NR2-; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-; W1is hydrogen; each R2is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6 alkyl or phenyl; or two R3on the same or on adjacent atoms combine together with the atom(s) to which they are attached to form an optionally substituted C3-C6 cycloalkyl or optionally substituted 3 to 6-membered heterocycloalkyl; j1 is 0 or 1; and m1 and n1 are each independently an integer from 0-3.

[0032] In some embodiments, the polyamide comprises the structure of Formula (A-5), or a pharmaceutically acceptable salt thereof:Formula (A-5), wherein: Ring A” is an optionally substituted C3-C6cycloalkyl or optionally substituted 3 to 6-membered heterocycloalkyl; each X1, X2, X3, X4, X5, X6, X7, and X8is independently -NR2-; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-; W1is hydrogen; each R2is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; j1 is 0 or 1; and m1 and n1 are each independently an integer from 0-3.

[0033] In some embodiments, the polyamide comprises the structure of Formula (A-6), or a pharmaceutically acceptable salt thereof:Formula (A-6), wherein: each X1, X2, X3, X4, X5, X6, X7, and X8is independently -NR2-; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-; W1is hydrogen; each R2is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6 alkyl or phenyl; or two R3on the same or on adjacent atoms combine together with the atom(s) to which they are attached to form an optionally substituted C3-C6 cycloalkyl or optionally substituted 3 to 6-membered heterocycloalkyl; j1 is 0 or 1; and m1 and n1 are each independently an integer from 0-3.

[0034] In some embodiments, the polyamide comprises the structure of Formula (A-7), or a pharmaceutically acceptable salt thereof:Formula (A-7), wherein: each X1, X2, X3, X4, X5, X7, and X8is independently -NR2-; each Y1, Y2, Y3, Y4, Y5, Y7, and Y8is independently -CH- or -N-; W1is hydrogen; each R2is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C1-C20haloalkyl, optionally substituted C1-C20hydroxyalkyl, optionally substituted C3-C10cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20alkyl, optionally substituted C1-C20 heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6 alkyl or phenyl; or two R3on the same or on adjacent atoms combine together with the atom(s) to which they are attached to form an optionally substituted C3-C6 cycloalkyl or optionally substituted 3 to 6-membered heterocycloalkyl; j1 is 0 or 1; and m1 is an integer from 0-3.

[0035] In some embodiments of Formula (A-1) through (A-7), each X1, X2, X3, X4, X5, X6, X7, and X8is independently -O- or -S-. In some embodiments of Formula (A-1) through (A-7), X1, X2, X3, X4, X5, X6, X7, and X8are each independently -NR2.

[0036] In some embodiments of Formula (A-1) through (A-7), each Y1is independently -CH-. In some embodiments of Formula (A-1) through (A-7), Y1is independently -N-.

[0037] In some embodiments of Formula (A-1) through (A-7), Y2is -CH-. In some embodiments of Formula (A-1) through (A-7), Y2is -N-.

[0038] In some embodiments of Formula (A-1) through (A-7), Y3is -CH-. In some embodiments of Formula (A-1) through (A-7), Y3is -N-.

[0039] In some embodiments of Formula (A-1) through (A-7), Y4is -CH-. In some embodiments of Formula (A-1) through (A-7), Y4is -N-.

[0040] In some embodiments of Formula (A-1) through (A-7), each Y5is independently -CH-. In some embodiments of Formula (A-1) through (A-7), each Y5is independently -N-.

[0041] In some embodiments of Formula (A-1) through (A-7), each Y6is independently -CH.- In some embodiments of Formula (A-1) through (A-7), each Y6is independently -N-.

[0042] In some embodiments of Formula (A-1) through (A-7), Y7is -CH-. In some embodiments of Formula (A-1) through (A-7), Y7is -N-.

[0043] In some embodiments of Formula (A-1) through (A-7), Y2, Y4, and Y7are each -N-; and Y3is - CH-.

[0044] In some embodiments of Formula (A-1) through (A-7), Y2, Y4, and Y7are each -N-; and Y1and Y3are each -CH-.

[0045] In some embodiments, the polyamide comprises the structure of Formula (A-8), or a pharmaceutically acceptable salt thereof:Formula (A-8), wherein: Y8is -CH- or -N-; W1is hydrogen; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20 alkyl, optionally substituted C1-C20heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6alkyl or phenyl; and R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C1-C20haloalkyl, optionally substituted C1-C20hydroxyalkyl, optionally substituted C3-C10cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl.

[0046] In some embodiments, the polyamide moiety comprises the structure of Formula (A-9), or a pharmaceutically acceptable salt thereof:Formula (A-9), wherein: Y8is -CH- or -N-; W1is hydrogen; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6alkyl or phenyl; and R2A, R2B, R2D, R2E, R2F, and R2Gare each independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C1-C20haloalkyl, optionally substituted C1-C20hydroxyalkyl, optionally substituted C3-C10cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl.

[0047] In some embodiments, the polyamide comprises the structure of Formula (A-10), or a pharmaceutically acceptable salt thereof:Formula (A-10), wherein: Y8is -CH- or -N-; W1is hydrogen; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6alkyl or phenyl; and R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl.

[0048] In some embodiments of Formula (A-8), (A-9), or (A-10) Y8is -N-. In some embodiments of Formula (A-8), (A-9), or (A-10), Y8is -CH-.

[0049] In some embodiments of Formula (A-8), (A-9), or (A-10), R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently optionally substituted C1-C20 alkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, or optionally substituted C1-C20 alkylamino. In some embodiments of Formula (A-8), (A-9), or (A-10), R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 haloalkyl, or optionally substituted C1-C20 heteroalkyl. In some embodiments of Formula (A-8), (A-9), or (A-10), R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently optionally substituted C1-C20 heteroalkyl. In some embodiments of Formula (A-8), (A-9), or (A-10), R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently optionally substituted (PEG)n, wherein n is 1-20.

[0050] In some embodiments of Formula (A-8), (A-9), or (A-10), R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently optionally substituted C1-C20alkyl. In some embodiments of Formula (A-8), (A-9), or (A-10) R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently optionally substituted C1-C10alkyl. In some embodiments of Formula (A-8), (A-9, or (A-10), R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently unsubstituted C1-C6alkyl. In some embodiments of Formula (A-8), (A-9), or (A-10), R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments of Formula (A-8), (A-9), or (A-10), R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently methyl or ethyl. In some embodiments of Formula (A-8), (A-9), or (A-10), R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each methyl.

[0051] In some embodiments of Formula (A-1) through (A-4) or (A-6) through (A-10), each R3is independently hydrogen, halogen, amino, cyano, or -NHC(O)R3A. In some embodiments of Formula (A-1) through (A-4) or (A-6) through (A-10), each R3is independently optionally substituted C1-C20alkyl or optionally substituted C1-C20heteroalkyl. In some embodiments of Formula (A-1) through (A-4) or (A-6)through (A-10), each R3is independently hydrogen, -NH2, -NHCH3, or -NHC(O)CH3. In some embodiments of Formula (A-1) through (A-4) or (A-6) through (A-10), each R3is independently hydrogen or -NH2. In some embodiments of Formula (A-1) through (A-4) or (A-6) through (A-10), each R3is hydrogen.

[0052] In some embodiments of Formula (A-1) through (A-4) or (A-6) through (A-10), two R3together with the atom(s) to which they are attached form an optionally substituted C3-C6 cycloalkyl or optionally substituted 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A-1) through (A-4) or (A- 6) through (A-10), two R3together with the atom(s) to which they are attached form an optionally substituted C3-C6 cycloalkyl. In some embodiments of Formula (A-1) through (A-4) or (A-6) through (A- 10), two R3together with the atom(s) to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of Formula (A-1) through (A-4) or (A-6) through (A-10) two R3together with the atom(s) to which they are attached form a cyclopropyl. In some embodiments of Formula (A-1) through (A-4) or (A-6) through (A-10), two R3together with the atom(s) to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl, containing 1 or 2 heteroatoms selected from N, O, or S. In some embodiments of Formula (A-1) through (A-4) or (A-6) through (A-10), two R3together with the atom(s) to which they are attached form an oxetane, tetrahydrofuran, or tetrahydro- 2H-pyran.

[0053] In some embodiments of Formula (A-1) through (A-4), or (A-7), two R3on adjacent atoms together with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments, the cyclization occurs between the α and the β carbon atoms. In some embodiments, the cyclization occurs between the β and the δ carbon atoms.

[0054] In some embodiments of Formula (A-1) through (A-7), j1is 0. In some embodiments of Formula (A-1) through (A-7), j1 is 1.

[0055] In some embodiments of Formula (A-1) through (A-7), m1is 0. In some embodiments of Formula (A-1) through (A-7), m1is 1. In some embodiments of Formula (A-1) through (A-7), m1is 2. In some embodiments of Formula (A-1) through (A-7), m1is 3.

[0056] In some embodiments of Formula (A-1), (A-2), (A-4), (A-5), or (A-6) n1is 0. In some embodiments of Formula (A-1), (A-2), (A-4), (A-5), or (A-6), n1is 1. In some embodiments of Formula (A- 1), (A-2), (A-4), (A-5), or (A-6), n1is 2. In some embodiments of Formula (A-1), (A-2), (A-4), (A-5), or (A- 6), n1is 3.

[0057] In some embodiments, the polyamide comprises a structure of Formula (A-11), or a pharmaceutically acceptable salt thereof:Formula (A-11), wherein: each X9, X10, X11, and X12is independently -O-, -S-, or -NR2-; each Y9, Y10, Y11, and Y12is independently -CH- or -N-; W1is hydrogen, optionally substituted C1-C6alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, -N(R1D)2, - ZB-P(O)(OR1C)2,-ZB-(CH2)p3-P(O)(OR1C)2,-ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZB is N or O; p3is an integer from 1-10; W2is optionally substituted C1-C6alkyl or C(O)NR1CR1D; each R2is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each LXAis independently an optionally substituted C1-C6 alkylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 3 to 7-membered heterocyclene, or optionally substituted 5 to 6- membered heteroarylene; each Rxxis hydrogen or an C1-C6 alkyl; or Rxxand LXAjoin together with the atom(s) to which they are attached to form a 4 to 7-membered heterocyclic ring; each R1Cis independently hydrogen or optionally substituted C1-C20 alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20 alkyl, optionally substituted C2-C10 heteroalkyl, or (AA)p2, wherein each AA is an amino acid; p2 is an integer from 1-10; or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6- membered heterocycloalkyl; m0 is 0, 1, or 2; m2 is 1-4; andn2is 0-3; wherein the oligomeric backbone is attached at W1, W2, or one of R2.

[0058] In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-11) at W1or W2. In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-11) at W1. In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-11) at W2.

[0059] In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-11) at one of R2.

[0060] In some embodiments of Formula (A-11), W2is -C(O)NR1CR1D, wherein W2is attached to the oligomeric backbone; R1Cis hydrogen and R1Dis AA, wherein AA is a beta alanine. In some embodiments of Formula (A-11), W2is -C(O)NH(CRyRy)2C(O)-, wherein each Ryis independently hydrogen, halogen, - CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl; or two Ryon the same or on adjacent atoms together with the atom(s) to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A-11), W2is -C(O)NH-.

[0061] In some embodiments of Formula (A-11), W2is -C(O)NH(CRyRy)2C(O)-**, wherein the oligomeric backbone is attached at **. In some embodiments of Formula (A-11), W2is -C(O)NH-**, wherein the oligomeric backbone is attached at **.

[0062] In some embodiments of Formula (A-11), each X9, X10, X11, and X12is independently -O- or -S-. In some embodiments of Formula (A-11), X9, X10, X11, and X12are each independently -NR2.

[0063] In some embodiments of Formula (A-11), each LXAis independently an optionally substituted C1- C6alkylene. In some embodiments of Formula (A-11), each LXAis independently an optionally substituted C1-C4alkylene. In some embodiments of Formula (A-11), each LXAis independently an optionally substituted C1-C2alkylene. In some embodiments of Formula (A-11), each LXAis independently - C(Rx)2C(Rx)2-, wherein each Rxis hydrogen, halogen, -CN, -OH, -NH2, C1-C6alkyl, or C1-C6haloalkyl; or two Rxon the same or on adjacent atoms join together to form a C3-C6cycloalkyl or 3 to 6-membered heterocycloalkyl.

[0064] In some embodiments of Formula (A-11) each LXAis independently an optionally substituted C3- C7cycloalkylene. In some embodiments of Formula (A-11), each LXAis independently cyclopentylene or cyclohexylene.

[0065] In some embodiments of Formula (A-11), each Rxxis independently hydrogen. In some embodiments of Formula (A-11), each Rxxis independently C1-C6 alkyl.

[0066] In some embodiments of Formula (A-11), LXAand Rxxjoin together with the atoms to which they are attached to form a 4 to 7-membered heterocyclic ring.

[0067] In some embodiments, the polyamide comprises a structure of Formula (A-12), or a pharmaceutically acceptable salt thereof:Formula (A-12), wherein: each Y9, Y10, Y11, and Y12is independently -CH- or -N-; W1is hydrogen, optionally substituted C1-C6 alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, -N(R1D)2, - ZB-P(O)(OR1C)2, -ZB-(CH2)p3-P(O)(OR1C)2, -ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZB is N or O; p3 is an integer from 1-10; each R1Cis independently hydrogen or optionally substituted C1-C20 alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20 alkyl, optionally substituted C2-C10 heteroalkyl, or (AA)p2; or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6-membered heterocycloalkyl; each AA is an amino acid; p2 is an integer from 1-10; each R2J, R2K, R2L, and R2Mis independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each Rxand Ryis independently hydrogen, halogen, -CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl; or two Rxor two Ryon the same or on adjacent atoms together with the atom(s) to which they are attached form a C3-C6cycloalkyl or 3 to 6-membered heterocycloalkyl; m0is 0, 1, or 2; m2is 1-4; and n2is 0-3.

[0068] In some embodiments of Formula (A-12), each Rxis independently hydrogen, halogen, -CN, -OH, -NH2, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of Formula (A-12), each Rxis independently hydrogen, halogen, or -OH. In some embodiments of Formula (A-12), each Rxis hydrogen.

[0069] In some embodiments of Formula (A-12), two Rxon the same or on adjacent atoms together with the atom(s) to which they are attached form a C3-C6cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A-12), two Rxon the same or adjacent atoms together with the atom(s) to which they are attached form a C3-C6cycloalkyl. In some embodiments of Formula (A-12), two Rxon the same or adjacent atoms together with the atom(s) to which they are attached form a 3 to 6-membered heterocycloalkyl.

[0070] In some embodiments of Formula (A-12), each Ryis independently hydrogen, halogen, -CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of Formula (A-12), each Ryis independently hydrogen, halogen, or -OH. In some embodiments of Formula (A-12), each Ryis hydrogen.

[0071] In some embodiments of Formula (A-12), two Ryon the same or on adjacent atoms together with the atom(s) to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A-12), two Ryon the same or on adjacent atoms join together to form a C3- C6 cycloalkyl. In some embodiments of Formula (A-12), two Ryon the same or on adjacent atoms join together to form a 3 to 6-membered heterocycloalkyl.

[0072] In some embodiments of Formula (A-11) or (A-12), each Y9is -CH-. In some embodiments of Formula (A-11) or (A-12), each Y9is -N-.

[0073] In some embodiments of Formula (A-11) or (A-12), each Y10is -CH-. In some embodiments of Formula (A-11) or (A-12), each Y10is -N-.

[0074] In some embodiments of Formula (A-11) or (A-12), each Y9is -N- and each Y10is CH.

[0075] In some embodiments of Formula (A-11) or (A-12), Y11is -CH-. In some embodiments of Formula (A-11) or (A-12), Y11is -N-.

[0076] In some embodiments of Formula (A-11) or (A-12), m0is 1 or 2. In some embodiments of Formula (A-11) or (A-12), m0is 1. In some embodiments of Formula (A-11) or (A-12), m0is 0.

[0077] In some embodiments, the polyamide comprises a structure of Formula (A-13), or a pharmaceutically acceptable salt thereof:Formula (A-13), wherein: each Y12is independently -CH- or -N-; W1is hydrogen;each R2J, R2K, R2L, and R2Mis independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C1-C20haloalkyl, optionally substituted C1-C20hydroxyalkyl, optionally substituted C3-C10cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; m2is 1-4; and n2is 0-3.

[0078] In some embodiments of Formula (A-12) or (A-13), each R2J, R2K, R2L, and R2Mis independently optionally substituted C1-C20 alkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, or optionally substituted C1-C20 alkylamino. In some embodiments of Formula (A-12) or (A- 13), each R2J, R2K, R2L, and R2Mis independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 haloalkyl, or optionally substituted C1-C20 heteroalkyl. In some embodiments of Formula (A-12) or (A-13), each R2J, R2K, R2L, and R2Mis independently optionally substituted C1-C20 heteroalkyl. In some embodiments of Formula (A-12) or (A-13, each R2J, R2K, R2L, and R2Mis independently optionally substituted (PEG)n, wherein n is 1-20.

[0079] In some embodiments of Formula (A-12) or (A-13), each R2J, R2K, R2L, and R2Mis independently optionally substituted C1-C20 alkyl. In some embodiments of Formula (A-12) or (A-13), each R2J, R2K, R2L, and R2Mis independently optionally substituted C1-C10alkyl. In some embodiments of Formula (A-12) or (A-13), each R2J, R2K, R2L, and R2Mis independently unsubstituted C1-C6 alkyl. In some embodiments of Formula (A-12) or (A-13), each R2J, R2K, R2L, and R2Mis independently methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments of Formula (A-12) or (A-13), each R2J, R2K, R2L, and R2Mis independently methyl or ethyl. In some embodiments of Formula (A-12) or (A-13), each R2J, R2K, R2L, and R2Mis methyl.

[0080] In some embodiments of Formula (A-13), each Y12is -CH-. In some embodiments of Formula (A- 13), each Y12is -N-.

[0081] In some embodiments, the polyamide comprises a structure of Formula (A-14), or a pharmaceutically acceptable salt thereof:Formula (A-14), wherein:m2is 2 or 3; and n2is 0-3.

[0082] In some embodiments of Formula (A-11), (A-12), (A-13), or (A-14), m2 is 2 or 3. In some embodiments of Formula (A-11), (A-12), (A-13), or (A-14), m2is 3. In some embodiments of Formula (A- 11), (A-12), (A-13), or (A-14), m2 is 2.

[0083] In some embodiments of Formula (A-11), (A-12), (A-13), or (A-14), n2 is 0 or 1. In some embodiments of Formula (A-11), (A-12), (A-13), or (A-14), n2 is 3. In some embodiments of Formula (A- 11), (A-12), (A-13), or (A-14), n2 is 2. In some embodiments of Formula (A-11), (A-12), (A-13), or (A-14), n2 is 1. In some embodiments of Formula (A-11), (A-12), (A-13), or (A-14), n2 is 0.

[0084] In some embodiments, the polyamide comprises a structure of Formula (A-15), or a pharmaceutically acceptable salt thereof:Formula (A-15), wherein: each X13and X14is independently -O-, -S-, or -NR2-; each Y13and Y14is independently -CR2”- or -N-; W1is hydrogen, optionally substituted C1-C6alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, -N(R1D)2, - ZB-P(O)(OR1C)2,-ZB-(CH2)p3-P(O)(OR1C)2,-ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZBis N or O; p3is an integer from 1-10; each R1Cis independently hydrogen or optionally substituted C1-C20alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20alkyl, optionally substituted C2-C10heteroalkyl, or (AA)p2, wherein or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6-membered heterocycloalkyl; each AA is an amino acid; p2 is an integer from 1-10; each R2is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each R2” is independently hydrogen, halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy; andn3is 1-10.

[0085] In some embodiments of Formula (A-15), each X13and X14is independently -O- or -S-. In some embodiments of Formula (A-15), X13and X14are each independently -NR2

[0086] In some embodiments of Formula (A-15), each Y13is -CR2”-. In some embodiments of Formula (A-15), each Y13is -N-.

[0087] In some embodiments of Formula (A-15), each Y14is -CR2”-. In some embodiments of Formula (A-15), each Y14is -N-.

[0088] In some embodiments of Formula (A-15) each Y13is -N- and each Y14is -N-.

[0089] In some embodiments, the polyamide comprises a structure of Formula (A-16), or a pharmaceutically acceptable salt thereof:Formula (A-16), wherein: W1is hydrogen; and n3is 1-10.

[0090] In some embodiments of Formula (A-15) or (A-16), n3is 2-6. In some embodiments of Formula (A-15) or (A-16), n3is 2, 3, or 4. In some embodiments of Formula (A-15) or (A-16), n3is 3. In some embodiments of Formula (A-15) or (A-16), n3is 2.

[0091] In some embodiments of Formula (A-1) through (A-7), (A-11), or (A-15), each R2is independently optionally substituted C1-C20alkyl, optionally substituted C1-C20haloalkyl, optionally substituted C1-C20heteroalkyl, or optionally substituted C1-C20alkylamino. In some embodiments of Formula (A-1) through (A-7), (A-11), or (A-15), each R2is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C1-C20haloalkyl, or optionally substituted C1-C20heteroalkyl. In some embodiments of Formula (A-1) through (A-7), (A-11), or (A-15), each R2is independently optionally substituted C1-C20 heteroalkyl. In some embodiments of Formula (A-1) through (A-7), (A-11), or (A-15), each R2is independently optionally substituted (PEG)n, wherein n is 1-20.

[0092] In some embodiments of Formula (A-1) through (A-7), (A-11), or (A-15), each R2is independently optionally substituted C1-C20 alkyl. In some embodiments of Formula (A-1) through (A-7), (A-11), or (A-15), each R2is independently optionally substituted C1-C10alkyl. In some embodiments of Formula (A-1) through (A-7), (A-11), or (A-15), each R2is independently unsubstituted C1-C6 alkyl. In some embodiments of Formula (A-1) through (A-7), (A-11), or (A-15), each R2is independently methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments of Formula (A-1) through(A-7), (A-11), or (A-15), each R2is independently methyl or ethyl. In some embodiments of Formula (A-1) through (A-7), (A-11), or (A-15), each R2is methyl.

[0093] In some embodiments of Formula (A-1), (A-2), (A-3), (A-11), (A-12), or (A-15), W1is -N(R1D)2, - C(O)NR1CR1D, -NR1CC(O)R1D, or -NR1CC(O)NR1CR1D. In some embodiments of Formula (A-1), (A-2), (A- 3), (A-11), (A-12), or (A-15), W1is -C(O)NR1CR1D. In some embodiments of Formula (A-1), (A-2), (A-3), (A-11), (A-12), or (A-15), W1is -NR1CC(O)R1D.

[0094] In some embodiments of Formula (A-1), (A-2), (A-3), (A-11), (A-12), or (A-15), W1is -ZB- P(O)(OR1C)2, -ZB-(CH2)p3-P(O)(OR1C)2. -ZB-(CH2)p3-O-PO2(OR1C)2, wherein ZB is O or N, and p3 is an integer from 1-10. In some embodiments, wherein ZB is O. In some embodiments, wherein ZB is N. In some embodiments, p3 is an integer from 1-4. In some embodiments, p3 is 1 or 2.

[0095] In some embodiments of Formula (A-1), (A-2), (A-3), (A-11), (A-12), or (A-15), W1is.

[0096] In some embodiments of Formula (A-1) through (A-16), W1is hydrogen.

[0097] In some embodiments of Formula (A-1), (A-2), (A-3), (A-11), (A-12), or (A-15), each R1Cis independently optionally substituted C1-C20 alkyl. In some embodiments of Formula (A-1), (A-2), (A-3), (A- 11), (A-12), or (A-15) each R1Cis hydrogen.

[0098] In some embodiments of Formula (A-1), (A-2), (A-3), (A-11), (A-12), or (A-15), each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20 alkyl, optionally substituted C2-C10 heteroalkyl, or (AA)p2, wherein each AA is an amino acid; and p2 is an integer from 1-10. In some embodiments of Formula (A-1), (A-2), (A-3), (A-11), (A-12), or (A-15), each R1Dis independently optionally substituted C1-C20 alkyl. In some embodiments of Formula (A-1), (A-2), (A-3), (A- 11), (A-12), or (A-15), each R1Dis independently (AA)p2. In some embodiments of Formula (A-1), (A-2), (A-3), (A-11), (A-12), or (A-15), each R1Dis hydrogen.

[0099] 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.

[0100] 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 Kdof the polyamide for the target sequence at either 24 ºC or 37 °C, and using either standard polyamide assay solution conditions or approximate intracellular solution conditions.

[0101] 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.

[0102] 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. N-methyl pyrrole (Py) favors T, A, and C bases, excluding G; N-methylimidazole (Im) is a G-reader; and 3-hydroxyl- N-methylpyrrol (Hp) is specific for thymine base. The nucleotide base pairs can be recognized using different pairings of the amino acid subunits using the pairing principle shown in Table 1A. For example, an Im / Py pairing reads G·C by symmetry, a Py / Im pairing reads C·G, an Hp / Py pairing can distinguish T·A from A·T, G·C, and C·G, and a Py / Py pairing nonspecifically discriminates both A·T and T·A from G·C and C·G. Table 1A. Base pairing for single amino acid subunit (Favored (+), disfavored (-)).nucleotides. The binding property of HpBi, ImBi, and PyBi corresponds to Hp-Py, Im-Py, and Py-Py respectively.

[0103] The monomer subunits of the polyamide can be strung together based on the pairing principles shown in Table 1A.

[0104] Recognition of a nucleotide repeat or DNA sequence by two antiparallel polyamide strands depends on a code of side-by-side aromatic amino acid pairs in the minor groove, usually oriented N to C with respect to the 5’ to 3’ direction of the DNA helix. Second Terminus – Regulatory Protein Binding Moiety

[0105] 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 a repetitive nucleotide sequence.

[0106] In some embodiments, the second terminus comprises a bromodomain binding moiety.

[0107] In some embodiments, the second terminus comprises a moiety capable of binding to a bromodomain and extra terminal domain (BET) family member.

[0108] 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.

[0109] 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 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.

[0110] In some embodiments, the regulatory molecule is CBP / p300.

[0111] In some embodiments, the regulatory molecule is PCAF (P300 / CBP-Associated Factor).

[0112] In some embodiments, the regulatory molecule is CECR2 (cat eye syndrome chromosome region candidate 2).

[0113] In some embodiments, the regulatory molecule is BRPF (bromodomain and PHD finger- containing protein).

[0114] In some embodiments, the regulatory molecule is a ATAD2 or ATAD2B chromatin remodeling protein.

[0115] In some embodiments, the regulatory molecule is BAZ2 (Bromodomain Adjacent Zinc Finger.

[0116] In some embodiments, the regulatory molecule is TAF1 (TBP associated factor).

[0117] In some embodiments, the regulatory molecule is TRIM24 (tripartite motif-containing 24).

[0118] In some embodiments, the regulatory molecule is BRD7 / 9.

[0119] In some embodiments, the regulatory molecule is BPTF (Bromodomain PHD Finger Transcription Factor).

[0120] In some embodiments, the regulatory molecule is SMARCA2 / 4.

[0121] In some embodiments, the regulatory molecule is PBRM1.

[0122] In some embodiments, the regulatory molecule modulates the rearrangement of histones.

[0123] In some embodiments, the regulatory molecule modulates the glycosylation, phosphorylation, alkylation, or acylation of histones.

[0124] In some embodiments, the regulatory molecule is a transcription factor.

[0125] In some embodiments, the regulatory molecule is an RNA polymerase.

[0126] In some embodiments, the regulatory molecule is a moiety that regulates the activity of RNA polymerase.

[0127] 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.

[0128] 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.

[0129] 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, the second 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.

[0130] In some embodiments, the second terminus has a triazolodiazepine structure. In some embodiments, the second terminus has a thiazolodiazepine structure.

[0131] In some embodiments, 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 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 C1-C6 alkyl; R6is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; and x1 is an integer from 1-6.

[0132] In some embodiments, D is N and E is N. In some embodiments, D is C and E is O.

[0133] 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 optionally substituted 6-membered monocyclic aryl or heteroaryl; YAis -NH- or -O-; R5is hydrogen or C1-C6alkyl; R6is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; R7is hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; and x1 is an integer from 1-6.

[0134] In some embodiments, Ring A is an optionally substituted aryl. 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.

[0135] 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 optionally substituted 6-membered monocyclic aryl or heteroaryl; YAis -NH- or -O-; R5is hydrogen or C1-C6alkyl; R6is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; R7is hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl;or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1-C20alkyl, or optionally substituted C1-C20heteroalkyl; R8and R9are each independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; and x1is an integer from 1-6.

[0136] In some embodiments, R8and R9are each independently an optionally substituted C1-C6 alkyl, C1- C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments, R8and R9are each independently an optionally substituted C1-C6 alkyl. In some embodiments, R8and R9are each independently methyl, ethyl, or propyl. In some embodiments, R8and R9are each methyl. In some embodiments, R8and R9are each ethyl. In some embodiments, R8and R9are each propyl.

[0137] 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 optionally substituted 6-membered monocyclic aryl or heteroaryl; YAis -NH- or -O-; R5is hydrogen or C1-C6alkyl; R6is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; R7is hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1-C20alkyl, or optionally substituted C1-C20heteroalkyl; R10is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; and x1is an integer from 1-6.

[0138] In some embodiments, R5is C1-C6 alkyl. In some embodiments, R5is methyl or ethyl. In some embodiments, R5is methyl. In some embodiments, R5is ethyl. In some embodiments, R5is hydrogen.

[0139] In some embodiments, R7is hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R7ishalogen. In some embodiments, R7is Br, Cl, or F. In some embodiments, R7is Cl. In some embodiments, R7is F. In some embodiments, R7is Br.

[0140] In some embodiments, R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen or optionally substituted C1-C6alkyl.

[0141] In some embodiments, R10is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R10is optionally substituted C1-C6 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.

[0142] In some embodiments, R6is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R6is optionally substituted C1-C6 alkyl. In some embodiments, R6is methyl, ethyl, or propyl. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is propyl.

[0143] In some embodiments, YA is -NH-. In some embodiments, YA is -O-.

[0144] In some embodiments, YA is NH and x1 is 1.

[0145] In some embodiments, x1is an integer from 1-5, 1-4, 1-3, or 1-2. In some embodiments, x1is 1. In some embodiments, x1is 2.

[0146] In some embodiments, Ring B is an optionally substituted 6-membered monocyclic aryl or optionally substituted 6-membered monocyclic 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.

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

[0148] In some embodiments, the second terminus comprises the structure of Formula (2-F), or a pharmaceutically acceptable salt thereof:

[0149] In some embodiments, the second terminus comprises the structure of Formula (2-G), or a pharmaceutically acceptable salt thereof:

[0150] In some embodiments, the second terminus comprises the structure of Formula (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 C1-C6alkyl; R12is hydrogen, halogen, -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; R14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; or R14is -NRARB; R16is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C2- C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6hydroxyalkyl, - S(O)(=NH)RA, -SO2RA, or -NHSO2RA; RYAis hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted 5-6-membered monocyclic aryl or heteroaryl;each RAand RBis independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; and y1is 1-3; wherein Formula (3-A) is attached to the oligomeric backbone at either R14or at RYA.

[0151] 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 optionally substituted 4 to 8-membered heterocycloalkyl; YBis -NH-, -CH2NH-, -CH2O-, or -O-; R11Aand R11Bare each independently hydrogen or optionally substituted C1-C6alkyl; R12is hydrogen, optionally substituted C1-C6alkyl, C(O)RA, or C(O)NRARB; wherein each RAand RBis independently hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C1-C6heteroalkyl; R13is hydrogen, substituted aryl, substituted heteroaryl, or substituted oxydibenzene; and y2is an integer from 0-2.

[0152] 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 C1-C6alkyl; R13is hydrogen, substituted aryl, substituted heteroaryl, or substituted oxydibenzene; and y2is an integer from 0-2.

[0153] In some embodiments, y2 is 0. In some embodiments, y2 is 1. In some embodiments, y2 is 2.

[0154] In some embodiments, R13is substituted aryl or substituted heteroaryl. In some embodiments, R13is hydrogen.

[0155] In some embodiments, R13is substituted oxydibenzene.

[0156] In some embodiments,, wherein R14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; or R14is -NRARB; R16is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C2- C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6hydroxyalkyl, - S(O)(=NH)RA, -SO2RA, or -NHSO2RA; each RAand RBis independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; and y1 is 1-3.

[0157] 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; YB is -CH2NH-, -CH2O-, -NH-, or -O-; R11Aand R11Bare each independently hydrogen or optionally substituted C1-C6 alkyl; R12is hydrogen, halogen, -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; R14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; or R14is -NRARB; R16is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C2- C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6hydroxyalkyl, - S(O)(=NH)RA, -SO2RA, or -NHSO2RA;each RAand RBis independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; and y1is an integer from 1-3.

[0158] In some embodiments, YB is -NH-. In some embodiments, YB is -CH2NH-. In some embodiments, YB is -CH2O-. In some embodiments, YB is -O-.

[0159] 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.

[0160] In some embodiments, Ring C is absent.

[0161] 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 C1-C6alkyl; R12is hydrogen or an optionally substituted C1-C6alkyl; each R15is independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; R16is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C2- C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6hydroxyalkyl, - S(O)(=NH)RA, -SO2RA, or -NHSO2RA; RAis hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6- membered heteroaryl; and y1is an integer from 1-3.

[0162] In some embodiments, R11Aand R11Bare each independently optionally substituted C1-C6alkyl. In some embodiments, R11Aand R11Bare each independently methyl, ethyl, propyl, or tert-butyl. In some embodiments, R11Aand R11Bare each methyl. In some embodiments, R11Aand R11Bare each ethyl. In some embodiments, R11Aand R11Bare each hydrogen.

[0163] In some embodiments, R11Ais C1-C6 alkyl, optionally substituted with haloalkyl or phosphorous hydroxide. In some embodiments, R11Ais C1-C6 alkyl substituted with -OP(O)(OH)2. In some embodiments, R11Ais unsubstituted C1-C6 alkyl. In some embodiments, R11Ais methyl, ethyl, or tert-butyl. In some embodiments, R11Ais methyl. In some embodiments, R11Ais ethyl. In some embodiments, R11Ais hydrogen.

[0164] In some embodiments, R11Bis C1-C6 alkyl, optionally substituted with haloalkyl or phosphorous hydroxide. In some embodiments, R11Bis C1-C6 alkyl substituted with -OP(O)(OH)2. In some embodiments, R11Bis unsubstituted C1-C6 alkyl. In some embodiments, R11Bis methyl, ethyl, or tert-butyl. In some embodiments, R11Bis methyl. In some embodiments, R11Bis ethyl. In some embodiments, R11Bis hydrogen

[0165] In some embodiments, R12is optionally substituted C1-C6 alkyl. In some embodiments, R12is hydrogen.

[0166] 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 C1-C6 alkyl.

[0167] In some embodiments, R14and R15are each independently hydrogen, -CN, or -NO2. In some embodiments, R14and R15are each independently halogen or optionally substituted C1-C6alkyl. In some embodiments, R14and R15are each independently Br, Cl, F, methyl, or ethyl. In some embodiments, R14and R15are each independently F or methyl.

[0168] In some embodiments, R16is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6hydroxyalkyl, each of which is optionally substituted with amido, alkyl, alkynyl, azido, amino, halogen, haloalkyl, hydroxy, nitro, oxo (=O), phosphorous hydroxide, or PEG.

[0169] In some embodiments, R16is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C1-C6hydroxyalkyl. In some embodiments, R16is C1-C6alkyl or C1-C6heteroalkyl, each or which optionally substituted with -CN, -NH2, -N3, -OH, CF3, or -OP(O)(OH)2.

[0170] In some embodiments, R16is -SO2RA, wherein RAis optionally substituted C1-C6 alkyl. In some embodiments, R16is -SO2RA, wherein RAis substituted C1-C6 alkyl, which is optionally substituted with. some embodiments, R16is -SO2Et. In some embodiments, R16is -SO2Me.

[0171] In some embodiments, R16is -NHSO2RA, wherein RAis C1-C6alkyl. In some embodiments, R16is -NHSO2Et. In some embodiments, R16is -NHSO2Me. In some embodiments, R16is -NHSO2RA, wherein RAis C1-C6alkyl which is optionally substituted.

[0172] In some embodiments, y1 is 1. In some embodiments, y1 is 2. In some embodiments, y1 is 3.

[0173] In some embodiments, Ring C is an optionally substituted 5 or 6-membered monocyclic aryl or optionally substituted 5 or 6-membered monocyclic heteroaryl, each of which is optionally substituted with alkyl, amino, halogen, hydroxy, hydroxyalkyl, or PEG.

[0174] In some embodiments, the second terminus comprises the structure of Formula (3-E) or Formula (3-F), or a pharmaceutically acceptable salt thereof:o ua - .

[0175] 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).

[0176] In some embodiments, the second terminus comprising the structure of Formula (3-I), or a pharmaceutically acceptable salt thereof:

[0177] 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; G1and G2are each independently C or N, wherein one of G1or G2is N; L2is absent, optionally substituted alkylene, -O-, or -NRD-, wherein RDis hydrogen or optionally substituted C1-C3alkyl; R18is an optionally substituted 5 to 6-membered heteroaryl; R19is an optionally substituted C3-C8cycloalkyl or optionally substituted 4 to 8-membered heteroaryl; each R20is independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; x3is an integer from 1-3;and y4is an integer from 1-4; wherein Formula (4-A) is attached to the oligomeric backbone at either R19or at one of R20.

[0178] In some embodiments, Formula (4-A) is attachment to the oligomeric backbone at R19. In some embodiments, Formula (4-A) is attachment to the oligomeric backbone at one of R20.

[0179] 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; G1and G2are each independently C or N, wherein one of G1or G2is N; L2is absent, optionally substituted alkylene, -O-, or -NRD-, wherein RDis hydrogen or optionally substituted C1-C3 alkyl; R18is an optionally substituted 5 to 6-membered heteroaryl; R19is an optionally substituted C3-C8cycloalkyl or optionally substituted 4 to 7-membered heteroaryl; and x3 is an integer from 1-3.

[0180] In some embodiments, G1is N; and G2is C. In some embodiments, G1is C; and G2is N.

[0181] 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-, wherein RDis hydrogen or optionally substituted C1-C3alkyl; R18is an optionally substituted 5 to 6-membered heteroaryl; R19is an optionally substituted C3-C8cycloalkyl or optionally substituted 4 to 8-membered heteroaryl; and x3is an integer from 1-3.

[0182] 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.

[0183] In some embodiments, R19is an optionally substituted C3-C8cycloalkyl. In some embodiments, R19is optionally substituted 4 to 8-membered heteroaryl.

[0184] In some embodiments, the second terminus comprises the structure of Formula (4-D), or a pharmaceutically acceptable salt thereof:wherein: L2is an optionally substituted alkylene, -O-, or -NRD-, wherein RDis hydrogen or optionally substituted C1- C3 alkyl; R18is an optionally substituted 5 to 6-membered heteroaryl; R20is hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; x3 is an integer from 1-3; and y3 is an integer from 1-4.

[0185] 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.

[0186] In some embodiments, L2is -NRD-. In some embodiments, L2is -NH-.

[0187] 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.

[0188] In some embodiments, R20is halogen, -CN, -NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl.

[0189] In some embodiments, x3is 1. In some embodiments, x3is 2. In some embodiments, x3is 3.

[0190] In some embodiments, y4 is 1 or 2. In some embodiments, y4 is 1. In some embodiments, y4 is 2. In some embodiments, y4is 3. In some embodiments, y4is 4.

[0191] 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).

[0192] In some embodiments, the second terminus comprises the structure of Formula (4-G), or a pharmaceutically acceptable salt thereof:

[0193] In some embodiments, the second terminus comprises the structure of Formula (5-A), or a pharmaceutically acceptable salt thereof:Formula (5-A), wherein: Ring E is absent, optionally substituted phenyl, or optionally substituted 5 to 6-membered heteroaryl; X15is -CH- or -N-; L3is -NRE- or -CRERE-, wherein each REis independently hydrogen or optionally substituted C1-C3alkyl; R21is C1-C6alkyl or C3-C6cycloalkyl; and R22is halogen, CN, NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl.

[0194] 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.

[0195] In some embodiments, X15is -CH- and L3is -NRE-. In some embodiments, X15is -N- and L3is - CRERE-.

[0196] In some embodiments, R21is C1-C6 alkyl. In some embodiments, R21is methyl.

[0197] In some embodiments, R22is halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R22is CN, F, Cl, Br, or methyl.

[0198] In some embodiments, the second terminus comprises the structure of Formula (5-B) or Formula (5-C), or a pharmaceutically acceptable salt thereof:

[0199] 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 an optionally substituted C3-C6 cycloalkylene or optionally substituted 4 to 6-membered heterocycloalkylene; L6is -O-(optionally substituted alkylene); R28is an optionally substituted 5 to 6-membered heteroaryl; R29is optionally substituted C1-C6 alkylene(C6-C10 aryl) or optionally substituted C1-C6 alkylene(6 to 10- membered heteroaryl); and R30is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1- C6 hydroxyalkyl.

[0200] In some embodiments, Ring G is an optionally substituted C3-C6 cycloalkylene. In some embodiments, Ring G is an optionally substituted 4 to 6-membered heterocycloalkylene.

[0201] In some embodiments, L6is -O-(optionally substituted C1-C6alkylene). In some embodiments, L6is -O-CH2-.

[0202] In some embodiments, R28is an optionally substituted 5-membered heteroaryl. In some embodiments, R28is an optionally substituted 6-membered heteroaryl.

[0203] In some embodiments, R29is -C1-C6alkylene(phenyl). In some embodiments, R29is -C1-C6alkylene(6-membered heteroaryl).

[0204] In some embodiments, R30is optionally substituted C1-C6alkyl. In some embodiments, R30is optionally substituted C1-C6haloalkyl. In some embodiments, R30is optionally substituted C1-C6hydroxyalkyl.

[0205] 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-; Z3is CH or N; W is O or S; each R31is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10hydroxyalkyl, optionally substituted C2-C10alkenyl, optionally substituted C2-C10alkynyl, optionally substituted C3-C8cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; or two R31together with the atoms to which they are attached form an optionally substituted C5-C8cycloalkyl or optionally substituted 5 to 8-membered heterocycloalkyl; R32is hydrogen or optionally substituted C1-C10alkyl; R32Ais hydrogen or optionally substituted C1-C10alkyl; R33is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl; and q6 is 0-4; wherein Formula (7-A) is attached to the oligomeric backbone at R32Aor at one of R31.

[0206] In some embodiments, the second terminus comprises the structure of Formula (7-B), or a pharmaceutically acceptable salt thereof:Formula (7-B), wherein: A3is -O-, -NH-, or -CH2-; Z3is CH or N; W is O or S; each R31is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10hydroxyalkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C8cycloalkyl, 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 C5-C8cycloalkyl or optionally substituted 5 to 8-membered heterocycloalkyl; R32is hydrogen or optionally substituted C1-C10alkyl; R33is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl; and q6is 0-4.

[0207] In some embodiments, the second terminus comprises the structure of Formula (7-C), or a pharmaceutically acceptable salt thereof:Formula (7-C), 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-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10hydroxyalkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C8-cycloalkyl, or optionally substituted 3- to 8-membered heterocycloalkyl; or two R31together with the atoms to which they are attached form an optionally substituted C5-C8 cycloalkyl or optionally substituted 5 to 8-membered heterocycloalkyl; R32is hydrogen or optionally substituted C1-C10alkyl; and q6 is 1-4.

[0208] In some embodiments, A3is -O-. In some embodiments, A3is -NH-. In some embodiments, A3is - CH2-.

[0209] In some embodiments, Z3is CH. In some embodiments, Z3is N.

[0210] In some embodiments, W is O. In some embodiments, W is S.

[0211] In some embodiments, Ring F is an optionally substituted 5-membered heteroaryl. In some embodiments, Ring F is an optionally substituted 6-membered heteroaryl.

[0212] In some embodiments, each R31is independently an optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl. In some embodiments, each R31is independently an optionally substituted C3-C8-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.

[0213] In some embodiments, R32is an optionally substituted C1-C10alkyl. In some embodiments, R32is methyl. In some embodiments, R32is hydrogen.

[0214] In some embodiments, R33is hydrogen, halogen, -OH, -CN, -NO2, or -NH2. In some embodiments, R33is an optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl.

[0215] In some embodiments, the second terminus comprises the structure of Formula (7-D) or Formula (7-E), or a pharmaceutically acceptable salt thereof:

[0216] In some embodiments, the second terminus comprise the structure of Formula (7-F), or a pharmaceutically acceptable salt thereof:

[0217] 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; X16is CH or N; R34is an optionally substituted phenyl or optionally substituted 6-membered heteroaryl; R34Ais hydrogen, halogen, or optionally substituted C1-C3 alkyl; andR35is halogen, optionally substituted C1-C10alkyl, or optionally substituted 5 to 6-membered heteroaryl; wherein Formula (8-A) is attached to the oligomeric backbone at R35, ZA, or Ring H.

[0218] In some embodiments, Ring H is an optionally substituted phenyl. In some embodiments, Ring H is an optionally substituted 6-membered heteroaryl.

[0219] In some embodiments, Ring.

[0220] 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.

[0221] In some embodiments, X16is CH. In some embodiments, X16is N.

[0222] In some embodiments, R34is an optionally substituted phenyl. In some embodiments, R34is an optionally substituted 6-membered heteroaryl.

[0223] In some embodiments, R34Ais hydrogen or halogen. In some embodiments, R34Ais an optionally substituted C1-C3 alkyl. In some embodiments, R34Ais methyl.

[0224] In some embodiments, R35is optionally substituted 5 to 6-membered heteroaryl. In some embodiments, R35is optionally substituted 5-membered heteroaryl.

[0225] In some embodiments, Formula (8-A) is attached to the oligomeric backbone is at R35. In some embodiments, Formula (8-A) is attached to the oligomeric backbone at ZA. In some embodiments, Formula (8-A) is attached to the oligomeric backbone at Ring H.

[0226] In some embodiments, the second terminus comprises the structure of Formula (8-B) or Formula

[0227] In some embodiments, the second terminus comprises the structure of Formula (8-D), or a pharmaceutically acceptable salt thereof:Formula (8-D).

[0228] In some embodiments, the second terminus comprises the structure of Formula (9-A), or a pharmaceutically acceptable salt thereof:Formula (9-A).

[0229] 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).

[0230] In some embodiments, the second terminus comprises the structure of Formula (11-A), or a pharmaceutically acceptable salt thereof:

[0231] 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 C1-C10alkyl; R36is an optionally substituted 5 to 6-membered heteroaryl; each R37is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; R38is optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; R39is hydrogen, halogen, -OH, -CN, -NO2, -NH2, oxo (=O), =S, C1-C10haloalkyl, or C1-C10hydroxyalkyl; p11is 1-4; and q1 and q2 are each independently 0-2; wherein Formula (12-A) is attached to the oligomeric backbone at either R38or R40.

[0232] 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.

[0233] In some embodiments, each R37is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R37is independently halogen.

[0234] In some embodiments, R38is an optionally substituted C1-C10alkyl. In some embodiments, R38is an optionally substituted C3-C8cycloalkyl or optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R38is a 3 to 8-membered heterocycloalkyl.

[0235] In some embodiments, R39is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10haloalkyl, or C1- C10hydroxyalkyl. In some embodiments, R39is oxo or =S. In some embodiments, R39is oxo. In some embodiments, R39is =S.

[0236] In some embodiments, A4is -NR40. In some embodiments, A4is -NH. In some embodiments, A4is -NCH3. In some embodiments, A4is -CR40R40. In some embodiments, A4is -CH2-.

[0237] In some embodiments, each R40is independently optionally substituted C1-C10alkyl. In some embodiments, each R40is independently hydrogen.

[0238] In some embodiments, p11 is 3 or 4. In some embodiments, p11 is 2. In some embodiments, p11 is 1.

[0239] In some embodiments, q1 is 1 and q2 is 1. In some embodiments, q1 is 2 and q2 is 0.

[0240] 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.

[0241] In some embodiments, the second terminus comprises Formula (12-B) or Formula (12-C), or a pharmaceutically acceptable salt thereof:

[0242] In some embodiments, the second terminus comprises Formula (12-D) or Formula (12-E), or a pharmaceutically acceptable salt thereof:

[0243] 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 C1-C6 alkyl, optionally substituted C3-C8cycloalkyl, -C(O)R41A, -C(O)-, or - C(O)NR41BR41B, wherein R41Aand R41Bare each independently optionally substituted C1-C10alkyl or optionally substituted C3-C8cycloalkyl; R42is an optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C3-C8cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; R43is hydrogen or optionally substituted C1-C10alkyl; each R44is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, C1-C10hydroxyalkyl, optionally substituted C2-C10alkenyl,optionally substituted C2-C10alkynyl, optionally substituted C3-C8-cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; or R43and one of R44together with the atoms to which they are attached form an optionally substituted 5 to 8- membered heterocycloalkyl; p12is 1-4; and q3is 0 or 1; wherein Formula (13-A) is attached to the oligomeric backbone at Ring J or at R41.

[0244] In some embodiments, R41is optionally substituted C1-C6 alkyl or optionally substituted C3-C8cycloalkyl. 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.

[0245] In some embodiments, R41Ais optionally substituted C1-C10alkyl. In some embodiments, R41Ais optionally substituted C3-C8cycloalkyl.

[0246] In some embodiments, R41Bis optionally substituted C1-C10alkyl. In some embodiments, R41Bis optionally substituted C3-C8cycloalkyl.

[0247] In some embodiments, R42is optionally substituted C1-C10alkyl or optionally substituted C1-C10haloalkyl. In some embodiments, R42is optionally substituted C3-C8cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl. In some embodiments, R42is optionally substituted 3- to 8-membered heterocycloalkyl ring.

[0248] In some embodiments, R43is optionally substituted C1-C10alkyl. In some embodiments, R43is hydrogen.

[0249] In some embodiments, each R44is independently halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, C1-C10hydroxyalkyl, optionally substituted C2-C10alkenyl, optionally substituted C2-C10alkynyl, optionally substituted C3-C8-cycloalkyl, or optionally substituted 3 to 8-membered heterocycle. In some embodiments, each R44is independently halogen or C1- C10haloalkyl.

[0250] 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.

[0251] In some embodiments, p12 is 3 or 4. In some embodiments, p12 is 2. In some embodiments, p12 is 1.

[0252] In some embodiments, q3 is 1. In some embodiments, q3 is 0.

[0253] In some embodiments, Ring J is an optionally substituted 5-membered heteroaryl. In some embodiments, Ring J is absent.

[0254] In some embodiments, Formula (13-A) is connected to the oligomeric backbone at Ring J. In some embodiments, Formula (13-A) is connected to the oligomeric backbone at R41.

[0255] In some embodiments, the second terminus comprises the structure of Formula (13-B), or a pharmaceutically acceptable salt thereof:Formula (13-B).

[0256] In some embodiments, the second terminus comprises the structure of Formula (13-C1) or Formula (13-C2), or a pharmaceutically acceptable salt thereof:o ua - .

[0257] In some embodiments, the second terminus comprises the structure of Formula (13-D1) or Formula (13-D2), or a pharmaceutically acceptable salt thereof:o ua - .

[0258] In some embodiments, the second terminus comprises the structure of Formula (13-E), or a pharmaceutically acceptable salt thereof:Formula (13-E).

[0259] 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-C10alkyl, optionally substituted C1-C10haloalkyl, C1-C10hydroxyalkyl, optionally substituted C2-C10alkenyl, optionally substituted C2-C10alkynyl, optionally substituted C3-C8cycloalkyl, or optionally substituted 3 to 8- membered heterocycloalkyl; each R46is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10hydroxyalkyl, optionally substituted C2-C10alkenyl, optionally substituted C2-C10alkynyl, optionally substituted C3-C8cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; R47is optionally substituted C1-C10alkyl, -C(O)R47A, or -C(O)NR47AR47B, wherein each R47Aand R47Bis independently optionally substituted C1-C10alkyl or optionally substituted C3-C8cycloalkyl; q4 is 2-3; and q5is 0-2; wherein Formula (14-A) is attached to the oligomeric backbone at Ring K or at one of R45.

[0260] In some embodiments, A5is absent. In some embodiments, A5is -NH- or -O-. In some embodiments, A5is -NH-. In some embodiments, A5is -O-.

[0261] In some embodiments, L4is alkylene. In some embodiments, In some embodiments, L4is C1-C5 alkylene.

[0262] In some embodiments, L4is heteroalkylene. In some embodiments, L4is C1-C4heteroalkylene-. In some embodiments, L4is -O-CH2- or -O-CH2CH2-.

[0263] In some embodiments, each R45is independently halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, C1-C10hydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl. In some embodiments, each R45is independently optionally substituted C1-C10alkyl or optionally substituted C1-C10hydroxyalkyl. In some embodiments, each R45is independently C1-C10hydroxyalkyl. In some embodiments, each R45is independently -OCH3 or - OCH2CH3.

[0264] In some embodiments, each R46is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl. In some embodiments, each R46is independently hydrogen.

[0265] In some embodiments, R47is optionally substituted C1-C10alkyl. In some embodiments, R47is - C(O)R47A. In some embodiments, R47is -C(O)CH3 or -C(O)CH2CH3. In some embodiments, - C(O)NR47AR47B.

[0266] In some embodiments, R47Ais optionally substituted C1-C10alkyl. In some embodiments, R47Ais optionally substituted C3-C8cycloalkyl.

[0267] In some embodiments, R47Bis independently optionally substituted C1-C10alkyl. In some embodiments, R47Bis independently optionally substituted C3-C8cycloalkyl.

[0268] In some embodiments, Ring K is a 6-membered heterocycloalkyl.

[0269] In some embodiments, q4is 3. In some embodiments, q4is 2.

[0270] In some embodiments, q5 is 2. In some embodiments, q5 is 1. In some embodiments, q5 is 0.

[0271] In some embodiments, Formula (14-A) is connected to the oligomeric backbone at Ring K. In some embodiments, Formula (14-A) is connected to the oligomeric backbone at one of R45.

[0272] In some embodiments, the second terminus comprises the structure of Formula (14-B) or Formula (14-C), or a pharmaceutically acceptable salt thereof:

[0273] 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 aryl or heteroaryl; each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10alkyl, C1-C10haloalkyl, or C1-C10hydroxyalkyl; R49and R50are each independently hydrogen, optionally substituted C1-C10alkyl, optionally substituted C1- C10 haloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl; R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10hydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl; R52is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl; and p7 is 1-4.

[0274] In some embodiments, Ring L is 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.

[0275] 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-C10alkyl, C1-C10haloalkyl, or C1-C10hydroxyalkyl;R49and R50are each independently hydrogen, optionally substituted C1-C10alkyl, optionally substituted C1- C10haloalkyl, optionally substituted C2-C10alkenyl, or optionally substituted C2-C10alkynyl; R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10hydroxyalkyl, optionally substituted C2-C10alkenyl, or optionally substituted C2-C10alkynyl; and p7is 1-4.

[0276] In some embodiments, wherein the second terminus comprises the structure of Formula (15-C), or a pharmaceutically acceptable salt thereof:Formula (15-C), wherein: XAis CR48or N; each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10alkyl, C1-C10haloalkyl, or C1-C10hydroxyalkyl; R49and R50are each independently hydrogen, optionally substituted C1-C10alkyl, optionally substituted C1- C10haloalkyl, optionally substituted C2-C10alkenyl, or optionally substituted C2-C10alkynyl; R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10hydroxyalkyl, optionally substituted C2-C10alkenyl, or optionally substituted C2-C10 alkynyl; R53is hydrogen or optionally substituted C1-C10alkyl; and p7 is 1 or 2.

[0277] In some embodiments, XA is CR48. In some embodiments, XA is N.

[0278] In some embodiments, each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10alkyl, C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl.

[0279] In some embodiments, R49is hydrogen, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl. In some embodiments, R49is an optionally substituted C1-C10alkyl. In some embodiments, R49is methyl, ethyl, iso- propyl, or tert-butyl. In some embodiments, R49is hydrogen.

[0280] In some embodiments, R50is hydrogen, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl. In some embodiments, R50is an optionally substituted C1-C10alkyl or optionally substituted C2-C10 alkenyl. In some embodiments, R50is hydrogen.

[0281] In some embodiments, R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10hydroxyalkyl, optionally substituted C2-C10alkenyl, or optionally substituted C2-C10alkynyl.

[0282] In some embodiments, R52is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl. In some embodiments, R52is hydrogen.

[0283] In some embodiments, R53is hydrogen or optionally substituted C1-C10alkyl. In some embodiments, R53is an optionally substituted C1-C10alkyl. In some embodiments, R53is methyl, ethyl, iso- propyl, or tert-butyl. In some embodiments, R53is hydrogen.

[0284] In some embodiments, p7 is 4. In some embodiments, p7 is 3. In some embodiments, p7 is 2. In some embodiments, p7 is 1.

[0285] In some embodiments, the second terminus comprises the structure of Formula (15-D1), (15-D2), or (15-D3), or a pharmaceutically acceptable salt thereof:

[0286] 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-E2), or

[0287] In some embodiments, the second terminus comprises the structure of Formula (16-A), or a pharmaceutically acceptable salt thereof: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-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10heteroalkyl, or optionally substituted C1-C10hydroxyalkyl; R56is hydrogen, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl; R57is halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl; p9is 1-3; and q7is 0-2.

[0288] In some embodiments, B5is -O- or -S-. In some embodiments, B5is -O-. In some embodiments, B5is -S-.

[0289] In some embodiments, B6is N. In some embodiments, B6is CH.

[0290] In some embodiments, R54is an optionally substituted aryl. In some embodiments, R54is phenyl optionally substituted with one or more halogen, -CN, -NH2, -OH, C1-C10alkyl, C1-C10haloalkyl, or C1-C10hydroxyalkyl.

[0291] In some embodiments, each R55is independently halogen, -OH, -CN, -NH2, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl.

[0292] In some embodiments, R56is optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl. In some embodiments, R56is optionally substituted C1-C10alkyl.

[0293] In some embodiments, R57is halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C10alkyl.

[0294] In some embodiments, p9 is 3. In some embodiments, p9 is 2. In some embodiments, p9 is 1.

[0295] In some embodiments, q7 is 2. In some embodiments, q7 is 1. In some embodiments, q7 is 0.

[0296] In some embodiments, the second terminus comprises the structure of Formula (16-B), or a pharmaceutically acceptable salt thereof:Formula (16-B).

[0297] 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-C10alkyl, C1-C10haloalkyl, or C1-C10hydroxyalkyl; R59is hydrogen, -OH, -NH2, C1-C10alkyl, C1-C10haloalkyl, C1-C10hydroxyalkyl, or -NH(C1-C10alkyl); R60is hydrogen or optionally substituted C1-C10alkyl; and p10 is 1-4; wherein Formula (17-A) is attached to the oligomeric backbone at R59.

[0298] In some embodiments, Ring M is an aryl, optionally substituted with one or more halogen, CN, NH2, OH, C1-C10alkyl, C1-C10haloalkyl, or C1-C10hydroxyalkyl. 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-C10alkyl, C1-C10haloalkyl, or C1-C10hydroxyalkyl. In some embodiments, Ring M is an optionally substituted pyridine.

[0299] 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.

[0300] In some embodiments, A6is -O- or -NH-. In some embodiments, A6is -CH2-.

[0301] In some embodiments, each R58is independently -OH, -NH2, C1-C10alkyl, C1-C10haloalkyl, or C1- C10 hydroxyalkyl. In some embodiments, each R58is independently C1-C10alkyl, or C1-C10hydroxyalkyl. In some embodiments, each R58is independently C1-C10hydroxyalkyl.

[0302] In some embodiments, R59is -OH, -NH2, C1-C10hydroxyalkyl, or -NH(C1-C10alkyl). In some embodiments, R59is hydrogen.

[0303] In some embodiments, R60is optionally substituted C1-C10alkyl. In some embodiments, R60is methyl. In some embodiments, R60is hydrogen.

[0304] In some embodiments, p10is 3 or 4. In some embodiments, p10is 2. In some embodiments, p10is 1.

[0305] In some embodiments, the second terminus comprises the structure of Formula (17-B) or Formula (17-C), or a pharmaceutically acceptable salt thereof:

[0306] 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-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10heteroalkyl, or optionally substituted C1-C10hydroxyalkyl; R68and R69are each independently an optionally substituted 5-membered heteroaryl; and x5and x6are each independently 0-4.

[0307] In some embodiments, B7is N. In some embodiments, B7is CH.

[0308] In some embodiments, R67is halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10alkyl, C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl. In some embodiments, R67is halogen, -OH, -CN, -NO2, -NH2, or -CH3.

[0309] 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.

[0310] 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.

[0311] In some embodiments, x5is 2 or 3. In some embodiments, x5is 1. In some embodiments, x5is 0.

[0312] In some embodiments, x6is 3. In some embodiments, x6is 2. In some embodiments, x6is 1. In some embodiments, x6is 0.

[0313] In some embodiments, the second terminus comprise Formula (18-B), or a pharmaceutically acceptable salt thereof:Formula (18-B).

[0314] In some embodiments, the second terminus comprises Formula (19-A), or a pharmaceutically acceptable salt thereof:

[0315] 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 C1-C6 alkyl; each R62is independently halogen, -CN, -NO2, -OH, -OR62A, -NR62AR62B, -C(O)R62A, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10heteroalkyl, or optionally substituted C1-C10hydroxyalkyl; wherein each R62Aand R62Bis independently hydrogen or C1-C10alkyl; each R63is independently -OR63A, -NR63AR63B, optionally substituted C1-C10alkyl, optionally substituted C1- C10 haloalkyl, optionally substituted C1-C10heteroalkyl, or optionally substituted C1-C10hydroxyalkyl; wherein each R63Aand R63Bis independently hydrogen, C1-C10alkyl, C1-C10alkylamino, C1-C10haloalkyl, or C1-C10hydroxyalkyl; p13 is 1-3; and p14is 1-3; wherein Formula (20-A) is attached to the oligomeric backbone at one of R62or one of R63.

[0316] In some embodiments, A7is -NHC(O)-. In some embodiments, A7is -NHS(O)2-.

[0317] In some embodiments, A8is -O-. In some embodiments, A8is -NH-.

[0318] In some embodiments, each R61is independently C1-C6alkyl. In some embodiments, each R61is methyl. In some embodiments, each R61is hydrogen.

[0319] In some embodiments, each R62is independently optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10heteroalkyl, or optionally substituted C1-C10hydroxyalkyl. In some embodiments, each R62is independently optionally substituted C1-C10alkyl. In some embodiments, each R62is independently optionally substituted C1-C10haloalkyl. In some embodiments, each R62is independently optionally substituted C1-C10heteroalkyl. In some embodiments, each R62is independently optionally substituted C1-C10hydroxyalkyl.

[0320] In some embodiments, each R63is independently optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10heteroalkyl, or optionally substituted C1-C10hydroxyalkyl. In some embodiments, each R63is independently optionally substituted C1-C10alkyl. In some embodiments, each R63is independently optionally substituted C1-C10haloalkyl. In some embodiments, eachR63is independently optionally substituted C1-C10heteroalkyl. In some embodiments, each R63is independently optionally substituted C1-C10hydroxyalkyl.

[0321] In some embodiments, p13 is 1. In some embodiments, p13 is 2. In some embodiments, p13 is 3.

[0322] In some embodiments, p14 is 1. In some embodiments, p14 is 2. In some embodiments, p14 is 3.

[0323] In some embodiments, Formula (20-A) is attached to the oligomeric backbone at one of R62. In some embodiments, Formula (20-A) is attached to the oligomeric backbone at one of R63.

[0324] In some embodiments, the second terminus comprises the structure of Formula (20-B) or Formula (20-C), or a pharmaceutically acceptable salt thereof:

[0325] In some embodiments, the second terminus comprises the structure of Formula (21-A), or a pharmaceutically acceptable salt thereof:Formula (21-A), wherein: Ring Q is C3-C8cycloalkyl or 4 to 8-membered heterocycloalkyl; A9is -O-, -NH-, or -NHC(O)-; each R64is independently hydrogen or C1-C6 alkyl;each R65is independently halogen, -CN, -NO2, -OH, -OR65A, -NR65AR65B, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10heteroalkyl, or optionally substituted C1-C10hydroxyalkyl; wherein each R65Aand R65Bis independently hydrogen or C1-C10alkyl; each R66is independently halogen, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10heteroalkyl, or optionally substituted C1-C10hydroxyalkyl; p15is 0-3; and p16is 1-3; wherein Formula (21-A) is attached to the oligomeric backbone at one of R65or one of R66.

[0326] In some embodiments, A9is -O-. In some embodiments, A9is -NH-. In some embodiments, A9is - NHC(O)-.

[0327] In some embodiments, Ring Q is C3-C8cycloalkyl. In some embodiments, Ring Q is 4 to 8- membered heterocycloalkyl.

[0328] In some embodiments, each R64is independently C1-C6 alkyl. In some embodiments, each R64is methyl. In some embodiments, each R64is hydrogen.

[0329] In some embodiments, each R65is independently optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10heteroalkyl, or optionally substituted C1-C10hydroxyalkyl. In some embodiments, each R65is independently optionally substituted C1-C10alkyl. In some embodiments, each R65is independently optionally substituted C1-C10haloalkyl. In some embodiments, each R65is independently optionally substituted C1-C10heteroalkyl. In some embodiments, each R65is independently optionally substituted C1-C10hydroxyalkyl.

[0330] In some embodiments, each R66is independently optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, optionally substituted C1-C10heteroalkyl, or optionally substituted C1-C10hydroxyalkyl. In some embodiments, each R66is independently optionally substituted C1-C10alkyl. In some embodiments, each R66is independently optionally substituted C1-C10haloalkyl. In some embodiments, each R66is independently optionally substituted C1-C10heteroalkyl. In some embodiments, each R66is independently optionally substituted C1-C10hydroxyalkyl.

[0331] In some embodiments, p15is 0. In some embodiments, p15is 1. In some embodiments, p15is 2. In some embodiments, p15is 3.

[0332] In some embodiments, p16 is 1. In some embodiments, p16 is 2. In some embodiments, p16 is 3.

[0333] In some embodiments, Formula (21-A) is attached to the oligomeric backbone at one of R65. In some embodiments, Formula (21-A) is attached to the oligomeric backbone at one of R66.

[0334] In some embodiments, the second terminus comprises the structure of Formula (21-B), or a pharmaceutically acceptable salt thereof:Formula (21-B).

[0335] In some embodiments, the second terminus comprises the structure of Formula (22-A), or a pharmaceutically acceptable salt thereof:Formula (22-A) wherein: Ring W is optionally substituted phenyl or optionally substituted 5 or 6-membered heteroaryl; A12is a bond, -NRA12-, -NH-C1-C10alkylene, -C1-C12 alkyl, –NRA12C(O)-, or -C(O)NRA12-; A13is C2-C4 alkylene linker; R104is selected from an optionally substituted C6-C10 aryl, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- to 10 membered heteroaryl, or optionally substituted 5- to 10-membered heterocycloalkyl, each optionally substituted with one, two or three halogen or C1-C6 alkyl; each R105is independently selected from OH, -NO2, halogen, -NH2, -CN, -CF3, or C1-6 alkyl; w1 is 0, 1, 2, or 3; and each RA12is independently hydrogen or C1-C6 alkyl.

[0336] In some embodiments, the second terminus comprises the structure of Formula (22-B), or a pharmaceutically acceptable salt thereof:Formula (22-B).

[0337] In some embodiments, the second terminus comprises the structure of Formula (23-A), or a pharmaceutically acceptable salt thereof:Formula (23-A), wherein: R101is hydrogen, -NH2, or -NHSO2CH3; R102and R103are each independently halogen, -CN, -NO2, -OH, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl; R70is -S(O)R70Aor -S(O)2R70A, wherein R70Ais hydrogen or C1-C10alkyl; and R71is hydrogen or C1-C10alkyl; wherein Formula (23-A) is attached to the oligomeric backbone at R101or R71.

[0338] In some embodiments, R101is hydrogen. In some embodiments, R101is -NH2, or -NHSO2CH3.

[0339] In some embodiments, R102and R103are each independently optionally substituted C1-C10alkyl. In some embodiments, R102and R103are each methyl.

[0340] In some embodiments, R70is -S(O)2R70A. In some embodiments, R70is -S(O)2CH3.

[0341] In some embodiments, Formula (22-A) is attached to the oligomeric backbone at R67. In some embodiments, Formula (22-A) is attached to the oligomeric backbone at R71.

[0342] In some embodiments, the second terminus comprises the structure of Formula (23-B) or Formula (23-C), or a pharmaceutically acceptable salt thereof:

[0343] In some embodiments, the second terminus comprises the structure of Formula (24-A), or a pharmaceutically acceptable salt thereof:Formula (24-A) wherein:B9is -CH-CRB9-, -N-, or NRB10; B10is -N- or NRB10, wherein RB9is hydrogen or halogen; and RB10is hydrogen; R72is halogen, -CN, -NO2, -OH, optionally substituted C1-C10alkyl, optionally substituted C1-C10haloalkyl, or optionally substituted C1-C10hydroxyalkyl; and R73is hydrogen; wherein Formula (24-A) is attached to the oligomeric backbone at RB9, RB10, or R73.

[0344] In some embodiments, B9is -CH-CRB9- and B10is -N-. In some embodiments, B9is -N- and B10is NRB10. In some embodiments, B9is NRB10and B10is -N-.

[0345] In some embodiments, R72is an optionally substituted C1-C10alkyl. In some embodiments, R72is methyl.

[0346] In some embodiments, Formula (24-A) is attached to the oligomeric backbone at RB9or RB10. In some embodiments, Formula (24-A) is attached to the oligomeric backbone at R73.

[0347] In some embodiments, the second terminus comprises the structure of Formula (24-B) or Formula (24-C), or a pharmaceutically acceptable salt thereof:

[0348] In some embodiments, the second terminus comprises the structure of Formula (24-D) or Formula (24-E), 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:wherein: R74is -CH2-(optionally substituted 5-membered heteroaryl); R75is -O-(C1-C10alkyl)-R75A; wherein R75Ais -C(O)O-alkyl; R76is -OR76A, wherein R76Ais hydrogen or alkyl; R77is hydrogen or halogen; and R77Ais hydrogen or C1-C10alkyl; wherein Formula (25-A) is attached to the oligomeric backbone at R75Aor R76A.

[0350] In some embodiments, R75is -O-(C1-C10alkyl)C(O)O-alkyl. In some embodiments, R75is -O-(C1- C4alkyl)-C(O)O-(C1-C4alkyl).

[0351] In some embodiments, R76is -OH. In some embodiments, R76is -OCH3. In some embodiments, R76is -O-CH2CH3.

[0352] In some embodiments, R77is halogen. In some embodiments, R77is hydrogen.

[0353] In some embodiments, R77Ais hydrogen or methyl. In some embodiments, R77Ais methyl. In some embodiments, R77Ais hydrogen.

[0354] In some embodiments, Formula (25-A) is attached to the oligomeric backbone at R75A. In some embodiments, Formula (25-A) is attached to the oligomeric backbone at R76A.

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

[0356] In some embodiments, the second terminus comprises the structure of Formula (26-A), or a pharmaceutically acceptable salt thereof:wherein: B12is -NR80A- or -C(R80B)2-; R78is halogen, -CN, -NO2, -OH, or optionally substituted C1-C10alkyl; R79Aand R79Bare each independently halogen, -CN, -NO2, -NH2, -N(CH3)2, or optionally substituted C1-C10alkyl; 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-C10alkyl, or C1-C10alkoxy; R80Ais C1-C6 alkyl; each R80Bis independently hydrogen or C1-C6 alkyl; and r7 is 1, 2, or 3; wherein Formula (26-A) is attached to the oligomeric backbone at one of R80.

[0357] In some embodiments, B12is -NR80A-. In some embodiments, B12is -C(R80B)2-.

[0358] 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-C10alkyl.

[0359] In some embodiments, R79Aand R79Bare each independently halogen, -NH2, or -N(CH3)2.

[0360] In some embodiments, R79Aand R79Btogether with the atoms to which they are attached form a 6- membered aryl.

[0361] In some embodiments, each R80is independently hydrogen. In some embodiments, each R80is independently C1-C10alkyl. In some embodiments, each R80is independently C1-C10alkoxy. In some embodiments, each R80is independently -OCH3.

[0362] In some embodiments, the second terminus comprises the structure of Formula (26-B) or Formula (26-C), or a pharmaceutically acceptable salt thereof:o u a - .

[0363] In some embodiments, the second terminus comprises the structure of Formula (27-A), or a pharmaceutically acceptable salt thereof:Formula (27-A), wherein: B11is -O- or -NR82-; A10is -NR84- or -NR84CH2-; R81Aand R81Bare each independently C1-C10alkyl; or R81Aand R81Bcombine together to form oxo (=O); R82is hydrogen or C1-C3 alkyl; each R83is independently halogen, -CN, -NO2, -OH, -OR83A, or optionally substituted C1-C10alkyl; wherein R83Ais C1-C10alkyl;R84is hydrogen, C1-C3alkyl, C3-C6cycloalkyl, or phenyl; R85is hydrogen or C1-C10alkyl; and r4is 1, 2, or 3; wherein Formula (27-A) is attached to the oligomeric backbone at one of R83.

[0364] In some embodiments, B11is -O-. In some embodiments, B11is -NR82-. In some embodiments, B11is NCH3.

[0365] In some embodiments, A10is -NR84-. In some embodiments, A10is -NR84CH2-.

[0366] In some embodiments, R81Aand R81Bare each methyl. In some embodiments, R81Aand R81Bcombine together to form oxo (=O).

[0367] In some embodiments, each R83is independently -CN, -OH, -OR83A, or optionally substituted C1- C10 alkyl. In some embodiments, each R83is independently -OH or -OR83A.

[0368] In some embodiments, R84is C3-C6cycloalkyl or phenyl. In some embodiments, R84is phenyl.

[0369] In some embodiments, R85is C1-C10alkyl. In some embodiments, R85is methyl. In some embodiments, R85is hydrogen.

[0370] In some embodiments, the second terminus comprises the structure of Formula (27-B) or Formula (27-C), or a pharmaceutically acceptable salt thereof:Formula (27-C).

[0371] In some embodiments, the second terminus comprises the structure of Formula (27-D) or Formula (27-E), or a pharmaceutically acceptable salt thereof:Formula (27-E).

[0372] In some embodiments, the second terminus comprises the structure of Formula (28-A), or a pharmaceutically acceptable salt thereof:Formula (28-A).

[0373] In some embodiments, the second terminus comprises the structure of Formula (29-A), or a pharmaceutically acceptable salt thereof:Formula (29-A), wherein: A11is C1-C6 alkylene; B13is N or CR100; R97is C1-C6alkyl; R98is halogen; R99is hydrogen, halogen, or optionally substituted C1-C10alkyl; and R100is -OR100Aor optionally substituted C1-C10alkyl; wherein R100Ais hydrogen or C1-C10alkyl; or R99and R100together with the atoms to which they are attached form a heterocycloalkyl.

[0374] In some embodiments, A11is C1-C4alkylene. In some embodiments, A11is -CH2CH2-.

[0375] In some embodiments, B13is N. In some embodiments, B13is CR100.

[0376] In some embodiments, R97is methyl.

[0377] In some embodiments, R98is -Cl.

[0378] In some embodiments, R100is -OR100A. In some embodiments, R100is an optionally substituted C1- C10 alkyl.

[0379] In some embodiments, R99and R100together with the atoms to which they are attached from a heterocycloalkyl.

[0380] In some embodiments, the second terminus comprises the structure of Formula (29-B), or a pharmaceutically acceptable salt thereof:Formula (29-B).

[0381] In some embodiments, the second terminus comprises the structure of Formula (29-C), or a pharmaceutically acceptable salt thereof:Formula (29-C).

[0382] In some embodiments, the second terminus comprises the structure of Formula (30-A), or a pharmaceutically acceptable salt thereof:Formula (30-A).

[0383] In some embodiments, the second terminus comprises the structure of Formula (31-A), or a pharmaceutically acceptable salt thereof:

[0384] In some embodiments, the second terminus comprises the structure of Formula (32-A), or a pharmaceutically acceptable salt thereof:Formula (32-A), wherein: R94is halogen; R94Ais hydrogen or C1-C3alkyl; and R95is hydrogen, halogen, -OH, -OCH3, or optionally substituted C1-C10alkyl.

[0385] In some embodiments, R94is -Cl.

[0386] In some embodiments, R94Ais C1-C3 alkyl. In some embodiments, R94Ais methyl. In some embodiments, R94Ais hydrogen.

[0387] In some embodiments, R95is halogen, -OH, -OCH3, or optionally substituted C1-C10alkyl. In some embodiments, R95is hydrogen.

[0388] In some embodiments, the second terminus comprises the structure of Formula (32-B) or Formula (32-C), or a pharmaceutically acceptable salt thereof:Formula (32-C).

[0389] In some embodiments, the second terminus comprises the structure of Formula (33-A), or a pharmaceutically acceptable salt thereof:

[0390] In some embodiments, the second terminus comprises the structure of Formula (34-A), or a pharmaceutically acceptable salt thereof:Formula (34-A).

[0391] In some embodiments, the second terminus comprises the structure of Formula (35-A), or a pharmaceutically acceptable salt thereof:Formula (35-A).

[0392] In some embodiments, the second terminus comprises the structure of Formula (36-A), or a pharmaceutically acceptable salt thereof:Formula (36-A).

[0393] In some embodiments, the second terminus comprises the structure of Formula (37-A) or Formula (37-B), or a pharmaceutically acceptable salt thereof:-B).

[0394] In some embodiments, the second terminus comprises the structure of Formula (38-A), or a pharmaceutically acceptable salt thereof:Formula (38-A), wherein: Ring T is a C5-C6 cycloalkyl, 5 to 6-membered heterocycloalkyl, or phenyl; each R86is independently halogen, -CN, -NO2, -OH, -OR86A, -N(R86B)2, or optionally substituted C1-C10alkyl; wherein each R86Ais independently C1-C10alkyl; each R86Bis independently hydrogen or C1-C10alkyl; R87is C5-C6cycloalkyl or phenyl; each R88is independently halogen, -CN, -NO2, -OH, -OR88A, -NR88BR88B, or optionally substituted C1-C10alkyl; wherein each R88Ais independently C1-C10alkyl; each R88Bis independently hydrogen or C1-C10alkyl; R89Aand R89Bare each independently hydrogen or C1-C10alkyl; or R89Aand R89Btogether with the atom to which they are attached form a 5 to 6-membered heterocycloalkyl; R96is hydrogen or -CH3; and r5and r6are each independently 0, 1, 2, or 3.

[0395] In some embodiments, Ring T is a C5-C6cycloalkyl. In some embodiments, Ring T is a 5 to 6- membered heterocycloalkyl. In some embodiments, Ring T is phenyl.

[0396] 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.

[0397] In some embodiments, R87is C5-C6 cycloalkyl. In some embodiments, R87is phenyl.

[0398] In some embodiments, R89Aand R89Bare each independently C1-C10alkyl. In some embodiments, R89Aand R89Bare each hydrogen.

[0399] In some embodiments, R89Aand R89Btogether with the atom to which they are attached form a 5 to 6-membered heterocycloalkyl.

[0400] In some embodiments, R96is -CH3. In some embodiments, R96is hydrogen.

[0401] In some embodiments, r5 and r6 are each independently 0, 1, or 2.

[0402] In some embodiments, the second terminus comprises the structure of Formula (38-B) or Formula (38-C), or a pharmaceutically acceptable salt thereof:.

[0403] In some embodiments, the second terminus is selected from the group consisting of:,,

[0404] In some embodiments, the second terminus is selected from a moiety described in Table 1B, or a pharmaceutically acceptable salt thereof. Table 1B. Exemplary binding moieties.Oligomeric Backbone – Linker Moiety

[0405] 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.

[0406] 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.

[0407] In some embodiments, the oligomeric backbone comprises between 5 and 50 chain atoms.

[0408] 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 -((CR1bR1b)x-O)y-, - ((CR1bR1b)x-NR1a)y-, -((CR1bR1b)x-CH=CH-(CR1bR1b)x-O)y-, optionally substituted C1-C12 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C6-C10 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)NR1a-, - NR1aC(O)-, -C(O)-, -NR1a-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR1a-, -NR1aS(O)2-, and -P(O)OH-, and any combinations thereof; wherein each x is independently 2-4; each y is independently 1-10; each R1ais independently a hydrogen or optionally substituted C1-C6alkyl; and each R1bis independently selected from hydrogen, 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.

[0409] 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-C12alkyl, -((CH2)x-O)y-, -((CH2)x-NH)y-, -O-, -C(O)NH-, -NH-, and any combinations thereof.

[0410] 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, -(CR1aOH)h-, optionally substituted C6-C10 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 –(CR1bR1b-CR1bR1b-O)n-CR1bR1b-; (i) (modified PEG)n has the structure of replacing at least one -(CR1bR1b-CR1bR1b-O)- in (PEG)n with -(CH2-CR1b=CR1b-CH2-O)- or -(CR1bR1b-CR1bR1b-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)-, -NR1a-, -C(O)NR1a-, -NR1aC(O)-, -CONR1a-C1-C4alkyl-, -NR1aC(O)-C1-C4alkyl-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR1a-, -NR1aS(O)2- and -P(O)OH-; (l) each R1ais independently hydrogen or an optionally substituted C1-C6alkyl; and (m) each R1bis independently selected from hydrogen, 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.

[0411] 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.

[0412] In some embodiments, n is 3-9. In some embodiments, n is 4-8. In some embodiments, n is 5 or 6.

[0413] In some embodiments, T1, T2, T3, and T4, and T5are each independently selected from C1-C12alkyl, substituted C1-C12alkyl, (EA)w, (EDA)m, (PEG)n, (modified PEG)n, (AA)p, -(CR1bOH)h-, phenyl, substituted phenyl, piperidin-4-amino (P4A), para-amino-benzyloxycarbonyl (PABC), meta-amino- benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), meta-amino-benzyloxy (MABO), para- aminobenzyl, 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)p and (AA)p-PABC-(AA)p. In some embodiments, piperidin-4-amino (P4A) is, wherein R1a is hydrogen or C1-C6 alkyl.

[0414] In some embodiments, T1, T2, T3, T4and T5are each independently selected from (C1-C12)alkyl, substituted C1-C12 alkyl, (EA)w, (EDA)m, (PEG)n, (modified PEG)n, (AA)p,-(CR2aOH)h-, optionally substituted C6-C10 arylene, 4 to 10-membered heterocycloalkene, optionally substituted 5 to 10-membered heteroarylene. In some embodiments, EA has the following structure:.

[0415] In some embodiments, x is 2-3 and q is 1-3 for EA and EDA. In some embodiments, R1ais hydrogen or C1-C6alkyl.

[0416] In some embodiments, T4or T5is an optionally substituted C6-C10 arylene.

[0417] In some embodiments, T4or T5is phenylene or substituted phenylene. In some embodiments, T4or T5is phenylene or phenylene substituted with 1-3 substituents selected from C1-C6 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 heterocyclene. In some embodiments, T4or T5is heteroarylene or heterocyclene optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, OH or amine.

[0418] In some embodiments, T1, T2, T3, T4and T5and V1, V2, V3, V4and V5are selected from the following Table 2. Table 2. Exemplary linker segments.

[0419] In some embodiments, the oligomeric backbone comprises N(R1a)(CH2)xN(R1a)(CH2)xN–, wherein each R1ais independently selected from hydrogen or optionally substituted C1-C6 alkyl; and each x is independently an integer in the range of 1-6.

[0420] In some embodiments, the oligomeric backbone comprises -(CH2-C(O)N(R1a)-(CH2)q-N(R1a)- (CH2)q-N(R1a)C(O)-(CH2)x-C(O)N(R1a)-A-, -(CH2)x-C(O)N(R1a)-(CH2CH2O)y(CH2)x-C(O)N(R1a)-A-, or - C(O)N(R1a)-(CH2)q-N(R1a)-(CH2)q-N(R1a)C(O)-(CH2)x-A-; wherein each q is independently an integer from 2 to 10; each x is independently an integer from 1-6; and each A is independently selected from a bond, an optionally substituted C1-C12 alkyl, an optionally substituted C6-C10 arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5 to 10-membered heteroarylene, and optionally substituted 4 to 10- membered heterocycloalkylene.

[00421] In some embodiments, the oligomeric backbone comprises –(CH2CH2-O)x7- or –(CH2CH2-O)x8-A- (CH2CH2-O)x9-, wherein A is an optionally substituted 4 to 10-membered heterocycloalkylene or spirocyclene, and each x7, x8, and x9 is independently an integer from 1-15.

[0422] In some embodiments, the oligomeric backbone comprises -NR1a-(CH2CH2O)y(CH2)x- or -NR1a- (CH2)q-C(O)NR1a(CH2CH2O)y(CH2)x-, wherein q is 2-10, x is 1-4, y is 1-50, and each R4ais independently hydrogen or an optionally substituted C1-C6alkyl. In some embodiments, the oligomeric backbone comprises -NR1a-(CH2CH2O)y(CH2)x,. In some embodiments, the oligomeric backbone comprises -NR1a- (CH2)q-C(O)NR1a(CH2CH2O)y(CH2)x-.

[0423] 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-.

[0424] 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.

[0425] In some embodiments, A is selected from, ,, . In some embodiments, A is

[0426] In some embodiments, A comprises a moiety having the structure, or a pharmaceutically acceptable salt thereof: wherein:A2is absent or -C(O)-; and R27is optionally substituted C1-C50alkyl or optionally substituted C1-C50heteroalkyl.

[0427] In some embodiments, A2is -C(O)-. In some embodiments, A2is absent.

[0428] 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-C10alkyl. 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-C10heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG) having 1 to 20 PEG units.

[0429] In some embodiments, the oligomeric backbone comprises a moiety having a structure of Formula (C-1), or a pharmaceutically acceptable salt thereof:Formula (C-1), wherein: Ring P is absent, arylene, or heterocycloalkylene; L5is absent, optionally substituted C2-C6alkylene, or optionally substituted C2-C6alkynylene; B1and B2are each independently -CH- or -N-; s1and s2are each independently 0-3; and ** denotes attachment to the second terminus.

[0430] In some embodiments, Ring P is absent. In some embodiments, Ring P is a 3 to 7-membered heterocycloalkylene.

[0431] In some embodiments, B1is N. In some embodiments, B1is CH.

[0432] 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; and B2, B3and B4are each independently -N- or -CH-.

[0433] In some embodiments, each of B3and B4is independently -N- or -CH-; and B2is -N-.

[0434] In some embodiments, B2is N. In some embodiments, B2is CH.

[0435] In some embodiments, L5is absent. In some embodiments, L5is C2-C4 alkylene or C2-C4 alkynylene. In some embodiments, L5is C2-C4 alkynylene.

[0436] In some embodiments, L5is -(CR1GR1G)x10-(alkylene)2-(CR1GR1G)y11-; wherein x10 and y11 are each independently 0 or 1; and each R1Gis independently hydrogen or C1-C3 alkyl.

[0437] In some embodiments, L5is -CH2-, -CH2CH2-,, . In some embodiments, L5is -CH2- or -CH2CH2-. In some embodiments, L5is . In some embodiments, L5is .

[0438] In some embodiments, the oligomeric backbone comprises a moiety having the structure of Formula (C-3), or a pharmaceutically acceptable salt thereof:Formula (C-3), wherein: s1and s2are each independently 0-3; r1is an integer from 1-3;R26is -C(O)-optionally substituted C1-C20alkylene, -C(O)-optionally substituted C2-C20heteroalkylene, optionally substituted C1-C20alkylene, or optionally substituted C2-C20heteroalkylene; each R1Gis independently hydrogen or C1-C3alkyl; and ** denotes attachment to the second terminus.

[0439] In some embodiments, R26is -C(O)(optionally substituted C1-C20 heteroalkylene). In some embodiments, R26is an optionally substituted C1-C20 heteroalkylene. In some embodiments, R26is polyethylene glycol having 1 to 20 PEG units.

[0440] 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.

[0441] In some embodiments, s1 and s2 are each independently is 0, 1, or 2. In some embodiments, s1 and s2 are each independently 0. In some embodiments, s1 and s2 are each independently 1.

[0442] In some embodiments, r1 is 1 or 2. In some embodiments, r1 is 1. In some embodiments, r1 is 2.

[0443] In some embodiments, the oligomeric backbone comprises:

[0444] 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)-, -NR1a-, -C(O)NR1a-, -NR1aC(O)-, -C(O)NR1a-C1- C4alkyl-, -NR1aC(O)-C1-C4alkyl-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR1a-, -NR1S(O)2-, - P(O)OH-, -((CH2)x-O)-, -((CH2)y-NR1a)-, optionally substituted C1-C12 alkylene, optionally substituted C2- C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C6-C10 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 R1ais independently a hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, the oligomeric backbone is joined with the first terminus with a group selected from -O-, -C(O)-, -NR1a-, C1-C12alkyl, -C(O)NR1a-, and -NR1aC(O)-. In some embodiments, the oligomeric backbone is joined with the first terminus with a group selected from -O- or -NR1a-.

[0445] In some embodiments, the oligomeric backbone is joined with the second terminus with a group selected from -C(O)-, -NR1a-, -C(O)NR1a-, -NR1aC(O)-, -((CH2)x-O)-, -((CH2)y-NR1a)-, -O-, optionally substituted C1-C12 alkyl, optionally substituted C6-C10 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 R1ais independently a hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, the oligomeric backbone is joined with the second terminus with a group selected from -O-, -C(O)-, -NR1a-, C1-C12 alkyl, - C(O)NR1a-, and -NR1aC(O)-. In some embodiments, the oligomeric backbone is joined with the second terminus with a group selected from -O- or -NR1a-.

[0446] In some embodiments, non-limiting examples of the transcription modulator compounds described herein are presented below in Table 3A, Table 3B, and Table 3C..sdnuop mo C.A.3 p.elmo1-2-3- b o N A A A a C T. erusolcsid e htfosdnuop mo C.4 B.7- 5 7-3p.o1- A Aelm b o N B a C T73 8 93- 3 3- 3 3 B B - B. erusolcsid e htfosdnuop mo C.C.3 p.elmo1-2-3-4- b o N C C C C a C T

[0447] In an aspect, provided herein are methods of increasing expression of a gene in an individual that is heterozygous for a mutation in a gene where the mutant allele of the gene does not produce sufficient gene product and the individual has a disease (i.e., the individual has a mutant copy of the gene and a wildtype copy of the gene). In various embodiments of methods herein, the individual has a haploinsufficient gene and in some embodiments, increasing expression of the haploinsufficient gene treats the disease. In some embodiments, the method comprises increasing expression of the wildtype copy of the gene to compensate for lack of expression from the mutant copy of the gene. In some embodiments, the method comprises increasing expression of a haploinsufficient gene. In some embodiments, the method comprises a 20%, 50%, 80%, 90%, 95%, or 99% increase in expression of a haploinsufficient gene. In some embodiments, the method comprises a 20% increase in expression of a haploinsufficient gene. In some embodiments, the method comprises a 50% increase in expression of a haploinsufficient gene. In some embodiments, the method comprises an 80% increase in expression of a haploinsufficient gene. In some embodiments, the method comprises a 90% increase in expression of a haploinsufficient gene. In some embodiments, the method comprises a 95% increase in expression of a haploinsufficient gene. In some embodiments, the method comprises a 99% increase in expression of a haploinsufficient gene.

[0448] In some embodiments, the method restores expression of a haploinsufficient gene. In some embodiments, the method restores expression of a haploinsufficient gene to 80%, 90%, 95%, 99%, or 100% of the wild type expression levels. In some embodiments, the method restores expression of a haploinsufficient gene to 80% of wild type expression levels. In some embodiments, the method restores expression of a haploinsufficient gene to 90% of wild type expression levels. In some embodiments, the method restores expression of a haploinsufficient gene to 95% of wild type expression levels. In some embodiments, the method restores expression of a haploinsufficient gene to 99% of wild type expression levels. In some embodiments, the method restores expression of a haploinsufficient gene to 100% of wild type expression levels.

[0449] In some embodiments, the haploinsufficient gene is TCF4. In some embodiments, the haploinsufficient gene is COL3A1. In some embodiments the haploinsufficient gene is SLC2A1. In some embodiments, the haploinsufficient gene is TNXB. In some embodiments, the haploinsufficient gene is GLUT1. In some embodiments, the haploinsufficient gene is ELN, RHO, p27Kip1, p53, DMP1, NF1, PTEN, AML1, EGR1, TGFβR1 / 2, SMAD4, RUNX2, GRN, TBX5, FBN1, SHANK3, GLI3, SCN1A, FOXP1, or NR4A2.

[0450] In some embodiments, the haploinsufficiency disorder or disease is Pitt-Hopkins syndrome (PHTS). In some embodiments, the method reduces one or more symptoms of PTHS. In some embodiments, the one or more symptoms is selected from intellectual disability, developmental delay, breathing problems, recurrent seizures, or facial features

[0451] In some embodiments, the haploinsufficiency disorder or disease is Ehlers-Danlos Syndrome. In some embodiments, the method reduces one or more symptoms of Ehlers-Danlos Syndrome.

[0452] In some embodiments, the haploinsufficiency disorder or disease is GLUT1 Deficiency Syndrome (DiVivo syndrome). In some embodiments, the method reduces one or more symptoms of GLUT1 Deficiency Syndrome (DiVivo syndrome).

[0453] In some embodiments, the haploinsufficiency disorder or disease is Williams syndrome, autosomal dominant retinitis pigmentosa, cancer, 1q21.1 deletion syndrome, 5q syndrome, 22q11.2 deletion syndrome, cleidocranial dysostosis, frontotemporal dementia, Holt-Oram syndrome, Marfan syndrome, Phelan-McDermid syndrome, Polydactyly, Dravet Syndrome, FOXP1 syndrome, or NR4A2-related syndrome. In some embodiments, the haploinsufficiency disorder or disease is Williams syndrome. In some embodiments, the haploinsufficiency disorder or disease is autosomal dominant retinitis pigmentosa. In some embodiments, the haploinsufficiency disorder or disease is 1q21.1 deletion syndrome. In some embodiments, the haploinsufficiency disorder or disease is 5q syndrome. In some embodiments, the haploinsufficiency disorder or disease is 22q11.2 deletion syndrome. In some embodiments, the haploinsufficiency disorder or disease is cleidocranial dysostosis. In some embodiments, the haploinsufficiency disorder or disease is frontotemporal dementia. In some embodiments, the haploinsufficiency disorder or disease is Holt-Oram syndrome. In some embodiments, the haploinsufficiency disorder or disease is Marfan syndrome. In some embodiments, the haploinsufficiency disorder or disease is Phelan-McDermid syndrome. In some embodiments, the haploinsufficiency disorder or disease is Polydactyly. In some embodiments, the haploinsufficiency disorder or disease is Dravet syndrome. In some embodiments, the haploinsufficiency disorder or disease is FOXP1 syndrome. In some embodiments, the haploinsufficiency disorder or disease is NR4A2-related syndrome.

[0454] In some embodiments, the method reduces one or more symptoms of Williams syndrome, autosomal dominant retinitis pigmentosa, cancer, 1q21.1 deletion syndrome, 5q syndrome, 22q11.2 deletion syndrome, cleidocranial dysostosis, frontotemporal dementia, Holt-Oram syndrome, Marfan syndrome, Phelan-McDermid syndrome, Polydactyly, Dravet syndrome, FOXP1 syndrome, or NR4A2-related syndrome. 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 acceptable excipient. 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: TheScience 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 & Wilkins1999), herein incorporated by reference for such disclosure.

[0457] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling 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 optimal dose, 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] As used herein, “haploinsufficiency” or “haploinsufficient” refers to a situation in an individual having a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele (e.g., a loss of function allele) which is insufficient to produce the wild-type phenotype.

[0463] When ranges of values are disclosed, and the notation “from n1 … to n2” or “between n1 … and n2” is used, where n1 and n2 are 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 µM (micromolar),” which is intended to include 1 µM, 3 µM, and everything in between to any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

[0464] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0465] “oxo” refers to =O.

[0466] “Carboxyl” refers to -COOH.

[0467] “Cyano” refers to -CN.

[0468] “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-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-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 “C1-C6 alkyl” or “C1-6alkyl”, 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 C1-C10alkyl. In some embodiments, the alkyl is a C1-C6alkyl. In some embodiments, the alkyl is a C1-C5alkyl. In some embodiments, the alkyl is a C1-C4alkyl. In some embodiments, the alkyl is a C1-C3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amido, 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, -N3, -CN, -C(O)OH, -C(O)OMe, -C(O)N(PEG)1-20, -OH, -OMe, -NH2, -N(PEG)1-20, or -NO2. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -N3, -OH, -NH2, -N(PEG)1-20, or -C(O)N(PEG)1-20. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -N3, -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.

[0469] “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(CH3)=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.

[0470] “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- 6alkynyl”, 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.

[0471] “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.

[0472] “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, -N3, -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.

[0473] "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) ^–electron system in accordance with the Hückel 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.

[0474] “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-C15fully saturated cycloalkyl or C3-C15cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10fully saturated cycloalkyl or C3-C10cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8fully saturated cycloalkyl or C3-C8cycloalkenyl), from three to six carbon atoms (e.g., C3-C6fully saturated cycloalkyl or C3-C6cycloalkenyl), from three to five carbon atoms (e.g., C3-C5fully saturated cycloalkyl or C3-C5cycloalkenyl), or three to four carbon atoms (e.g., C3-C4fully 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, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis- decalin, trans-decalin, bicyclo[2.1.1]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, -N3, -CN, -C(O)OH, C(O)OMe, -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.

[0475] "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.

[0476] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0477] 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.

[0478] "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, 1-fluoromethyl-2-fluoroethyl, and the like.

[0479] “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.

[0480] “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.

[0481] “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 C1-C6 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.

[0482] “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 quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15fully saturated heterocycloalkyl or C2-C15heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10fully saturated heterocycloalkyl or C2-C10heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8fully saturated heterocycloalkyl or C2-C8heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6fully saturated heterocycloalkyl or C2- C6 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[1,3]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-1-yl, 3-oxo- 1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-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.

[0483] “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 quaternized. 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][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-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-1H-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.

[0484] 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.

[0485] 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.

[0486] 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.

[0487] 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.

[0488] 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= C1-4alkyl. In some embodiments, the linker comprises an arylene, cycloalkylene, or heterocycloalkylene moiety.

[0489] 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.

[0490] 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 C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6heteroalkyl, C3-C7carbocyclyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 3-10 membered heterocyclyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 3-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), aryl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1- C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., –CF3), halo(C1-C6)alkoxy (e.g., –OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)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, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0491] 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.

[0492] 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.

[0493] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,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.

[0494] 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.

[0495] 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,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,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.

[0496] In certain embodiments, the compounds disclosed herein have some or all of the1H 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.

[0497] 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.

[0498] 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.

[0499] 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.

[0500] 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.

[0501] 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.

[0502] 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.

[0503] 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- toluenesulfonic 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.

[0504] 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.

[0505] 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 corn 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, corn 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.

[0506] 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.

[0507] 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.

[0508] 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.

[0509] 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.

[0510] 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

[0511] 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

[0512] 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 materialsused to prepare compounds of the present disclosure are commercially available or can be prepared using routine methods known in the art.

[0513] 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

[0514] Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; Boc = tert-butyloxycarbonyl; Bu3SnH = tributyltin hydride; CD3OD = deuterated methanol; CDCl3 = 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-d6 = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EDC.HCl = EDCI.HCl = 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; EtOAc or EA = ethyl acetate; EtOH = ethanol; h = hour; HATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i- PrOH = isopropanol; LAH = lithium aluminium hydride; LiHMDS = Lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeI = 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-chlorosuccinimide; 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 = tert-butanol; T3P = Propylphosphonic Anhydride; TBS = TBDMS = tert- butyldimethylsilyl; TBSCl = TBDMSCl = tert-butyldimethylchlorosilane; TCFH = chloro-N, N, N’, N’- tetramethylformamidium hexafluorophosphate; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; Tol = toluene; TsCl = tosyl chloride; XPhos = 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

[0515] SYNTHESIS OF REPRESENTATIVE POLYAMIDES

[0516] Example 1. Synthesis of 3-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(4-(1-methyl-4-(1-methyl- 4-(3-(1-methyl-4-(1-methyl-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)propanamido)- 1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)butanamido)-1H-imidazole-2- carboxamido)propanamido)-1H-pyrrole-2-carboxamido)-1H-imidazole-2-carboxamido)propanoic acid

[0517] Scheme 1.

[0518] Step 1. Into a 1000 ml flask was added 4-[3-[(tert-butoxycarbonyl)amino] propanamido]-1- methylimidazole-2-carboxylic acid (11.00 g, 35.22 mmol, 1.00 eq.), DMF (300.00 mL), the mixture wascooled to 0 °C, then HATU (20.09 g, 52.83 mmol, 1.50 eq.), DIEA (18.21 g, 140.88 mmol, 4.00 eq.) was added dropwise, the mixture was stirred for 10 mins, methyl 3-aminopropanoate (3.63 g, 35.22 mmol, 1.00 eq.) was added in portions. The reaction was stirred at room temperature for 1.0 h. The reaction mixture was poured into water / ice (600 mL), the solid was filtered out and dried under vacuum. The aqueous phase was extracted with EA (3x200 mL), the organic phases were combined and washed with H2O (1x200 mL) and NaCl (1x200 mL), and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure and crude product was purified with a silica gel column eluted with pure EA. Methyl 3-[(4- [3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazol-2-yl)formamido]propanoate (13.00 g, 88% ) was obtained as a yellow solid. LC / MS: mass calcd. For C17H27N5O6: 397.20, found: 398.20 [M+H]+.

[0519] Step 2. The procedure was the same as methyl 4-[4-(3-aminopropanamido)-1-methylimidazole-2- amido]-1-methylpyrrole-2-carboxylate hydrochloride, but the reaction time was 1.0 h.11.00 g of methyl 3- [(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazol-2-yl)formamido]propanoate was used and 11.00 g crude of the desired product was obtained as a yellow oil. LC / MS: mass calcd. For C12H19N5O4: 297.14, found: 298.20 [M+H]+.

[0520] Step 3. To a stirred solution of 1-methylimidazole-2-carboxylic acid (10.00 g, 79.29 mmol, 7.00 eq.) in DMF (150.00 mL) was added TBTU (38.19 g, 118.94 mmol, 1.50 eq.), methyl 4-amino-1- methylpyrrole-2-carboxylate hydrochloride (16.63 g, 87.24 mmol, 1.10 eq.) and DIEA (30.74 g, 237.88 mmol, 3.00 eq.) at 0 °C. The resulting mixture was stirred for 17.0 h at room temperature. Then the reaction was poured into water / ice (450 mL). The precipitated solids were collected by filtration, washed with H2O (3x50 mL), and dried under vacuum. Methyl 1-methyl-4-(1-methylimidazole-2- amido)pyrrole-2-catboxylate (16.5 g, 78%) was obtained as a white solid. LC / MS: mass calcd. For C12H14N4O3: 262.11, found: 263.15 [M+H]+.

[0521] Step 4. The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino] propanamido]-1- methylimidazole-2-carboxylic acid.16.50 g of methyl 1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2- carboxylate was used, and 12.00 g (77% yield) of 1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2- carboxylic acid was obtained as a white solid. LC / MS: mass calcd. For C11H12N4O3: 248.09, found: 249.10 [M+H]+.

[0522] Step 5. The procedure was the same as ethyl 3-[(4-[3-[(tert-butoxycarbonyl)amino] propanamido]- 1-methylimidazol-2-yl)formamido]propanoate.9.00 g of 1-methyl-4-(1-methylimidazole-2-amido)pyrrole- 2-carboxylic acid was used, and 14.00 g (64% yield) of the desired product was obtained a yellow solid. LC / MS: mass calcd. For C26H30N10O6: 578.23, found: 579.10 [M+H]+.

[0523] Step 6. The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino] propanamido]-1 - methylimidazole-2-carboxylic acid.14.00 g of methyl 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1- methylimidazole-2-amido)pyrrol-2-yl]formamido]propanamido)imidazole-2-amido]pyrrole-2- yl]formamidocarboxylate was used, and 12.00 g of the desired product (81% yield) was obtained as a yellow solid. LC / MS: mass calcd. For C25H28N10O6: 564.22, found: 565.15 [M+H]+.

[0524] Step 7. The procedure was the same as ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1- methylimidazole-2-carboxylate.7.80 g of 4-[(tert- butoxycarbonyl)amino]butanoic acid was used, and 11.00 g of the desired product was obtained as a pink solid (81% yield). LC / MS: mass calcd. For C16H26N4O5: 354.19, found: 355.15 [M+H]+.

[0525] Step 8. The procedure was the same as methyl 4-[4-(3-aminopropanamido)-1- methylimidazole-2- amido]-1-methylpyrrole-2-carboxylate hydrochloride.9.40 g of ethyl 4-{4-[(tert- butoxycarbonyl)amino]butanamido}-1-methylimidazole-2-carboxylate was used, and 6.20 g of the desired product was obtained as a white solid (91% yield). LCMS: mass calcd. For C11H18N4O3: 254.14, found: 255.15 [M+H]+.

[0526] Step 9. To a stirred solution of 1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2- amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-amido]pyrrole-2-carboxylic acid (18.20 g, 32.24 mmol, 1.00 eq.) in DMF (250.00 mL) was added DIEA (12.50 g, 96.71 mmol, 3.00 eq.), ethyl 4-(4- aminobutanamido)-1-methylimidazole-2-carboxylate (9.02 g, 35.46 mmol, 1.10 eq.), and PyBOP (20.13 g, 38.68 mmol, 1.20 eq.) at 0 ºC. The resulting mixture was stirred for 1.0 h at room temperature. Then the reaction was poured into ice / water (800 mL). The precipitated solids were collected by filtration, washed with H2O (3x200 mL), and dried under vacuum.24.70 g of ethyl 1-methyl-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]imidazole-2-carboxylate was obtained as a yellow solid (96% yield). LC / MS: mass calcd. For C: 800.35, found: 801.30 [M+H]+.

[0527] Step 10. The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1- methylimidazole-2-carboxylic acid.24.00 g of ethyl 1-methyl-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]imidazole-2-carboxylate was used, and 23.10 g of the desired product was obtained as a yellow solid (99% yield). LC / MS: mass calcd. For C34H40N14O8: 772.32, found: 773.30 [M+H]+.

[0528] Step 11. To a stirred solution of 4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2- carboxylic acid (11.50 g, 47.87 mmol, 1.00 eq.) in DMF (200.00 mL) was added EDCI (22.94 g, 119.66 mmol, 2.50 eq.), ethyl 4-amino-1- methylimidazole-2-carboxylate (8.10 g, 47.87 mmol, 1.00 eq.), and DMAP (14.62 g, 119.66 mmol, 2.50 eq.) at 0 ºC. The resulting mixture was stirred for 17.0 h at 35 °C. Then the reaction was poured into 500 mL ice / water. The precipitated solids were collected by filtration, washed with water (3x50 mL), and dried under vacuum. This resulted in ethyl 4-{4-[(tert-butoxycarbonyl)amino]-1- methylpyrrole-2-amido}-1-methylimidazole-2-carboxylate (16.00 g, 85% yield) as a yellow solid. LC / MS: mass calcd. For C18H25N5O5: 391.19, found: 392.30 [M+H]+.

[0529] Step 12. To a stirred solution of ethyl 4-{4-[(tert-butoxycarbonyl)amino]-1- methylpyrrole-2- amido}-1-methylimidazole-2-carboxylate (16.00 g, 40.88 mmol, 1.00 eq.) in DCM (135.00 mL), TFA (45.00 mL) was added dropwise at room temperature. The resulting mixture was stirred for 2.0 h at room temperature and was then concentrated under vacuum. The residue was diluted with Et2O (200 mL) and theprecipitated solids were collected by filtration, washed with Et2O (2x100 mL), and dried under vacuum. This resulted in ethyl 4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate (16.00 g, crude) as a brown solid. LC / MS: mass calcd. For C13H17N5O3: 291.13, found: 292.15[M+H]+.

[0530] Step 13. A solution of ethyl 4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2- carboxylate (12.00 g, 41.19 mmol, 1.00 eq.) and 3-[(tert-butoxycarbonyl)amino] propanoic acid (7.50 g, 39.64 mmol, 0.96 eq.), PyBOP (22.00 g, 42.28 mmol, 1.03 eq.), DIEA (45.00 g, 348.18 mmol, 8.45 eq.) in DMF (120.00 mL) was stirred for 1.0 h at room temperature. The reaction was poured into ice water (400 mL), and the resulting mixture was stirred for 15 min. The precipitated solids were collected by filtration, washed with water (3x150 mL), and dried under vacuum. The crude product was purified with silica gel column chromatography and eluted with PE / EA (1:8) to give 17.00 g (89% yield) of ethyl 4-(4-{3- [(tert-butoxycarbonyl)amino]propanamido}-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate as a yellow solid. LC / MS: mass calcd. For C21H30N6O6: 462.22, found: 463.35 [M+H]+.

[0531] Step 14. The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino]propanamido] -1- methylimidazole-2-carboxylic acid.12.00 g of ethyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-1- methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate was used, and 10.00 g of the desired product was obtained as a white solid (89% yield). LC / MS: mass calcd. For C19H26N6O6: 434.19, found: 435.25[M+H]+..

[0532] Step 15. A solution of 4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-1- methylpyrrole-2- amido)-1-methylimidazole-2-carboxylic acid (10.00 g, 23.02 mmol, 1.00 eq.) and β-alanine ethyl ester hydrochloride (4.90 g, 31.90 mmol, 1.39 eq.), PyBOP (12.50 g, 24.02 mmol, 1.04 eq.), DIEA (9.00 g, 69.64 mmol, 3.03 eq.) in DMF (120.00 mL) was stirred for 1.0 h at room temperature. The reaction was quenched with the addition of water (500 mL) and the resulting mixture was extracted with EA (3x400 mL). The combined organic layers were washed with saturated NaCl (3x200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified with silica gel column chromatography and eluted with PE / EA (1:8) to afford ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-1- methylpyrrole-2-amido)-1-methylimidazol-2-yl]formamido}propanoate (12.00 g, 94%) as a yellow solid. LC / MS: mass calcd. For C24H35N7O7: 533.26, found: 534.30 [M+H]+.

[0533] Step 16. The procedure was the same as ethyl 4-(4-amino-1-methylpyrrole-2-amido)-1- methylimidazole-2-carboxylate.12.00 g of ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-1- methylpyrrole-2-amido)-1-methylimidazol-2-yl]formamido}propanoate was used, and 12.00 g crude of the desired product was obtained as white solid. LC / MS: mass calcd. For C19H27N7O5: 433.21, found: 434.25 [M+H]+.

[0534] Step 17. The procedure was the same as ethyl 1-methyl-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]imidazole-2-carboxylate.10.00 g of 1-methyl-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]imidazole-2-carboxylic acid was used, and 13.60 g (89% yield) of the desiredproduct was obtained as a yellow solid. HRMS: mass calcd. For C53H65N21O12: 1187.5122, found: 1188.5153 [M+H]+.

[0535] Step 18. The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1- methylimidazole-2-carboxylic acid, but the reaction temperature was 35 °C.10.60 g of ethyl 3-[(1-methyl-4- {1-methyl-4-[3-({1-methyl-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-2-yl}formamido)propanamido]pyrrole-2-amido}imidazol-2- yl)formamido]propanoate was used, and 10.00 g of the desired product was obtained as a yellow solid. LC / MS: mass calcd. For C51H61N21O12: 1159.48, found: 581.25 [M / 2+H]+.

[0536] Example 2. Synthesis of 1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(4-(1-methyl-4-(1-methyl-4- (3-(1-methyl-4-(1-methyl-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)propanamido)- 1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)butanamido)-1H-imidazole-2- carboxamido)propanamido)-1H-pyrrole-2-carboxamido)-1H-imidazole-2-carboxylic acid

[0537] Scheme 2.

[0538] Step 1. The procedure was the same as for ethyl 4-(4-amino-1-methylpyrrole-2-amido)-1- methylimidazole-2-carboxylate (Example 1).2.00 g of ethyl 4-(4-{3-[(tert- butoxycarbonyl)amino]propanamido}-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate was used, and 2.00 g (crude) of the desired product was obtained as a white solid. LC / MS: mass calcd. For C16H22N6O4: 362.17, found: 363.25 [M+H]+.

[0539] Step 2. The procedure was the same as ethyl 1-methyl-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]imidazole-2-carboxylate, but the solvent was changed to DMA.3.00 g of 1- methyl-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]imidazole-2-carboxylicacid was used, and 4.30 g (97% yield) of the desired product was obtained as a yellow solid. LC / MS: mass calcd. For C50H60N20O11: 1116.48, found:1117.60 [M+H]+.

[0540] Step 3. The procedure was the same as Example 1, but the reaction temperature was adjusted to 40 °C, and the reaction time was 5.0 h.4.20 g of ethyl 1-methyl-4-{1-methyl-4-[3-({1-methyl-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-2- yl}formamido)propanamido]pyrrole-2-amido}imidazole-2-carboxylate was used, and 4.00 g (98% yield) of the desired product was obtained as a yellow solid. LC / MS: mass calcd. For C48H56N20O11: 1088.44, found: 1089.55 [M+H]+.

[0541] Example 3. Synthesis of 3-([1-methyl-4-[3-([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)propanamido]imidazol-2-yl]formamido)propanoic acid

[0542] Scheme 3.

[0543] Step 1. To a solution of ethyl 1-methyl-4-nitroimidazole-2-carboxylate (30.00 g, 150.63 mmol, 1.00 eq.) 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 H2atmosphere. The reaction was filtered and the filtrate was concentrated under vacuum to afford ethyl 4-amino-1-methylimidazole-2-carboxylate (22.30 g, 75%) as a yellow solid. LC / MS: mass calcd. For C7H11N3O2: 169.09, found: 170.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 7.37 (s, 1H), 4.29 - 4.34 (m, 2H), 3.94 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0544] Step 2. Into a 500 mL flask, 3-[(tert-butoxycarbonyl) amino]propanoic acid (22.45 g, 118.65 mmol, 0.90 eq.) and DMF (180.00 mL) were added and the mixture was cooled to 0 °C. then HATU (75.18 g, 197.71 mmol, 1.50 eq.) and DIEA (51.11 g, 395.43 mmol, 3.00 eq.) were added and the mixture was stirred for 10 mins. Next ethyl 4-amino-1-methylimidazole-2-carboxylate (22.30 g, 131.81 mmol, 1.00 eq.) 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), and the resulting mixture was stirred for 15.0 min. The precipitated solids were collected by filtration, washed with water (3x50 mL), and dried under vacuum. This resulted in ethyl 4-[3-[(tert-butoxycarbonyl)amino] propanamido]-1-methylimidazole-2- carboxylate (34.50 g, 77%) as a yellow solid. LC / MS: mass calcd. For C15H24N4O5: 340.17, found: 341.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 10.63 (s, 1H), 7.52 (s, 1H), 6.80 (t, J = 5.6 Hz, 1H), 4.23 - 4.28 (m, 2H), 3.90 (s, 3H), 3.15 - 3.20 (m, 2H), 2.42 (t, J = 7.2 Hz, 2H), 1.37 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H).

[0545] Step 3. To a stirred solution of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1- methylimidazole-2-carboxylate (34.50 g, 101.36 mmol, 1.00 eq.) in MeOH (200.00 mL) was added LiOH solution (2M, 202.00 mL, 4.00 eq.) dropwise at room temperature. The resulting mixture was stirred for 2.0 h at 45 °C. The mixture was then concentrated under reduced pressure. The residue was dissolved in H2O (50 mL) and was acidified to pH 3~5 with 2M HCl. The precipitated solids were collected by filtration, washed with H2O (3x30 mL), and dried under vacuum.4-[3-[(Tert-butoxycarbonyl)amino]propanamido]-1- methylimidazole-2-carboxylic acid (30.00 g, 95%) was obtained as a white solid. LC / MS: mass calcd. For C13H20N4O5: 312.14, found: 313.15 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ: 10.53 (s, 1H), 7.48 (s, 1H), 6.79 (t, J = 5.4 Hz, 1H), 3.89 (s, 3H), 3.15 -3.22 (m, 2H), 2.43 (t, J = 7.2 Hz, 2H), 1.37 (s, 9H).

[0546] Step 4. To a stirred solution of 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1- methylimidazole-2-carboxylic acid (16.00 g, 51.23 mmol, 1.00 eq.) in CH3CN (150.00 mL) was added TCFH (21.56 g, 76.84 mmol, 1.50 eq.), NMI (12.62 g, 153.69 mmol, 3.00 eq.) and methyl 4-amino-1- methylpyrrole-2-carboxylate hydrochloride (10.74 g, 56.34 mmol, 1.10 eq.) in portions at 0 ºC. The resulting mixture was stirred for 2.0 h at room temperature. The precipitated solids were collected by filtration, washed with CH3CN (3x20 mL), and dried under vacuum. Methyl 4-(4-[3-[(tert- butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate (19.00 g, 83%) was obtained as a white solid. LC / MS: mass calcd. For C20H28N6O6: 448.21, found: 449.25 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ: 10.24 (s, 1H), 10.11 (s, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 6.99 (s, 1H), 6.82 (t, J = 5.1 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.74 (s, 3H), 3.16 - 3.23 (m, 2H), 2.47 (t, J = 6.9 Hz, 2H), 1.38 (s, 9H).

[0547] Step 5. A solution of methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1- methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate (19.00 g, 42.37 mmol, 1.00 eq.) in HCl / 1,4- dioxane (4M, 200.00 mL) was stirred for 2.0 h at room temperature. The resulting mixture was concentrated under vacuum to afford methyl 4-[4-(3-aminopropanamido)-1-methylimidazole-2-amido]-1-methylpyrrole- 2-carboxylate hydrochloride (19.00 g, crude) as a yellow solid. LC / MS: mass calcd. For C15H21ClN6O4: 348.15, found: 349.05 [M+H]+.1H NMR (300 MHz, CD3OD) δ: 7.37 (s, 2H), 6.91 (s, 1H), 4.03 (s, 3H), 3.88 (s, 3H), 3.79 (s, 3H), 3.09 (t, J = 6.6 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H).

[0548] Step 6. Into a 1000 ml flask was added 4-[3-[(tert-butoxycarbonyl)amino] propanamido]-1- methylimidazole-2-carboxylic acid (11.00 g, 35.22 mmol, 1.00 eq.) in DMF (300.00 mL) and the mixture was cooled to 0 °C. HATU(20.09 g, 52.83 mmol, 1.50 eq.) and DIEA (18.21 g, 140.88 mmol, 4.00 eq.) were added, and the mixture was stirred for 10 mins. Then methyl 3-aminopropanoate (3.63 g, 35.22 mmol, 1.00 eq.) was added in portions and the reaction was stirred at room temperature for 1.0 h. The reaction mixture was poured into water / ice (600 mL) and extracted with EA (3 x 200 mL). The combined organic phase was washed with H2O (1x200 mL) and NaCl (1x200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified with a silica gel column and eluted with pure EA. Methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1- methylimidazol-2- yl)formamido]propanoate (13.00 g, 88%) was obtained as a yellow solid. LC / MS: mass calcd. For C17H27N5O6: 397.20, found: 398.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 10.28 (s, 1H), 7.92 (t, J = 6.0 Hz, 1H), 7.37 (s, 1H), 6.77 (t, J = 6.0 Hz, 1H), 3.88 (s, 3H), 3.59 (s, 3H), 3.42 - 3.47 (m, 2H), 3.13 - 3.18 (m, 2H), 2.56 (t, J = 6.0 Hz, 2H), 2.42 (t, J = 6.0 Hz, 2H), 1.35 (s, 9H).

[0549] Step 7. A solution of methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1- methylimidazol-2-yl) formamido]propanoate (11.00 g, 27.678 mmol, 1.00 eq.) in HCl / 1,4 dioxane (4M, 110.00 mL) was stirred for 1.0 h at room temperature. The resulting mixture was concentrated under vacuum to afford methyl 3-[[4-(3-aminopropanamido)-1-methylimidazol-2- yl]formamido]propanoate hydrochloride (11.00 g, crude) as a yellow oil. LC / MS: mass calcd. For C12H19N5O4: 297.14, found: 298.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 10.57 (s, 1H), 7.92 (t, J = 6.0 Hz, 1H), 7.37 (s, 1H), 3.89 (s, 3H), 3.59 (s, 3H), 3.43 - 3.47 (m, 2H), 2.97 - 3.05 (m, 2H), 2.57 - 2.71 (m, 2H), 2.56 (t, J = 6.0 Hz, 2H).

[0550] Step 8. To a stirred solution of 1-methylimidazole-2-carboxylic acid (10.00 g, 79.29 mmol, 7.00 eq.) in DMF (150.00 mL) were added TBTU (38.19 g, 118.94 mmol, 1.50 eq.), methyl 4-amino-1- methylpyrrole-2-carboxylate hydrochloride (16.63 g, 87.24 mmol, 1.10 eq.), and DIEA (30.74 g, 237.88 mmol, 3.00 eq.) at 0 °C and the resulting mixture was stirred for 17 h at room temperature. The reaction was poured into water / ice (450 mL). The precipitated solids were collected by filtration, washed with H2O (3x50 mL), and dried under vacuum. This afforded methyl 1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2- catboxylate (16.50 g, 78%) as a white solid. LC / MS: mass calcd. For C12H14N4O3: 262.11, found: 263.15 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ: 10.54 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.04 (s, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 3.74 (s, 3H).

[0551] Step 9. To a stirred solution of methyl 1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2- carboxylate (16.50 g, 62.91 mmol, 1.00 eq.) in MeOH (100.00 mL) was added LiOH solution (2M, 158.00 mL, 5.00 eq.) dropwise at room temperature. The resulting mixture was stirred for 2.0 h at 45 °C. The mixture was concentrated under reduced pressure and the residue was dissolved in H2O (50 mL) and acidified to pH 3~5 with 2M HCl. The precipitated solids were collected by filtration, washed with H2O (3x30 mL), and dried under vacuum.1-Methyl-4-(1-methylimidazole-2-amido)pyrrole-2-carboxylic acid (12.00 g, 77%) was obtained as a white solid. LC / MS: mass calcd. For C11H12N4O3: 248.09, found: 249.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ: 10.52 (s, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 7.06 (s, 1H), 6.99 (s, 1H), 3.99 (s, 3H), 3.82 (s, 3H).

[0552] Step 10. To a stirred solution of 1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2-carboxylic acid (9.00 g, 36.255 mmol, 1.00 eq.) in DMF (150.00 mL) was added HATU (20.68 g, 54.38 mmol, 1.50 eq.), DIEA (14.06 g, 108.77 mmol, 3.00 eq.), and methyl 4-[4-(3-aminopropanamido)-1- methylimidazole-2-amido]-1-methylpyrrole-2-carboxylate (13.89 g, 39.872 mmol, 1.10 eq.) in at 0 °C. The resulting mixture was stirred for 17.0 h at room temperature. The reaction was poured into water / ice (450 mL). The precipitated solids were collected by filtration, washed with H2O (3x50 mL), and dried under vacuum. Methyl 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazole-2-amido)pyrrol-2- yl]formamido]propanamido)imidazole-2-amido]pyrrole-2-carboxylate (14.00 g, 64%) was obtained as a yellow solid. LC / MS: mass calcd. For C26H30N10O6: 578.23, found: 579.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ: 10.53 (s, 1H), 10.29 (s, 1H), 10.11 (s, 1H), 8.10 (t, J = 5.4 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 2H), 7.25 (s, 1H), 7.17 (s, 1H), 6.99 (s, 1H), 6.97 (s, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.69 (s, 3H), 3.42 - 3.49 (m, 2H), 2.60 (t, J = 7.2 Hz, 2H).

[0553] Step 11. A solution of methyl 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1- methylimidazole-2- amido)pyrrol-2-yl]formamido]propanamido)imidazole-2-amido]pyrrole-2- yl]formamidocarboxylate (14.00 g, 24.20 mmol, 1.00 eq.) in MeOH (70.00 mL) was added LiOH (2M,72.00 mL, 6.00 eq.) and the mixture was stirred at 45 °C for 2.0 h. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in H2O (50 mL) and acidified to pH 3~5 with 2 M HCl. The precipitated solids were collected by filtration, washed with H2O (3x20 mL), and dried under vacuum.1-Methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1- methylimidazole-2-amido)pyrrol-2-yl]formamido]propanamido)imidazole-2-affordamido] pyrrole-2- carboxylic acid (12.00 g, 81%) was obtained as a yellow solid. LC / MS: mass calcd. For C25H28N10O6: 564.22, found: 565.15[M+H]+.1H NMR (300 MHz, DMSO-d6) δ: 10.72 (s, 1H), 10.32 (s, 1H), 10.08 (s, 1H), 8.14 (t, J = 6.0 Hz, 1H), 7.51 (s, 1H), 7.47 (s, 2H), 7.27 (s, 1H), 7.23 (s, 1H), 6.98 (s, 1H), 6.94 (s, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 3.82 (s, 6H), 3.44 - 3.46 (m, 2H), 2.60 (t, J = 6.6 Hz, 2H).

[0554] Step 12. To a stirred solution of 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazole-2- amido)pyrrol-2-yl]formamido]propanamido)imidazole-2-amido] pyrrole-2-carboxylic acid (12.00 g, 21.26 mmol, 1.00 eq.) in DMF (100.00 mL) was added HATU (12.12 g, 31.88 mmol, 1.50 eq.), DIEA (8.24 g, 63.77 mmol, 3.00 eq.), and methyl 3-[[4-(3-aminopropanamido)-1-methylimidazol-2-yl]formamido]propanoate (6.95 g, 23.38 mmol, 1.10 eq.) in portions at 0 °C. The resulting mixture was stirred for 2.0 h at room temperature. The reaction was poured into water / ice (300 mL). The precipitated solids were collected by filtration, washed with H2O (3x30 mL), and dried under vacuum. Methyl 3-([1- methyl-4-[3-([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)propanamido]imidazol-2- yl]formamido)propanoate (13.00 g, 65%) was obtained as a yellow solid. LC / MS: mass calcd. For C37H45N15O9: 843.35, found: 844.55 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ: 10.41 (s, 1H), 10.37 (s, 1H), 10.32 (s, 1H), 9.96 (s, 1H), 8.08 (s, 2H), 7.96 (s, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 7.38 (s, 1H), 7.24 (s, 2H), 7.03 (s, 1H), 6.98 (s, 1H), 6.93 (s, 1H), 4.13 (s, 3H), 3.98 (s, 3H), 3.95 (s, 3H), 3.81 (s, 9H), 3.60 (s, 6H), 2.57 - 2.69 (m, 6H).

[0555] Step 13. A solution of methyl 3-([1-methyl-4-[3-([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)propanamido]imidazol-2-yl]formamido)propanoate (10.00 g, 10.59 mmol, 1.00 eq.) in MeOH (60.00 mL) was added 2M LiOH (21.20 mL, 42.40 mmol, 4.00 eq.), and the resulting mixture was stirred for 2.0 h at 45 °C. The reaction was concentrated under reduced pressure, and the residue was diluted with water (60 mL) and acidified to pH 3~5 with 2M HCl. The precipitated solids were collected by filtration, washed with water (3x20 mL), and dried under vacuum. This resulted in 3-([1-methyl-4-[3-([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)propanamido]imidazol-2-yl]formamido)propanoic acid (8.70 g, 84%) as a brown solid. LC / MS: mass calcd. For C36H43N15O9: 829.34, found: 830.25 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ: 10.46 (s, 1H), 10.39 (s, 1H), 10.31 (s, 1H), 9.93 (s, 1H), 8.05 -8.10 (m, 2H), 7.87 (t, J = 6.0 Hz, 1H), 7.42 - 7.46 (m, 3H), 7.20 - 7.23 (m, 2H), 7.07 (s, 1H), 6.90 - 6.95 (m, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.38 - 3.41 (m, 6H), 2.44 - 2.59 (m, 6H).

[0556] SYNTHESIS OF REPRESENTATIVE COMPOUNDS OF THE DISCLOSURE

[0557] Example 4. Synthesis of Compound A-27

[0558] Scheme 4.

[0559] Step 1. To a stirred solution of (S)-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)-N-(4-hydroxyphenyl)acetamide (27.00 mg, 0.05 mmol, 1.00 eq.) in CH3CN (1.50 mL) were added tert-butyl N-(86-bromo- 3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84- octacosaoxahexaoctacontan-1-yl)carbamate (80.00 mg, 0.05 mmol, 1.00 eq.) and K2CO3 (22.76 mg, 0.16 mmol, 3.00 eq.). The resulting mixture was stirred for 17.0 h at 70 °C. The mixture was filtered, washed with EA (3x8 mL), and concentrated under reduced pressure. The crude product was purified with prep-TLC (CH2Cl2 / MeOH; 8:1) to afford tert-butyl (S)-(86-(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)3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84- octacosaoxahexaoctacontyl)carbamate (81.00 mg, 77% yield) as a brown solid. LC / MS: mass calcd. For C88H147ClN6O32S: 1866.95, found: 623.90 [M / 3+H]+.

[0560] Step 2. A solution of tert-butyl (S)-(86-(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)- 3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84- octacosaoxahexaoctacontyl)carbamate (70.00 mg, 0.04 mmol, 1.00 eq.) and TFA (0.20 mL) in DCM (1.00 mL) was stirred for 1.0 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (S)-N-(4-((86-amino- 3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84- octacosaoxahexaoctacontyl)oxy)phenyl)-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)acetamide (70.00 mg, crude) as a yellow oil. LC / MS: mass calcd. For C83H139ClN6O30S: 1766.89, found: 590.60 [M / 3+H]+.

[0561] Step 3. To a stirred solution of 3-[(1-methyl-4-{1-methyl-4-[3-({1-methyl-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-2-yl}formamido)propanamido]pyrrole-2- amido}imidazol-2-yl)formamido]propanoic acid (37.80 mg, 0.03 mmol, 1.00 eq.) in DMF (1.00 mL) was added DIEA (25.27 mg, 0.19 mmol, 6.00 eq.), (S)-N-(4-((86-amino- 3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84- octacosaoxahexaoctacontyl)oxy)phenyl)-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)acetamide (57.62 mg, 0.03 mmol, 1.00 eq.), and PyBOP (25.43 mg, 0.05 mmol, 1.50 eq.) at 0 °C. The resulting mixture was stirred for 1.0 h at room temperature and was then concentrated under vacuum. The crude product was purified by Perp-HPLC with the following condonation: Column: XBridge Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 45% B to 65% B in 11 min, 65% B; Wave Length: 254 nm. The fractions were combined and lyophilized to afford (S)-N-(3-((5-((2-((1- (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)-88-oxo- 3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84-octacosaoxa-87- azanonacontan-90-yl)carbamoyl)-1-methyl-1H-imidazol-4-yl)carbamoyl)-1-methyl-1H-pyrrol-3-yl)amino)- 3-oxopropyl)-1-methyl-4-(4-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-1H-imidazole-2- carboxamido)-1H-pyrrole-2-carboxamido)propanamido)-1H-imidazole-2-carboxamido)-1H-pyrrole-2- carboxamido)butanamido)-1H-imidazole-2-carboxamide (13.80 mg, 14%) as a white solid. HRMS: mass calcd. For C134H198ClN27O41S: 2908.3648, found: 2909.3729 [M+H]+.

[0562] Example 5. General synthesis and purification of the compounds of the disclosure

[0563] Compounds of the disclosure were made by methods similar to Example 4 with the appropriate polyamide and second terminus. The compounds were subsequently purified by HRMS methods A or B.

[0564] Method A: Instrument: Waters Acquity I Class UPLC with Xevo G2-XSQT of HRMS; Column: ACQUITY UPLC BEH-C18, 2.1 x 50 mm, 2.7 μm; 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.

[0565] Method B: Instrument: Waters Acquity I Class UPLC with Xevo G2-XS QT of HRMS; Column: ACQUITY UPLC BEH-C18, 2.1 x 50 mm, 2.7μm; 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.

[0566] Experimental data for the compounds of the disclosure purified by Method A are provided in Table 4A and Table 4B.Table 4A. LCMS analysis of compounds of the disclosure.Table 4B. LCMS analysis of compounds of the disclosure.BIOLOGICAL EXAMPLES

[0567] Example B1. TCF4 RNA Assay

[0568] Materials

[0569] RPMI 8226 TCF4 RNA Assay Procedure

[0570] Plating: RPMI-8226 cells were plated in a 96-well plate using media at a concentration of 75,000 to 100,000 cells per well and incubated for 24 hrs at 37 °C and 5% CO2. Compounds dissolved in DMSO (0.1%) were added and further incubated for 48 hrs at 37°C and 5% CO2.

[0571] Lysing: On day 3, the media was removed and the plate was centrifuged at 1800 rpm for 4 mins to pellet the cell.100 to 150 µL of GITC was added per well and the plate was allowed to sit at room temperature for 15 mins.

[0572] RNA Isolation: 70% ETOH was added to the lysed cells with GITC and the plate was allowed to stand at room temperature for 8 mins. The contents of the plate were loaded into a 96-well filter plate, filtered under vacuum and washed twice with 200 µL of RNA wash buffer per well. The plate was then treated with 80 µL of DNase solution per well and was allowed to sit for 20 mins at room temperature.

[0573] The plate was treating with 8mL DNase buffer per plate with 10.6 µL of 338.5U / µL DNase and dried under vacuum after DNase treatment. The plate was further washed twice with 200 µL GITC wash buffer per well and then washed three times with 200 µL of RNA wash buffer per well. The plate was then placed atop a new, flat-bottom, non-treated 96-well plate and spun at 3500 rmp for 9 mins to dry.

[0574] 100 µL of water was added to each well and the plate was spun at 3500 rmp for 4 mins.

[0575] TCF4 RNA was analyzed via qPCR analysis.

[0576] Representative in vitro biochemical data is presented in FIG.1. Compound A-7 elevates TCF4 transcription. FIG 1A shows B cell lymphoma treated with A-7 for 48 hrs. FIG 1B shows PTHS patient fibroblasts (GM26038 fibroblasts) treated with A-7 for 96 hrs. TCF4 transcription was measured by qPCR.

[0577] The assay described above can be adapted for use with additional cell lines for testing in other haploinsufficient conditions such as COL3A1 haploinsufficient (for Ehlers-Danlos Syndrome, GM22778) and SLC2A1 haploinsufficient (for GLUT1 Deficiency Syndrome, GM27659).

[0578] Example B2. Biological Assays

[0579] Biological methodologies useful in screening and evaluation of the compounds described herein are disclosed in Table 5. The references are incorporated by reference in their entirety. Table 5. Biological Assay Conditions.

[0580] 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

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a haploinsufficiency disease or disorder in a subject in need thereof, wherein the subject has a haploinsufficient gene, the method comprising administering to the subject an effective amount of a compound having (i) a first terminus comprising a DNA-binding moiety capable of binding a haploinsufficient gene, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the first terminus and second terminus, or a pharmaceutically acceptable salt thereof, wherein the haploinsufficient gene comprises a repetitive DNA sequence comprising a motif selected from CCCCWG, CCCCWGC, CCCCWWC, CCGGGG, CCWCC, CCWCW, CCWCWW, CCWGC, CCWWC, CCWWWW, CWC, CWCWCCC, CWCWCG, CWCWCWC, CWCWGCW, CWW, CWWCCWC, CWWWW, G, GCC, GCW, GCWC, GGGCCW, GGGGC, GGGGCG, GGGGWG, GGGWCW, GWCCCWG, GWGGGW, GWWW, W, WC, WCCCCW, WCCWW, WCWGC, WCWWC, WCWWCWW, WCWWWC, WCWWWG, WGGCCCC, WGGG, WGGGWGG, WGWC, WGWGWC, WGWGWGW, WGWWGG, WGWWWWG, WWGG, WWGGGW, WWGWWGG, WWWWWC, or WWWWWWC, wherein each W is independently A or T.

2. The method of claim 1, wherein the DNA-binding moiety is a polyamide selected from a linear polyamide, a hairpin polyamide, a H-pin polyamide, a U-pin polyamide, an overlapped polyamide, a slipped polyamide, a cyclic polyamide, a tandem polyamide, and an extended polyamide.

3. The method of claim 1, wherein the DNA-binding moiety comprises a polyamide having one or more of the following subunits selected from-NH-phenylene-C(O)-, -NH-pyridinylene-C(O)-, -NH-piperidinylene-C(O)-, -NH-pyrimidinylene- C(O)-, -NH-anthracenylene-C(O)-, -NH-quinolinylene-, wherein each R’ is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1- C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10- membered heterocycloalkyl; each R” is independently hydrogen, halogen, -OH, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 haloalkyl; each R”’ is independently hydrogen, halogen, -CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl; or two R”’ on the same or on adjacent atoms together with the atom(s) to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; and Z is hydrogen, optionally substituted C1-C6 alkyl, (azaneylidene)methanediamine, (azaneylidene)-N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, - NR1CC(O)NR1CR1D, -N(R1D)2, -ZB-P(O)(OR1C)2, -ZB-(CH2)p3-P(O)(OR1C)2, -ZB-(CH2)p3-O- P(O)(OR1C)2, wherein each R1Cis independently hydrogen or optionally substituted C1-C20 alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20 alkyl, optionally substituted C2-C10 heteroalkyl, or (AA)p2; each AA is an amino acid; p2 is an integer from 1-10; ZB is N or O; and p3 is an integer from 1-10.

4. The method of claim 2, wherein polyamide comprises the structure of Formula (A-1), or a pharmaceutically acceptable salt thereof:Formula (A-1), wherein: Z1is absent, -O-, or -NH-; each X1, X2, X3, X4, X5, X6, X7, and X8is independently -O-, -S-, or -NR2-; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-; W1is hydrogen, optionally substituted C1-C6 alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, - N(R1D)2, -ZB-P(O)(OR1C)2, -ZB-(CH2)p3-P(O)(OR1C)2, -ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZB is N or O; p3 is an integer from 1-10; W2is optionally substituted C1-C6 alkyl or -C(O)NR1CR1D; each R2is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10- membered heterocycloalkyl; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6 alkyl or phenyl; or two R3on the same or on adjacent atoms combine together with the atom(s) to which they are attached to form an optionally substituted C3-C6 cycloalkyl or optionally substituted 3 to 6- membered heterocycloalkyl; each R1Cis independently hydrogen or optionally substituted C1-C20alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20alkyl, optionally substituted C2-C10heteroalkyl, or (AA)p2, whereineach AA is an amino acid; p2is an integer from 1-10; or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6-membered heterocycloalkyl; j1is 0 or 1; n0is 0 or 1; m1and n1are each independently an integer from 0-3; and p1is 2 or 3, provided that when Z1is -O- or -NH- then p1is 2 or when Z1is absent then p1is 3; wherein the oligomeric backbone is attached at W1, W2, one of R2, or one of R3.

5. The method of claim 4, wherein the polyamide comprises the structure of Formula (A-2), or a pharmaceutically acceptable salt thereof:Formula (A-2), wherein: Z1is absent; each X1, X2, X3, X4, X5, X6, X7, and X8is independently -NR2-; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-; W1is hydrogen, optionally substituted C1-C6alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N’,N’-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, - N(R1D)2, -ZB-P(O)(OR1C)2,-ZB-(CH2)p3-P(O)(OR1C)2,-ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZBis N or O; p3is an integer from 1-10; W2is optionally substituted C1-C6alkyl or -C(O)NR1CR1D; each R2is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C1-C20haloalkyl, optionally substitutedC1-C20hydroxyalkyl, optionally substituted C3-C10cycloalkyl, or optionally substituted 3 to 10- membered heterocycloalkyl; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6alkyl or phenyl; or two R3on the same or on adjacent atoms combine together with the atom(s) to which they are attached to form an optionally substituted C3-C6cycloalkyl or optionally substituted 3 to 6- membered heterocycloalkyl; each R1Cis independently hydrogen or optionally substituted C1-C20 alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20 alkyl, optionally substituted C2-C10 heteroalkyl, or (AA)p2, wherein each AA is an amino acid; p2 is an integer from 1-10; or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6-membered heterocycloalkyl; j1 is 0 or 1; m1 and n1 are each independently an integer from 0-3; and p1 is 3; wherein the oligomeric backbone is attached at W1, W2, one of R2, or one of R3.

6. The method of claim 4 or 5, wherein the oligomeric backbone is attached to the polyamide at W1or W2.

7. The method of claim 4 or 5, wherein the oligomeric backbone is attached to the polyamide at one of R2.

8. The method of claim 4 or 5, wherein the oligomeric backbone is attached to the polyamide at one of R3.

9. The method of claim 4 or 5, wherein W2is -C(O)NH(CH2)2C(O)-** or -C(O)NH-**, wherein the oligomeric backbone is attached at **.

10. The method of claim 4, wherein the polyamide comprises the structure of Formula (A-4), or a pharmaceutically acceptable salt thereof:Formula (A-4), wherein: each X1, X2, X3, X4, X5, X6, X7, and X8is independently -NR2-; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-; W1is hydrogen; each R2is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10- membered heterocycloalkyl; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6 alkyl or phenyl; or two R3on the same or on adjacent atoms combine together with the atom(s) to which they are attached to form an optionally substituted C3-C6 cycloalkyl or optionally substituted 3 to 6- membered heterocycloalkyl; j1 is 0 or 1; and m1 and n1 are each independently an integer from 0-3.

11. The method of claim 4, wherein the polyamide comprises the structure of Formula (A-6), or a pharmaceutically acceptable salt thereof:Formula (A-6), wherein: each X1, X2, X3, X4, X5, X6, X7, and X8is independently -NR2-; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-; W1is hydrogen; each R2is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10- membered heterocycloalkyl; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6 alkyl or phenyl; or two R3on the same or on adjacent atoms combine together with the atom(s) to which they are attached to form an optionally substituted C3-C6 cycloalkyl or optionally substituted 3 to 6- membered heterocycloalkyl; j1 is 0 or 1; and m1 and n1 are each independently an integer from 0-3.

12. The method of any one of claims 4-11, wherein Y2, Y4, and Y7are each -N-; and Y3is -CH-.

13. The method of any one of claims 4-12, wherein n1 is 1.

14. The method of any one of claims 4-12, wherein n1 is 0.

15. The method of any one of claims 4-13, wherein Y6is -CH-.

16. The method of any one of claims 4-15, wherein j1 is 1.

17. The method of any one of claims 4-15, wherein j1 is 0.

18. The method of any one of claims 4-16, wherein Y1is -CH-.

19. The method of any one of claims 4-18, wherein m1is 0 or 1.

20. The method of claim 10, wherein the polyamide comprises the structure of Formula (A-8), or a pharmaceutically acceptable salt thereof:Formula (A-8), wherein: Y8is -CH- or -N-; W1is hydrogen; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6alkyl or phenyl; and R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C1-C20haloalkyl, optionally substituted C1-C20hydroxyalkyl, optionally substituted C3-C10cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl.

21. The method of claim 11, wherein the polyamide comprises the structure of Formula (A-10), or a pharmaceutically acceptable salt thereof:Formula (A-10), wherein: Y8is -CH- or -N-; W1is hydrogen; each R3is independently hydrogen, halogen, amino, cyano, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, or -NHC(O)R3A, wherein each R3Ais independently C1-C6alkyl or phenyl; and R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl.

22. The method of claim 20 or 21, wherein R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 haloalkyl, or optionally substituted C1-C20 heteroalkyl.

23. The method of claim 22, wherein R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each independently optionally substituted C1-C20 alkyl.

24. The method of claim 23, wherein R2A, R2B, R2C, R2D, R2E, R2F, and R2Gare each methyl.

25. The method of any one of claims 4-24, wherein Y8is -N-.

26. The method of any one of claims 4-24, wherein Y8is -CH-.

27. The method of any one of claims 4-26 wherein each R3is independently hydrogen, amino, or - NHC(O)R3A.

28. The method of claim 27, wherein each R3is hydrogen.

29. The method of claim 3, wherein the polyamide comprises the structure of Formula (A-11), or a pharmaceutically acceptable salt thereof:Formula (A-11), wherein: each X9, X10, X11, and X12is independently -O-, -S-, or -NR2-; each Y9, Y10, Y11, and Y12is independently -CH- or -N-;W1is hydrogen, optionally substituted C1-C6alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, - N(R1D)2, -ZB-P(O)(OR1C)2,-ZB-(CH2)p3-P(O)(OR1C)2,-ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZBis N or O; p3is an integer from 1-10; W2is optionally substituted C1-C6alkyl or -C(O)NR1CR1D; each R2is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10- membered heterocycloalkyl; each LXAis independently an optionally substituted C1-C6 alkylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 3 to 7-membered heterocyclene, or optionally substituted 5 to 6-membered heteroarylene; each Rxxis hydrogen or an C1-C6 alkyl; or Rxxand LXAjoin together with the atom(s) to which they are attached to form a 4 to 7-membered heterocyclic ring; each R1Cis independently hydrogen or optionally substituted C1-C20 alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20 alkyl, optionally substituted C2-C10 heteroalkyl, or (AA)p2, wherein each AA is an amino acid; p2 is an integer from 1-10; or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6-membered heterocycloalkyl; m0 is 0, 1, or 2; m2 is 1-4; and n2 is 0-3; wherein the oligomeric backbone is attached at W1, W2, or one of R2.

30. The method of claim 29, wherein the oligomeric backbone is attached to the polyamide at one of R2.

31. The method of claim 29, wherein the oligomeric backbone is attached to the polyamide at W1or W2.

32. The method of claim 29, wherein W2is –NHC(Ry)2C(Ry)2C(O)-**, wherein ** denotes the attachment point to the oligomeric backbone.

33. The method of any one of claims 29-32, wherein each LXAis independently an optionally substituted C1-C6alkylene and Rxxis hydrogen.

34. The method of any one of claims 29-33, wherein each X9, X10, X11, and X12is independently -NR2-.

35. The method of claim 29, wherein the polyamide has the structure of Formula (A-12), or a pharmaceutically acceptable salt thereof:Formula (A-12), wherein: each Y9, Y10, Y11, and Y12is independently -CH- or -N-; W1is hydrogen, optionally substituted C1-C6 alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, - N(R1D)2, -ZB-P(O)(OR1C)2, -ZB-(CH2)p3-P(O)(OR1C)2, -ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZB is N or O; p3 is an integer from 1-10; each R1Cis independently hydrogen or optionally substituted C1-C20 alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20 alkyl, optionally substituted C2-C10 heteroalkyl, or (AA)p2; or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6-membered heterocycloalkyl; each AA is an amino acid; p2 is an integer from 1-10; each R2J, R2K, R2L, and R2Mis independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each Rxand Ryis independently hydrogen, halogen, -CN, -OH, -NH2, -C1-C6 alkyl, or -C1-C6 haloalkyl; or two Rxor two Ryon the same or on adjacent atoms join together with the atom(s) to which they are attached form a C3-C6cycloalkyl or 3 to 6-membered heterocycloalkyl; m0is 0, 1, or 2; m2is 1-4; and n2is 0-3.

36. The method of claim 35, wherein each Rxis independently hydrogen, halogen, or -OH.

37. The method of claim 35 or 36, wherein each Ryis independently hydrogen, halogen, or -OH.

38. The method of any one of claims 35-37, wherein each Rxis hydrogen and each Ryis hydrogen.

39. The method of any one of claims 35-38, wherein m0is 1.

40. The method of any one of claims 35-39, wherein each Y9is -N-.

41. The method of any one of claims 35-38, wherein m0is 0.

42. The method of any one of claims 35-38, wherein each Y10is -CH- and Y11is -N-.

43. The method of claim 35, wherein the polyamide has the structure of Formula (A-13), or a pharmaceutically acceptable salt thereof:Formula (A-13), wherein: W1is hydrogen; each Y12is independently -CH- or -N-; each R2J, R2K, R2L, and R2Mis independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; m2 is 1-4; and n2 is 0-3.

44. The method of claim 43, wherein each Y12is -CH-.

45. The method of claim 43, wherein each Y12is -N-.

46. The method of any one of claims 35-45, wherein each R2J, R2K, R2L, and R2Mis independently optionally substituted C1-C20 alkyl.

47. The method of claim 46, wherein each R2J, R2K, R2L, and R2Mis methyl.

48. The method of claim 43, wherein the polyamide has the structure of Formula (A-14), or a pharmaceutically acceptable salt thereof:Formula (A-14), wherein: m2is 2 or 3; and n2is 0-3.

49. The method of any one of claims 29-48, wherein m2is 2.

50. The method of any one of claims 29-48, wherein n2is 1.

51. The method of any one of claims 29-48, wherein n2is 0.

52. The method of claim 3, wherein the polyamide has the structure of Formula (A-15), or a pharmaceutically acceptable salt thereof:Formula (A-15), wherein: each X13and X14is independently -O-, -S-, or -NR2-; each Y13and Y14is independently -CR2”- or -N-; W1is hydrogen, optionally substituted C1-C6alkyl, (azaneylidene)methanediamine, (azaneylidene)- N,N,N',N'-tetramethylmethanediamine, -C(O)NR1CR1D, -NR1CC(O)R1D, -NR1CC(O)NR1CR1D, - N(R1D)2, -ZB-P(O)(OR1C)2,-ZB-(CH2)p3-P(O)(OR1C)2,-ZB-(CH2)p3-O-P(O)(OR1C)2, wherein ZBis N or O; p3is an integer from 1-10; each R1Cis independently hydrogen or optionally substituted C1-C20alkyl; each R1Dis independently hydrogen, optionally substituted 5-membered heteroaryl, optionally substituted C1-C20alkyl, optionally substituted C2-C10heteroalkyl, or (AA)p2, wherein or R1Cand R1Dtogether with the atoms to which they are attached from an optionally substituted 3 to 6-membered heterocycloalkyl; each AA is an amino acid; p2 is an integer from 1-10;each R2is independently hydrogen, optionally substituted C1-C20alkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20alkynyl, optionally substituted C1-C20aminoalkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C1-C20haloalkyl, optionally substituted C1-C20hydroxyalkyl, optionally substituted C3-C10cycloalkyl, or optionally substituted 3 to 10- membered heterocycloalkyl; each R2” is independently hydrogen, halogen, -OH, C1-C6alkyl, or C1-C6alkoxy; and n3is 1-10.

53. The method of claim 52, wherein each Y13is -N- and each Y14is -N-.

54. The method of claim 52 or 53, wherein each X13and X14is independently -NR2-.

55. The method of claim 54, wherein each R2is independently hydrogen or optionally substituted C1-C20 alkyl.

56. The method of claim 52, wherein the polyamide has the structure of Formula (A-16), or a pharmaceutically acceptable salt thereof:Formula (A-16), wherein: W1is hydrogen; and n3 is 1-10.

57. The method of any one of claims 52-56, wherein n3 is 2 or 3.

58. The method of any one of claims 1-57, wherein the oligomeric backbone is a linker having a length of less than about 50 Angstroms.

59. The method of any one of claims 1-57, wherein the oligomeric backbone is a linker having a length of about 15 to 40 Angstroms.

60. The method of any one of claims 1-57, wherein the linker comprises between 5 and 50 chain atoms.

61. The method of any one of claims 1-57, 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 -((CR1bR1b)x-O)y-, - ((CR1bR1b)x-NR1a)y-, -((CR1bR1b)x-CH=CH-(CR1bR1b)x-O)y-, optionally substituted C1-C10alkyl, optionally substituted C2-C10alkenyl, optionally substituted C2-C10alkynyl, optionally substituted C6-C10arylene, optionally substituted C3-C7cycloalkylene, optionally substituted 5 to 10- membered heteroarylene, optionally substituted 4 to 10-membered heterocycloalkylene, amino acid residue, -O-, -C(O)NR1a-, -NR1aC(O)-, -C(O)-, -NR1a-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR1a-, - NR1aS(O)2-, and -P(O)OH-, and any combinations thereof; whereineach x is independently 2-4; each y is independently 1-10; each R1ais independently a hydrogen or optionally substituted C1-C6alkyl; and each R1bis independently hydrogen, optionally substituted C1-C6alkyl or optionally substituted C1-C6haloalkyl.

62. The molecule of claim 61, 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.

63. The method of any one of claims 1-62, or a pharmaceutically acceptable salt thereof, wherein the second terminus comprises a bromodomain binding moiety or a moiety capable of binding to a bromodomain and extra terminal domain (BET) family member.

64. The method of claim 63, or a pharmaceutically acceptable salt thereof, wherein the BET family member is BRD2, BRD3, BRD4, or BRDT.

65. The method of any one of claims 1-62, 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.

66. The method of claim 65, or a pharmaceutically acceptable salt thereof, wherein the second terminus comprises a CBP / p300 binding moiety.

67. The method of claim 65, or a pharmaceutically acceptable salt thereof, wherein the second terminus comprises a PCAF binding moiety.

68. The method of claims 1-62, 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 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 C1-C6alkyl; R6is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; R7is hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1- C20 alkyl, or optionally substituted C1-C20 heteroalkyl; and x1 is an integer from 1-6.

69. The method of claim 68, 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 optionally substituted 6-membered monocyclic aryl or heteroaryl; YAis -NH- or -O-; R5is hydrogen or C1-C6alkyl; R6is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; R7is hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1- C20alkyl, or optionally substituted C1-C20heteroalkyl; and x1is an integer from 1-6.

70. The method of claim 68, wherein the second terminus comprises the structure of Formula (2-C), or pharmaceutically acceptable salt thereof:Formula (2-C), wherein: Ring B is absent or optionally substituted 6-membered monocyclic aryl or heteroaryl; YA is -NH- or -O-; R5is hydrogen or C1-C6 alkyl; R6is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; R7is hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1- C20 alkyl, or optionally substituted C1-C20 heteroalkyl; R8and R9are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; and x1is an integer from 1-6.

71. The method of claim 68, 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 optionally substituted 6-membered monocyclic aryl or heteroaryl; YA is -NH- or -O-; R5is hydrogen or C1-C6 alkyl; R6is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl;R7is hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1- C20alkyl, or optionally substituted C1-C20heteroalkyl; R10is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6hydroxyalkyl; and x1is an integer from 1-6.

72. The method of any one of claims 1-71, wherein the molecule is a molecule described in Table 3A,3B, or 3C, or a pharmaceutically acceptable salt thereof.

73. The method of any one of claims 1-72, wherein the method comprises a 20%, 50%, 80%, 90%,95%, or 99% increase in expression of the haploinsufficient gene.

74. The method of any one of claims 1-72, wherein the method restores expression of thehaploinsufficient gene to 80%, 90%, 95%, 99%, or 100% of wild type expression levels.

75. The method of any one of claims 1-74, wherein the haploinsufficient gene is TCF4.

76. The method of any one of claims 1-75, wherein the haploinsufficiency disease or disorder is Pitt-Hopkins syndrome (PHTS).

77. The method of any one of claims 1-74, wherein the haploinsufficient gene is COL3A1.

78. The method of any one of claims 1-74 or claim 77, wherein the haploinsufficiency disease ordisorder is Ehlers-Danlos Syndrome.

79. The method of any one of claims 1-74, wherein the haploinsufficient gene is SLC2A1.

80. The method of any one of claims 1-74 or claim 79, wherein the haploinsufficiency disease ordisorder is GLUT1 Deficiency Syndrome.

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