Soluble formulations

Abstract

The present disclosure relates to pharmaceutical compositions comprising a compound having (i) a first terminus comprising a polyamide, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the polyamide and the protein-binding moiety; and a solubilizer.

Description

WSGR Docket No. 56009-757.601SOLUBLE FORMULATIONSCROSS REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 721,760 filed November 18, 2024, which is herein incorporated by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] Disclosed herein are soluble and stable pharmaceutical compositions comprising a chimeric heterocyclic polyamide compound and a solubilizer.BACKGROUND OF THE DISCLOSURE

[0003] The therapeutic efficacy of polyamides can be limited by poor solubility and stability. The chemical stability of a polyamide in aqueous formulations can be increased by altering the chemical structure of the polyamide. However, such formulations may still have poor physical stability due to low solubility in aqueous environments. The solubility of a polyamide can be increased by using excipients, but such compositions also often fall short due to inadequate solubilization of large particles.

[0004] The chimeric heterocyclic polyamides described herein can be solubilized in aqueous solutions with an amphiphilic polymer described herein. The chimeric heterocyclic polyamides described herein are chemically stable (in an aqueous solution) for an extended period of time, such as for 7 or more days at room temperature. Moreover, the chimeric heterocyclic polyamide compositions described herein maintain physical stability for an extended period of time, such as for 7 or more days. The stable compositions described herein maintain a particle diameter of less than 250 nanometers (nm), such as about 10 nm to about 60 nm as measured by dynamic light scattering, for an extended period of time at room temperature.SUMMARY OF THE DISCLOSURE

[0005] Disclosed herein are pharmaceutical compositions comprising a compound having (i) a first terminus comprising a polyamide, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the polyamide and the protein -binding moiety; and a solubilizer. In some embodiments, the solubilizer is an amphiphilic polymer that encapsulates a compound described herein and forms a particle. In some embodiments, the solubilizer encapsulates a compound described herein and forms a micelle. In some embodiments, the solubilizer encapsulates a compound described herein and forms a reverse micelle. In some embodiments, the solubilizer non-covalently binds with the compound described herein and forms a dendrimer. In some embodiments, the pharmaceutical compositions described herein are soluble in an aqueous solution comprising a solubilizer described herein. In some embodiments, the pharmaceutical compositions described herein are physically stable in an aqueous solution comprising a solubilizer described herein for an extended period of time. In some embodiments, the compounds described herein are chemically stable in an aqueous solution comprising a solubilizer described herein for an extended period of time.WSGR Docket No. 56009-757.601

[0006] The DNA binding moiety of compounds described herein 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.

[0007] 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.

[0008] 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

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.DETAILED DESCRIPTION

[0010] The disclosure provides pharmaceutical compositions comprising a compound having (i) a first terminus comprising a polyamide, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the polyamide and the protein -binding moiety; and a solubilizer. The disclosure also provides a particle comprising a compound having (i) a first terminus comprising a polyamide, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the polyamide and the protein-binding moiety; and a block co-polymer.WSGR Docket No. 56009-757.601

[0011] Provided in some embodiments herein is a pharmaceutical composition comprising a compound disclosed herein and a solubilizer disclosed herein. In some embodiments, the pharmaceutical composition described herein is a soluble solution. In some embodiments, the pharmaceutical composition described herein is a stable solution. In some embodiments, the pharmaceutical composition described herein is a soluble solution that is shelf-stable at room temperature, such as for an extended period of time (e. g., 7 days or more, 14 days or more, or 21 days or more). In some embodiments, the solubilizer encapsulates the compound to provide a soluble composition, such as a soluble solution that is shelf-stable at room temperature, such as for an extended period of time (e.g., 7 days or more, 14 days or more, or 21 days or more).

[0012] In some embodiments, the compound described herein comprises a polyamide. In some embodiments, the compound described herein comprises a protein-binding moiety. In some embodiments, the compound described herein comprises an oligomeric backbone that links the polyamide and the proteinbinding moiety. In some embodiments, the compound described herein comprises (i) a first terminus comprising a polyamide, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the polyamide and the protein-binding moiety.

[0013] In some embodiments, the polyamide selected from a linear polyamide, a hairpin polyamide, a lipin polyamide, a U-pin polyamide, an overlapped polyamide, a slipped polyamide, a cyclic polyamide, a tandem polyamide, and an extended polyamide.

[0014] In some embodiments, the polyamide is a linear polyamide. In some embodiments, the polyamide is a hairpin polyamide. In some embodiments, the polyamide is an H-pin polyamide. In some embodiments, the polyamide is an overlapped polyamide. In some embodiments, the polyamide is a U-pin polyamide. In some embodiments, the polyamide is a slipped polyamide. In some embodiments, the polyamide is a cyclic polyamide. In some embodiments, the polyamide is a tandem polyamide. In some embodiments, the polyamide is an extended polyamide.

[0015] In some embodiments, a compound described herein comprises a binding moiety that binds to one or more repeats of a GAA, CCTG, TGGAA, GGGGCC, CTG, CAG, or CGG oligonucleotide sequence. In some embodiments, a compound described herein comprises a polyamide that is or comprises a GAA repeat expansion binding moiety. In some embodiments, a compound described herein comprises a polyamide that is or comprises a GAA repeat expansion polyamide. In some embodiments, a compound described herein comprises a polyamide that is or comprises a CAG repeat expansion binding moiety. In some embodiments, a compound described herein comprises a polyamide that is or comprises a CAG repeat expansion polyamide. In some embodiments, a compound described herein comprises a polyamide that is or comprises a CCTG repeat expansion binding moiety. In some embodiments, a compound described herein comprises a polyamide that is or comprises a CCTG repeat expansion polyamide. In some embodiments, a compound described herein comprises a polyamide that is or comprises a TGGAA repeat expansion binding moiety. In some embodiments, a compound described herein comprises a polyamide that is or comprises a TGGAA repeat expansion polyamide. In some embodiments, a compound described herein comprises a polyamideWSGR Docket No. 56009-757.601that is or comprises a GGGGCC repeat expansion binding moiety. In some embodiments, a compound described herein comprises a polyamide that is or comprises a GGGGCC repeat expansion polyamide. In some embodiments, a compound described herein comprises a polyamide that is or comprises a CAG repeat expansion binding moiety. In some embodiments, a compound described herein comprises a polyamide that is or comprises a CAG repeat expansion polyamide. In some embodiments, a compound described herein comprises a polyamide that is or comprises a CGG repeat expansion binding moiety. In some embodiments, a compound described herein comprises a polyamide that is or comprises a CGG repeat expansion polyamide.

[0016] In some embodiments, a compound described herein comprises a polyamide that is or comprises a pyrrole-imidazole polyamide. In some embodiments, a compound described herein comprises a polyamide that comprises a pyrrole-imidazole polyamide. In some embodiments, a compound described herein is or comprises penta(Arylcarboxamido)-octaoxa-2,6-diazadotriacontan-pyrrolopyridine-carboxamide. In some embodiments, a compound described herein is or comprises penta(heteroarylcarboxamindo)-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide. In some embodiments, a compound described herein is or comprises a hexa(Arylcarboxamido)-octaoxa-2,6-diazadotriacontan-pyrrolopyridine-carboxamide. In some embodiments, a compound described herein is or comprises hexa(heteroarylcarboxamindo)-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide. In some embodiments, a compound described herein is or comprises a septa(Arylcarboxamido)-octaoxa-2,6-diazadotriacontan-pyrrolopyridine-carboxamide. In some embodiments, a compound described herein is or comprises septa(heteroarylcarboxamindo)-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide. In some embodiments, a compound described herein is or comprises poly-heteroarylcarboxamido-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide. In some embodiments, a compound described herein is or comprises poly-heteroarylcarboxamido-octaoxa-triazolodiazepine. In some embodiments, a compound described herein is or comprises Pyrrolopyridine-carboxamido-polyethyleneglycolyl-penta(heteroarylaminoacid). In some embodiments, a compound described herein is or comprises Pyrrolopyridine-carboxamido-polyethyleneglycolyl-hexa(heteroaryl aminoacid). In some embodiments, a compound described herein is or comprises Pyrrolopyridine-carboxamido-polyethyleneglycolyl-hepta(heteroarylaminoacid).

[0017] In some embodiments, a polyamide described herein comprises a structure of Formula (A-l), or a pharmaceutically acceptable salt thereof:RiNFormula (A-l),WSGR Docket No. 56009-757.601wherein:each Y9, Y10, Y11, and Y12is independently -CH- or -N-;each X9, X10, X11, and X12is independently -O-, -S-, or -NR2-;W1is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl; -NRleRlf, - NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, -NRleC(O)ORlf, -N=C(N(Rle)2)2, -ZB- PO(ORle)2, -ZB-(CH2)p3-PO(ORle)2, or -ZB-(CH2)p3-O-PO(ORle)2, whereineach Rleis independently hydrogen or optionally substituted C1-C10 alkyl;each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- Cio heteroalkyl, AAp2, or optionally substituted 5-membered heteroaryl, wherein each AA is an amino acid and p2is an integer from 1-10;ZBis N or O;P3 is 1-10;W2is optionally substituted Ci-C2o alkyl or optionally substituted Ci-C2o heteroalkyl;or W2is -L'-Z-R4; whereinL1is Ci-C2o alkylene or C2-C2o heteroalkylene;Z is absent or -C(O)-;R4is absent, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted Ci-C2o alkyl, or optionally substituted Ci-C2o heteroalkyl; R4bis optionally substituted Ci-C2o alkyl, optionally substituted C2-C2o alkenyl, optionally substituted C2-C2o alkynyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci- C2o haloalkyl, optionally substituted Ci-C2o heteroalkyl, optionally substituted Ci-C2o hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl;or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 8-membered heterocycloalkyl;Rwis hydrogen or optionally substituted Ci-C2o alkyl;or Rwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 8-membered heterocycloalkyl;each R2is independently hydrogen, optionally substituted Ci-C2o alkyl, optionally substituted C2-C2o alkenyl, optionally substituted C2-C2o alkynyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci-C2o heteroalkyl, optionally substituted C2-C2o heteroalkenyl, optionally substituted C2-C2o heteroalkynyl, optionally substituted Ci-C2o haloalkyl, optionally substituted Ci-C2o hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each LXAis independently an optionally substituted Ci-Ce alkylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 3 to 7-membered heterocyclene, or optionally substituted 5 to 6- membered heteroarylene;WSGR Docket No. 56009-757.601each Rxxis hydrogen or an Ci-Ce alkyl; oreach Rxxand LXAcombine with the atom(s) to which they are attached to form a 4- to 7-membered heterocyclic ring;mo is 0, 1, or 2;m2 is 1-4; andn2 is 0-3;wherein the oligomeric backbone is attached at W1, W2, or one of R2.

[0018] In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-l) at W1. In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-l) at W2. In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-l) at one of R2.

[0019] In some embodiments of Formula (A-l), W2is optionally substituted C1-C20 alkyl, optionally substituted with oxo. In some embodiments of Formula (A-l), W2is -CH2CH2C O)-*, wherein * is the attachment point to the oligomeric linker.

[0020] In some embodiments of Formula (A-l), eachX9, X10, Xn, and X12is independently -O- or-S-. In some embodiments of Formula (A-l), X9, X10, X11, and X12are each independently -NR2.

[0021] In some embodiments of Formula (A-l), each LXAis independently an optionally substituted Ci-C4 alkylene. In some embodiments of Formula (A-l), each LXAis independently an optionally substituted C1-C2 alkylene. In some embodiments of Formula (A-l), each LXAis independently -C(RX)2C(RX)2-, wherein each Rxis hydrogen, halogen, -CN, -OH, -NH2, -Ci-Ce alkyl, or-Ci-Ce haloalkyl; or two Rxon the same or adjacent atoms together with the atom(s) to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl.

[0022] In some embodiments of Formula (A-l) each LXAis independently an optionally substituted C3-C7 cycloalkylene. In some embodiments of Formula (A-l), each LXAis independently cyclopentylene or cyclohexylene.

[0023] In some embodiments of Formula (A-l), each Rxxis independently hydrogen. In some embodiments of Formula (A-l), each Rxxis independently Ci-Ce alkyl.

[0024] In some embodiments of Formula (A-l), LXAand Rxxjoin together with the atoms to which they are attached to form a 4 to 7-membered heterocyclic ring.

[0025] In some embodiments, a polyamide described herein comprises a structure of Formula (A- 2), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601n2Formula (A- 2),wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, whereineach Rleis independently hydrogen or C1-C3 alkyl;each Y9, Y10, Y11, and Y12is independently -CH- or -N-;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 Rxis independently hydrogen, halogen, -CN, -OH, -NH2, -Ci-Ce alkyl, or -Ci-Ce haloalkyl; or two Rxon the same or adjacent atoms together with the atom(s) to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl;mo is 0, 1, or 2;m2 is 1-4; andn2 is 0-3.

[0026] In some embodiments of Formula (A-l) or (A- 2), each Y9is -N-. In some embodiments of Formula (A-l) or (A- 2), Y11is -N-. In some embodiments of Formula (A-l) or (A-2), each Y10is independently -CH-.

[0027] In some embodiments of Formula (A-l) or (A-2), mo is 1.

[0028] In some embodiments, a polyamide described herein comprises a structure of Formula (A-3), or a pharmaceutically acceptable salt thereof:WVn2WSGR Docket No. 56009-757.601Formula (A-3),wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, whereineach Rleis independently hydrogen or C1-C3 alkyleach Y12is independently -CH- or -N-;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;m2 is 1-4; andmis 0-3.

[0029] In some embodiments of Formula (A-3), each Y12is -CH-. In some embodiments of Formula (A-3), each Y12is -N-.

[0030] In some embodiments, a polyamide described herein comprises a structure of Formula (A-4), or a pharmaceutically acceptable salt thereof:O Formula (A-4),wherein:W1is hydrogen, halogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl - NRleRlf, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, -NRleC(O)ORlf, - N=C(N(Rle)2)2, -ZB-PO(ORle)2, -ZB-(CH2)p3-PO(ORle)2,or -ZB-(CH2)P3-O-PO(ORle)2, wherein each Rleis independently hydrogen or optionally substituted C1-C10 alkyl;each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- C10 heteroalkyl, AAP2, or optionally substituted 5-membered heteroaryl, wherein each AA is an amino acid and p2 is an integer from 1-10;WSGR Docket No. 56009-757.601ZB is -N- or -O-;P3 is 1-10;W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl;or W2is L1-Z-R4; whereinL1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted Ci- C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl;or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;Rwis hydrogen or optionally substituted C1-C20 alkyl;or Rwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl;each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -N- or -CH-;each X1, X2, X3, X4, X5, X6, X7, and X8is independently -S-, -O-, or -NR2-;each R2is independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1-50;each R3is independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;or two R3together with the atom(s) to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl;each Rxand Ryis independently hydrogen, halogen, -CN, -OH, -NH2, C1-C10 alkyl, or C1-C10 haloalkyl; or two Rxor two Rytogether with the atoms to which they are attached to form a C3-C6 cycloalkyl or 3 to 6- membered heterocycloalkyl;ji is 0 or 1;no is 0 or 1;m1and n1are each independently an integer from 0-3; andWSGR Docket No. 56009-757.601pi is 3 or 4;wherein the oligomeric backbone is attached at W1, W2, one of R2, or one of R3.

[0031] In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-4) at W1. In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-4) at W2. In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-4) at one of R2. In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-4) at one of R3.

[0032] In some embodiments of Formula (A-4), W2is optionally substituted C1-C20 alkyl, optionally substituted with oxo. In some embodiments of Formula (A-4), W2is -CH2CH2C O)-*, wherein * is the attachment point to the oligomeric linker.

[0033] In some embodiments of Formula (A-4), each X1, X2, X3, X4, X5, X6, X7, and X8is independently -S- or -O-. In some embodiments of Formula (A-4), each X1, X2, X3, X4, X5, X6, X7, and X8is independently -NR2-.

[0034] In some embodiments of Formula (A-4), each Rxand Ryis independently hydrogen, halogen, or -OH. In some embodiments of Formula (A-4), each Rxand Ryis independently hydrogen.

[0035] In some embodiments of Formula (A-4), two Rxtogether with the atoms to which they are attached to form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A-4), two Rytogether with the atoms to which they are attached to form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl.

[0036] In some embodiments of Formula (A-4), no is 1. In some embodiments of Formula (A-4), no is 0.

[0037] In some embodiments of Formula (A-4), pi is 3.

[0038] In some embodiments, a polyamide described herein comprises the structure of Formula (A-5), or a pharmaceutically acceptable salt thereof:Formula (A-5),wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, whereinWSGR Docket No. 56009-757.601each Rleis independently hydrogen or C1-C3 alkyl;each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 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 of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl;each Rzis independently -CN, -OH, -OR23, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinR / aand Rzbare each independently hydrogen, alkyl, or PEG;RZtis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;ji is 0 or 1; andm1 and n1 are each independently an integer from 0-3.

[0039] In some embodiments, a polyamide described herein comprises the structure of Formula (A-6), or a pharmaceutically acceptable salt thereof:Formula (A-6),wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, whereineach Rleis independently hydrogen or C1-C3 alkyl;WSGR Docket No. 56009-757.601each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 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 of which is optionally substituted with one or more Rz; each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl;each Rzis independently -CN, -OH, -OR23, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinR / aand Rzbare each independently hydrogen, alkyl, or PEG;RZtis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;ji is 0 or 1; andm1 and n1 are each independently an integer from 0-3.

[0040] In some embodiments of Formula (A-4), W2is -L'-Z-R4and Rwis hydrogen.

[0041] In some embodiments of (A-4), (A-5), or (A-6), ji is 1.

[0042] In some embodiments, a polyamide described herein comprises the structure of structure of Formula (A- 7), or a pharmaceutically acceptable salt thereof:Formula (A- 7),wherein:WSGR Docket No. 56009-757.601W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, whereineach Rleis independently hydrogen or C1-C3 alkyl;each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl;or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1-50; each of which is optionally substituted with one or more Rz;each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; andeach Rzis independently -CN, -OH, -OR23, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, - NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinR / aand Rzbare each independently hydrogen, alkyl, or PEG;RZtis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;n1 and m1 are each independently 0 or 1;wherein the oligomeric backbone is attached at one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2h, one of R3a; or one of R3b.

[0043] In some embodiments of Formula (A- 7), the oligomeric backbone is attached to the polyamide of Formula (A- 7) at one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2h.WSGR Docket No. 56009-757.601

[0044] In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-7) at one of R3a. In some embodiments, the oligomeric backbone is attached to the polyamide of Formula (A-7) at one of R3b.

[0045] In some embodiments of Formula (A-4), (A-5), (A-6), or (A-7), each Y1, Y3, and Y6is -CH-. In some embodiments of Formula (A-4), (A-5), (A-6), or (A-7), each Y2, Y4, Y7, and Y8is -NH-.

[0046] In some embodiments of Formula (A-4), (A-5), (A-6), or (A-7), each R3, R3a, and R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e. In some embodiments of Formula (A-4), (A-5), (A-6), or (A-7), each R3, R3a, and R3bis independently hydrogen or -NR3cR3d. In some embodiments of Formula (A-4), (A-5), (A-6), or (A-7), each R3, R3a, and R3bis hydrogen.

[0047] In some embodiments of F ormula (A-5), (A-6), or (A-7), two R3atogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A-5), (A-6), or (A-7), two R3atogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0048] In some embodiments of Formula (A-5), (A-6), or (A-7), two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A-5), (A-6), or (A-7), two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0049] In some embodiments of Formula (A-l), (A-4) or (A-7), L1is C1-C20 alkylene. In some embodiments of Formula (A-l), (A-4), or (A-7), L1is C2-C20 heteroalkylene.

[0050] In some embodiments of Formula (A-l), (A-4) or (A-7), Z is absent or -C(O)-. In some embodiments of Formula (A-l), (A-4), or (A-7), Z is -C(O)-. In some embodiments of Formula (A-l), (A-4), or (A-7), Z is absent.

[0051] In some embodiments of Formula (A-l), (A-4), or (A-7), R4is C1-C3 alkyl or -NR4aR4b.

[0052] In some embodiments of Formula (A-l), (A-4), or (A-7), R4is -NR4aR4b; wherein R4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; and R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted Ci-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl. In some embodiments of Formula (A-l), (A-4), or (A-7), R4ais hydrogen or optionally substituted C1-C20 alkyl; and R4bis optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl. In some embodiments of Formula (A-l), (A-4), or (A-7), R4ais optionally substituted C1-C20 alkyl; and R4bis optionally substituted C1-C20 alkyl.

[0053] In some embodiments of Formula (A-l), (A-4), or (A-7), R4is -NR4aR4b; wherein R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10 -membered heterocycloalkyl which is partially or fully saturated. In some embodiments, the heterocycloalkyl is monocyclic, bicyclic, spirocyclic, or bridged.WSGR Docket No. 56009-757.601

[0054] In some embodiments of Formula (A-4), (A-5), (A-6), or (A-7), n1 is 0.

[0055] In some embodiments of Formula (A-4), (A-5), (A-6), or (A-7), mi is 1.

[0056] In some embodiments, a polyamide described herein comprises the structure of structure of Formula (A-8), or a pharmaceutically acceptable salt thereof:Formula (A-8),wherein:each X13and X14is independently -O-, -S-, or -NR2-;each Y13and Y14is independently -CR2- or -N-;W1is hydrogen, halogen, optionally substituted Ci-Cio alkyl, optionally substituted Ci-Cio haloalkyl - NRleRlf, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, -NRleC(O)ORlf, - N=C(N(Rle)2)2, -ZB-PO(ORle)2, -ZB-(CH2)p3-PO(ORle)2,or -ZB-(CH2)p3-O-PO(ORle)2, wherein each Rleis independently hydrogen or optionally substituted Ci-Cio alkyl;each Rlfis independently hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted Ci- Cio heteroalkyl, AAp2, or optionally substituted 5-membered heteroaryl, wherein each AA is an amino acid and p2is an integer from 1-10;ZBis -N- or -O-;p3is 1-10;each R2is independently hydrogen, optionally substituted Ci-C2o alkyl, optionally substituted C2-C2o alkenyl, optionally substituted C2-C2o alkynyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci-C2o heteroalkyl, optionally substituted C2-C2o heteroalkenyl, optionally substituted C2-C2o heteroalkynyl, optionally substituted Ci-C2o haloalkyl, optionally substituted Ci-C2o hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each R2” is independently hydrogen, halogen, -OH, Ci-Ce alkyl, or Ci-Ce alkoxy; andn3is 1-10.

[0057] In some embodiments of Formula (A-8), each X13and X14is independently -O- or -S-. In some embodiments of Formula (A-8), X13and X14are each independently -NR2-.

[0058] In some embodiments of Formula (A-8), each Y13is -CR2”-. In some embodiments of Formula (A-8), each Y13is -N-.

[0059] In some embodiments of Formula (A-8), each Y14is -CR2”-. In some embodiments of Formula (A-8), each Y14is -N-.

[0060] In some embodiments of Formula (A-8), each R2” is independently hydrogen, halogen, or -OH. In some embodiments of Formula (A-8), each R2” is hydrogen.WSGR Docket No. 56009-757.601

[0061] In some embodiments of Formula (A-8), n3 is 1, 2, or 3. In some embodiments of Formula (A-8), n3 is 3. In some embodiments of Formula (A-8), n3 is 2.

[0062] In some embodiments of Formula (A- 1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), or (A-8), each R2, R2a, R2b, R2c, R2d, R2e, R2f, R2h, R2J, R2K, R2L, or R2Mis independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments of Formula (A- 1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), or (A-8), each R2, R2a, R2b, R2c, R2d, R2e, R2f, R2h, R2J, R2K, R2L, or R2Mis independently optionally substituted C1-C10 alkyl or optionally substituted C3-C8 cycloalkyl. In some embodiments of Formula (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), or (A-8), each R2, R2a, R2b, R2c, R2d, R2e, R2f, R2h, R2J, R2K, R2L, or R2Mis independently optionally substituted C1-C10 alkyl.

[0063] In some embodiments of Formula (A-5), (A-6), or (A-7), each R2a, R2b, R2c, R2d, R2e, R2f, or R2his independently C1-C10 alkyl optionally substituted with one or more Rz.

[0064] In some embodiments of Formula (A-5), (A-6), or (A-7), each Rzis independently -OH, -OR23, -NRZaRZb, -CO(O)RZc, -C(O)ORZc, -C(O)NRZaRzb, or -NHC(O)RZc.

[0065] In some embodiments of Formula (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), or (A-8), W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2. In some embodiments of Formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), or (A-8), W1is hydrogen.

[0066] In some embodiments, a polyamide described herein comprises the structure of structure of Formula (A-9), or a pharmaceutically acceptable salt thereof:Formula (A-9),wherein:Y16, Y17, Y18, Y19, Y20, Y21, Y22, and Y23are each independently CH, COH, or N;each R2aais independently hydrogen or alkyl;R3Jand R3Kare each independently hydrogen, -NHR3L, or -Ymx-Zm;each R3Lis hydrogen, biotin, or a fluorescent groupWSGR Docket No. 56009-757.601Bxis an acetyl group or -Ymx-Zm;Ymx is an amide bond, a phosphodisulfide bond, an ester bond, a coordination bond, or an ether bond, or represents a moiety containing a functional group that forms one or more of these bonds; wherein mx is an integer from 0-5;Zm is an agent;wherein at least one of R3J, R3K, Ax, and Bxis -Ymx-Zm;when the complex includes a plurality of structures represented by Ym-Zm, each of Ymin the plurality of Ym-Zmmay be the same as or different from the other Ymand each of Zmin the plurality of Ym-Zmmay be the same as or different from the other Zm;wherein one of the pyrroles may be substituted with a O ; andwherein the oligomeric backbone is attached at one Zm.

[0067] In some embodiments, a polyamide described herein comprises the structure of structure of Formula (A-10A) or (A-10B), or a pharmaceutically acceptable salt thereof:Formula (A-10A) orWSGR Docket No. 56009-757.601Formula (A-10B),wherein:Y16, Y17, Y18, Y19, Y20, Y21, Y22, and Y23are each independently CH or N;Ymx is an amide bond, a phosphodisulfide bond, an ester bond, a coordinate bond, or an ether bond, or a moiety containing a functional group that forms a bond; wherein mx is an integer from 0-5; each R2aais independently hydrogen or alkyl;R3Jand R3Kare each independently hydrogen or -NHR3L; andeach R3Lis independently hydrogen, biotin, or a fluorescent group.

[0068] In some embodiments, a polyamide described herein comprises the structure of structure of Formula (A-ll), or a pharmaceutically acceptable salt thereof:wxFormula (A-ll),wherein:wx is 5, 6, 7, 8, 9, or 10;each Zxis independently selected from, and -CH2CH2-;ZYis or

[0069] In some embodiments, a polyamide described herein comprises the structure of structure of Formula (A-12A), (A-12B), or (A-12C), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (A-12A), HFormula (A-12B), orFormula (A-12C).

[0070] In some embodiments, the compound described herein comprises a second terminus. In some embodiments, the compound described herein comprises a second terminus comprising a protein-binding moiety.

[0071] 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 an expanded nucleotide repeat.

[0072] In some embodiments, the second terminus comprises a bromodomain binding moiety.

[0073] In some embodiments, the second terminus is a small molecule. In some embodiments, the protein-binding moiety is a small molecule.

[0074] In some embodiments, the second terminus comprises a moiety capable of binding to a bromodomain and extra terminal domain (BET) family member.

[0075] 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.WSGR Docket No. 56009-757.601

[0076] 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.

[0077] In some embodiments, the protein-binding moiety binds to an E3 ligase.

[0078] In some embodiments, the regulatory molecule is CBP / p300.

[0079] In some embodiments, the regulatory molecule is PCAF (P 300 / CBP -Associated Factor).

[0080] In some embodiments, the regulatory molecule is CECR2 (cat eye syndrome chromosome region candidate 2).

[0081] In some embodiments, the regulatory molecule is BRPF (bromodomain and PHD fingercontaining protein).

[0082] In some embodiments, the regulatory molecule is a ATAD2 or ATAD2B chromatin remodeling protein.

[0083] In some embodiments, the regulatory molecule is BAZ2 (Bromodomain Adjacent Zinc Finger.

[0084] In some embodiments, the regulatory molecule is TAF1 (TBP associated factor).

[0085] In some embodiments, the regulatory molecule is TRIM24 (tripartite motif-containing 24).

[0086] In some embodiments, the regulatory molecule is BRD7 / 9.

[0087] In some embodiments, the regulatory molecule is BPTF (Bromodomain PHD Finger Transcription Factor).

[0088] In some embodiments, the regulatory molecule is SMARCA2 / 4.

[0089] In some embodiments, the regulatory molecule is PBRM1.

[0090] In some embodiments, the regulatory molecule modulates the rearrangement of histones.

[0091] In some embodiments, the regulatory molecule modulates the glycosylation, phosphorylation, alkylation, or acylation of histones.

[0092] In some embodiments, the regulatory molecule is a transcription factor.

[0093] In some embodiments, the regulatory molecule is an RNA polymerase.

[0094] In some embodiments, the regulatory molecule is a moiety that regulates the activity of RNA polymerase.

[0095] 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.

[0096] 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.WSGR Docket No. 56009-757.601

[0097] 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 an optionally substituted 6-membered monocyclic aryl or heteroaryl;D is C or N;E is O or N;YA is -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; andxi is an integer from 1-6;wherein the oligomeric linker is attached through either Ring B or through R7.

[0098] In some embodiments, D is N and E is N. In some embodiments, D is C and E is O.

[0099] In some embodiments, the second terminus comprises the structure of Formula (2-B), or a pharmaceutically acceptable salt thereof:Formula (2-B),wherein:WSGR Docket No. 56009-757.601Ring A is an optionally substituted aryl or optionally substituted 5 to 6-membered heteroaryl;Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;YA is -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; andxi is an integer from 1-6.

[0100] In some embodiments, Ring A is an optionally substituted aryl ring. In some embodiments, Ring A is an optionally substituted phenyl. In some embodiments, Ring A is an optionally substituted 5 membered heteroaryl. In some embodiments, Ring A is an optionally substituted oxazolyl. In some embodiments, Ring A is an optionally substituted furanyl. In some embodiments, Ring A is an optionally substituted thiophenyl.

[0101] In some embodiments, the second terminus comprising the structure of Formula (2-C), or a pharmaceutically acceptable salt thereof:Formula (2-C),wherein:Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;YA is -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;WSGR Docket No. 56009-757.601or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R8and R9are each independently selected from hydrogen, -C(O)OR8a, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; andR8ais hydrogen, C1-C20 alkyl, or C1-C20 heteroalkyl; andxi is an integer from 1-6.

[0102] In some embodiments, R8and R9are each independently selected from optionally substituted Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce hydroxyalkyl. In some embodiments, R8and R9are each independently selected from optionally substituted Ci-Ce alkyl. In some embodiments, R8and R9are each independently methyl, ethyl, or propyl. In some embodiments, R8and R9are each independently methyl. In some embodiments, R8and R9are each independently ethyl. In some embodiments, R8and R9are each independently propyl.

[0103] In some embodiments, the second terminus comprising the structure of Formula (2-D), or a pharmaceutically acceptable salt thereof:R7R6Formula (2-D),wherein:Ring B is absent or an optionally substituted 6-membered monocyclic aryl or heteroaryl;YA is -NH- or -O-;R5is hydrogen or Ci-Ce alkyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;R7is selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ci-Ce hydroxyalkyl;or R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R10is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl; andxi is an integer from 1-6.WSGR Docket No. 56009-757.601

[0104] In some embodiments, R5is Ci-Ce alkyl. In some embodiments, R5is methyl or ethyl. In some embodiments, R5is methyl. In some embodiments, R5is ethyl. In some embodiments, R5is hydrogen.

[0105] In some embodiments, R7is selected from hydrogen, halogen, optionally substituted Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce hydroxyalkyl. In some embodiments, R7is halogen. In some embodiments, R7is Br, Cl, or F. In some embodiments, R7is Cl. In some embodiments, R7is F. In some embodiments, R7is Br.

[0106] In some embodiments, R7is -NR7AR7B, wherein R7Aand R7Bare each independently hydrogen or optionally substituted Ci-Ce alkyl.

[0107] In some embodiments, R10is selected from optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl. In some embodiments, R10is selected from optionally substituted Ci-Ce alkyl. In some embodiments, R10is methyl, ethyl, or propyl. In some embodiments, R10is methyl. In some embodiments, R10is optionally substituted Ci-6 hydroxy alkyl. In some embodiments, R10is -OMe.

[0108] In some embodiments, R6is selected from optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl. In some embodiments, R6is an optionally substituted Ci-Ce alkyl. In some embodiments, R6is methyl, ethyl, or propyl. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is propyl. In some embodiments, R6is hydrogen.

[0109] In some embodiments, YA is -NH-. In some embodiments, YA is -O-.

[0110] In some embodiments, YA is NH and xi is 1.

[0111] In some embodiments, xi is an integer from 1-5, 1-4, 1-3, or 1-2. In some embodiments, xi is 1. In some embodiments, xi is 2.

[0112] In some embodiments, Ring B is an optionally substituted 6-membered monocyclic aryl or heteroaryl, each of which is optionally substituted with alkyl, amino, halogen, hydroxy, hydroxyalkyl, or PEG. In some embodiments Ring B is phenyl. In some embodiments, Ring B is 6-membered monocyclic heteroaryl. In some embodiments, Ring B is pyridine or pyrimidine. In some embodiments, Ring B is absent.

[0113] In some embodiments, the second terminus comprises the structure of Formula (2-E), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601

[0114] In some embodiments, the second terminus comprises the structure of Formula (3-A), or a pharmaceutically acceptable salt thereof:Formula (3-A),wherein:YB is -CH2NH-, -CH2O-, -NH-, or -O-;R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R12is hydrogen, halogen, -OH, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;R14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;or R14is -NRARB;R16is an optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, -S(O)(=NH)RA, -SO2RA, or -NHSO2RA;RYAis hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted 5-6-membered monocyclic aryl or heteroaryl;each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionallyWSGR Docket No. 56009-757.601substituted C3-C6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; andyi is 1-3;wherein the attachment to the oligomeric backbone is at either R14or at RYA.

[0115] In some embodiments, the second terminus comprises the structure of Formula (3-B), or a pharmaceutically acceptable salt thereof:Formula (3-B),wherein:Ring C is absent, optionally substituted 5 to 6-membered monocyclic aryl or heteroaryl or 4 to 8-membered heterocycle;YB is -NH-, -CH2NH-, -CH2O-, or -O-;R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R12is hydrogen, optionally substituted Ci-Ce alkyl, C(O)RA, or C(O)NRARB; wherein each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl; R13is hydrogen, substituted aryl, substituted heteroaryl, or substituted oxy dibenzene; andy2 is an integer from 0-2

[0116] In some embodiments, the second terminus comprises the structure of Formula (3-B1), or a pharmaceutically acceptable salt thereof:R13Formula (3-B1),wherein:R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R13is hydrogen, substituted aryl, substituted heteroaryl, or substituted oxy dibenzene; andy2 is an integer from 0-2

[0117] In some embodiments, y2 is 0. In some embodiments, y2 is 1. In some embodiments, y2 is 2.

[0118] In some embodiments, R13is substituted aryl or substituted heteroaryl. In some embodiments, R13is hydrogen.

[0119] In some embodiments, R13is substituted oxy dibenzene.WSGR Docket No. 56009-757.601

[0120] In some embodiments, R13is, whereinR14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;or R14is -NRARB;R16is an optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, -S(O)(=NH)RA, -SO2RA, or -NHSO2RA;each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; andyi is 1-3.

[0121] In some embodiments, the second terminus comprises the structure of Formula (3-C), or a pharmaceutically acceptable salt thereof:R11A OFormula (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 Ci-Ce alkyl;R12is hydrogen, optionally substituted Ci-Ce alkyl, C(O)RA, or C(O)NRARB;R14and R15are each independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;or R14is -NRARB;R16is an optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, -S(O)(=NH)RA, -SO2RA, or -NHSO2RA;WSGR Docket No. 56009-757.601each RAand RBis independently hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; andyi is an integer from 1-3.

[0122] In some embodiments, YB is -NH-. In some embodiments, YB is -CH2NH-. In some embodiments, YB is -CH2O-. In some embodiments, YB is -O-.

[0123] In some embodiments, Ring C is an optionally substituted 5 or 6-membered monocyclic aryl or heteroaryl, each of which is optionally substituted with alkyl, amino, halogen, hydroxy, hydroxyalkyl, or PEG.

[0124] 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. In some embodiments, Ring C is absent.

[0125] In some embodiments, the second terminus comprises the structure of Formula (3-D), or a pharmaceutically acceptable salt thereof:R11AOFormula (3-D),wherein:R11Aand R11Bare each independently hydrogen or optionally substituted Ci-Ce alkyl;R12is hydrogen or an optionally substituted Ci-Ce alkyl;each R15is independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;R16is an optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce hydroxyalkyl, -S(O)(=NH)RA, -SO2RA, or -NHSO2RA;RAis hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C3-C6WSGR Docket No. 56009-757.601cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6- membered heteroaryl; andyi is an integer from 1-3.

[0126] In some embodiments, R11Aand R11Bare each independently optionally substituted Ci-Ce alkyl. In some embodiments, R11Aand R11Bare each independently methyl, ethyl, propyl, or tert-butyl. In some embodiments, R11Aand R11Bare each independently methyl. In some embodiments, R11Aand R11Bare each independently hydrogen.

[0127] In some embodiments, R11Ais Ci-Ce alkyl, optionally substituted with haloalkyl or phosphorous hydroxide. In some embodiments, R11Ais Ci-Ce alkyl substituted with -OP(O)(OH)2. In some embodiments, R11Ais unsubstituted Ci-Ce alkyl. In some embodiments, R11Ais methyl, ethyl, or tert-butyl. In some embodiments, R11Ais methyl. In some embodiments, R11Ais hydrogen.

[0128] In some embodiments, R12is optionally substituted Ci-Ce alkyl. In some embodiments, R12is hydrogen.

[0129] In some embodiments, R12is C(O)RAor C(O)NRARB. In some embodiments, R12is C(O)NRARB, wherein RAand RBare each independently hydrogen or optionally substituted Ci-Ce alkyl.

[0130] In some embodiments, R14and R15are each independently hydrogen, -CN, or -NO2. In some embodiments, R14and R15are each independently halogen or optionally substituted Ci-Ce alkyl. In some embodiments, R14and R15are each independently Br, Cl, F, methyl, or ethyl. In some embodiments, R14and R15are each independently F or methyl.

[0131] In some embodiments, R16is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted Ci-Ce hydroxyalkyl, each of which is optionally substituted with one or more amido, alkyl, alkynyl, azido, amino, halogen, haloalkyl, hydroxy, nitro, oxo (=0), phosphorous hydroxide, or PEG.

[0132] In some embodiments, R16is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, or optionally substituted Ci-Ce hydroxyalkyl. In some embodiments, R16is Ci-Ce alkyl or Ci-Ce heteroalkyl, each or which optionally substituted with one or more -CN, -NH2, -N3, -OH, -CF3, or -OP(O)(OH)2.

[0133] In some embodiments, R16is -SO2RA, wherein RAis optionally substituted Ci-Ce alkyl. In some embodiments, R16is -SO2RA, wherein RAis substituted Ci-Ce alkyl, which is optionally substituted withembodiments, R16is -S02Et. In some embodiments, R16is -SO2Me.WSGR Docket No. 56009-757.601

[0134] In some embodiments, R16is -NHSO2RA, wherein RAis Ci-Ce alkyl. In some embodiments, R16is -NHSO2Et. In some embodiments, R16is -NHSO2Me. In some embodiments, R16is -NHSO2RA, wherein RAis Ci-Ce alkyl which is optionally substitutedwith

[0135] In some embodiments, yi is 1. In some embodiments, yi is 2. In some embodiments, yi is 3.

[0136] In some embodiments, the second terminus comprises the structure of Formula (3-E) or Formula (3-F), or a pharmaceutically acceptable salt thereof:Formula (3-E) or Formula (3-F).

[0137] 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-G) or Formula (3-H).

[0138] In some embodiments, the second terminus comprising the structure of Formula (3-1), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601

[0139] 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;Xjand X1kare each independently C or N, wherein one of Xjor Xkis 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-C8 cycloalkyl or optionally substituted 4 to 7-membered heteroaryl; each R20is independently hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;X3 is an integer from 1-3; andy4 is an integer from 1-4;wherein the attachment to the oligomeric backbone is at either R19or at one of R20.

[0140] In some embodiments, attachment to the oligomeric backbone is at R19.

[0141] In some embodiments, attachment to the oligomeric backbone is at one of R20.

[0142] In some embodiments, the second terminus comprises the structure of Formula (4-B), or a pharmaceutically acceptable salt thereof:IL*XR19Formula (4-B),wherein:Ring D is absent, optionally substituted phenyl, or optionally substituted 5 to 6-membered heteroaryl;WSGR Docket No. 56009-757.601Xjand Xkare each independently C or N, wherein one of Xjor Xkis 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-C8 cycloalkyl or optionally substituted 4 to 7-membered heteroaryl; and X3 is an integer from 1-3.

[0143] In some embodiments, Xjis N; and X1kis C. In some embodiments, Xjis C; and Xkis N.

[0144] In some embodiments, the second terminus comprises the structure of Formula (4-C), or a pharmaceutically acceptable salt thereof:R19Formula (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-C3 alkyl;R18is an optionally substituted 5 to 6-membered heteroaryl;R19is an optionally substituted C3-C8 cycloalkyl or optionally substituted 4 to 7-membered heteroaryl; and X3 is an integer from 1-3.

[0145] 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.

[0146] In some embodiments, R19is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R19is optionally substituted 4 to 7-membered heteroaryl.

[0147] In some embodiments, the second terminus comprises the structure of Formula (4-D), or a pharmaceutically acceptable salt thereof:y4NFormula (4-D),wherein:L2is an optionally substituted alkylene, -O-, or -NRD-, whereinWSGR Docket No. 56009-757.601RDis hydrogen or optionally substituted C1-C3 alkyl;R18is an optionally substituted 5 to 6-membered heteroaryl;R20is hydrogen, halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl;X3 is an integer from 1-3; andy4 is an integer from 1-4.

[0148] 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.

[0149] In some embodiments, L2is -NRD-. In some embodiments, L2is -NH-.

[0150] 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.

[0151] In some embodiments, R20is halogen, -CN, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl.

[0152] In some embodiments, X3 is 1. In some embodiments, X3 is 2. In some embodiments, X3 is 3.

[0153] In some embodiments, y4 is 1 or 2. In some embodiments, y4 is 1. In some embodiments, y4 is 2. In some embodiments, y4 is 3. In some embodiments, y4 is 4.

[0154] 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).

[0155] In some embodiments, the second terminus comprises the structure of Formula (4-G), or a pharmaceutically acceptable salt thereof:

[0156] In some embodiments, the second terminus comprises the structure of Formula (5 -A), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601wherein:Ring E is absent or an optionally substituted phenyl or optionally substituted 5 to 6-membered heteroaryl; Xhis CH or N;L3is -NRE- or -CRERE-, wherein each REis independently hydrogen or optionally substituted C1-C3 alkyl; R21is Ci-Ce alkyl or C3-C6 cycloalkyl; andR22is halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl.

[0157] 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.

[0158] In some embodiments, Xhis CH and L3is -NRE-. In some embodiments, Xhis N and L3is -CRERE-.

[0159] In some embodiments, R21is Ci-Ce alkyl. In some embodiments, R21is methyl.

[0160] In some embodiments, R22is halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, or optionally substituted Ci-Ce hydroxyalkyl. In some embodiments, R22is CN, F, Cl, Br, or methyl.

[0161] In some embodiments, the second terminus comprises the structure of Formula (5-B) or Formula (5-C), or a pharmaceutically acceptable salt thereof:Formula (5-B) or Formula (5-C).

[0162] In some embodiments, the second terminus comprises the structure of Formula (6-A), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (6- A),wherein:Ring G is absent or an optionally substituted C3-C6 cycloalkyl or optionally substituted 4 to 6-membered heterocycloalkyl;L6is -O-(optionally substituted alkylene);R28is an optionally substituted 5 to 6-membered heteroaryl;R29is optionally substituted Ci-Ce alkyl-(C6-Cio aryl) or optionally substituted Ci-Ce alkyl-(6 to 10- membered heteroaryl); andR30is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl. optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4 to 6-membered heterocycloalkyl.

[0163] In some embodiments, the second terminus comprises the structure of Formula (7 -A), or a pharmaceutically acceptable salt thereof:wherein:A3is -O-, -NH-, or -CH2-;Z2is CH or N;W is O or S;each R31is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C2-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 Cs-Cs cycloalkyl or optionally substituted 5 to 8-membered heterocycloalkyl;R32is hydrogen or optionally substituted C1-C10 alkyl;R32ais hydrogen or optionally substituted C1-C10 alkyl;R33is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl; andWSGR Docket No. 56009-757.601qe is 0-4;wherein Formula (7-A) is atached to the oligomeric backbone is at R32aor at one of R31.

[0164] In some embodiments, the second terminus comprises the structure of Formula (7-B), or a pharmaceutically acceptable salt thereof:(R31)q6NR32<NFormula (7-B),wherein:Ring F is an optionally substituted 5 to 6-membered heteroaryl;A3is -O-, -NH-, or -CH2-;Z3is CH or N;W is O or S;each R31is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted Ci-Ciohydroxyalkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-Cioalkynyl, 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-C8cycloalkyl or optionally substituted 5 to 8-membered heterocycloalkyl;R32is hydrogen or optionally substituted C1-C10 alkyl; andqe is 1-4.

[0165] In some embodiments, A3is -O-. In some embodiments, A3is -NH-. In some embodiments, A3is -CH2-.

[0166] In some embodiments, Z3is CH. In some embodiments, Z3is N.

[0167] In some embodiments, W is O. In some embodiments, W is S.

[0168] In some embodiments, Ring F is an optionally substituted 5-membered heteroaryl. In some embodiments, Ring F is an optionally substituted 6-membered heteroaryl.

[0169] In some embodiments, each R31is independently an optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl. 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.

[0170] In some embodiments, R32is an optionally substituted C1-C10 alkyl. In some embodiments, R32is methyl. In some embodiments, R32is hydrogen.

[0171] In some embodiments, R32ais an optionally substituted C1-C10 alkyl. In some embodiments, R32ais hydrogen.WSGR Docket No. 56009-757.601

[0172] In some embodiments, R33is hydrogen, halogen, -OH, -CN, -NO2, or -NH2. In some embodiments, R33is an optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl.

[0173] In some embodiments, Formula (7- A) is attached to the oligomeric backbone is at R32a. In some embodiments, Formula (7- A) is attached to the oligomeric backbone at one of R31.

[0174] In some embodiments, the second terminus comprises the structure of Formula (7 -C), Formula (7-D), or Formula (7-E), or a pharmaceutically acceptable salt thereof:Formula (7-C), Formula (7-D), or Formula (7-E).

[0175] In some embodiments, the second terminus comprises the structure of Formula (8 -A), or a pharmaceutically acceptable salt thereof:o34'"\KR34AFormula (8-A),wherein:Ring H is an optionally substituted phenyl or optionally substituted 6-membered heteroaryl; / , N-NI — )=Oor Ring His ';ZA is absent or an optionally substituted phenyl formamide;Xdis CH or N;R34is an optionally substituted phenyl or optionally substituted 6-membered heteroaryl;R34Ais hydrogen, halogen, or optionally substituted C1-C3 alkyl; andR35is independently halogen, optionally substituted C1-C10 alkyl, or optionally substituted 5 to 6-membered heteroaryl;wherein the attachment to the oligomeric backbone is at R35, ZA, or Ring H.

[0176] In some embodiments, Ring H is an optionally substituted phenyl. In some embodiments, Ring H is an optionally substituted 6-membered heteroaryl.WSGR Docket No. 56009-757.601 / N-N

[0177] In some embodiments, RingH is

[0178] 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.

[0179] In some embodiments, Xdis CH. In some embodiments, Xdis N.

[0180] In some embodiments, R34is an optionally substituted phenyl. In some embodiments, R34is an optionally substituted 6-membered heteroaryl.

[0181] In some embodiments, R34Ais hydrogen or halogen. In some embodiments, R34Ais an optionally substituted C1-C3 alkyl. In some embodiments, R34Ais methyl.

[0182] In some embodiments, Formula (8-A) is attached to the oligomeric backbone 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.

[0183] In some embodiments, the second terminus comprises the structure of Formula (8-B) or FormulaFormula (8-B) or Formula (8-C).

[0184] In some embodiments, the second terminus comprises the structure of Formula (8-D), or a pharmaceutically acceptable salt thereof:Formula (8-D).

[0185] In some embodiments, the second terminus comprises the structure of Formula (9-A), or a pharmaceutically acceptable salt thereof:Formula (9-A).WSGR Docket No. 56009-757.601

[0186] 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-A) or Formula (10-B).

[0187] In some embodiments, the second terminus comprises the structure of Formula (11 -A), or a pharmaceutically acceptable salt thereof:Formula (11 -A).

[0188] In some embodiments, the second terminus comprises the structure of Formula (12-A), or a pharmaceutically acceptable salt thereof:R38Formula (12-A),wherein:A4is -CR40R40- or -NR40-, wherein each R40is independently hydrogen or optionally substituted Ci-Cio alkyl;R36is an optionally substituted 5 to 6-membered heteroaryl;each R37is independently hydrogen, halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl;R38is optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl;WSGR Docket No. 56009-757.601R39is hydrogen, halogen, -OH, -CN, -NO2, -NH2, oxo (=O), =S, C1-C10haloalkyl, or C1-C10hydroxyalkyl; pn is 1-4; andqi and q2 are each independently 0-2;wherein the oligomeric backbone is attached to Formula (12-A) at either R38or R40.

[0189] 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.

[0190] In some embodiments, each R37is independently halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each R37is independently halogen.

[0191] In some embodiments, R38is an optionally substituted C1-C10 alkyl. In some embodiments, R38is an optionally substituted C3-C8 cycloalkyl or optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R38is a 3 to 8-membered heterocycloalkyl.

[0192] In some embodiments, R39is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10 haloalkyl, or Ci-C10 hydroxyalkyl. In some embodiments, R39is oxo or =S. In some embodiments, R39is oxo. In some embodiments, R39is =S.

[0193] In some embodiments, A4is -NR40. In some embodiments, A4is -NH. In some embodiments, A6is -NCH3. In some embodiments, A4is -CR40R40. In some embodiments, A4is -CH2-.

[0194] In some embodiments, each R40is independently optionally substituted C1-C10 alkyl. In some embodiments, each R40is independently hydrogen.

[0195] In some embodiments, pn is 3 or 4. In some embodiments, pn is 2. In some embodiments, pn is 1.

[0196] In some embodiments, qi is 1 and q2 is 1. In some embodiments, qi is 2 and q2 is 0.

[0197] In some embodiments, the oligomeric backbone is attached to Formula (12-A) through R38. In some embodiments, the oligomeric backbone is attached to Formula (12-A) through R40.

[0198] In some embodiments, the second terminus comprises Formula (12-B) or Formula (12-C), or a pharmaceutically acceptable salt thereof:Formula (12-B) or Formula (12-C).

[0199] In some embodiments, the second terminus comprises Formula (12-D) or Formula (12-E), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (12-D) or Formula (12-E).

[0200] In some embodiments, the second terminus comprises the structure of Formula (13 -A), or a pharmaceutically acceptable salt thereof:Formula (13-A),wherein:Ring J is absent or optionally substituted 5 to 6-membered heteroaryl;R41is optionally substituted Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, -C(O)R41a, -C(O)-, or - C(O)NR41aR41b, wherein R41aand R41bare each independently optionally substituted Ci-Cio alkyl or optionally substituted Cs-Cs cycloalkyl;R42is an optionally substituted Ci-Cio alkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted Cs-Cs cycloalkyl, or optionally substituted 3 to 8 membered heterocycloalkyl;R43is hydrogen or optionally substituted C1-C10 alkyl;each R44is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, Ci-Ciohydroxyalkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted O-Cs-cycloalkyl. or optionally substituted 3 to 8-membered heterocycloalkyl; orR43and one of R44together with the atoms to which they are attached form an optionally substituted 5 to 8- membered heterocycloalkyl;p12is 1-4; andq3is 0 or 1;wherein Formula (13-A) is connected to the oligomeric backbone at Ring J, R41, or R42.

[0201] In some embodiments, R41is optionally substituted Ci-Ce alkyl or optionally substituted C3-C8 cycloalkyl. In some embodiments, R41is -C(O)R41a. In some embodiments, R41is -C(O)CH3 or -C(O)CH2CH3. In some embodiments, R41is -C(O)-NR41aR41b.WSGR Docket No. 56009-757.601

[0202] In some embodiments, R41ais optionally substituted C1-C10 alkyl. In some embodiments, R41ais optionally substituted C3-C8 cycloalkyl.

[0203] In some embodiments, R41bis optionally substituted C1-C10 alkyl. In some embodiments, R41bis optionally substituted C3-C8 cycloalkyl.

[0204] In some embodiments, R42is optionally substituted C1-C10 alkyl or optionally substituted C1-C10 haloalkyl. In some embodiments, R42is optionally substituted C3-C8 cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl. In some embodiments, R42is optionally substituted 3- to 8-membered heterocycloalkyl ring.

[0205] In some embodiments, R43is optionally substituted C1-C10 alkyl. In some embodiments, R43is hydrogen.

[0206] In some embodiments, each R44is independently halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, Ci-Ciohydroxyalkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C8-cycloalkyl. or optionally substituted 3 to 8-membered heterocycle. In some embodiments, each R44is independently halogen or Ci-C10 haloalkyl.

[0207] 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.

[0208] In some embodiments, p12is 3 or 4. In some embodiments, p12is 2. In some embodiments, p12is 1.

[0209] In some embodiments, q3is 1. In some embodiments, q3is 0.

[0210] In some embodiments, Ring J is an optionally substituted 5 -membered heteroaryl. In some embodiments, Ring J is absent.

[0211] 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. In some embodiments, Formula (13-A) is connected to the oligomeric backbone at R42.

[0212] In some embodiments, the second terminus comprises the structure of Formula (13-B), or a pharmaceutically acceptable salt thereof:Formula (13-B).

[0213] In some embodiments, the second terminus comprises the structure of Formula (13 -Cl) or Formula (13-C2), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (13-C1) or Formula (13-C2).

[0214] In some embodiments, the second terminus comprises the structure of Formula (13-D1) or Formula (13-D2), or a pharmaceutically acceptable salt thereof:Formula (13-D1) or Formula (13-D2).

[0215] In some embodiments, the second terminus comprises the structure of Formula (13-E), or a pharmaceutically acceptable salt thereof:Formula (13-E).

[0216] 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;WSGR Docket No. 56009-757.601A5is absent, CH2, -NH-, or -O-;L4is alkylene or heteroalkylene;each R45is independently halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci -Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, Ci-Ciohydroxyalkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted Ci-Cs-cycloalkyl. or optionally substituted 3 to 8-membered heterocycloalkyl;each R46is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, optionally substituted Ci-Ciohydroxyalkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; R47is optionally substituted C1-C10 alkyl, -C(O)R47a, or -C(O)-NR47aR47b, whereinR47aand R47bare each independently optionally substituted C1-C10 alkyl or optionally substituted C3-C8 cycloalkyl;q4is 2-3; andq5is 0-2;wherein the Formula (14-A) is connected to the oligomeric backbone through Ring K or through one of R45.

[0217] In some embodiments, A5is absent. In some embodiments, A5is -NH- or -O-. In some embodiments, A5is -NH-. In some embodiments, A5is -O-.

[0218] In some embodiments, L4is alkylene. In some embodiments, L4is C1-C5 alkylene.

[0219] In some embodiments, L4is heteroalkylene. In some embodiments, L4is C1-C4 heteroalkylene. In some embodiments, L4is -O-CH2- or -O-CH2CH2-.

[0220] In some embodiments, each R45is independently halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci -Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, Ci-Ciohydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl. In some embodiments, each R45is independently optionally substituted C1-C10 alkyl or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, each R45is independently Ci-C10hydroxyalkyl. In some embodiments, each R45is independently -OCH3 or -OCH2CH3.

[0221] In some embodiments, each R46is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci -Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted Ci-Ciohydroxyalkyl. In some embodiments, each R46is independently -OCH3. In some embodiments, each R46is independently hydrogen.

[0222] In some embodiments, R47is optionally substituted C1-C10 alkyl. In some embodiments, R47is -C(O)R47a. In some embodiments, R47is -C(O)CH3 or -C(O)CH2CH3. In some embodiments, -C(O)-NR47aR47b.

[0223] In some embodiments, R47ais optionally substituted C1-C10 alkyl. In some embodiments, R47ais optionally substituted C3-C8 cycloalkyl.WSGR Docket No. 56009-757.601

[0224] In some embodiments, R47bis optionally substituted C1-C10 alkyl. In some embodiments, R47bis an optionally substituted C3-C8 cycloalkyl.

[0225] In some embodiments, Ring K is a 6-membered heterocycloalkyl.

[0226] In some embodiments, q4 is 3. In some embodiments, q4 is 2.

[0227] In some embodiments, q5is 2. In some embodiments, q5is 1. In some embodiments, q5is 0.

[0228] In some embodiments, Formula (14-A) is connected to the oligomeric backbone through Ring K. In some embodiments, Formula (14-A) is connected to the oligomeric backbone through one of R45.

[0229] In some embodiments, the second terminus comprises the structure of Formula (14-B) or Formula (14-C), or a pharmaceutically acceptable salt thereof:Formula (14-B) or Formula (14-C).

[0230] In some embodiments, the second terminus comprises the structure of Formula (15 -A), or a pharmaceutically acceptable salt thereof:O R52Formula (15-A),wherein:Ring L is an aryl or heteroaryl;each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10 alkyl, Ci-Ciohaloalkyl, or C1-C10 hydroxy alkyl;R49and R50are each independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- Ciohaloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl;R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted Ci-Ciohydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl;WSGR Docket No. 56009-757.601R52is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, or optionally substituted Ci-Ciohydroxyalkyl; andp7is 1-4.

[0231] In some embodiments, Ring L is an aryl. In some embodiments, the aryl is phenyl. In some embodiments, Ring Lis heteroaryl. In some embodiments, Ring L is a bicyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from N and O.

[0232] In some embodiments, wherein the second terminus comprises the structure of Formula (15-B), or a pharmaceutically acceptable salt thereof:Formula (15-B),wherein:each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10 alkyl, Ci-Ciohaloalkyl, or C1-C10 hydroxy alkyl;R49and R50are each independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- Ciohaloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl;R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted Ci-Ciohydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl; andp7is 1-4.

[0233] In some embodiments, wherein the second terminus comprises the structure of Formula (15-C), or a pharmaceutically acceptable salt thereof:Formula (15-C),wherein:Xcis CR48or N;WSGR Docket No. 56009-757.601each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10 alkyl, Ci-Ciohaloalkyl, or C1-C10 hydroxy alkyl;R49and R50are each independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci- Ciohaloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl;R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted Ci-Ciohydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl;R53is hydrogen or optionally substituted C1-C10 alkyl; andp7is 1-3.

[0234] In some embodiments, each R48is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C10alkyl, C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl.

[0235] In some embodiments, R49is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci -C10 haloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl. In some embodiments, R49is an optionally substituted C1-C10 alkyl. In some embodiments, R49is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R49is hydrogen.

[0236] In some embodiments, R50is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci -C10 haloalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl. In some embodiments, R50is an optionally substituted C1-C10 alkyl or optionally substituted C2-C10 alkenyl. In some embodiments, R50is hydrogen.

[0237] In some embodiments, R51is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted Ci-Ciohydroxyalkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl.

[0238] In some embodiments, R52is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, R52is hydrogen.

[0239] In some embodiments, R53is hydrogen or optionally substituted C1-C10 alkyl. In some embodiments, R53is an optionally substituted C1-C10 alkyl. In some embodiments, R53is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R53is hydrogen.

[0240] In some embodiments, p7is 4. In some embodiments, p7is 3. In some embodiments, p7is 2. In some embodiments, p7is 1.

[0241] In some embodiments, the second terminus comprises the structure of Formula (15-D1), Formula (15-D2), or Formula (15-D3), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (15-D3).

[0242] In some embodiments, the second terminus comprises the structure of Formula (15-E1), Formula (15-E2), or Formula (15-E3), or a pharmaceutically acceptable salt thereof:Formula (15-E1), Formula (15-E2), or Formula (15-E3).

[0243] In some embodiments, the second terminus comprises the structure of Formula (16-A), or a pharmaceutically acceptable salt thereof:Formula (16-A),wherein:B5is -O-, -NH-, or S;B6is N or CH;WSGR Docket No. 56009-757.601R54is optionally substituted aryl or optionally substituted heteroaryl;each R55is independently halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci -Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxy alkyl;R56is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, or optionally substituted C1-C10 hydroxyalkyl;R57is halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl;p9is 1-3; andq7is 0-2.

[0244] In some embodiments, B5is -O- or -S-. In some embodiments, B5is -O-. In some embodiments, B5is -S-.

[0245] In some embodiments, B6is N. In some embodiments, B6is CH.

[0246] In some embodiments, R54is an optionally substituted aryl. In some embodiments, R54is phenyl optionally substituted with one or more halogen, -CN, -NH2, -OH, C1-C10 alkyl, C1-C10 haloalkyl, or C1-C10 hydroxy alkyl.

[0247] In some embodiments, each R55is independently halogen, -OH, -CN, -NH2, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl.

[0248] In some embodiments, R56is optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted Ci-Ciohydroxyalkyl. In some embodiments, R56is optionally substituted C1-C10 alkyl.

[0249] In some embodiments, R57is halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C10 alkyl.

[0250] In some embodiments, p9is 3. In some embodiments, p9is 2. In some embodiments, p9is 1.

[0251] In some embodiments, q7is 2. In some embodiments, q7is 1. In some embodiments, q7is 0.

[0252] In some embodiments, the second terminus comprises the structure of Formula (16-B), or a pharmaceutically acceptable salt thereof:H N H N NHO ClFormula (16-B).

[0253] In some embodiments, the second terminus comprises the structure of Formula (17 -A), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601R60I N;Formula (17-A),wherein:Ring M is optionally substituted aryl or optionally substituted heteroaryl;Ring N is absent or 4 to 8-membered heterocycloalkyl;A6is -O-, -NH-, or -CH2-;each R58is independently halogen, -OH, -CN, -NO2, -NH2, C1-C10 alkyl, Ci-Ciohaloalkyl, or C1-C10 hydroxy alkyl;R59is hydrogen, -OH, -NH2, C1-C10 alkyl, Ci-Ciohaloalkyl, Ci-Ciohydroxyalkyl, or -NH-C1-C10 alkyl; R60is hydrogen or optionally substituted C1-C10 alkyl; andp10is 1-4;wherein Formula (17-A) is connected to the oligomeric backbone through R59.

[0254] In some embodiments, Ring M is an aryl, optionally substituted with one or more halogen, CN, NH2, OH, C1-C10 alkyl, Ci-C10haloalkyl, or Ci-Ciohydroxyalkyl. In some embodiments, Ring M is phenyl. In some embodiments, Ring M is an optionally substituted 6 -membered heteroaryl, optionally substituted with one or more halogen, CN, NH2, OH, C1-C10 alkyl, Ci-Ciohaloalkyl, or C1-C10 hydroxyalkyl. In some embodiments, Ring M is an optionally substituted pyridine.

[0255] In some embodiments, RingN is 4 to 8-membered heterocycloalkyl. In some embodiment, RingN 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.

[0256] In some embodiments, A6is -O- or -NH-. In some embodiments, A6is -CH2-.

[0257] In some embodiments, each R58is independently -OH, -NH2, C1-C10alkyl, Ci-Ciohaloalkyl, or Ci-C10 hydroxyalkyl. In some embodiments, each R58is independently C1-C10 alkyl, or C1-C10 hydroxyalkyl. In some embodiments, each R58is independently Ci-Ciohydroxyalkyl.

[0258] In some embodiments, R59is -OH, -NH2, C1-C10 hydroxy alkyl, or -NH-C1-C10 alkyl. In some embodiments, R59is hydrogen.

[0259] In some embodiments, R60is optionally substituted C1-C10 alkyl. In some embodiments, R60is methyl. In some embodiments, R60is hydrogen.

[0260] In some embodiments, p10is 3 or 4. In some embodiments, p10is 2. In some embodiments, p10is 1.

[0261] In some embodiments, the second terminus comprises the structure of Formula (17-B) or Formula (17-C) or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (17-B)or Formula (17-C).

[0262] In some embodiments, the second terminus comprises the structure of Formula (18 -A), or a pharmaceutically acceptable salt thereof:Formula (18-A),wherein:B7is N or CH;R67is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxy alkyl;R68and R69are each independently an optionally substituted 5 -membered heteroaryl; andxs and xe are each independently 0-4.

[0263] In some embodiments, B7is N. In some embodiments, B7is CH.

[0264] In some embodiments, R67is halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C10 alkyl, Ci-Ciohaloalkyl, or optionally substituted Ci-Cwhydroxyalkyl. In some embodiments, R67is halogen, -OH, -CN, -NO2, -NH2, or -CH3.

[0265] 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.

[0266] 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.

[0267] In some embodiments, X5 is 2 or 3. In some embodiments, X5 is 1. In some embodiments, X5 is 0.WSGR Docket No. 56009-757.601

[0268] In some embodiments, X6 is 3. In some embodiments, xeis 2. In some embodiments, X6 is 1. In some embodiments, X6 is 0.

[0269] In some embodiments, the second terminus comprise Formula (18-B), or a pharmaceutically acceptable salt thereof:Formula (18-B).

[0270] In some embodiments, the second terminus comprises Formula (19-A), or a pharmaceutically acceptable salt thereof:

[0271] In some embodiments, the second terminus comprises the structure of Formula (20 -A), or a pharmaceutically acceptable salt thereof:wherein:A7is -NHC(O)- or -NHS(O)2-;A8is -O- or -NH-;each R61is independently hydrogen or Ci-Ce alkyl;each R62is independently halogen, -CN, -NO2, -OH, -OR62a, -NR62aR62b, -C(O)R62a, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl; wherein each R62aand R62bis independently hydrogen or Ci- C10 alkyl;each R63is independently -OR63a, -NR63aR63b, optionally substituted C1-C10 alkyl, optionally substituted Ci- Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl; wherein each R63aand R63bis independently hydrogen, C1-C10 alkyl, C1-C10 alkylamino, C1-C10 haloalkyl, or C1-C10 hydroxyalkyl;WSGR Docket No. 56009-757.601pi3 is 1-3; andpi4 is 1-3;wherein the oligomeric backbone is connected to Formula (20-A) through one of R62or one of R63.

[0272] In some embodiments, A7is -NHC(O)-. In some embodiments, A7is -NHS(O)2-.

[0273] In some embodiments, A8is -O-. In some embodiments, A8is -NH-.

[0274] In some embodiments, each R61is independently Ci-Ce alkyl. In some embodiments, each R61is methyl. In some embodiments, each R61is hydrogen.

[0275] In some embodiments, each R62is independently optionally substituted Ci-Cio alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted Ci-Cio heteroalkyl, or optionally substituted Ci-Cio hydroxyalkyl. In some embodiments, each R62is independently optionally substituted Ci-Cio alkyl. In some embodiments, each R62is independently optionally substituted Ci-Ciohaloalkyl. In some embodiments, each R62is independently optionally substituted Ci-Cio heteroalkyl. In some embodiments, each R62is independently optionally substituted Ci-Ciohydroxyalkyl.

[0276] In some embodiments, each R63is independently optionally substituted Ci-Cio alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted Ci-Cio heteroalkyl, or optionally substituted Ci-Cio hydroxyalkyl. In some embodiments, each R63is independently optionally substituted Ci-Cio alkyl. In some embodiments, each R66is independently optionally substituted Ci-Ciohaloalkyl. In some embodiments, each R63is independently optionally substituted Ci-Cio heteroalkyl. In some embodiments, each R63is independently optionally substituted Ci-Ciohydroxyalkyl.

[0277] In some embodiments, pi3 is 1. In some embodiments, pi3 is 2. In some embodiments, pi3 is 3.

[0278] In some embodiments, pu is 1. In some embodiments, pu is 2. In some embodiments, pu is 3.

[0279] In some embodiments, the oligomeric backbone is connected to Formula (20-A) through one of R62. In some embodiments, the oligomeric backbone is connected to Formula (20-A) through one of R63.

[0280] In some embodiments, the second terminus comprises the structure of Formula (20 -B) or Formula (20-C), or a pharmaceutically acceptable salt thereof:Formula (20-B) or Formula (20-C).

[0281] In some embodiments, the second terminus comprises the structure of Formula (21 -A), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (21 -A),wherein:Ring Q is C3-C8 cycloalkyl or 4 to 8-membered heterocycloalkyl;A9is -O-, -NH-, or -NHC(O)-;each R64is independently hydrogen or Ci-Ce alkyl;each R65is independently halogen, -CN, -NO2, -OH, -OR65a, -NR65aR65b, optionally substituted C1-C10 alkyl, optionally substituted Ci-Ciohaloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl; wherein each R65aand R65bis independently hydrogen or C1-C10 alkyl; each R66is independently halogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxy alkyl; pis is 0-3; andpie is 1-3;wherein Formula (21-A) is connected to the oligomeric backbone at one of R65or one of R66.

[0282] In some embodiments, A9is -O-. In some embodiments, A9is -NH-. In some embodiments, A9is -NHC(O)-.

[0283] In some embodiments, Ring Q is C3-C8 cycloalkyl. In some embodiments, ring Q is 4 to 8-membered heterocycloalkyl.

[0284] In some embodiments, each R64is independently Ci-Ce alkyl. In some embodiments, each R64is methyl. In some embodiments, each R64is hydrogen.

[0285] In some embodiments, each R65is independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, each R65is independently optionally substituted C1-C10 alkyl. In some embodiments, each R65is independently optionally substituted Ci-Ciohaloalkyl. In some embodiments, each R65is independently optionally substituted C1-C10 heteroalkyl. In some embodiments, each R65is independently optionally substituted Ci-Ciohydroxyalkyl.

[0286] In some embodiments, each R66is independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 hydroxyalkyl. In some embodiments, each R66is independently optionally substituted C1-C10 alkyl. In some embodiments, each R66is independently optionally substituted Ci-Ciohaloalkyl. In some embodiments, each R66is independently optionally substituted C1-C10 heteroalkyl. In some embodiments, each R66is independently optionally substituted Ci-Ciohydroxyalkyl.WSGR Docket No. 56009-757.601

[0287] In some embodiments, pis is 0. In some embodiments, pis is 1. In some embodiments, pis is 2. In some embodiments, pis is 3.

[0288] In some embodiments, pie is 1. In some embodiments, pie is 2. In some embodiments, pie is 3.

[0289] In some embodiments, Formula (21-A) is connected to the oligomeric backbone at one of R65. In some embodiments, Formula (21-A) is connected to the oligomeric backbone at one of R66.

[0290] In some embodiments, the second terminus comprises the structure of Formula (21 -B), or a pharmaceutically acceptable salt thereof:Formula (21-B).

[0291] In some embodiments, the second terminus comprises the structure of Formula (22 -A), or a pharmaceutically acceptable salt thereof:Formula (22- A),wherein:R90is hydrogen, -NH2, or -NHSO2CH3;R91and R92are each independently halogen, -CN, -NO2, -OH, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl;R70is -S(O)R70aor -S(O)2R70a, wherein R70ais hydrogen or C1-C10 alkyl; andR71is hydrogen or C1-C10 alkyl;wherein Formula (22-A) is attached to the oligomeric backbone at R90or R71.

[0292] In some embodiments, R90is hydrogen. In some embodiments, R90is -NH2, or -NHSO2CH3.

[0293] In some embodiments, R91andR92are each independently optionally substituted C1-C10 alkyl. In some embodiments, R91and R92are each methyl.

[0294] In some embodiments, R70is -S(O)2R70a. In some embodiments, R70is -S(O)2CH3.

[0295] In some embodiments, Formula (22-A) is attached to the oligomeric backbone at R92. In some embodiments, Formula (22-A) is attached to the oligomeric backbone at R71.WSGR Docket No. 56009-757.601

[0296] In some embodiments, the second terminus comprises the structure of Formula (22 -B) or Formula (22-C), or a pharmaceutically acceptable salt thereof:Formula (22-B) or Formula (22-C).

[0297] In some embodiments, the second terminus comprises the structure of Formula (23 -A), or a pharmaceutically acceptable salt thereof:Formula (23 -A)wherein:B9is -CH-CRB9-, -N-, or NRB1°;B10is -N- or NRB1°, whereinRB9is hydrogen or halogen; and RB1° is hydrogen;R72is halogen, -CN, -NO2, -OH, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted C1-C10 hydroxyalkyl; andR73is hydrogen;wherein Formula (23-A) is attached to the oligomeric backbone at RB9, RB1°, or R73.

[0298] In some embodiments, B9is -CH-CRB9- and B10is -N-. In some embodiments, B9is -N- and B10is NRB1°. In some embodiments, B9is NRB1° and B10is -N-.

[0299] In some embodiments, R72is an optionally substituted C1-C10 alkyl. In some embodiments, R72is methyl.

[0300] In some embodiments, Formula (23-A) is attached to the oligomeric backbone at RB9or RB1°. In some embodiments, Formula (23-A) is attached to the oligomeric backbone at R73.

[0301] In some embodiments, the second terminus comprises the structure of Formula (23 -B) or Formula (23-C), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (23-B), or Formula (23-C).

[0302] In some embodiments, the second terminus comprises the structure of Formula (23 -D) or Formula (23-E), or a pharmaceutically acceptable salt thereof:Formula (23-D) or Formula (23-E).

[0303] In some embodiments, the second terminus comprises the structure of Formula (24 -A), or a pharmaceutically acceptable salt thereof:wherein:R74is -CH2-(optionally substituted 5-membered heteroaryl);R75is -0-(Ci-Cio alkyl)-R75a; wherein R75ais -C(O)O-alkyl;R76is -OR76a, wherein R76ais hydrogen or alkyl;R77is hydrogen or halogen; andR77ais hydrogen or Ci-Cio alkyl;wherein Formula (24-A) is attached to the oligomeric backbone at R75aor R76a.

[0304] In some embodiments, R75is -0-(Ci-Cio alkyl)-C(O)O-alkyl. In some embodiments, R75is -O-(Ci- C4alkyl)-C(O)O-Ci-C4alkyl.

[0305] In some embodiments, R76is -OH. In some embodiments, R76is -OCH3. In some embodiments, R76is -O-CH2CH3.

[0306] In some embodiments, R77is halogen. In some embodiments, R77is hydrogen.

[0307] In some embodiments, R77ais hydrogen or methyl. In some embodiments, R77ais methyl. In some embodiments, R77ais hydrogen.

[0308] In some embodiments, Formula (24-A) is attached to the oligomeric backbone at R75a. In some embodiments, Formula (24-A) is attached to the oligomeric backbone at R76a.WSGR Docket No. 56009-757.601

[0309] In some embodiments, the second terminus comprises the structure of Formula (24 -B) or Formula (24-C), or a pharmaceutically acceptable salt thereof:Formula (24-B) or Formula (24-C).

[0310] In some embodiments, the second terminus comprises the structure of Formula (25 -A), or a pharmaceutically acceptable salt thereof:Formula (25- A),wherein:B12is -NR80a- or -C(R80b)2-;R78is halogen, -CN, -NO2, -OH, or optionally substituted C1-C10 alkyl;R79aand R79bare each independently halogen, -CN, -NO2, -NH2, -N(CH3)2, or optionally substituted C1-C10 alkyl;or R79aand R79btogether with the atoms to which they are attached form a 6-membered aryl;each R80is independently hydrogen, -O-C1-C3 alkyl, C1-C10 alkyl, or C1-C10 alkoxy;R80ais Ci-C6alkyl;each R80bis independently hydrogen or Ci-Ce alkyl; andr? is 1, 2, or 3;wherein Formula (25-A) is attached to the oligomeric backbone at one of R80.

[0311] In some embodiments, B12is -NR80a-. In some embodiments, B12is -C(R80b)2-.

[0312] In some embodiments, R78is -CN, -NO2, or -OH. In some embodiments, R78is -OH. In some embodiments, R78is halogen. In some embodiments, R78is an optionally substituted C1-C10 alkyl.

[0313] In some embodiments, R79aand R79bare each independently halogen, -NH2, or -N(CH3)2.WSGR Docket No. 56009-757.601

[0314] In some embodiments, R79aand R79btogether with the atoms to which they are attached form a 6-membered aryl.

[0315] In some embodiments, each R80is independently hydrogen. In some embodiments, each R80is independently Ci-Cio alkyl. In some embodiments, each R80is independently Ci-Cio alkoxy. In some embodiments, each R80is independently -OCH3.

[0316] In some embodiments, the second terminus comprises the structure of Formula (25-B) or Formula (25-C), or a pharmaceutically acceptable salt thereof:Formula (25-B) or Formula (25-C).

[0317] In some embodiments, the second terminus comprises the structure of Formula (26 -A), or a pharmaceutically acceptable salt thereof:B11 R81a(R®3)r4oxX / p jf X TR81bS ^1R85Formula (26- A),wherein:B11is -O- or -NR82-;A10is -NR84- or -NR84CH2-;R81aand R81bare each independently C1-C10 alkyl;or R81aand R81bcombine together to form oxo (=0);R82is hydrogen or C1-C3 alkyl;each R83is independently halogen, -CN, -NO2, -OH, -OR83a, or optionally substituted C1-C10 alkyl; wherein R83ais C1-C10 alkyl;R84is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or phenyl;R85is hydrogen or C1-C10 alkyl; andr4is 1, 2, or 3;wherein Formula (26-A) is attached to the oligomeric backbone at one of R83.

[0318] In some embodiments, B11is -O-. In some embodiments, B11is -NR82-. In some embodiments, B11is NCH3.WSGR Docket No. 56009-757.601

[0319] In some embodiments, A10is -NR84-. In some embodiments, A10is -NR84CH2-.

[0320] In some embodiments, R81aand R81bare each methyl. In some embodiments, R81aand R81bcombine together to form oxo (=0).

[0321] In some embodiments, each R83is independently -CN, -OH, -OR83a, or optionally substituted Ci-Cio alkyl. In some embodiments, each R83is independently -OH or -OR83a.

[0322] In some embodiments, R84is C3-C6 cycloalkyl or phenyl. In some embodiments, R84is phenyl.

[0323] In some embodiments, R85is Ci-Cio alkyl. In some embodiments, R85is methyl. In some embodiments, R85is hydrogen.

[0324] In some embodiments, the second terminus comprises the structure of Formula (26 -B) or Formula (26-C), or a pharmaceutically acceptable salt thereof:Formula (26-B) or Formula (26-C).

[0325] In some embodiments, the second terminus comprises the structure of Formula (26-D) or Formula (26-E), or a pharmaceutically acceptable salt thereof:Formula (26-D) or Formula (26-E).

[0326] In some embodiments, the second terminus comprises the structure of Formula (27 -A), or a pharmaceutically acceptable salt thereof:Formula (27- A).

[0327] In some embodiments, the second terminus comprises the structure of Formula (28 -A), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (28- A),wherein:A11is C1-C6alkylene;B13is N or CR100;R97is C1-C6alkyl;R98is halogen;R99is hydrogen, halogen, or optionally substituted C1-C10 alkyl; andR100is -OR100aor optionally substituted C1-C10 alkyl; wherein R100ais hydrogen or C1-C10 alkyl;or R99and R100together with the atoms to which they are attached form a heterocycloalkyl.

[0328] In some embodiments, A11is C1-C4 alkylene. In some embodiments, A11is -CH2CH2-.

[0329] In some embodiments, B13is N. In some embodiments, B13is CR100.

[0330] In some embodiments, R97is methyl.

[0331] In some embodiments, R98is -Cl.

[0332] In some embodiments, R100is -OR100a. In some embodiments, R100is an optionally substituted Ci-C10 alkyl.

[0333] In some embodiments, R99and R100together with the atoms to which they are attached form a heterocycloalkyl.

[0334] In some embodiments, the second terminus comprises the structure of Formula (28 -B), or a pharmaceutically acceptable salt thereof:

[0335] In some embodiments, the second terminus comprises the structure of Formula (28 -C), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (28-C).

[0336] In some embodiments, the second terminus comprises the structure of Formula (29 -A), or a pharmaceutically acceptable salt thereof:Formula (29- A).

[0337] In some embodiments, the second terminus comprises the structure of Formula (30 -A), or a pharmaceutically acceptable salt thereof:

[0338] In some embodiments, the second terminus comprises the structure of Formula (31 -A), or a pharmaceutically acceptable salt thereof:Formula (31 -A),wherein:R94is halogen;R94ais hydrogen or C1-C3 alkyl; andR95is hydrogen, halogen, -OH, -OCH3, or optionally substituted C1-C10 alkyl.

[0339] In some embodiments, R94is -Cl.

[0340] In some embodiments, R94ais C1-C3 alkyl. In some embodiments, R94ais methyl. In some embodiments, R94ais hydrogen.

[0341] In some embodiments, R95is halogen, -OH, -OCH3, or optionally substituted C1-C10 alkyl. In some embodiments, R95is hydrogen.WSGR Docket No. 56009-757.601

[0342] In some embodiments, the second terminus comprises the structure of Formula (31 -B) or Formula (31-C), or a pharmaceutically acceptable salt thereof:Formula (31 -B) or Formula (31-C).

[0343] In some embodiments, the second terminus comprises the structure of Formula (32-A), or a pharmaceutically acceptable salt thereof:

[0344] In some embodiments, the second terminus comprises the structure of Formula (33 -A), or a pharmaceutically acceptable salt thereof:Formula (33-A).

[0345] In some embodiments, the second terminus comprises the structure of Formula (34-A), or a pharmaceutically acceptable salt thereof:Formula (34-A).

[0346] In some embodiments, the second terminus comprises the structure of Formula (35 -A), or a pharmaceutically acceptable salt thereof:Formula (35-A).WSGR Docket No. 56009-757.601

[0347] In some embodiments, the second terminus comprises the structure of Formula (36-A) or Formula (36-B), or a pharmaceutically acceptable salt thereof:Formula (36-A) or Formula (36-B).

[0348] In some embodiments, the second terminus comprises the structure of Formula (37 -A), or a pharmaceutically acceptable salt thereof:Formula (37-A),wherein:Ring T is a C5-C6cycloalkyl, 5 to 6-membered heterocycloalkyl, or phenyl;each R86is independently halogen, -CN, -NO2, -OH, -OR86a, -N(R86b)2, or optionally substituted C1-C10 alkyl; whereineach R86ais independently C1-C10 alkyl;each R86bis independently hydrogen or C1-C10 alkyl;R87is C5-C6cycloalkyl or phenyl;each R88is independently halogen, -CN, -NO2, -OH, -OR88a, -NR88bR88b, or optionally substituted C1-C10 alkyl; whereineach R88ais independently C1-C10 alkyl;each R88bis independently hydrogen or C1-C10 alkyl;R89aand R89bare each independently hydrogen or C1-C10 alkyl;or R89aand R89btogether with the atom to which they are attached form a 5 to 6-membered heterocycloalkyl; R96is hydrogen or -CH3; andrs and re are each independently 0, 1, 2, or 3.

[0349] 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.

[0350] 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.WSGR Docket No. 56009-757.601

[0351] In some embodiments, R87is C5-C6cycloalkyl. In some embodiments, R87is phenyl.

[0352] In some embodiments, R89aand R89bare each independently C1-C10 alkyl. In some embodiments, R89aand R89bare each hydrogen.

[0353] In some embodiments, R89aand R89btogether with the atom to which they are attached form a 5 to 6-membered heterocycloalkyl.

[0354] In some embodiments, R96is -CH3. In some embodiments, R96is hydrogen.

[0355] In some embodiments, rs and re are each independently 0, 1, or 2.

[0356] In some embodiments, the second terminus comprises the structure of Formula (37 -B) or Formula (37-C), or a pharmaceutically acceptable salt thereof:Formula (37-C).

[0357] In some embodiments, the second terminus is selected from a moiety described in Table 1, or a pharmaceutically acceptable salt thereof.WSGR Docket No. 56009-757.601BET(BD1)o o ——Orz\ 1' O — / )= / ^yJX\-N 7 O 7 - \VNCQ PCAF( OoHN^f==\ JXF ^=NCBP / P300 / "~OH r - \ / ■—- / ^N J \-NV—N / / '° Il - \ Yz> NF CBP / P300 cotN—N^NT ifO / =\L J I 1 JI 1 NHCECR2 / O i L tN ^OWSGR Docket No. 56009-757.601o=s=oN^NBPTF II J H IHI H I PCAF NA^ UH0 n?10L JL J BRD7 / 9 JUL1H 1fl NTAF1 CX, N„H0 n0U H UQ BRD7 / 9 L YlX)^O^'N'^Yu°HNX^y / UN^ / ^NXX ^°BRPFcAWSGR Docket No. 56009-757.601ATAD2 / ATAD2B Ioo / / \ ^\ / CNiz yM \ / i= i o ATAD2 / ATAD2B \ / —x AII S J d <° H“ / \ I I'XOX’X'XT: I X ( ' ' z — —\ / I -n _ ^-^NH2" Z l —« b.( y o o OTZ—T Iz—-szz\ / / _I / \ / °= - ^\ / > o O —TRIM24z —jf / OUR\A J LXZ>TAF1N\ / \AH II0BET0U H BET6 / xb 1WSGR Docket No. 56009-757.601\o BET / °\z^\XNHN—X T, MOx / OI J.BET CM.00M~N MNHULNC I I I J BET M N\-0 s '€X MNN BET -N^N^^NN^yO / y Xy I / W T y<]r B OV+L E M0H" T r INHO\ / N I^ °INr L ii A|NA JI I 7 l H BRD46 " °'WSGR Docket No. 56009-757.601BRD4 HH\ JI J \dh - BET / X^v z^ oz^J / pZ T\==° / < / = IL!1 ' z OOMe\o BRD4 HN— V > V ) —W ' e o 1oI\=Nooo BRD4Y °ZI^z -W —'x <xi^z / Z-^ BRD4 ^i Ozz oCl Cl□ <5 Q \HO^° )\N=\ BRD4 \ ( / 0 N Vs i \ / / v\HU I / N, 75n H ii / >- N^\0 N'NHH< VNY° H HN " fBRD4uA'NwHN^> N^JV / 0WSGR Docket No. 56009-757.6019. XX 1 XX BRDR; non-Kac (X'SoCFsI N)H2N^\\ / rf O'n' N XI BRD4 O II IrfoONH / o u x BZ Zxo RD4 IH2NXX 0 / XOIZ^\ T_ Xo BRD4 O IJ °I0 o>" ' BRD4O °HO''O\ BRD4NHH2NOL N A / =A I y^N^NBRIM; CBP / P300 'N)=y= / u NHo=( \ 0^4\ / / , " OHN-^ / u

[0358] In some embodiments, the compound described herein comprises an oligomeric backbone. In some embodiments, the compound described herein comprises an oligomeric backbone that links theWSGR Docket No. 56009-757.601polyamide and the protein-binding moiety. In some embodiments, 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.

[0359] 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.

[0360] In some embodiments, the oligomeric backbone comprises between 5 and 50 chain atoms.

[0361] In some embodiments, the oligomeric backbone comprises a multimer having 2 to 50 spacing moieties, whereineach spacing moiety is independently selected from the group consisting of -((CRlbRlb)x-O)y-, -((CRlbRlb)x-NRla)y-, -((CRlbRlb)x-CH=CH-(CRlbRlb)x-O)y-, optionally substituted C1-C12 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C6-C10arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5 to 10-membered heteroarylene, optionally substituted 4- to 10-membered heterocycloalkylene, amino acid residue, -O-, -C(O)NRla-, -NRlaC(O)-, -C(O)-, -NRla-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2NRla-, -NRlaS(O)2-, and -P(O)OH-, and any combinations thereof; whereineach x is independently 2-4;eachy is independently 1-10;each Rlais independently a hydrogen or optionally substituted Ci-Ce alkyl; andeach Rlbis 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.

[0362] In some embodiments, the oligomeric backbone comprises a multimer having 2 to 50 spacing moieties, wherein each spacing moiety is independently selected from the group consisting of optionally substituted C1-C12 alkyl, -((CH2)X-O)y-, -((CH2)x-NH)y-, -O-, -C(O)NH-, -NH-, and any combinations thereof.

[0363] In some embodiments, the oligomeric backbone comprises polyethylene glycol. In some embodiments, the oligomeric backbone comprises polyethylene glycol of a molecule weight of about 200 Da to about 5000 Da. In some embodiments, the oligomeric backbone comprises polyethylene glycol of a molecule weight of about 200 Da to about 1000 Da.

[0364] In some embodiments, non-limiting examples of the transcription modulator compounds described herein are presented below in Table 2A, 2B, 2C, 2D, or 2E.Table 2A. Compounds of the disclosureWSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.6010 Il T V A NA MMoA AJ Ah^ A ■ ■'\= A 19 A,NY-\ F, H°kC1° O o0 JHN0. °x, Pxun i! 0^0=°0kx AT M AAX>< Y '0A \0'NJA20M M k- “"" 'o 7 AA ¥k H N? AAXHV "H, M 10N NJ M *if N K / ou< INHo 0 1o o -O t O^A \;? } / _$A T iz oX A ZZ1\ Xr4■WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601Jp 1 y ‘t i^\P" Z^ZJK PZry B31-w ry%v ^Q J. A / z5o4 o4 Z X _ oXJ / ZZ X d° \ Z X o _A / =V p= / dH-< > A / z' d d °^\ Z X dB3 oo 2- do Jozo? z$ ooz z3- z / z3 B k z Z z?zo N H N- o o / \ U L-PNdfT n, V1°d °|ONN 00 N 0^ P^^^^^-'NNN^^''N\ / \| n, / H H N..^^. A\A B34- o y\ \ N N > >= / UN k) oo Qx ° N / v111? A H H 'xz xz xz10TZd r xz\ xz d d xz^° ^z- p' xz B35 d- ° ^z- xzIZ IZd xz d xz d rIZ xzfr- xz p xzxz ff- p° \=° \^o xz\^°pp IZ xz xz xz d x d d xz z xz rxzxz d- xz d° £xz LH~ p° )=oz^\ zP\=o xzzd )^° P / Z—P / Z~z^\[^ / Z —WSGR Docket No. 56009-757.601CMB36- rrIzy° / _ S NM. N y XZ JI H ' IZs YQQ O 8 ° ° '\ I N 1\I II I U -Z X. N^ H 1- 0. zlv N - X, -l. zx 0 -N^' ■ *zuu^^O O^O KYX 1N H H^ NX- H^- ] I)?< 9^5N H~ '—t15 V H 1? 2 H" ■ Xv^Oi^OV «zAz- xz xzB38- r x r xz z\^ox°1z" 1 "Zr~xz xzx° \^oxz xzr B39- o oo oN o o. H? Y / Y ft I 00NftX] ftNN^ O N 1il^HN^N 0LNAN^ ' H NAAA H, NN I V? 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A M NH"r o / > orNKNKoHIJM? >- " ° TZXM? vNNVHJ N / > V H jTZ^=° / z^ / Z^\TZ 'TZ / ^°Z^TZZ^°z=\WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601Table 2C. Compounds of the disclosure.Comp. No. StructureWSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601XA H L JL N° i N oy A BYSr N 00I J J t II \ 0 -\ I |o 0-y6AJ" “SXYS D6-VH HX 1h vj " »1 J 1 / NZN HN^^,XO ON o \Q XI A oY?1HN # JY JX JV ° ° °X.......' ”1!o o= °!y D7. y-. / JYW' • - XNT IA H X0Nz\kl_fl100JL \ Nx_,X 1?HN / HVAJ A 00Ar1nY \ / J J NOOOOOO 00 N \=L L J J VH / A^H1 JN-s N Hy / ? '^ XwI0( o? 0 < I N — k ASNY UhA °11 O0HX Z AOJY^ 10 O00■QWSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601Table 2E. Compounds of the disclosure.WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601E24-X / z-IZ° \,ZIXZE25^z V- / LAz- «>?— o■"" j- x>° l H < I I OH^TT B YHnTYBB H Y ^^^^0» YYC > O _N. _N. _N. J 'rV n r „,Hi X; O(O)O H YY Y>n VZ °'NH'Xu XJ °i. V nUx ° > i O=(XJ \ _ / / —-Z I. O HWSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601WSGR Docket No. 56009-757.601Solubilizers

[0365] In some embodiments, a solubilizer described herein is an amphiphilic polymer. In some embodiments, the solubilizer is a block co-polymer. In some embodiments, the solubilizer is described in Chem. Soc. Rev. 2012, Mar. 5; 41(7): 2971-3010, which is herein incorporated by reference in its entirety.

[0366] In some embodiments, the solubilizer is a dendrimer.

[0367] In some embodiments, the solubilizer comprises ethylene glycol. In some embodiments, the block co-polymer comprises one or more ethylene glycol units. In some embodiments, the block copolymer comprises polyethylene glycol (PEG). In some embodiments, the block co-polymer comprises about 1-1000 PEG units. In some embodiments, the block co-polymer comprises about 1-500 PEG units. In some embodiments, the block co-polymer comprises about 1-100 PEG units. In some embodiments, the block co-polymer comprises about 1-50 PEG units. In some embodiments, the block co-polymer comprises about 1-40 PEG units. In some embodiments, the block co-polymer comprises about 1-30 PEG units. In some embodiments, the block co-polymer comprises about 1-20 PEG units. In some embodiments, the block co-polymer comprises about 1-10 PEG units.

[0368] In some embodiments, the solubilizer does not comprise polyethylene glycol (PEG).

[0369] In another embodiment, the solubilizer comprises a PEG derivative. In some embodiments, the PEG derivative is a PEGylated lipid. In some embodiments, the PEG derivative is a PEGylated phospholipid. In some embodiments, the PEG derivative is DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine). In some embodiments, the solubilizer comprises DSPE-PEG.

[0370] In some embodiments, the solubilizer comprises a vitamin E derivative. In some embodiments, solubilizer comprises a vitamin derivative and PEG. In some embodiments, the solubilizer comprises TPGS ((tocopheryl polyethylene glycol succinate). In some embodiments, the solubilizer is TPGS NF, TPGS 200, TPGS 300, TPGS 400, TPGS 1400, TPGS 2000, or TPGS 4000.

[0371] In some embodiments, the solubilizer comprises an amino acid. In some embodiments, the block co-polymer comprises an amino acid. In some embodiments, the block co-polymer comprises an alanine unit. In some embodiments, the block co-polymer comprises an arginine unit. In some embodiments, the block co-polymer comprises an asparagine unit. In some embodiments, the block copolymer comprises an aspartic acid unit. In some embodiments, the block co-polymer comprises a cysteine unit. In some embodiments, the block co-polymer comprises a glutamic acid unit. In some embodiments, the block co-polymer comprises a glutamine unit. In some embodiments, the block copolymer comprises a glycine unit. In some embodiments, the block co-polymer comprises a histidine unit. In some embodiments, the block co-polymer comprises an isoleucine unit. In some embodiments, the block co-polymer comprises a leucine unit. In some embodiments, the block co-polymer comprises a lysine unit. In some embodiments, the block co-polymer comprises a methionine unit. In some embodiments, the block co-polymer comprises a phenylalanine unit. In some embodiments, the block copolymer comprises a proline unit. In some embodiments, the block co-polymer comprises a serine unit. In some embodiments, the block co-polymer comprises a threonine unit. In some embodiments, the blockWSGR Docket No. 56009-757.601co-polymer comprises a tryptophan unit. In some embodiments, the block co-polymer comprises a tyrosine unit. In some embodiments, the block co-polymer comprises a valine unit. In some embodiments, the block co-polymer comprises a canonical amino acid unit. In some embodiments, the block co-polymer comprises a non-canonical amino acid unit.

[0372] In some embodiments, the block co-polymer comprises a poly amino acid. In some embodiments, the block co-polymer comprises a poly glutamic acid. In some embodiments, the block copolymer comprises a polyleucine. In some embodiments, the block co-polymer comprises a polyphenylalanine. In some embodiments, the block co-polymer comprises blocks of different amino acids. In some embodiments, the block co-polymer comprises a D-amino acid unit. In some embodiments, the block co-polymer comprises multiple D-amino acid units. In some embodiments, the block copolymer comprises an L- amino acid unit. In some embodiments, the block co-polymer comprises multiple L-amino acid units. In some embodiments, the block co-polymer comprises a poly(D-amino acid). In some embodiments, the block co-polymer comprises a poly(L-amino acid). In some embodiments, the block co-polymer comprises both D-amino acid and L-amino acid units. In some embodiments, the block co-polymer comprises a poly(D, L-amino acid). In some embodiments, the block co-polymer comprises blocks of the same amino acid. In some embodiments, the block co-polymer comprises blocks of different amino acids. In some embodiments, the ratio of the different amino acid blocks is the same. In some embodiments, the ratio of the different amino acid blocks is different. In some embodiments, the ratio of different amino acid units is 1:1. In some embodiments, the ratio of the different amino acid units is not 1:1, for example, 1:2, 1:3, 1:4, 1:5, 2:3, 2:4, or 2:5.

[0373] In some embodiments, the solubilizer comprises a peptoid. In some embodiments, the block copolymer is a peptoid. In some embodiments, the block co-polymer comprises N-methylglycine. In some embodiments, the block co-polymer comprises N-octylglycine. In some embodiments, the block copolymer comprises N-2-ethyl-1-hexylglicene. In some embodiments, the block co-polymer comprises N-ethylglycine. In some embodiments, the block co-polymer comprises N-propylglycine. In some embodiments, the block co-polymer comprises N-butylglycine. In some embodiments, the block copolymer comprises N-benzylglycine. In some embodiments, the block co-polymer comprises N-phenylglycine. In some embodiments, the block co-polymer comprises N-methylalanine. In some embodiments, the block co-polymer comprises N-ethylalanine. In some embodiments, the block copolymer comprises N-(2-phenylethyl)glycine. In some embodiments, the block co-polymer comprises N-(4-methoxybenzyl)glycine. In some embodiments, the block co-polymer comprises N-(3,4-dimethoxybenzyl)glycine. In some embodiments, the block co-polymer comprises N-naphthylmethylglycine. In some embodiments, the block co-polymer comprises N-(2-aminoethyl)glycine. In some embodiments, the block co-polymer comprises N-(3-aminopropyl)glycine. In some embodiments, the block co-polymer comprises N-(carboxymethyl)glycine. In some embodiments, the block co-polymer comprises N-(2-carboxyethyl)glycine. In some embodiments, the block co-polymer comprises N-(2-hydroxyethyl)glycine. In some embodiments, the block co-polymer comprises N-(2-methoxyethyl)glycine. In some embodiments, the block co-polymer comprises N-(3-WSGR Docket No. 56009-757.601hydroxypropyl)glycine. In some embodiments, the block co-polymer comprises N-cyclopropylglycine. In some embodiments, the block co-polymer comprises N-cyclohexylglycine. In some embodiments, the block co-polymer comprises N-cyclopentylglycine. In some embodiments, the block co-polymer comprises N-isopropylglycine. In some embodiments, the block co-polymer comprises N-isobutylglycine. In some embodiments, the block co-polymer comprises N-tert-butylglycine. In some embodiments, the block co-polymer comprises N-(2-fluoroethyl)glycine. In some embodiments, the block co-polymer comprises N-(trifluoroethyl)glycine. In some embodiments, the block co-polymer comprises N-allylglycine.

[0374] In some embodiments, the solubilizer comprises a polypeptoid. In some embodiments, the block co-polymer comprises a polypeptoid. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more of the same peptoid subunits. In some embodiments, the block copolymer comprises a polypeptoid comprising two or more repeating N-methylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-ethylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-propylgly cine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-butylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-benzylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-phenylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-methylalanine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-ethylalanine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(2-phenylethyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(4-methoxybenzyl)gly cine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(3,4-dimethoxybenzyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-naphthylmethylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(2-aminoethyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(3-aminopropyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(carboxymethyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(2-carboxyethyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(2-hydroxyethyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(2-methoxyethyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(3-hydroxypropyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-cyclopropylglycine subunits. In some embodiments, the block co-WSGR Docket No. 56009-757.601polymer comprises a polypeptoid comprising two or more repeating N-cyclohexylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-cyclopentylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-isopropylglycine subunits. In some embodiments, the block copolymer comprises a polypeptoid comprising two or more repeating N-isobutylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-tert-butylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(2-fluoroethyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-(trifluoroethyl)glycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more repeating N-allylglycine subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more different peptoid subunits. In some embodiments, the block co-polymer comprises a polypeptoid comprising two or more different peptoid subunits, of which one is N-methylglycine.

[0375] In some embodiments, the solubilizer comprises a polyester. In some embodiments, the block co-polymer comprises a polyester. In some embodiments, the block co-polymer comprises a poly lactide. In some embodiments, the block co-polymer comprises a poly glycolide. In some embodiments, the block co-polymer comprises a poly(lactide-co-glycolide). In some embodiments, the block co-polymer comprises a poly caprolactone. In some embodiments, the block co-polymer comprises a poly lactic acid. In some embodiments, the block co-polymer comprises a poly(D, L-lactic acid).

[0376] In some embodiments, the solubilizer comprises a sarcosine. In some embodiments, the solubilizer comprises a poly sarcosine. In some embodiments, the block co-polymer comprises a poly sarcosine.

[0377] In some embodiments, the solubilizer comprises one or more block co-polymers. In some embodiments, each block co-polymer is a different block. In some embodiments, the solubilizer comprises one type of block co-polymer. In some embodiments, the solubilizer comprises two types of block copolymers. In some embodiments, the solubilizer comprises three types of block co-polymers.

[0378] In some embodiments, each block has a different average number of units. In some embodiments, the average number of units is 1 -500. In some embodiments, the average number of units is 3-300. In some embodiments, the average number of units is 3-200. In some embodiments, the average number of units is 3-300. In some embodiments, the average number of units is 3-150. In some embodiments, the average number of units is 3-100. In some embodiments, the average number of units is 3-80. In some embodiments, the average number of units is 3-50. In some embodiments, the average number of units is 3-40. In some embodiments, the average number of units is 3-30. In some embodiments, the average number of units is 3-20. In some embodiments, the average number of units is 3-10.

[0379] In some embodiments, the solubilizer comprises two types of block co-polymer, for example block A and block B. In some embodiments, the ratio of the blocks is about 1:500 to 500:1. In some embodiments, the ratio of the blocks is about 1:200 to 200: 1. In some embodiments, the ratio of the blocksWSGR Docket No. 56009-757.601is about 1:150 to 150:1. In some embodiments, the ratio of the blocks is about 1:100 to 100:1. In some embodiments, the ratio of the blocks is about 1:150 to 150:1. In some embodiments, the ratio of the blocks is about 1:80 to 80:1. In some embodiments, the ratio of the blocks is about 1:50 to 50:1. In some embodiments, the ratio of the blocks is about 100:200 to 200: 100. In some embodiments, the ratio of the blocks is about 50:200 to 200:50. In some embodiments, the ratio of the blocks is about 30:200 to 200:30. In some embodiments, the ratio of the blocks is about 20:200 to 200:20.

[0380] In some embodiments, the block co-polymer comprises one or more of a polyethylene glycol (PEG), polyester, polypeptoid, poly lactide, poly glycolide, polyamide, polycaprolactone, poly lactic acid, poly amino acid, and / or poly sarcosine.

[0381] In some embodiments, the block co-polymer comprises PEG and a poly amino acid. In some embodiments, the block co-polymer comprises PEG and a poly sarcosine. In some embodiments, the block co-polymer comprises PEG and a polypeptoid. In some embodiments, the block co-polymer comprises PEG and a polyamide. In some embodiments, the block co-polymer comprises polypeptoid and a poly amino acid. In some embodiments, the block co-polymer comprises polypeptoid and a polyamide. In some embodiments, the block co-polymer comprises polypeptoid and a poly sarcosine. In some embodiments, the block co-polymer comprises a poly sarcosine and a poly amino acid. In some embodiments, the block co-polymer comprises poly sarcosine and a polyamide. In some embodiments, the block co-polymer comprises PEG and a polyester. In some embodiments, the block co-polymer comprises PEG and a poly lactide. In some embodiments, the block co-polymer comprises PEG and a poly glycolide. In some embodiments, the block co-polymer comprises PEG and a poly(lactide-co-glycolide). In some embodiments, the block co-polymer comprises PEG and a poly caprolactone. In some embodiments, the block co-polymer comprises PEG and a poly lactic acid. In some embodiments, the block co-polymer comprises PEG and a poly(D, L-lactic acid). In some embodiments, the block copolymer comprises polyester and a poly amino acid. In some embodiments, the block co-polymer comprises polyester and a polypeptoid. In some embodiments, the block co-polymer comprises polyester and a polyamide. In some embodiments, the block co-polymer comprises polyester and a poly sarcosine. In some embodiments, the block co-polymer comprises poly lactide and a poly amino acid. In some embodiments, the block co-polymer comprises poly lactide and a polypeptoid. In some embodiments, the block co-polymer comprises poly lactide and a polyamide. In some embodiments, the block co-polymer comprises poly lactide and a poly sarcosine. In some embodiments, the block co-polymer comprises poly glycolide and a poly amino acid. In some embodiments, the block co-polymer comprises poly glycolide and a polypeptoid. In some embodiments, the block co-polymer comprises poly glycolide and a polyamide. In some embodiments, the block co-polymer comprises poly glycolide and a poly sarcosine. In some embodiments, the block co-polymer comprises poly(lactide-co-glycolide) and a poly amino acid. In some embodiments, the block co-polymer comprises poly(lactide-co-glycolide) and a polypeptoid. In some embodiments, the block co-polymer comprises poly(lactide-co-glycolide) and a polyamide. In some embodiments, the block co-polymer comprises poly(lactide-co-glycolide) and a poly sarcosine. In some embodiments, the block co-polymer comprises poly caprolactone and a poly amino acid. In someWSGR Docket No. 56009-757.601embodiments, the block co-polymer comprises poly caprolactone and a polypeptoid. In some embodiments, the block co-polymer comprises poly caprolactone and a polyamide. In some embodiments, the block co-polymer comprises poly caprolactone and a poly sarcosine. In some embodiments, the block co-polymer comprises polyamide and a poly amino acid.

[0382] In some embodiments, the solubilizer has a molecular weight of about 1 kDa to about 100 kDa.

[0383] In some embodiments, the solubilizer has a molecular weight of about 1 kDa to about 50 kDa. In some embodiments, the solubilizer has a molecular weight of about 1 kDa to about 30 kDa. In some embodiments, the solubilizer has a molecular weight of about 1 kDa to about 20 kDa. In some embodiments, the solubilizer has a molecular weight of about 10 kDa to about 20 kDa. In some embodiments, the solubilizer has a molecular weight of about 10 kDa, about 11 kDa, about 12 kDa, about 13 kDa, about 14 kDa, about 15 kDa, about 16 kDa, about 17 kDa, about 18 kDa, about 19 kDa, or about 20 kDa. In some embodiments, the solubilizer has a molecular weight of about 10 kDa. In some embodiments, the solubilizer has a molecular weight of about 11 kDa. In some embodiments, the solubilizer has a molecular weight of about 12 kDa. In some embodiments, the block solubilizer has a molecular weight of about 13 kDa. In some embodiments, the solubilizer has a molecular weight of about 14 kDa. In some embodiments, the solubilizer has a molecular weight of about 15 kDa. In some embodiments, the solubilizer has a molecular weight of about 16 kDa. In some embodiments, the solubilizer has a molecular weight of about 17 kDa. In some embodiments, the solubilizer has a molecular weight of about 18 kDa. In some embodiments, the solubilizer has a molecular weight of about 19 kDa. In some embodiments, the solubilizer has a molecular weight of about 20 kDa.

[0384] In some embodiments, the block co-polymer has a molecular weight of about 1 kDa to about 100 kDa. In some embodiments, the block co-polymer has a molecular weight of about 1 kDa to about 50 kDa. In some embodiments, the block co-polymer has a molecular weight of about 1 kDa to about 30 kDa. In some embodiments, the block co-polymer has a molecular weight of about 1 kDa to about 20 kDa. In some embodiments, the block co-polymer has a molecular weight of about 10 kDa to about 20 kDa. In some embodiments, the block co-polymer has a molecular weight of about 10 kDa, about 11 kDa, about 12 kDa, about 13 kDa, about 14 kDa, about 15 kDa, about 16 kDa, about 17 kDa, about 18 kDa, about 19 kDa, or about 20 kDa. In some embodiments, the block co-polymer has a molecular weight of about 10 kDa. In some embodiments, the solubilizer has a molecular weight of about 11 kDa. In some embodiments, the block co-polymer has a molecular weight of about 12 kDa. In some embodiments, the block co-polymer has a molecular weight of about 13 kDa. In some embodiments, the block co-polymer has a molecular weight of about 14 kDa. In some embodiments, the block co-polymer has a molecular weight of about 15 kDa. In some embodiments, the block co-polymer has a molecular weight of about 16 kDa. In some embodiments, the block co-polymer has a molecular weight of about 17 kDa. In some embodiments, the block co-polymer has a molecular weight of about 18 kDa. In some embodiments, the block co-polymer has a molecular weight of about 19 kDa. In some embodiments, the block co-polymer has a molecular weight of about 20 kDa.WSGR Docket No. 56009-757.601

[0385] In some embodiments, the solubilizer encapsulates the compound. In some embodiments, the block co-polymer encapsulates and solubilizes the compound.

[0386] In some embodiments, the solubilizer encapsulates the compound and forms a particle. In some embodiments, the solubilizer encapsulates the compound and forms a micelle. In some embodiments, the solubilizer encapsulates a compound described herein and forms a reverse micelle.

[0387] In some embodiments, the solubilizer non-covalently binds the compound and forms a particle. In some embodiments, the solubilizer non-covalently binds the compounds and forms a dendrimer.

[0388] In some embodiments, the block co-polymer encapsulates and solubilizes the compound.

[0389] In some embodiments, non-limiting examples of the solubilizer described herein are presented below in Table 3.Table 3. Select SolubilizersAbbreviation NameTPGS tocopherol polyethylene glycol succinatePEG-DSPE 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) PEG-PVCY poly (ethylene oxide) -b- poly (vinyl cyclohexane)PEG-PPO poly(ethylene oxide)-b-poly(propylene oxide)PEG-PGLA methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide)PEG-PCL methoxy poly(ethylene glycol)-b-polycaprolactonePVyNa-PAsp poly(2-vinyl naphthalene)-b-poly(acrylic acid)PEG-PGlu methoxy poly(ethylene glycol)-b-poly(L-glutamic acid)POx-PDLLA methyl-poly(2-ethyl-2-oxazoline)-b-poly(D, L-lactic acid)PEG-PLG methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide)PEG-PDLLA methoxy poly(ethylene glycol)-b-poly(D, L-lactide)PEG-PBLG poly(ethylene glycol)-b-poly(benzylglutamate)PEG-PBDLG poly(ethylene glycol)-b-poly(D / L-benzylglutamate)PEG-PLeu poly(ethylene glycol)-b-poly(leucine)PEG-PPhe poly(ethylene glycol)-b-poly(phenylalanine)PEG-P(BLG36 / Sar4) poly(ethylene glycol)-b-poly(benzylglutamate-co-sarcosine)PEG-P(BLG32 / Sar8) poly(ethylene glycol)-b-poly(benzylglutamate-co-sarcosine)PEG-PLA poly(ethylene glycol)-b-poly(lactic acid)PEG-PLGA poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)PEG-PPS poly(ethylene glycol)-b-poly(propylene sulfide)PEG-PCL poly(ethylene glycol)-b-poly caprolactoneEG-PDMS poly(ethylene glycol)-b-poly(dimethylsiloxane)PEG-PPO-PEG poly(ethylene glycol)-b-poly(propylene oxide)-b-poly(ethylene glycol) PEG-PAsp poly(ethylene glycol)-b-poly(aspartic acid)PEG-PLys poly(ethylene glycol)-b-poly(lysine)PEG-PHis poly(ethylene glycol)-b-poly(histidine)PEG-PCys poly(ethylene glycol)-b-poly(cysteine)PEG-PTyr poly(ethylene glycol)-b-poly(tyrosine)PLA-PEG-PLA poly(lactic acid)-b-poly(ethylene glycol)-b-poly(lactic acid)PLGA-PEG-PLGA poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)WSGR Docket No. 56009-757.601PCL-PEG-PCL polycaprolactone-b-poly(ethylene glycol)-b-poly caprolactonePOx poly(2-oxazoline)-based copolymersPEG-PBAE poly(ethylene glycol)-b-poly(β-amino ester)PEG-POE poly(ethylene glycol)-b-poly(ortho ester)PEG-PAnh poly(ethylene glycol)-b-poly(anhydride)PEG-PγGlu poly(ethylene glycol)-b-poly(γ-glutamic acid)PEG-PεLys poly(ethylene glycol)-b-poly(ε-lysine)ELP elastin-like polypeptide conjugatesPEG-dendron poly(ethylene glycol)-dendron hybridsPSar-PLLeu poly(sarcosine)-b-poly(L-leucine)PSar-PDLeu poly(sarcosine)-b-poly(D-leucine)PSar-PLPhe poly(sarcosine)-b-poly(L-phenylalanine)PSar-PDPhe poly(sarcosine)-b-poly(D-phenylalanine)PSar-PLTyr poly(sarcosine)-b-poly(L-tyrosine)PSar-PDTyr poly(sarcosine)-b-poly(D-tyrosine)PSar-PLTrp poly(sarcosine)-b-poly(L-tryptophan)PSar-PLVal poly(sarcosine)-b-poly(L-valine)PSar-PLIle poly(sarcosine)-b-poly(L-isoleucine)PSar-PDLeu-Tyr poly(sarcosine)-b-poly(D-leucine-co-tyrosine)PSar-PLLeu-Phe poly(sarcosine)-b-poly(L-leucine-co-phenylalanine)PSar-PDPhe- Tyr poly(sarcosine)-b-poly(D-phenylalanine-co-tyrosine)PSar-PDLeu-Val poly(sarcosine)-b-poly(L-leucine-co- valine)PSar-PDLeu-Trp poly(sarcosine)-b-poly(D-leucine-co-tryptophan)PSar-PLLys poly(sarcosine)-b-poly(L-lysine)PSar-PLGlu poly(sarcosine)-b-poly(L-glutamic acid)PSar-PLAsp poly(sarcosine)-b-poly(L-aspartic acid)PSar-PLArg poly(sarcosine)-b-poly(L-arginine)Particle

[0390] Provided herein is a particle comprising a compound having (i) a first terminus comprising a polyamide, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the polyamide and the protein-binding moiety; and a block co-poly mer.

[0391] Provided in some embodiments herein is a particle comprising a compound disclosed herein and a block co-polymer disclosed herein. In some embodiments, the particle described herein comprises a polyamide. In some embodiments, the particle described herein comprises a protein -binding moiety. In some embodiments, the particle described herein comprises an oligomeric backbone that links the polyamide and the protein-binding moiety. In some embodiments, the particle described herein comprises (i) a first terminus comprising a polyamide, (ii) a second terminus comprising a protein -binding moiety, and (iii) an oligomeric backbone that links the polyamide and the protein-binding moiety.

[0392] Provided herein is a particle comprising a pyrrole-imidazole polyamide; and a block copolymer.

[0393] Provided herein is a particle comprising a GAA repeat expansion binding moiety linked to a transcriptional ligand; and a block co-polymer.WSGR Docket No. 56009-757.601

[0394] Provided herein is a particle comprising a GAA repeat expansion binding polyamide linked to a transcriptional ligand; and a block co-polymer.

[0395] Provided herein is a particle comprising a GAA repeat expansion binding moiety linked to a ligand; and a block co-polymer.

[0396] Provided herein is a particle comprising a CAG repeat expansion binding moiety linked to a transcriptional ligand; and a block co-polymer.

[0397] Provided herein is a particle comprising a CAG repeat expansion binding polyamide linked to a transcriptional ligand; and a block co-polymer.

[0398] Provided herein is a particle comprising a CAG repeat expansion binding moiety linked to a ligand; and a block co-polymer.

[0399] Provided herein is a particle comprising a CTG repeat expansion binding moiety linked to a transcriptional ligand; and a block co-polymer.

[0400] Provided herein is a particle comprising a CTG repeat expansion binding polyamide linked to a transcriptional ligand; and a block co-polymer.

[0401] Provided herein is a particle comprising a CTG repeat expansion binding moiety linked to a ligand; and a block co-polymer.

[0402] Provided herein is a particle comprising a CGG repeat expansion binding moiety linked to a transcriptional ligand; and a block co-polymer.

[0403] Provided herein is a particle comprising a CGG repeat expansion binding polyamide linked to a transcriptional ligand; and a block co-polymer.

[0404] Provided herein is a particle comprising a CGG repeat expansion binding moiety linked to a ligand; and a block co-polymer.

[0405] Provided herein is a particle comprising a CCTG repeat expansion binding moiety linked to a transcriptional ligand; and a block co-polymer.

[0406] Provided herein is a particle comprising a CCTG repeat expansion binding polyamide linked to a transcriptional ligand; and a block co-polymer.

[0407] Provided herein is a particle comprising a CCTG repeat expansion binding moiety linked to a ligand; and a block co-polymer.

[0408] Provided herein is a particle comprising a TGGAA repeat expansion binding moiety linked to a transcriptional ligand; and a block co-polymer.

[0409] Provided herein is a particle comprising a TGGAA repeat expansion binding polyamide linked to a transcriptional ligand; and a block co-polymer.

[0410] Provided herein is a particle comprising a TGGAA repeat expansion binding moiety linked to a ligand; and a block co-polymer.

[0411] Provided herein is a particle comprising a GGGGCC repeat expansion binding moiety linked to a transcriptional ligand; and a block co-polymer.

[0412] Provided herein is a particle comprising a GGGGCC repeat expansion binding polyamide linked to a transcriptional ligand; and a block co-polymer.WSGR Docket No. 56009-757.601

[0413] Provided herein is a particle comprising a GGGGCC repeat expansion binding moiety linked to a ligand; and a block co-polymer.

[0414] Provided herein is a particle comprising penta(Arylcarboxamido)-octaoxa-2,6-diazadotriacontan-pyrrolopyridine-carboxamide; and a block co-polymer.

[0415] Provided herein is a particle comprising penta(heteroarylcarboxamindo)-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide; and a block co-polymer.

[0416] Provided herein is a particle comprising poly-heteroarylcarboxamido-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide; and a block co-polymer.

[0417] Provided herein is a particle comprising pyrrolopyridine-carboxamido-polyethyleneglycolyl-penta(heteroarylaminoacid); and a block co-polymer.

[0418] Provided herein is a particle comprising hexa(Arylcarboxamido)-octaoxa-2,6-diazadotriacontan-pyrrolopyridine-carboxamide; and a block co-polymer.

[0419] Provided herein is a particle comprising hepta(Arylcarboxamido)-octaoxa-2,6-diazadotriacontan-pyrrolopyridine-carboxamide; and a block co-polymer.

[0420] Provided herein is a particle comprising hexa(heteroarylcarboxamindo)-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide; and a block co-polymer.

[0421] Provided herein is a particle comprising hepta(heteroarylcarboxamindo)-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide; and a block co-polymer.

[0422] Provided herein is a particle comprising poly-heteroarylcarboxamido-octaoxa-triazolodiazapine; and a block co-polymer.

[0423] Provided herein is a particle comprising a compound having a pyrrole-imidazole polyamide attached to a linker; and an amphiphilic polymer.

[0424] Provided herein is a particle comprising a compound having pyrrole-imidazole polyamide, a small molecule ligand, and a linker attaching the polyamide and ligand; and an amphiphilic polymer.

[0425] Provided herein is a particle comprising a pyrrole-imidazole polyamide attached to a bromodomain ligand; and an amphiphilic polymer; and a block co-polymer.

[0426] In some embodiments, the particle comprises a compound described herein and a solubilizer described herein. In some embodiments, the particle comprises a compound provided in any of Tables 2A, 2B, 2C, 2D, or 2E and a solubilizer provided in Table 3.

[0427] In some embodiments, the particle is an amphiphilic micelle.

[0428] In some embodiments, the particle is a dendrimer.

[0429] In some embodiments, the compound is encapsulated in the solubilizer.

[0430] In some embodiments, the compound is non-covalently bound to the solubilizer.

[0431] In some embodiments, the particle has a diameter of at most about 800 nm. In some embodiments, the particle has a diameter of at most about 500 nm. In some embodiments, the particle has a diameter of at most about 250 nm. In some embodiments, the particle has a diameter of less than about 500 nm. In some embodiments, the particle has a diameter of less than about 250 nm.WSGR Docket No. 56009-757.601

[0432] In some embodiments, the particle has a diameter of about 50 nm to about 200 nm. In some embodiments, the particle has a diameter of about 1 nm to about 100 nm. In some embodiments, the particle has a diameter of about 1 nm to about 80 nm. In some embodiments, the particle has a diameter of about 1 nm to about 60 nm. In some embodiments, the particle has a diameter of about 1 nm to about 50 nm. In some embodiments, the particle has a diameter of about 10 nm to about 30 nm. In some embodiments, the diameter is measured by dynamic light scattering, for an extended period of time at room temperature.Pharmaceutical Compositions and Administration

[0433] Provided herein is a pharmaceutical composition comprising a GAA repeat expansion binding moiety linked to a transcriptional ligand; and a solubilizer.

[0434] Provided herein is a pharmaceutical composition comprising a GAA repeat expansion binding polyamide linked to a transcriptional ligand; and a solubilizer.

[0435] Provided herein is a pharmaceutical composition comprising a GAA repeat expansion binding moiety linked to a ligand; and a solubilizer.

[0436] Provided herein is a pharmaceutical composition comprising a CAG repeat expansion binding moiety linked to a transcriptional ligand; and a solubilizer.

[0437] Provided herein is a pharmaceutical composition comprising a CAG repeat expansion binding polyamide linked to a transcriptional ligand; and a solubilizer.

[0438] Provided herein is a pharmaceutical composition comprising a CAG repeat expansion binding moiety linked to a ligand; and a solubilizer.

[0439] Provided herein is a pharmaceutical composition comprising a CTG repeat expansion binding moiety linked to a transcriptional ligand; and a solubilizer.

[0440] Provided herein is a pharmaceutical composition comprising a CTG repeat expansion binding polyamide linked to a transcriptional ligand; and a solubilizer.

[0441] Provided herein is a pharmaceutical composition comprising a CTG repeat expansion binding moiety linked to a ligand; and a solubilizer.

[0442] Provided herein is a pharmaceutical composition comprising a CGG repeat expansion binding moiety linked to a transcriptional ligand; and a solubilizer.

[0443] Provided herein is a pharmaceutical composition comprising a CGG repeat expansion binding polyamide linked to a transcriptional ligand; and a solubilizer.

[0444] Provided herein is a pharmaceutical composition comprising a CGG repeat expansion binding moiety linked to a ligand; and a solubilizer

[0445] Provided herein is a pharmaceutical composition comprising a CCTG repeat expansion binding moiety linked to a transcriptional ligand; and a solubilizer.

[0446] Provided herein is a pharmaceutical composition comprising a CCTG repeat expansion binding polyamide linked to a transcriptional ligand; and a solubilizer.WSGR Docket No. 56009-757.601

[0447] Provided herein is a pharmaceutical composition comprising a CCTG repeat expansion binding moiety linked to a ligand; and a solubilizer.

[0448] Provided herein is a pharmaceutical composition comprising a TGGAA repeat expansion binding moiety linked to a transcriptional ligand; and a solubilizer.

[0449] Provided herein is a pharmaceutical composition comprising a TGGAA repeat expansion binding polyamide linked to a transcriptional ligand; and a solubilizer.

[0450] Provided herein is a pharmaceutical composition comprising a TGGAA repeat expansion binding moiety linked to a ligand; and a solubilizer.

[0451] Provided herein is a pharmaceutical composition comprising a GGGGCC repeat expansion binding moiety linked to a transcriptional ligand; and a solubilizer.

[0452] Provided herein is a pharmaceutical composition comprising GGGGCC repeat expansion binding polyamide linked to a transcriptional ligand; and a solubilizer.

[0453] Provided herein is a pharmaceutical composition comprising a GGGGCC repeat expansion binding moiety linked to a ligand; and a solubilizer.

[0454] Provided herein is a pharmaceutical composition comprising penta(Arylcarboxamido)-octaoxa- 2,6-diazadotriacontan-pyrrolopyridine-carboxamide; and a solubilizer.

[0455] Provided herein is a pharmaceutical composition comprising penta(heteroarylcarboxamindo)-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide; and a solubilizer.

[0456] Provided herein is a pharmaceutical composition comprising poly-heteroarylcarboxamido-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide; and a solubilizer.

[0457] Provided herein is a pharmaceutical composition comprising pyrrolopyridine-carboxamido-polyethyleneglycolyl-penta(heteroarylaminoacid); and a solubilizer.

[0458] Provided herein is a pharmaceutical composition comprising hexa(Arylcarboxamido)-octaoxa- 2,6-diazadotriacontan-pyrrolopyridine-carboxamide; and a solubilizer.

[0459] Provided herein is a pharmaceutical composition comprising hepta(Arylcarboxamido)-octaoxa- 2,6-diazadotriacontan-pyrrolopyridine-carboxamide; and a solubilizer.

[0460] Provided herein is a pharmaceutical composition comprising hexa(heteroarylcarboxamindo)-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide; and a solubilizer.

[0461] Provided herein is a pharmaceutical composition comprising hepta(heteroarylcarboxamindo)-octaoxa-2,6-diazadotriacontanylpyrrolopyridine-carboxamide; and a solubilizer.

[0462] Provided herein is a pharmaceutical composition comprising poly-heteroarylcarboxamido-octaoxa-triazolodiazepine; and a solubilizer.

[0463] Provided herein is a pharmaceutical composition comprising pyrrolopyridine-carboxamido-polyethyleneglycolyl-hexa(heteroarylaminoacid); and a solubilizer.

[0464] Provided herein is a pharmaceutical composition comprising pyrrolopyridine-carboxamido-polyethyleneglycolyl-hepta(heteroarylaminoacid); and a solubilizer.WSGR Docket No. 56009-757.601

[0465] In some embodiments, the composition described herein comprises a particle. In some embodiments, the composition described herein comprises a solubilizer. In some embodiments, the composition comprises one or more pharmaceutically acceptable excipients.

[0466] In some embodiments, the composition comprises a compound provided in any of Tables 2A, 2B, 2C, 2D, or 2E and a solubilizer provided in Table 3. In some embodiments, the composition comprises a compound provided in any of Tables 2A, 2B, 2C, 2E, or 2E and a solubilizer provided in Table 3, and one or more pharmaceutically acceptable excipients.

[0467] In some embodiments, the pharmaceutically acceptable excipient is selected from an antioxidant, an anti-foaming agent, a bulking agent, a buffer, a chelating agent, a co-solvent, a colorant, a cryoprotectant, a diluent, a disintegrating agent, dispersing agents, an isotonicity adjusting agent, an osmolality adjusting agent, a penetration enhancer, a pH adjusting agent, a preservative, a surfactant or emulsifier, a suspending agent, a stabilizer, a viscosity modifier, and any combinations thereof.

[0468] In some embodiments, the excipient is a preservative and / or anti-microbial agent. In some embodiments, the preservative prevents microbial growth in the solution. Examples of preservative may include parabens and benzalkonium chloride. In some embodiments, the preservative is methylparaben, propylparaben, or benzalkonium chloride. In some embodiments, the preservative is methylparaben. In some embodiments, the preservative is propylparaben. In some embodiments, the preservative is benzalkonium chloride.

[0469] In some embodiments, the excipient may include a cryoprotectant. Without being bound by theory, cryoprotectants may include sugars (e.g., trehalose, sorbitol, and mannitol) and polyethylene glycols. In some embodiments, the cryoprotectant is trehalose, sorbitol, glycine, mannitol, PEG, or a combination thereof. In some embodiments, the cryoprotectant is trehalose. In some embodiments, the cryoprotectant is sorbitol. In some embodiments, the cryoprotectant is glycine. In some embodiments, the cryoprotectant is mannitol. In some embodiments, the cryoprotectant is PEG. In some embodiments, the cryoprotectant is PEG 8000.

[0470] In some embodiments, the excipient comprises a buffer. In some embodiments the buffer includes citric acid, sodium hydroxide, or a phosphate buffer. In some embodiments, the buffer is citric acid. In some embodiments, the buffer is sodium hydroxide.

[0471] In some embodiments, the excipient comprises an antioxidant and / or stabilizer. In some embodiments, the antioxidant is ascorbic acid or butylated hydroxytoluene (BHT). In some embodiments, the antioxidant is ascorbic acid. In some embodiments, the antioxidant is BHT.

[0472] In some embodiments, the composition has a weight ratio of about 1:5 to about 1:80 of the compound to the excipient. In some embodiments, the composition has a weight ratio of about 1:5 to about 1: 50 of the compound to the excipient. In some embodiments, the composition has a weight ratio of about 1:5 to about 1:40 of the compound to the excipient. In some embodiments, the composition has a weight ratio of about 1:5 to about 1:30 of the compound to the excipient. In some embodiments, the composition has a weight ratio of about 1:5 to about 1:25 of the compound to the excipient. In some embodiments, the composition has a weight ratio of at least about 1:5, about 1:10, about 1:15, about 1:20,WSGR Docket No. 56009-757.601about 1:25, or more, of the compound to the excipient. In some embodiments, the composition has a weight ratio of at most about 1:50, about 1:40, about 1:30, about 1:25, about 1:20, about 1:15, about 1:10, or less, of the compound to the excipient.

[0473] In some embodiments, the composition has a weight ratio of about 0.1:1 to about 10: 1 of the solubilizer to the excipient. In some embodiments, the composition has a weight ratio of about 1: 1 of the solubilizer to the excipient. In some embodiments, the composition has a weight ratio of at least about 0.1:1, about 0.5:l, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9: 1, or more, of the solubilizer to the excipient. In some embodiments, the composition has a weight ratio of at most about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 0.5:1, or less, of the solubilizer to the excipient.

[0474] In some embodiments, the composition has a weight ratio of about 1:5 to about 1:80 of the compound to the solubilizer. In some embodiments, the composition has a weight ratio of about 1:5 to about 1: 50 of the compound to the solubilizer. In some embodiments, the composition has a weight ratio of about 1:5 to about 1:40 of the compound to the solubilizer. In some embodiments, the composition has a weight ratio of about 1:5 to about 1:30 of the compound to the solubilizer. In some embodiments, the composition has a weight ratio of about 1:5 to about 1:15 of the compound to the solubilizer. In some embodiments, the composition has a weight ratio of at least about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, or more, of the compound to the solubilizer. In some embodiments, the composition has a weight ratio of at most about 1:80, about 1:50, about 1:40, about 1:30, about 1:25, about 1:20, about 1:15, about 1:10, or less, of the compound to the solubilizer.

[0475] In some embodiments, the composition is a lyophilized powder. In some embodiments, the composition is a lyophilized cake.

[0476] In some embodiments, the composition is a solution. In some embodiments, the composition comprises saline. In some embodiments, the composition comprises an aqueous and isotonic solution. In some embodiments, the composition is reconstituted in saline. In some embodiments, the composition is reconstituted in water. In some embodiments, the composition is reconstituted in an isotonic solution.

[0477] In some embodiments, the composition comprises an osmolarity of about 250 mOsm to about 450 mOsm. In some embodiments, the composition comprises an osmolarity of about 250 mOsm to about 350 mOsm. In some embodiments, the composition comprises an osmolarity of about 250 mOsm. In some embodiments, the composition comprises an osmolarity of about 300 mOsm. In some embodiments, the composition comprises an osmolarity of about 350 mOsm. In some embodiments, the composition comprises an osmolarity of about 400 mOsm. In some embodiments, the composition comprises an osmolarity of about 450 mOsm.

[0478] In some embodiments, the composition is reconstituted to a compound concentration of about 1 mg / mL to about 10 mg / mL.

[0479] In some embodiments, the composition comprises about 0.1 % w / w to about 20 % w / w of the compound. In some embodiments, the composition comprises about 1 % w / w to about 10 % w / w of the compound.WSGR Docket No. 56009-757.601

[0480] In some embodiments, the composition comprises about 1 % w / w to about 80 % w / w of the solubilizer. In some embodiments, the composition comprises about 1 % w / w to about 50 % w / w of the solubilizer. In some embodiments, the composition comprises about 1 % w / w to about 40 % w / w of the solubilizer. In some embodiments, the composition comprises about 1 % w / w to about 30 % w / w of the solubilizer. In some embodiments, the composition comprises about 1 % w / w to about 20 % w / w of the solubilizer. In some embodiments, the composition comprises about 1 % w / w to about 10 % w / w of the solubilizer.

[0481] In some embodiments, the pharmaceutical composition comprises about 1 % w / w to about 50 % w / w of the excipient. In some embodiments, the pharmaceutical composition comprises about 1 % w / w to about 40 % w / w of the excipient. In some embodiments, the pharmaceutical composition comprises about 1 % w / w to about 30 % w / w of the excipient. In some embodiments, the pharmaceutical composition comprises about 1 % w / w to about 20 % w / w of the excipient. In some embodiments, the pharmaceutical composition comprises about 1 % w / w to about 10 % w / w of the excipient.

[0482] In some embodiments, the composition is a soluble solution.

[0483] In some embodiments, the composition does not comprise an organic solvent. In some embodiments, the composition comprises an organic solvent. In some embodiments, the composition comprises an organic co-solvent.

[0484] In some embodiments, the composition is a stable solution.

[0485] In some embodiments, the composition is shelf stable for at least 1 hour at room temperature. In some embodiments, the composition is shelf stable for about 1 hour to about 8 days at room temperature. In some embodiments, the composition is shelf stable for about 1 hour to about 1 day, about 1 hour to about 2 days, about 1 hour to about 3 days, about 1 hour to about 4 days, about 1 hour to about 5 days, about 1 hour to about 6 days, about 1 hour to about 7 days, about 1 hour to about 8 days, about 1 day to about 2 days, about 1 day to about 3 days, about 1 day to about 4 days, about 1 day to about 5 days, about 1 day to about 6 days, about 1 day to about 7 days, about 1 day to about 8 days, about 2 days to about 3 days, about 2 days to about 4 days, about 2 days to about 5 days, about 2 days to about 6 days, about 2 days to about 7 days, about 2 days to about 8 days, about 3 days to about 4 days, about 3 days to about 5 days, about 3 days to about 6 days, about 3 days to about 7 days, about 3 days to about 8 days, about 4 days to about 5 days, about 4 days to about 6 days, about 4 days to about 7 days, about 4 days to about 8 days, about 5 days to about 6 days, about 5 days to about 7 days, about 5 days to about 8 days, about 6 days to about 7 days, about 6 days to about 8 days, or about 7 days to about 8 days at room temperature. In some embodiments, the composition is shelf stable for about 1 hour, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, or about 8 days at room temperature. In some embodiments, the composition is shelf stable for at least about 1 hour, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days at room temperature. In some embodiments, the composition is shelf stable for at most about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, or about 8 days at room temperature.WSGR Docket No. 56009-757.601

[0486] In some embodiments, the composition is shelf stable for at least 2 days at 2 °C to 8 °C. In some embodiments, the composition is shelf stable for about 2 days to about 10 days at 2 °C to 8 °C. In some embodiments, the composition is shelf stable for about 2 days to about 3 days, about 2 days to about 4 days, about 2 days to about 5 days, about 2 days to about 6 days, about 2 days to about 7 days, about 2 days to about 8 days, about 2 days to about 9 days, about 2 days to about 10 days, about 3 days to about 4 days, about 3 days to about 5 days, about 3 days to about 6 days, about 3 days to about 7 days, about 3 days to about 8 days, about 3 days to about 9 days, about 3 days to about 10 days, about 4 days to about 5 days, about 4 days to about 6 days, about 4 days to about 7 days, about 4 days to about 8 days, about 4 days to about 9 days, about 4 days to about 10 days, about 5 days to about 6 days, about 5 days to about 7 days, about 5 days to about 8 days, about 5 days to about 9 days, about 5 days to about 10 days, about 6 days to about 7 days, about 6 days to about 8 days, about 6 days to about 9 days, about 6 days to about 10 days, about 7 days to about 8 days, about 7 days to about 9 days, about 7 days to about 10 days, about 8 days to about 9 days, about 8 days to about 10 days, or about 9 days to about 10 days at 2 °C to 8 °C. In some embodiments, the composition is shelf stable for about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days at 2 °C to 8 °C. In some embodiments, the composition is shelf stable for at least about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, or about 9 days at 2 °C to 8 °C. In some embodiments, the composition is shelf stable for at most about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days at 2 °C to 8 °C.

[0487] In some embodiments, the composition is shelf stable for at least 2 days at -20 °C. In some embodiments, the composition is shelf stable for about 2 days to about 60 days at -20 °C. In some embodiments, the composition is shelf stable for about 2 days to about 5 days, about 2 days to about 7 days, about 2 days to about 14 days, about 2 days to about 21 days, about 2 days to about 28 days, about 2 days to about 35 days, about 2 days to about 42 days, about 2 days to about 49 days, about 2 days to about 56 days, about 2 days to about 60 days, about 5 days to about 7 days, about 5 days to about 14 days, about 5 days to about 21 days, about 5 days to about 28 days, about 5 days to about 35 days, about 5 days to about 42 days, about 5 days to about 49 days, about 5 days to about 56 days, about 5 days to about 60 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28 days, about 7 days to about 35 days, about 7 days to about 42 days, about 7 days to about 49 days, about 7 days to about 56 days, about 7 days to about 60 days, about 14 days to about 21 days, about 14 days to about 28 days, about 14 days to about 35 days, about 14 days to about 42 days, about 14 days to about 49 days, about 14 days to about 56 days, about 14 days to about 60 days, about 21 days to about 28 days, about 21 days to about 35 days, about 21 days to about 42 days, about 21 days to about 49 days, about 21 days to about 56 days, about 21 days to about 60 days, about 28 days to about 35 days, about 28 days to about 42 days, about 28 days to about 49 days, about 28 days to about 56 days, about 28 days to about 60 days, about 35 days to about 42 days, about 35 days to about 49 days, about 35 days to about 56 days, about 35 days to about 60 days, about 42 days to about 49 days, about 42 days to about 56 days, about 42 days to about 60 days, about 49 days to about 56 days, about 49 days to about 60 days, or about 56 days to about 60 days atWSGR Docket No. 56009-757.601-20 °C. In some embodiments, the composition is shelf stable for about 2 days, about 5 days, about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, about 56 days, or about 60 days at -20 °C. In some embodiments, the composition is shelf stable for at least about 2 days, about 5 days, about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, or about 56 days at -20 °C. In some embodiments, the composition is shelf stable for at most about 5 days, about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, about 56 days, or about 60 days at -20 °C.

[0488] In some embodiments, the shelf stability of the composition is measured by methods and ranges known to the person of skill in the art. In some embodiments, the shelf stability of the composition is measured by dynamic light scattering. In some embodiments, the shelf stability of the composition is measured by high performance liquid chromatography. In some embodiments, the shelf stability of the composition is measured by visual inspection. In some embodiments, the shelf stability of the composition is measured by visual inspection for turbidity and / or sedimentation.

[0489] 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.

[0490] 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: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, (N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure.

[0491] 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.

[0492] 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 factorsWSGR Docket No. 56009-757.601described 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

[0493] 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.

[0494] 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.

[0495] 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.

[0496] When ranges of values are disclosed, and the notation “from m... to m” or “between m... and m” is used, where and m 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 pM (micromolar),” which is intended to include 1 pM, 3 pM, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).

[0497] The terms below, as used herein, have the following meanings, unless indicated otherwise:WSGR Docket No. 56009-757.601

[0498] “oxo” refers to =0.

[0499] “Carboxyl” refers to -COOH.

[0500] “Cyano” refers to -CN.

[0501] “Alkyl” refers to a straight- chain, or branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l -pentyl, 3-methyl-l-pentyl, 4-methyl-1 -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-1 -butyl, 2-ethyl- 1-butyl, n-butyl, isobutyl, sec- butyl, t- butyl, n-pentyl, isopentyl, neopentyl, tertamyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” or “Ci -ealkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a 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, 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, -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.

[0502] “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-ealkenyl”, 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.

[0503] “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,WSGR Docket No. 56009-757.6011,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-ealkynyr, 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.

[0504] “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, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0505] “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.

[0506] " 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 Hiickel 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 mayWSGR Docket No. 56009-757.601be 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.

[0507] “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-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). 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. l.l]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2. l]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.

[0508] " 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.WSGR Docket No. 56009-757.601

[0509] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0510] 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, l-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., tri chloromethane, tri bromomethane, 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.

[0511] " 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.

[0512] “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, hydroxy ethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0513] “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.

[0514] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen,WSGR Docket No. 56009-757.601methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0515] “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, the heterocycloalkyl 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-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-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[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered fully saturatedWSGR Docket No. 56009-757.601heterocycloalkyl. 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.

[0516] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl,WSGR Docket No. 56009-757.601pyrimidinyl, 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.

[0517] 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.

[0518] 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.

[0519] 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.

[0520] 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 β-alanine or dimethylaminopropylamine during synthesis of the polyamide by methods well known in the art.

[0521] 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 leastWSGR Docket No. 56009-757.601one of the two other groups to which it is attached. In some embodiments, the linker forms an amine or amide bond with at least one of the two other groups to which it is attached. In some embodiments, the linker comprises -(CH2OCH2)- units. In some embodiments, the linker comprises -(CH(CH3)OCH2)-units. In some embodiments, the linker comprises -(CH2NRNCH2) units, for RN = Ci-4alkyl. In some embodiments, the linker comprises an arylene, cycloalkylene, or heterocycloalkylene moiety.

[0522] 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.

[0523] 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 or group. Unless otherwise indicated, when a group is deemed to be “substituted” or “optionally substituted” it is meant that the group is substituted with one or more substituents independently selected from Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Ci-Ce heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalky 1, and Ci-Ce haloalkoxy), C3-C7-carbocyclyl-Ci-C6-alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 3-10 membered heterocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 3-10 membered heterocyclyl-Ci-Ce-alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), aryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), aryl(Ci-Ce)alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 5-10 membered heteroaryl(Ci-C6)alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), halo, cyano, hydroxy, Ci-Ce alkoxy, Ci-Ce aJkoxy(Ci-Ce)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(Ci-Ce)alkyl (e.g.,-CF3), halo(Ci-Ce) alkoxy (e.g.,-OCF3), Ci-Ce alkylthio, arylthio, amino, amino(Ci-Ce)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanate, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=0). Wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0524] 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.

[0525] 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 variousWSGR Docket No. 56009-757.601tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0526] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U. S. Patent Nos. 5,846,514 and 6,334,997. As described in U. S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0527] 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 the present 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.

[0528] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine- 125 (125I) or carbon- 14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. In some embodiments, where isotopic variations are illustrated, the remaining atoms of the compound may optionally contain unnatural portions of atomic isotopes.

[0529] In certain embodiments, the compounds disclosed herein have some or all of the4H 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.

[0530] 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.

[0531] 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.

[0532] 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.WSGR Docket No. 56009-757.601

[0533] 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.

[0534] 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.

[0535] 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.

[0536] 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.

[0537] 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.WSGR Docket No. 56009-757.601

[0538] 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's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0539] 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.

[0540] 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.

[0541] 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.

[0542] 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.

[0543] 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

[0544] 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, alongWSGR Docket No. 56009-757.601with 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

[0545] Compounds of the present disclosure can be prepared using methods illustrated in general synthetic schemes and experimental procedures detailed below. General synthetic schemes and experimental procedures are presented for purposes of illustration and are not intended to be limiting. Starting materials used to prepare compounds of the present disclosure are commercially available or can be prepared using routine methods known in the art.

[0546] 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 Abbreviation

[0547] AC2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; Boc = tert-butyloxy carbonyl; Bu3SnH = tributyltin hydride; CD3OD = deuterated methanol; CDCI3 = deuterated chloroform; CDI = 1,1'-Carbonyldiimidazole; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = di-iso-butyl aluminium hydride; DIEA = DIPEA = N, N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N, N-dimethylformamide; DMSO-de = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EDC. HC1 = EDCI. HC1 = 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = hour; HATU=2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate methanaminium; HMDS = hexamethyldisilazane; HOBT = 1 -hydroxybenzotriazole; i-PrOH = isopropanol; LAH = lithium aluminium hydride; LiHMDS = Lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; Mel = methyl iodide; MeOH = methanol; MP-carbonate resin = macroporous triethylammonium methylpolystyrene carbonate resin; MsCl = mesyl chloride; MTBE = methyl tertiary butyl ether; MW = microwave irradiation; n-BuLi = n-butyllithium; NaHMDS = Sodium bis(trimethylsilyl)amide; NaOMe = sodium methoxide; NaOtBu = sodium t-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMI = 1-methylimidazole; NMP = N-Methyl-2-pyrrolidone; OAc = acetoxy; Pd(Phs)4 = tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); PdC12(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; prep-HPLC = preparative high-performance liquid chromatography; PyBop = (benzotriazol -l-yloxy)tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; sat. = saturated; ss =WSGR Docket No. 56009-757.601saturated solution; t-BuOH = tert-butanol; T3P = Propylphosphonic Anhydride; TBS = TBDMS = tert-butyldimethylsilyl; TBSC1 = TBDMSC1 = fert-butyldi methyl chlorosilane; TCFH = chloro-N, N, N’, N’-tetramethylformamidiumhexafluorophosphate; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; Tol = toluene; TsCl = tosyl chloride; XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.SYNTHESIS OF REPRESENTATIVE COMPOUNDS

[0548] Example 1. Synthesis of Compound E-2

[0549] Scheme 1.NH2TFA, DCM r.t., 1.0 hWSGR Docket No. 56009-757.601

[0550] Step 1.

[0551] To a solution of ethyl 4-nitro-lH-imidazole-2-carboxylate (5.00 g, 27.01 mmol, 1.00 eq) in EtOH (60.00 mL) and EA (50.00 mL) was added Pd / C (50 mg, 25% w / w). Then the reaction was stirred for 6.0 h at room temperature under H2 atmosphere. The mixture was filtered and the filtrate was concentrated to afford ethyl 4-amino-lH-imidazole-2-carboxylate (4.30 g, 71%) as a white solid. LC / MS: mass calcd. For C6H9N3O2: 155.07, found: 156.10.10 [M+H]+.

[0552] Step 2.

[0553] To a stirred solution of 4-[(tert-butoxycarbonyl)amino]-l-methylpyrrole-2-carboxylic acid (5.00 g, 20.81 mmol, 1.00 eq) in DMF (50.00 mL) was added DIEA (10.76 g, 83.24 mmol, 4.00 eq) and allyl bromide (3.02 g, 24.97 mmol, 1.20 eq) at 0 °C. The resulting mixture was stirred for 16.0 h at room temperature. The reaction mixture was poured into ice / water (150 mL). The precipitated solids were collected by filtration and the filter cake was washed with H2O (3x150 mL), dried under vacuum.WSGR Docket No. 56009-757.601prop-2-en-l-yl 4-[(tert-butoxycarbonyl)amino]-l-methylpyrrole-2-carboxylate (5.89 g, 92%) as a white solid. LC / MS: mass calcd. For C14H20N2O4: 280.14, found: 281.10[M+H]+.

[0554] Step 3.

[0555] To a stirred solution of prop-2-en-l-yl 4-[(tert-butoxycarbonyl)amino]-l-methylpyrrole-2-carboxylate (1.30 g, 4.64 mmol, 1.00 eq) in DCM (9.00 mL) was added TFA (3.00 mL). The resulting mixture was stirred for 1.0 h at room temperature. The resulting mixture was concentrated under vacuum. Prop-2-en-l-yl 4-amino-l-methylpyrrole-2-carboxylate (1.30 g, crude) was obtained as a yellow oil. LC / MS: mass calcd. For C9H12N2O2: 180.09, found: 181.10[M+H]+.

[0556] Step 4.

[0557] To a stirred solution of l-methyl-4-(l-methylimidazole-2-amido)pyrrole-2-carboxylic acid (5.00 g, 20.14 mmol, 1.00 eq) in DMF (50.00 mL) was added DIEA (7.81 g, 60.43 mmol, 3.00 eq), 0β-alanine ethyl ester (3.09 g, 20.14 mmol, 1.00 eq) and PyBOP (12.58 g, 24.17 mmol, 1.20 eq) in portions at 0 °C. The resulting mixture was stirred for 1.0 h at room temperature. The reaction was poured into ice / water (150 mL). The precipitated solids were collected by filtration and washed with H2O (3x150 mL), dried under vacuum. Ethyl 3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanoate (6.50 g, 84%) was obtained as a white solid. LC / MS: mass calcd. For C16H21N5O4: 347.16, found: 348.30 [M+H]+.

[0558] Step 5.

[0559] To a stirred solution of ethyl 3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido} propanoate (6.40 g, 18.42 mmol, 1.00 eq) in MeOH (100.0 mL) and THF (50.00 mL) was added Li OH (46.06 mL, 92.12 mmol, 5.00 eq, 2 M in H2O) dropwise at room temperature. The resulting mixture was stirred for 2.0 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in H2O (150 mL). The mixture was acidified to pH = 3~5 with 2M HC1. The precipitated solids were collected by filtration and washed with H2O (3x150 mL), dried under vacuum. 3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanoic acid (5.50 g, 93%) was obtained as a white solid. LC / MS: mass calcd. For C14H17N5O4: 319.13, found: 320.15 [M+H]+.

[0560] Step 6.

[0561] To a stirred solution of 3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanoic acid (411.61 mg, 1.29 mmol, 1.00 eq) in DMF (10.00 mL) was added DIEA (499.80 mg, 3.87 mmol, 3.00 eq), PyBOP (872.05 mg, 1.68 mmol, 1.30 eq) and ethyl 4-amino-lH-imidazole-2-carboxylate (200.00 mg, 1.29 mmol, 1.00 eq) at 0 °C. The resulting mixture was stirred for 1.0 h at room temperature. The reaction was poured into ice / water (30 mL). The precipitated solids were collected by filtration and the filter cake was washed with H2O (3x30 mL), dried under vacuum, ethyl 4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-carboxylate (500.00 mg, 81%) was obtained as alight brown solid. LC / MS: mass calcd. For C20H24N8O5: 456.19, found: 457.15 [M+H]+.

[0562] Step 7.WSGR Docket No. 56009-757.601

[0563] To a stirred solution of ethyl 4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl] formamido}propanamido)-lH-imidazole-2-carboxylate (5.50 g, 12.05 mmol, 1.00 eq) in MeOH (60.00 mL) was added LiOH (60.30 mL, 120.50 mmol, 10.00 eq, 2 M in H2O,) at room temperature. The resulting mixture was stirred for 5.0 h at 45 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O (100 mL). The mixture was acidified to pH 3~5 with 2 M HC1. The precipitated solids were collected by filtration and washed with H2O (3x100 mL), dried under vacuum. 4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-carboxylic acid (4.40 g, 82%) was obtained as a purple solid. LC / MS: mass calcd. For C18H20N8O5: 428.16, found: 429.15 [M+H]+.

[0564] Step 8.

[0565] To a stirred solution of 4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-carboxylic acid (2.00 g, 4.67 mmol, 1.00 eq) in DMF (30.00 mL) was added DIEA (3.62 g, 28.01 mmol, 6.00 eq), PyBOP (3.16 g, 6.07 mmol, 1.30 eq) and prop-2-en-l-yl 4-amino-l-methylpyrrole-2-carboxylate (840.12 mg, 4.67 mmol, 1.00 eq) at 0 °C. The resulting mixture was stirred for 1.0 h at room temperature. The reaction was poured into ice water (100 mL). The precipitated solids were collected by filtration and the filter cake was washed with H2O (3x100 mL), dried under vacuum, prop-2-en-l-yl l-methyl-4-[4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-amido]pyrrole-2-carboxylate (2.65 g, 67%) was obtained as a white solid. LC / MS: mass calcd. For C27H30N10O6: 590.24, found: 591.25 [M+H]+.

[0566] Step 9.

[0567] To astirred solution of prop-2-en-l-yl l-methyl-4-[4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-amido]pyrrole-2-carboxylate (2.63 g, 4.45 mmol, 1.00 eq) in DMF (30.00 mL) was added CS2CO3 (4.35 g, 13.36 mmol, 3.00 eq) and tert-butyl 6-bromohexanoate (1.45 g, 5.79 mmol, 1.30 eq). The resulting mixture was stirred at 50 °C for 2.0 h. After filtration, the filtrate was purified by reverse column under the conditions: Cl 8 column; mobile phase, ACN in water (0.05% TFA), 10% to 70% gradient in 30 min; detector, UV 254 nm. The fractions were combined and concentrated, prop-2-en-l-yl 4-{l-[6-(tert-butoxy)-6-oxohexyl]-4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-amido}-l-methylpyrrole-2-carboxylate (1.82 g, 48%) was obtained as a brown solid. LC / MS: mass calcd. For C37H48N10O8: 760.37 found: 761.45 [M+H]+.

[0568] Step 10.

[0569] To a stirred solution of prop-2-en-l-yl 4-{l-[6-(tert-butoxy)-6-oxohexyl]-4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-amido}-l-methylpyrrole-2-carboxylate (1.80 g, 2.37 mmol, 1.00 eq) in DMF (18.00 mL) was added phenylsilane (512.01 mg, 4.73 mmol, 2.00 eq) and Pd(PPh3)4 (273.39 mg, 0.24 mmol, 0.10 eq) at room temperature. The resulting mixture was stirred for 1.0 h at room temperature. The reaction was poured into ice / water (60 mL). The mixture was acidified to pH 3~5 with 2 M HC1. The precipitated solids were collected by filtration and theWSGR Docket No. 56009-757.601filter cake was washed with H2O (3x20 mL), dried under vacuum. 4- { 1 -[6-(tert-butoxy)-6-oxohexyl]-4-(3-{ [ 1 -methyl-4-(l -methylimidazole-2-amido)pyrrol-2-yl]formamido} propanamido)imidazole-2-amido} - 1 -methylpyrrole-2-carboxylic acid (2.00 g, 92%) was obtained as a brown solid. LC / MS: mass calcd. For C34H44N10O8: 720.33, found:721.35 [M+H]+.

[0570] Step 11.

[0571] To a stirred solution of 4-{l-[6-(tert-butoxy)-6-oxohexyl]-4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-amido}-l-methylpyrrole-2-carboxylic acid (500.00 mg, 0.69 mmol, 1.00 eq) in DMF (10.00 mL) was added DIEA (537.94 mg, 4.16 mmol, 6.00 eq), PyBOP (469.29 mg, 0.90 mmol, 1.30 eq) and 4-[4-(3-{[4-(4-aminobutanamido)-l-methylimidazol-2-yl]formamido}propanamido)-l-methylpyrrole-2-amido]-l-methyl-N-[3-oxo-3-(piperidin-l-yl)propyl] imidazole-2-carboxamide (472.24 mg, 0.69mmol, 1.00 eq) at 0 °C. The resulting mixture was stirred for 1.0 h at room temperature. The reaction was poured into ice / water (30 mL). The precipitated solids were collected by filtration and the filter cake was washed with H2O (3x30 mL), dried under vacuum. The solid was purified by silica gel column chromatography, eluted with DCM / MeOH (12:1) to afford tert-butyl 6-[4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-2-{[l-methyl-5-({3-[(l-methyl-2-{[2-({l-methyl-5-[(l-methyl-2-{[3-oxo-3-(piperidin-l-yl)propyl] carbamoyl} imidazol-4-yl)carbamoyl]pyrrol-3-yl}carbamoyl)ethyl] carbamoyl} imidazol-4-yl)carbamoyl]propyl} carbamoyl)pyrrol-3-yl]carbamoyl}imidazol-l-yl]hexanoate (677.00 mg, 63%) as ayellow solid. LC / MS: mass calcd. For C65H86N22O13: 1382.67, found: 1383.90 [M+H]+.

[0572] Step 12.

[0573] To a stirred solution of tert-butyl 6-[4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-2-{[l-methyl-5-({3-[(l-methyl-2-{[2-({l-methyl-5-[(l-methyl-2-{[3-oxo-3-(piperi din- 1 -yl)propyl] carbamoyl} imidazol-4-yl)carbamoyl] pyrrol-3-yl} carbamoyl)ethyl] carbamoyl } imidazol-4-yl)carbamoyl]propyl}carbamoyl)pyrrol-3-yl]carbamoyl}imidazol-1-yl]hexanoate (400.00 mg, 0.47 mmol, 1.00 eq) in DCM (10.00 mL) was added TFA (3.00 mL) dropwise at room temperature. The resulting mixture was stirred for 1.0 h at room temperature. The resulting mixture was concentrated under vacuum. 6-[4-(3-{[1-methyl-4-(1-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-2-{[1-methyl-5-({3-[(1-methyl-2-{[2-({1-methyl-5-[(1-methyl-2-{[3-oxo-3-(piperidin-1-yl)propyl]carbamoyl}imidazol-4-yl)carbamoyl]pyrrol-3-yl}carbamoyl)ethyl]carbamoyl}imidazol-4-yl)carbamoyl]propyl}carbamoyl)pyrrol-3-yl]carbamoyl}imidazol-1-yl]hexanoic acid (400.00 mg, crude) was obtained as yellow solid. LC / MS: mass calcd. For C61H78N22O13: 1326.61, found: 664.70 [M / 2+H]+.

[0574] Step 13. Synthesis of Compound 2.

[0575] To a solution of 6-[4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido} propanamido)-2- {[l-methyl-5-({3-[(l-methyl-2-{[2-({l-methyl-5-[(l -methyl-2- {[3-oxo-3-(piperi din- 1-yl)propyl] carbamoyl} imidazol-4-yl)carbamoyl]pyrrol-3-yl}carbamoyl)ethyl]carbamoyl}imidazol-4-yl) carbamoyl]propyl}carbamoyl)pyrrol-3-yl]carbamoyl}imidazol-l-yl]hexanoic acid (384.00 mg, 0.29 mmol, 1.00 eq) in DMF (5.00 mL) was added DIEA (224.33 mg, 1.73 mmol, 6.00 eq), PyBOP (195.70WSGR Docket No. 56009-757.601mg, 0.38 mmol, 1.30 eq) and (S)-N-(4-((50-amino-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxapentacontyl)oxy)phenyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo [4,3-a][l,4]diazepin-6-yl)acetamide (430.42 mg, 0.35 mmol, 1.20 eq) at 0 °C. The resulting mixture was stirred for 1.0 h at room temperature. The reaction mixture was filtered and purified by Perp-HPLC: Column: XBridge Shield RP 18 OBD Column, 19*250 mm, 5pm; Mobile Phase A: Water (lOmmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / minmL / min; Gradient: 5%Bto 95% B in7min; Wave Length: 254nm nm; RTl(min): 5.2. The fractions were combined and lyophilized directly. (S)-4-(4-(4-(l-(l-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4] diazepin-6-yl)acetamido)phenoxy)-52-oxo-3.6.9.12.15.18.21.24.27.30.33.36.39.42.45.48-hexadecaoxa-51-azaheptapentacontan-57-yl)-4-(3-(l-methyl-4-(l-methyl-lH-imidazole-2-carboxamido)-lH-pyrrole-2-carboxamido)propanamido)-lH-imidazole-2-carboxamido)-l-methyl-lH-pyrrole-2-carboxamido) butanamido)-l-methyl-N-(3-((l-methyl-5-((l-methyl-2-((3-oxo-3-(piperidin-l-yl)propyl)carbamoyl)-lH-imidazol-4-yl)carbamoyl)-lH-pynol-3-yl)amino)-3-oxopropyl)-lH-imidazole-2-carboxamide (125.90 mg, 16%) was obtained as a white solid HRMS: mass calcd. For C120H167ClN28O30S:2547.1812, found: 2548.1816 [M+H]+. HPLC: 96.369 % purity.

[0576] Example 2. Synthesis of 3-[(4-{4-[3-({4-[4-({l-cyclohexyl-4-[l-methyl-4-(3-[[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-amido]pyrrol-2-yl}formamido)butanamido]-l-methylimidazol-2-yl}formamido)propanamido]-l-methylpyrrole-2-amido}-l-methylimidazol-2-yl)formamido]propanoic acid

[0577] Scheme 2.WSGR Docket No. 56009-757.601PyBOP, DIEA, DMF, r.t., 1.0 hLiOH, MeOH, THF45 °C, 2.0 h

[0578] Step 1.

[0579] To a solution of ethyl 4-nitro-lH-pyrrole-2-carboxylate (500.00 mg, 2.72 mmol, 1.00 eq) in THF (10.0 mL) was added Ph3P (1.43 g, 5.43 mmol, 2.00 eq) and DIAD (1.10 mL, 5.43 mmol, 2.00 eq) at 0 °C under N2 atmosphere. Then the reaction was stirred at 0 °C for 1.0 h under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 1 -cyclohexyl-4-nitropyrrole-2-carboxylate (350.00 mg, 48%) as a yellow liquid was obtained. LC / MS: mass calcd. For C13H18N2O4: 266.13, found: 267.05 [M+H]+.

[0580] Step 2.

[0581] The procedure was the same as ethyl 4-amino-lH-imidazole-2-carboxylate, but the solvent was MeOH and the reaction time was 17.0 h. 170.00 mg of ethyl l-cyclohexyl-4-nitropyrrole-2-carboxylate was used, 150.00 mg of desired product was obtained as yellow oil (99% yield). LC / MS: mass calcd. For C13H20N2O2: 236.15, found: 237.05 [M+H]+.

[0582] Step 3.

[0583] The procedure was the same as prop-2-en-l-yl l-methyl-4-[4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-amido]pyrrole-2-carboxylate. 156.00 mg of l-methyl-4-(3-{[l-methyl-4-(l-methylimidazole-2-amido) pyrrol-2-yl] formamido} propanamido) imidazole-2-carboxylic acid was used, 215.00 mg of desired product was obtained as yellow solid (92% yield). LC / MS: mass calcd. For C32H40N10O6: 660.31, found: 661.30 [M+H]+.

[0584] Step 4.WSGR Docket No. 56009-757.601

[0585] The procedure was the same as 4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-carboxylic acid. 190.00 mg of ethyl l-cyclohexyl-4-[l-methyl-4-(3- { [1 -methyl-4-( 1 -methylimidazole-2-amido)pyrrol-2-yl]formamido} propanamido)imidazole-2-amido]pyrrole-2-carboxylate was used, 160.00 mg of desired product was obtained as white solid (88% yield). LC / MS: mass calcd. For C30H36N10O6: 632.28, found: 633.25 [M+H]+.

[0586] Step 5.

[0587] The procedure was the same as prop-2-en-l-yl l-methyl-4-[4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-amido]pyrrole-2-carboxylate. 160.00 mg of ethyl 3-({4-[4-(3-{[4-(4- aminobutanamido)-l-methylimidazol-2-yl] formami do} propanami do)- 1 -methylpyrrol e-2-ami do] - 1 -methylimidazol-2-yl} formamido)propanoate was used, 255.00 mg of desired product was obtained as yellow solid (69% yield). LC / MS: mass calcd. For C58H73N21O12: 1255.57, found: 629.05 [M / 2+H]+.

[0588] Step 6.

[0589] The procedure was the same as 4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-carboxylic acid. 225.00 mg of ethyl 3-[(4-{4-[3-({4-[4-({l-cyclohexyl-4-[l-methyl-4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-amido]pyrrol-2-yl}formamido)butanamido]-l-methylimidazol-2-yl} formami do)propanarmdo]-l-methylpyrrole-2-armdo}-l-methylimidazol -2 -yl)formamido]propanoate was used, 195.00 mg of desired product was obtained as white solid (89% yield). LC / MS: mass calcd. For C56H69N21O12: 1227.54, found: 615.05 [M / 2+H]+.

[0590] Example 3. Synthesis of Compound E-l

[0591] Scheme 3.OHPhtNH, DIAD, Ph3P H2, Pd / C O2N THF, 0 °C, 1.0 h EA, r.t., 2.0 hN2H4. H2O, EtOH 45 °C, 4.0 hWSGR Docket No. 56009-757.601PyBOP, DIEA, DMF, r.t., 1.0 h

[0592] Step 1

[0593] A solution of 50-(4-nitrophenoxy)-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxapentacontan-l-ol (500.00 mg, 0.563 mmol, 1.00 eq), 2, 3-dihydro-lH-isoindole-l, 3-dione (99.41 mg, 0.68 mmol, 1.20 eq) and Ph3P (295.37 mg, 1.13 mmol, 2.00 eq) in THF (5.00 mL) was added DIAD (227.71 mg, 1.13 mmol, 2.00 eq) dropwise at 0 °C. The reaction mixture was stirred for 1.0 h at 0 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (3 mLx3). The filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (column, Cl 8 silica gel; mobile phase, ACN in water (0.05% TFA), 10% to 80% gradient in 30 min; detector, UV 254 nm.) to afford 2-[50-(4-nitrophenoxy)-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxapentacontan-l-yl]isoindole-l,3-dione (497.00 mg, 86%) as yellow oil. LC / MS: mass calcd. For C48H76N2O21: 1016.49, found: 509.50 [M / 2+H]+.

[0594] Step 2.

[0595] The procedure was the same as ethyl 4-amino-lH-imidazole-2-carboxylate. 280.00 mg of 2-[50-(4-nitrophenoxy)-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxapentacontan-l-yl]isoindole-1,3-dione was used, 218.00 mg of desired product was obtained as yellow oil (79% yield). LC / MS: mass calcd. For C48H78N2O19: 986.52, found: 987.45 [M+H]+.

[0596] Step 3.

[0597] The procedure was the same as prop-2-en-l-yl l-methyl-4-[4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-amido]pyrrole-2-carboxylate, but the crude was purified by silica gel column chromatography. 190.00 mg of 2-[50-(4-aminophenoxy)-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxapentacontan-l-yl]isoindole-WSGR Docket No. 56009-757.6011,3-dione was used, 171.00 mg of desired product was obtained as yellow oil (61% yield). LC / MS: mass calcd. For C71H95F2N5O24S: 1471.61, found: 737.25 [M / 2+H]+.

[0598] Step 4.

[0599] A solution of 4-[2-(2,4-difluorophenoxy)-5-ethanesulfonamidophenyl]-N-(4-{[50-(l,3-dioxoisoindol-2-yl)-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxapentacontan-l-yl]oxy}phenyl)-6-methyl-7-oxo-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (193.00 mg, 0.13 mmol, 1.00 eq) and hydrazine hydrate (12.74 pL, 0.26 mmol, 2.00 eq) in EtOH (2.00 mL) was stirred for 4.0 h at 45 °C. The solid was filtered out and the filtrate was concentrated under vacuum. This resulted in N-{4-[(50-amino-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxapentacontan-l-yl)oxy]phenyl}-4-[2-(2,4-difluorophenoxy)-5-ethanesulfonamidophenyl]-6-methyl-7-oxo-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (193.00 mg, crude) as yellow solid. LC / MS: mass calcd. For C63H93F2N5O22S: 1341.60, found: 672.10 [M / 2+H]+.

[0600] Step 5. Synthesis of Compound 1.

[0601] The procedure was the same as prop-2-en-l-yl l-methyl-4-[4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-amido]pyrrole-2-carboxylate, but the reaction mixture was purified by Prep-HPLC. 70.00 mg ofN-{4-[(50-amino-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxapentacontan-l-yl)oxy]phenyl}-4-[2-(2,4-difluorophenoxy)-5-ethanesulfonarmdophenyl]-6-methyl-7-oxo-lH-pyrrolo[2,3-c]pyridine-2-carboxamide was used, 40.9 mg of desired product was obtained as white solid (32% yield). HRMS: mass calcd. For C119H160F2N26O33S: 2551.1330, found: 2552.1500 [M+H]+.

[0602] Example 4. Synthesis of 4-[2-(2,4-difhiorophenoxy)-5-ethanesulfonamidophenyl]-6-methyl-7-oxo-lH-pyrrolo[2,3-c] pyridine- 2-carboxylic acid

[0603] Scheme 4.WSGR Docket No. 56009-757.601F°V° cr \ Et3N, DCM, 0 °C~r.t., 3.0 h 2) 10% NaOH, dioxane, 100 °C, 2.0 h

[0604] Step 1

[0605] To a stirred solution of 2, 4-difluorophenol (2.66 g, 20.45 mmol, 1.50 eq) and2-bromo-l-fluoro-4-nitrobenzene (3.00 g, 13.64 mmol, 1.00 eq) in DMF (50.00 mL) was stirred at 85 °C for 3.0 h. After cooling to room temperature, the reaction mixture was diluted with water (150 mL) and the precipitate solid was filtered. The filter cake was washed with water and dried to afford 2-bromo-l-(2,4-difluorophenoxy)-4-nitrobenzene (4.40 g, 98%) as light yellow solid.XH NMR (300 MHz, DMSO- e) 5: 8.56-8.58 (m, 1H), 8.18-8.22 (m, 1H), 7.48-7.63 (m, 2H), 7.22-7.28(m, 1H), 6.99 (d, J= 9.0 Hz, 1H).

[0606] Step 2.

[0607] Fe powder (7.78 g, 139.36 mmol, 10.00 eq) was added in portions to a stirred solution of 2-bromo-l-(2,4-difluorophenoxy)-4-nitrobenzene (4.40 g, 13.37 mmol, 1.00 eq) in EtOH (20.00 mL) and THF (20.00 mL), NH4CI (7.45 g, 139.36 mmol, 10.00 eq), H2O (20.00 mL) at room temperature. The mixture was heated at 70 °C for 2.0 h. After cooling to the room temperature, the reaction mixture was filtered through a celite pad and the filtrate was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated to afford 3-bromo-4-(2,4-difluorophenoxy)aniline (3.77 g, 65%) as a brown solid. LC / MS: mass calcd. For C12H8BrF2NO: 298.98, found: 299.90, 301.90 [M+H, M+H+2]+.

[0608] Step 3.

[0609] To a mixture of 3-bromo-4-(2,4-difluorophenoxy)aniline (2.51 g, 8.36 mmol, 1.00 eq) and EtsN (3.39 g, 33.45 mmol, 4.00 eq) in DCM (10.00 mL) was added the solution of ethanesulfonyl chloride (3.23 g, 25.09 mmol, 3.00 eq) in DCM (10.00 mL) dropwise at 0 °C. Then the mixture was stirred at room temperature for 3.0 h. The reaction mixture was evaporated under vacuum, diluted with water (20 mL),WSGR Docket No. 56009-757.601and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine, dried over Na2SC>4, and concentrated in vacuum. The resulting crude was suspended in 1,4-dioxane (30.00 mL) and 10% NaOH (6.00 mL), then the mixture was heated at 100 °C for 2.0 h. The reaction mixture was evaporated in vacuum, diluted with water (20 mL), and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. This resulted inN-[3-bromo- 4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide (3.00 g, 92% yield) as brown solid. LC / MS: mass calcd. For Ci4Hi2BrF2NO3S: 390.97, found: 392.21 [M+H]+.! H NMR (300 MHz, DMSO- L) 8: 9.94(s, 1H), 7.46-7.53 (m, 2H), 7.20-7.24 (m, 1H), 7.07-7.15(m, 2H), 6.88-7.04 (m, 1H), 3.09-3.16(m, 2H), 1.21(t, J= 7.2 Hz, 3H).

[0610] Step 4.

[0611] A mixture of N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide (1.00 g, 2.55 mmol, 1.00 eq) and ethyl 6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-c]pyridine-2-carboxylate (970.00 mg, 2.80 mmol, 1.10 eq), Pd(dtbpf)C12 (166.00 mg, 0.25 mmol, O.lO eq), KaPChQ.lO g, 5.18mmol, 2.03 eq) in toluene (8.00 mL) and H2O (2.00 mL) was stirred for 1.0 h at 75 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (70.00 mL) at room temperature. The resulting mixture was extracted with EtOAc (50 mLx3). The combined organic layers were washed with water (40 mLx2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elutedwith CTECh / MeOH (15:1) to afford ethyl 4-[2-(2,4-difluorophenoxy)-5-ethanesulfonamidophenyl]-6-methyl-7-oxo-lH-pyrrolo[2,3-c]pyridine-2-carboxylate (1.20g, 89%) as brown solid. LC / MS: mass calcd. For C25H23F2N3O6S: 531.13, found: 532.10 [M+H]+.

[0612] Step 5.

[0613] The procedure was the same as 4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)pyrrol-2-yl]formamido}propanamido)-lH-imidazole-2-carboxylic acid. 1.10 g of ethyl 4-[2-(2,4-difluorophenoxy)- 5-ethanesulfonamidophenyl]-6-methyl-7-oxo-lH-pyrrolo[2,3-c]pyridine-2-carboxylate was used, 1.00 g of desired product was obtained as grey solid (95.97% yield). LC / MS: mass calcd. For C23H19F2N3O6S: 503.10, found: 504.10 [M+H]+.

[0614] Compounds of the disclosure can be made by the methods of any of Examples 1-4.FORMULATION EXAMPLES

[0615] Example B-L Soluble Formulations

[0616] Solubilizer Screening

[0617] A screening formulation method is developed to evaluate each solubilizer provided in Tables 3.A ratio of 1:20 (weight / weight) of API (the compound describe herein, for example in any of Tables 2A, 2B, 2C, 2D, or 2E) to a solubilizer used for the screening. The general procedure of the screening formulation method is as follows.WSGR Docket No. 56009-757.601

[0618] The solubilizer (e.g., 20x w / w API) and optionally a cryoprotectant (e.g., 20x w / w API) are dissolved in a solvent, each to a concentration of 10 mg / mL. The API is added to the solubilizer solution and dissolved using a sonicating water bath with gentle heating (e.g., ~30 °C). The resulting solution is filtered through a 0.22 pm PTFE or PES filter. Vials are filled (e.g., 20 mL vials filled with 5-15 mL) and lyophilized on a benchtop freezer dryer (Labconco Corporation).

[0619] The lyophilized compositions are reconstituted in saline to a final concentration of between 1 mg / mL to 5 mg / mL API and subjected to the following tests within 2 hours of full reconstitution:• (1) Visual inspection for any undissolved particulate matter or sedimentation.• (2) Quantification of API measured by HPLC screening methods after filtration.• (3) Average particle diameter measured by DLS.

[0620] The following criteria are used to identify hits from the screening formulations:• (1) Visual inspection = pass• (2) API post-filter > 75%• (3) Particle diameter < 800 nm

[0621] Analytical Methods

[0622] HPLC: HPLC analysis is performed on a Shimadzu LC-20AD instrument. Two HPLC methods are used: screening ID method to quantify API and a purity method for determining purity of API in a formulation.

[0623] DLS: Particle size data is collected on a Dynamic Light Scattering (DLS) instrument (Wyatt Technology, DynaPro Plate Reader III) with the following parameters: 1 second acquisition time, 5 acquisitions, 25 °C. Data is processed with DYNAMICS (Wyatt Technology, v8.0).

[0624] Osmolarity: Osmolarity is measured on a Wescor 5500 Vapor Pressure Osmometer. Normal saline is used to calibrate.

[0625] Turbidity: Turbidity is measured on a Thermo Fisher Orion AQ3010 nephelometer.

[0626] Polymeric Formulations

[0627] A pharmaceutical composition comprising a compound provided in Table 2A, 2B, 2C, 2D, or 2E, and a solubilizer provided in Table 3 are formulated using methods described herein. The composition may be a lyophilized powder or a liquid. The composition may be reconstituted. The composition may be formulated as aqueous solution. For example, the aqueous phase of the aqueous solution can be saline, water, or an aqueous buffer, such as phosphate-buffered saline (PBS) or dextrose in saline. An alcohol co-solvent may be added to the composition. For example, the alcohol co-solvent can be ethanol. The composition can have a compound concentration of about 1 mg / mL to about 10 mg / mL. The composition can have a compound to solubilizer ratio of 1: 1 to 1: 50, such as a ratio of 1: 1 to 1:25, 1:1 to 1:20, 1:1 to 1:15, or 1:1 to 1:10. A composition described herein has a shelf life of about 1 hour to 7 days (or more) at room temperature. A composition described herein has a shelf life of 5 days or more at 2-8 °C. A composition described herein has a shelf life of 46 days or more at -20 °C. A pharmaceutical composition comprising a compound from Table 2A, 2B, 2C, 2D, or 2E and a solubilizer from Table 3 may combine to provide a particle, such as a particle that is stable for an extended period of time. TheWSGR Docket No. 56009-757.601composition may comprise a particle that has a particle diameter of about 1 nanometer (nm) to about 100 nm, such as about 10 nm to about 30 nm as measured by dynamic light scattering. A composition described herein comprises a cryoprotectant. For example, the cryoprotectant can be trehalose, sorbitol, glycine, mannitol, PEG 8000, or any combination thereof. Compositions comprising a cryoprotectant can have a solubilizer to cryoprotectant ratio of 1:0.5 to 1:2.

[0628] Example B-2. Exemplary F ormulations

[0629] The formulations were prepared using the screening formulation method described in Example B- 1. The resulting formulations were reconstituted to a API concentration of 3 mg / mL in saline and tested (Table 4)Table 4: Results of the solubilizer screening Formulations; 1:20 API to solubilizer reconstituted to 3 mg / mL in saline.Solubilizer Visual Inspection * API Post-Filter (Ih) f Particle Diameter TPGS Pass 99% 12 nm PEG-DSPE Fail - - PEG-P(BLG36 / Sar4) Pass 70% 740 nm PEG-P(BLG32 / Sar8) Pass 25% 370 nm* Presence of undissolved particulate matter or sedimentation = Fail; absence = Pass

[0630] Example B-3. F ormulation optimization

[0631] Formulations were developed with TPGS as a solubilizer. Optional ratio of API to solubilizer was explored. Lyophilized formulations were prepared with 1:50, 1:33, and 1:25 API to TPGS. These formulations were reconstituted to an API concentration of 5 mg / mL and tested (Table 5).Table 5: Results of TPGS Formulations.API: Solubilizer API Post-Filter (2hr) f Particle Diameter1:50 99% 78 nm 1:33 93% 152 nm1:25 57% 1524 nmf API quantified before and after filtration through a 0.22 mm filter expressed as percentage remaining post-filtration.

[0632] The collective results of TPGS formulations tested led to the conclusion that 3 mg / mL API reconstituted in saline was the maximum achievable.

[0633] Dilution Properties

[0634] A critical property for the formulation is the ability to dilute a reconstituted drug product from the vial concentration (>3 mg / mL) to lower concentrations for use in for example intravenous infusion. The formulation was reconstituted to 3 mg / mL API in saline, and then further diluted in saline (Table 6).WSGR Docket No. 56009-757.601Table 6: TPGS formulations diluted to various concentrations of API.Solubilizer API dilution API Post-Filter (2hr) f API Post-Filter (6hr) f TPGS 3 mg / mL 99% 99%TPGS 1.0 mg / mL 99% 99%TPGS 0.25 mg / mL 96% 95%TPGS 0.08 mg / mL 93% 93%f API quantified before and after fdtration through a 0.22 pm filter expressed as percentage remaining post-filtration.

[0635] 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

WSGR Docket No. 56009-757.601CLAIMS WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising:(a) a compound having (i) a first terminus comprising a polyamide, (ii) a second terminus comprising a protein-binding moiety, and (iii) an oligomeric backbone that links the polyamide and the protein-binding moiety; and(b) a solubilizer.

2. The pharmaceutical composition of claim 1, wherein the solubilizer is an amphiphilic polymer.

3. The pharmaceutical composition of claim 1 or 2, wherein the solubilizer is a block co-polymer.

4. The pharmaceutical composition of claim 3, wherein the block co-polymer comprises PEG.

5. The pharmaceutical composition of claim 3, wherein the block co-polymer does not comprise PEG.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the second terminus is a small molecule.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the polyamide is represented by the structure of Formula (A-l), or a pharmaceutically acceptable salt thereof:RiNFormula (A-l),wherein:each Y9, Y10, Y11, and Y12is independently -CH- or -N-;each X9, X10, X11, and X12is independently -O-, -S-, or -NR2-;W1is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl; - NRleRlf, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, -NRleC(O)ORlf, -N=C(N(Rle)2)2, -ZB-PO(ORle)2, -ZB-(CH2)P3-PO(ORK)2. or -ZB-(CH2)p3-O-PO(ORle)2, wherein each Rleis independently hydrogen or optionally substituted C1-C10 alkyl;each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, AAp2, or optionally substituted 5-membered heteroaryl, wherein each AA is an amino acid and p2is an integer from 1-10;ZBis N or O;p3is 1-10;W2is optionally substituted Ci-C2o alkyl or optionally substituted Ci-C2o heteroalkyl;or W2is L'-Z-R4; whereinWSGR Docket No. 56009-757.601L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent or -C(O)-;R4is absent, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl;or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 8-membered heterocycloalkyl;Rwis hydrogen or optionally substituted C1-C20 alkyl;or Rwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 8-membered heterocycloalkyl;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 LXAis independently an optionally substituted Ci-Ce alkylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 3 to 7-membered heterocy cl ene, or optionally substituted 5 to 6-membered heteroarylene;each Rxxis hydrogen or an Ci-Ce alkyl;or each Rxxand LXAjoin together with the atom(s) to which they are attached to form a 4- to 7- membered heterocyclic ring;mo is 0, 1, or 2;m2 is 1-4; andn2 is 0-3;wherein the oligomeric backbone is attached at W1, W2, or one of R2.

8. The pharmaceutical composition of any one of claims 1 to 6, wherein the polyamide is represented by the structure of Formula (A-2), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601n2Formula (A- 2),wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, whereineach Rleis independently hydrogen or C1-C3 alkyl;each Y9, Y10, Y11, and Y12is independently -CH- or -N-;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 Rxis independently hydrogen, halogen, -CN, -OH, -NH2, -Ci-Ce alkyl, or -Ci-Ce haloalkyl; or two Rxon the same or adjacent atoms together with the atom(s) to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl;mo is 0, 1, or 2;m2 is 1-4; andn2 is 0-3.The pharmaceutical composition of any one of claims 1 to 6, wherein the polyamide is represented by the structure of Formula (A-3), or a pharmaceutically acceptable salt thereof:Formula (A-3),wherein:W1is hydrogen, optionally substituted Ci-Cio haloalkyl, or -N=C(N(Rle)2)2, whereineach Rleis independently hydrogen or C1-C3 alkyleach Y12is independently -CH- or -N-;WSGR Docket No. 56009-757.601each 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; m2 is 1-4; andmis 0-3.

10. The pharmaceutical composition of any one of claims 1 to 6, wherein the polyamide is represented by the structure of Formula (A-4), or a pharmaceutically acceptable salt thereof:O Formula (A-4),wherein:W1is hydrogen, halogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl -NRleRlf, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, - NRleC(O)ORlf, -N=C(N(Rle)2)2, -ZB-PO(ORle)2,-ZB-(CH2)p3-PO(ORle)2,or -ZB-(CH2)P3-O- PO(ORle)2, whereineach Rleis independently hydrogen or optionally substituted C1-C10 alkyl;each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, AAP2, or optionally substituted 5-membered heteroaryl, wherein each AA is an amino acid and p2 is an integer from 1-10;ZB is -N- or -O-;P3 is 1-10;W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl;or W2is L1-Z-R4; whereinL1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinWSGR Docket No. 56009-757.601R4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl;R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl;or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated; Rwis hydrogen or optionally substituted C1-C20 alkyl;or Rwand W2combine together with the atoms to which they are attached to form an optionally substituted 4 to 10-membered heterocycloalkyl;each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -N- or -CH-;each X1, X2, X3, X4, X5, X6, X7, and X8is independently -S-, -O-, or -NR2-;each R2is independently hydrogen, optionally substituted C1-C50 alkyl, optionally substituted C2- C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1-50; each R3is independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;or two R3together with the atom(s) to which they are attached form a C3-C6 cycloalkyl or 3 to 6- membered heterocycloalkyl;each Rxand Ryis independently hydrogen, halogen, -CN, -OH, -NH2, C1-C10 alkyl, or C1-C10 haloalkyl;or two Rxor two Rytogether with the atoms to which they are attached to form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl;ji is 0 or 1;no is 0 or 1;m1and n1are each independently an integer from 0-3; andpi is 3 or 4;wherein the oligomeric backbone is attached at W1, W2, one of R2, or one of R3.

11. The pharmaceutical composition of any one of claims 1 to 6, wherein the polyamide is represented by the structure of Formula (A-5), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (A-5),wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, whereineach Rleis independently hydrogen or C1-C3 alkyl;each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;each R2a, R2b, R2c, R2d, R2e, R2f, R2g. and R2his independently hydrogen, optionally substituted Ci- 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 of which is optionally substituted with one or more Rz;each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or - NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl;each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, - C(O)NRZaRzb, -NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinR / aand Rzbare each independently hydrogen, alkyl, or PEG;RZtis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;ji is 0 or 1; andm1 and n1 are each independently an integer from 0-3.

12. The pharmaceutical composition of any one of claims 1 to 6, wherein the polyamide is represented by the structure of Formula (A-6), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (A-6),wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, whereineach Rleis independently hydrogen or C1-C3 alkyl;each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;each R2a, R2b, R2c, R2d, R2e, R2f, R2g. and R2his independently hydrogen, optionally substituted Ci- 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 of which is optionally substituted with one or more Rz;each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or - NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl;each Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, - C(O)NRZaRzb, -NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinR / aand Rzbare each independently hydrogen, alkyl, or PEG;RZtis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;ji is 0 or 1; andm1 and n1 are each independently an integer from 0-3.

13. The pharmaceutical composition of any one of claims 1 to 6, wherein the polyamide is represented by the structure of Formula (A-7), or a pharmaceutically acceptable salt thereof:WSGR Docket No. 56009-757.601Formula (A- 7),wherein:W1is hydrogen, optionally substituted C1-C10 haloalkyl, or -N=C(N(Rle)2)2, whereineach Rleis independently hydrogen or C1-C3 alkyl;each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;L1is C1-C20 alkylene or C2-C20 heteroalkylene;Z is absent, -C(O)-, or -C(=NH)-;R4is C1-C3 alkyl, -OR4b, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C20 alkyl, or optionally substituted C1-C20 heteroalkyl; R4bis optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C1-C20 aminoalkyl, optionally substituted C1-C20 haloalkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl;or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 10-membered heterocycloalkyl which is partially or fully saturated;each R2a, R2b, R2c, R2d, R2e, R2f, R2g. and R2bis independently hydrogen, optionally substituted Ci- C50 alkyl, optionally substituted C2-C50 alkenyl, optionally substituted C2-C50 alkynyl, optionally substituted C1-C50 heteroalkyl, optionally substituted C2-C50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted PEG1-50; each of which is optionally substituted with one or more Rz;each R3aand R3bis independently hydrogen, halogen, Ci-Ce alkyl, -OR3c, -NR3cR3d, or - NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, or PEG;WSGR Docket No. 56009-757.601R3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; andeach Rzis independently -CN, -OH, -ORZa, -N3, -NRZaRzb, -CO(O)RZc, -C(O)ORZc, - C(O)NRZaRzb, -NHC(O)RZc, -NHC(O)ORZc, -OC(O)NRZaRzb, or optionally substituted 5 to 10-membered heteroaryl; whereinR / aand Rzbare each independently hydrogen, alkyl, or PEG;RZtis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;n1 and m1 are each independently 0 or 1;wherein the oligomeric backbone is attached at one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2h, one of R3a; or one of R3b.

14. The pharmaceutical composition of any one of claims 1 to 6, wherein the polyamide is represented by the structure of Formula (A-8), or a pharmaceutically acceptable salt thereof:Formula (A-8),wherein:each X13and X14is independently -O-, -S-, or -NR2-;each Y13and Y14is independently -CR2”- or -N-;W1is hydrogen, halogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl -NRleRlf, -NRleC(O)Rlf, -NRleC(O)NRleRlf, -C(O)NRleRlf, -OC(O)NRleRlf, - NRleC(O)ORlf, -N=C(N(Rle)2)2, -ZB-PO(ORle)2,-ZB-(CH2)p3-PO(ORle)2,or -ZB-(CH2)p3-O- PO(ORle)2, whereineach Rleis independently hydrogen or optionally substituted C1-C10 alkyl; each Rlfis independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, AAp2, or optionally substituted 5-membered heteroaryl, wherein each AA is an amino acid and p2is an integer from 1-10; ZBis -N- or -O-;P3 is 1-10;each R2is independently hydrogen, optionally substituted Ci-C2o alkyl, optionally substituted C2- C2o alkenyl, optionally substituted C2-C2o alkynyl, optionally substituted Ci-C2o aminoalkyl, optionally substituted Ci-C2o heteroalkyl, optionally substituted C2-C2o heteroalkenyl, optionally substituted C2-C2o heteroalkynyl, optionally substituted Ci-C2o haloalkyl, optionally substituted Ci-C2o hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl;WSGR Docket No. 56009-757.601each R2” is independently hydrogen, halogen, -OH, Ci-Ce alkyl, or Ci-Ce alkoxy; andns is 1-10.

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