Method and compound for controlling Huntington's disease

Abstract

The present disclosure relates to a transcription regulator molecule having a first end, a second end, and an oligomer backbone, and a method for treating Huntington's disease (HD).

Description

Technology Field

[0001] Cross-reference

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 587,625 filed on October 3, 2023, the entirety of which is incorporated herein by reference.

[0003] Field of disclosure

[0004] The present invention discloses novel chimeric heterocyclic polyamide compounds and compositions, and their use as pharmaceuticals for the treatment of diseases. A method for regulating the expression of a target gene comprising a CAG trinucleotide repeat sequence in a subject is also provided for the treatment of diseases such as Huntington's disease ("HD"). Background Technology

[0005] Huntington's disease ("HD") was first identified in the late 19th century as an autosomal dominant neurodegenerative disorder. Symptoms of HD, including various motor, cognitive, and psychiatric disorders, typically appear in adulthood. HD is caused by the huntingtin gene, which codes for a protein called huntingtin ( HTT It is associated with the presence of CAG trinucleotide repeat sequences within. Subjects with approximately 36 or more trinucleotide repeat sequences generally exhibit symptoms of HD, and the higher the number of trinucleotide repeat sequences, the earlier the onset of symptoms. The pathology originates from the following series of steps: the production of poly-Q huntingtin, followed by the fragmentation of elongated huntingtin into smaller peptides, which bind and accumulate within neurons. The effects of this chain reaction are prominent in the basal ganglia and cortex of the brain.

[0006] Huntington's disease-like syndrome has symptoms similar to those of Huntington's disease, but HTT It refers to a group of diseases without characteristic gene mutations. Huntington's disease-like syndrome ("HDL2") is zygophyllin 3 ( Jph3It is associated with the number of approximately 40 or more CAG trinucleotide repeat sequences within the gene. HDL2 is a genetic disorder found in subjects of African descent. The age of onset is inversely correlated with the number of trinucleotide repeat sequences. Symptoms of this syndrome include dystonia and chorea (involuntary movements), affective disorders, dysarthria, bradykinesia, inability to integrate new learning, and difficulty with decision-making. Life expectancy can vary from several years to over 10 years after diagnosis. Current theories are Jph3 Poly-Q proteins encoded by genes form aggregates within neurons, which are considered to be the cause of the disease's pathology. However, evidence suggesting the acquisition of toxic functions by mRNA has also been revealed, indicating the possibility of a dual pathway to the pathology.

[0007] In some embodiments, the mechanism presented above provides an opportunity for effective treatment of a disease or disorder characterized by the presence of an excessive number of CAG trinucleotide repeat sequences within a target gene.

[0008] In some embodiments, the pathology of the disease or disorder is due to the presence of mRNA containing an excessive number of CAG trinucleotide repeat sequences. In some embodiments, the pathology of the disease or disorder is due to the presence of a translation product containing an excessive number of glutamine amino acid residues. In some embodiments, the pathology of the disease or disorder is due to a loss of function of the translation product. In some embodiments, the pathology of the disease or disorder is due to an acquisition of function of the translation product. In some embodiments, the pathology of the disease or disorder may be alleviated by increasing the transcription rate of the defective gene. In some embodiments, the pathology of the disease or disorder may be alleviated by decreasing the transcription rate of the defective gene.

[0009] The present disclosure utilizes regulatory molecules present within the cell nucleus that control gene expression. Eukaryotic cells provide various mechanisms for controlling gene replication, transcription, and / or translation. Regulatory molecules generated by various biochemical mechanisms within the cell can regulate various processes involved in converting genetic information into cellular components. Several regulatory molecules are known to regulate the production of mRNA and target genes (e.g., HTT When induced, for example, by regulating the production of target gene mRNA that causes diseases such as Huntington's disease or Huntington's disease-like syndrome, the progression of these diseases can be reversed.

[0010] Transcriptional regulator molecules for recruiting a regulatory molecule to proximity to a target gene are provided herein. In some embodiments, a transcriptional regulator molecule having a first end, a second end, and an oligomeric backbone moiety, or a pharmaceutically acceptable salt thereof, is provided herein, wherein:

[0011] a) The first end comprises a DNA-binding moiety having the structure of chemical formula (A-8):

[0012]

[0013] Chemical formula (A-8),

[0014] In the above formula:

[0015] W 1 Silver is hydrogen, -C1-C6 haloalkyl, or -N=C(N(R 1e )2)2, where R 1e Each is independently a hydrogen or optionally substituted C1-C3 alkyl;

[0016] Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8Each is independently N or CH;

[0017] R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with;

[0018] R 3a and R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e and, in the above formula,

[0019] R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;

[0020] R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0021] 2 Rs 3a or 2 Rs 3b...forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0022] One R 3a and one R 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0023] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0024] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0025] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0026] b) The second end comprises a protein-binding moiety capable of binding to a regulatory molecule that regulates gene expression;

[0027] c) The oligomer backbone connects the first end and the second end.

[0028] In some embodiments, the DNA binding moiety may selectively bind, for example, to the trinucleotide repeat sequence of HTT. The recruitment moiety linked to the DNA binding moiety is consequently maintained in proximity to the target gene; will recruit regulatory molecules in proximity to the gene; and the regulatory molecules will regulate expression to counteract the generation of the defective target gene through direct interaction with the target gene. This mechanism can provide an effective treatment for HD caused by the expression of defective HTT, and thus, the correction of the expression of the defective target gene represents an effective method for treating such diseases.

[0029] DNA binding moiety comprises polyamide segments that selectively bind to a target CAG sequence. For example, polyamides designed by Dervan (U.S. Patents No. 9,630,950 and 8,524,899) and other researchers can selectively bind to selected DNA sequences. These polyamides are located in the minor grooves of double-helix DNA and form hydrogen bond interactions with Watson-Crick base pairs. Polyamides that selectively bind to specific 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, and each building block binds non-covalently and selectively to one of the DNA base pairs: A / T, T / A, G / C, and C / G. Following these guidelines, trinucleotides bind to molecules having three amide units, i.e., triamides. Generally, these polyamides can be oriented in any direction of the DNA sequence.

[0030] 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 of a polyamide would simply be equal to the sum of the interactions between each individual monoamide / DNA base pair. However, in practice, due to a geometric mismatch between the significantly rigid polyamide and DNA structures, longer polyamide sequences do not bind as tightly to longer DNA sequences as would be expected from simple additive contributions. This geometric mismatch between the longer polyamide sequence and the longer DNA sequence induces adverse geometric variations that reduce binding affinity more than would otherwise be expected.

[0031] The present disclosure provides a transcription regulator molecule comprising a DNA binding moiety (e.g., a polyamide containing multiple amine subunits) connected to a protein binding moiety by a spacer (e.g., a linker moiety or an oligomer backbone). The spacer may mitigate geometric deformations that could otherwise reduce the binding affinity of larger polyamide sequences.

[0032] However, it should be understood that while the detailed description and specific embodiments represent specific embodiments, various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description, and are provided only as examples.

[0033] Cross-reference regarding related applications

[0034] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is specifically and individually specified for inclusion by reference. Where any publication or patent or patent application incorporated by reference contradicts the disclosures contained in this specification, the specification is intended to replace and / or supersede such contradictory material. Specific details for implementing the invention

[0035] The present disclosure provides a transcription regulator molecule comprising a DNA binding moiety (e.g., a polyamide containing multiple amine subunits) connected to a protein binding moiety by a spacer (e.g., a linker moiety or an oligomer backbone). The spacer may mitigate geometric deformations that could otherwise reduce the binding affinity of larger polyamide sequences.

[0036] Treating subjects with these compounds regulates the expression of defective target genes, which can reduce the occurrence, severity, or frequency of symptoms associated with genetic diseases (e.g., HD). The compounds described herein recruit regulatory molecules to regulate the expression of defective target genes and effectively treat and alleviate symptoms associated with the disease.

[0037] Compound - Transcription regulator molecule

[0038] The compounds disclosed herein are transcription regulator molecules. They have useful activity for regulating the transcription of target genes (e.g., HTT) and can be used for the treatment or prevention of diseases or conditions in which the target gene plays an active role. Accordingly, in a wide range of embodiments, some embodiments also provide a pharmaceutical composition comprising one or more of the compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods for preparing and using the compounds and the composition.

[0039] In one embodiment, a transcription regulator molecule having a first terminal, a second terminal, and a linker moiety is provided herein, wherein:

[0040] a) The first end comprises a DNA-binding moiety;

[0041] b) The second end comprises a protein-binding moiety capable of binding to a regulatory molecule that regulates gene expression;

[0042] c) The oligomer backbone connects the first end and the second end.

[0043] 1st term - DNA binding moiety

[0044] The first end interacts with and binds to a gene, particularly a microglyph sequence. In one embodiment, the molecule disclosed herein provides a polyamide sequence.

[0045] In some embodiments, the DNA-binding moiety comprises a polyamide of one or more subunits selected from the following.

[0046] (Py), (Im), (Th), (Pz), (Nt), (Tn), (Nh), (Fr), (Tp), (iNt), (beta or β), (gAB), (PyT), (ImT), (iIm), (ImBi), (PyBi), (Dp), , , , , -NH-benzopyrazinilene-C(O)-, -NH-phenylene-C(O)-, -NH-pyridinylene-C(O)-, -NH-piperidinylene-C(O)-, -NH-pyrimidinylene-C(O)-, -NH-anthracenylene-C(O)-, -NH-quinolinylene-C(O)-, and And, in the above formula, each R' is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 haloalkyl, or optionally substituted C1-C 20It is an alkylamino; Z is H, NH2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-NH2.

[0047] In some embodiments, the DNA-binding moiety comprises the structure of formula (A-1) or a pharmaceutically acceptable salt thereof:

[0048]

[0049] Chemical formula (A-1),

[0050] In the above formula:

[0051] Z 1 is absent, -O- or -NH- and;

[0052] W 1 Silver hydrogen, halogen, selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, -NR 1e R 1f , -NR 1e C(O)R 1f , -NR 1e C(O)NR 1e R 1f , -C(O)NR 1e R 1f , -OC(O)NR 1e R 1f , -NR 1e C(O)OR 1f , -N=C(N(R 1e )2) 2, -Z B -PO(OR 1e ) 2, -Z B -(CH2) p3 -PO(OR 1e ) 2, or -Z B -(CH2) p3 -O-PO(OR 1e )2 and, in the above formula,

[0053] R 1e Each is independently hydrogen or optionally substituted C1-C 10 It is alkyl;

[0054] R1f Each is independently hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Heteroalkyl, AA p2 , or optionally substituted 5-membered heteroaryl, wherein each AA is an amino acid and p2 is an integer from 1 to 10;

[0055] Z B is N or O and;

[0056] p3 is 1-10 and;

[0057] W 2 is an optionally substituted C1-C6 alkyl, -C(O)NR 1e R 1e , or -C(O)NR 1e CH2CH2C(O)- and, in the above formula, R 1e Each is independently hydrogen or optionally substituted C1-C 10 It is alkyl;

[0058] Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 Each is independently N or CH;

[0059] X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 Each is independently S, O, or NR 2 And;

[0060] R 2 Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl;

[0061] R 3 Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e and, in the above formula,

[0062] R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;

[0063] R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0064] 2 Rs 3 They form a C3-C6 cycloalkyl or a 3 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0065] R x and R y Each is independently hydrogen, halogen, -CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl;

[0066] 2 Rs x or 2 Rs y ...to form a C3-C6 cycloalkyl or a 3 to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0067] j1 is 0 or 1 and;

[0068] m1 is 0 or 1 and;

[0069] n0 is 0 or 1 and;

[0070] n1 is 0 or 1 and;

[0071] p1 is 2 or 3, provided that Z 1 If this is -O- or -Nh-, p1 is 2 and Z 1 In this absence, p1 is 3;

[0072] In the above equation, W 1 or W 2 One of them is attached to the oligomer backbone.

[0073] In some embodiments of chemical formula (A-1), n0 is 1. In some embodiments, n0 is 0.

[0074] In some embodiments of chemical formula (A-1), p1 is 3. In some embodiments, p1 is 2.

[0075] In some embodiments of the formula (A-1), Z 1 is absent. In some embodiments, Z 1 is -O-. In some embodiments, Z 1 It is -NH-.

[0076] In some embodiments of chemical formula (A-1), the DNA-binding moiety is W 2 It is connected to the oligomeric backbone through. In some embodiments of formula (A-1), the DNA-binding moiety is W 1 It is connected to the oligomer backbone through.

[0077] In some embodiments of the formula (A-1), W 2 is -C(O)NR 1e R 1e is. In some embodiments, W 2 is -C(O)NH-. In some embodiments, W 2 is -C(O)NR 1e CH2CH2C(O)- is. In some embodiments, W 2is -C(O)NHCH2CH2C(O)-.

[0078] In some embodiments of the formula (A-1), W 2 is -C(O)NH(CH2)2C(O)-**, where the oligomer backbone is attached to **. In some embodiments, W 2 is -C(O)-NH-**, where the oligomer backbone is attached to **.

[0079] In some embodiments of the formula (A-1), R 3 Each is independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d , or -NHC(O)R 3e And, in the above equation, R 3c and R 3d Each is independently hydrogen, alkyl, or PEG; R 3e is an alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, R 3 Each independently -NR 3c R 3d is. In some embodiments, R 3 Each independently -NHC(O)R 3e is. In some embodiments, R 3 Each is independently hydrogen.

[0080] In some embodiments of formula (A-1), 2 R 3 They form optionally substituted C3-C6 cycloalkyl or 3 to 6 heterocycloalkyl groups together with the atoms to which they are attached. In some embodiments, two Rs 3 They form a C3-C6 cycloalkyl group together with the atoms to which they are attached. In some embodiments, two Rs 3 They form 4 to 6-membered heterocycloalkyl groups together with the atoms to which they are attached. In some embodiments, two Rs 3 They form a quaternary heterocycloalkyl with the atoms to which they are attached. In some embodiments, two Rs 3They form a pentatonic heterocycloalkyl with the atoms to which they are attached. In some embodiments, two Rs 3 They form a hexacyclic heterocycloalkyl group together with the atoms to which they are attached. In some embodiments, two Rs 3 They form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl together with the atoms to which they are attached. In some embodiments, two R 3 They form cyclopropyl together with the atoms to which they are attached. In some embodiments, two R 3 They form cyclobutyl together with the atoms to which they are attached. In some embodiments, two R 3 They form cyclopentyl together with the atoms to which they are attached. In some embodiments, two Rs 3 They form cyclohexyl together with the atoms to which they are attached.

[0081] In some embodiments, the DNA-binding moiety comprises the structure of formula (A-2) or a pharmaceutically acceptable salt thereof:

[0082]

[0083] Chemical formula (A-2),

[0084] In the above formula:

[0085] W 1 Silver is hydrogen, -C1-C6 haloalkyl, or -N=C(N(R 1e )2)2, where R 1e Each is independently a hydrogen or optionally substituted C1-C3 alkyl;

[0086] X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 Each is independently S, O, or NR 2 And;

[0087] Y 1 , Y2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 Each is independently N or CH;

[0088] R 2 Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl;

[0089] R 3a and R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e and, in the above formula,

[0090] R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;

[0091] R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0092] 2 Rs 3a or 2 Rs 3b...forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0093] One R 3a and one R 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0094] R x and R y Each is independently hydrogen, halogen, -CN, -OH, -NH2, C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0095] 2 Rs x or 2 Rs y ...to form a C3-C6 cycloalkyl or a 3 to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0096] j1 is 0 or 1 and;

[0097] m1 and n1 are each independently 0 or 1.

[0098] In some embodiments, the DNA-binding moiety comprises the structure of formula (A-3) or a pharmaceutically acceptable salt thereof:

[0099]

[0100] Chemical formula (A-3),

[0101] In the above formula:

[0102] W 1 Silver is hydrogen, -C1-C6 haloalkyl, or -N=C(N(R 1e )2)2, where R 1e Each is independently a hydrogen or optionally substituted C1-C3 alkyl;

[0103] X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7, and X 8 Each is independently S, O, or NR 2 And;

[0104] Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 Each is independently N or CH;

[0105] R 2 Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl;

[0106] R 3a and R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e and, in the above formula,

[0107] R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;

[0108] R 3eis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0109] 2 Rs 3a or 2 Rs 3b ...forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0110] One R 3a and one R 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0111] R x and R y Each is independently hydrogen, halogen, -CN, -OH, -NH2, C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0112] 2 Rs x or 2 Rs y ...to form a C3-C6 cycloalkyl or a 3 to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0113] j1 is 0 or 1 and;

[0114] m1 and n1 are each independently 0 or 1.

[0115] In some embodiments, the DNA-binding moiety comprises the structure of formula (A-4) or a pharmaceutically acceptable salt thereof:

[0116]

[0117] Chemical formula (A-4),

[0118] In the above formula:

[0119] W 1 Silver is hydrogen, -C1-C6 haloalkyl, or -N=C(N(R 1e )2)2, where R 1e Each is independently a hydrogen or optionally substituted C1-C3 alkyl;

[0120] X 1 , X 2 , X 3 , X 4 , X 5 , X 7 , and X 8 Each is independently S, O, or NR 2 And;

[0121] Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 7 , and Y 8 Each is independently N or CH;

[0122] R 2 Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10-membered heteroaryl;

[0123] R 3a and R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e and, in the above formula,

[0124] R 3c and R3d Each is independently hydrogen, alkyl, or PEG;

[0125] R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0126] 2 Rs 3a or 2 Rs 3b ...forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0127] One R 3a and one R 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0128] R x Each is independently hydrogen, halogen, -CN, -OH, -NH2, C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0129] 2 Rs x ...to form a C3-C6 cycloalkyl or a 3 to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0130] j1 is 0 or 1 and;

[0131] m1 is 0 or 1.

[0132] In some embodiments of formula (A-1), (A-2), (A-3), or (A-4), X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 Each independently -NR 2 is. In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X8 Each is independently O. In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 Each is independently S.

[0133] In some embodiments of formula (A-1), (A-2), (A-3), or (A-4), R 2 Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2 Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2 Each is an independently and selectively substituted C1-C 20It is an alkylamino. In some embodiments, R 2 Each is an independently and selectively substituted C1-C 10 It is an alkylamino. In some embodiments, R 2 Each is an independently and selectively substituted C1-C 20 It is a haloalkyl. In some embodiments, R 2 Each is an independently and selectively substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2 Each is an independently and selectively substituted C1-C 20 It is a heteroalkyl. In some embodiments, R 2 Each is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 2 Each is an independently and selectively substituted C1-C 20 It is a hydroxyalkyl. In some embodiments, R 2 Each is an independently and selectively substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2 Each is an independently and selectively substituted C3-C 10 It is a cycloalkyl or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2 Each is an independently and selectively substituted C3-C 10 It is a cycloalkyl. In some embodiments, R 2 Each is an independently optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2 Each is an independently optionally substituted phenyl. In some embodiments, R 2 Each is an independently selectively substituted 6-membered heteroaryl.

[0134] In some embodiments of formula (A-1), (A-2), (A-3), or (A-4), R 2 Each is an independently and selectively substituted C1-C 20 It is an alkyl. In some embodiments, R2 Each is an independently and selectively substituted C1-C 10 It is an alkyl. In some embodiments, R 2 Each is independently methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octenyl. In some embodiments, R 2 Each is independently methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octenyl. In some embodiments, R 2 Each is methyl. In some embodiments, R 2 Each is ethyl. In some embodiments, R 2 Each is isopropyl. In some embodiments, R 2 Each is butyl. In some embodiments, R 2 Each is pentyl. In some embodiments, R 2 Each is a hexyl. In some embodiments, R 2 Each is a heptyl. In some embodiments, R 2 Each is hydrogen.

[0135] In some embodiments of formula (A-1), (A-2) or (A-3), R x and R y Each is independently hydrogen, halogen, -CN, -OH, -NH2, C1-C 10 alkyl, or C1-C 10 It is a haloalkyl. In some embodiments, R x and R y Each independently consists of hydrogen, -OH, and C1-C 10 alkyl, or C1-C 10 It is a haloalkyl. In some embodiments, R x and R y Each is independently hydrogen.

[0136] In some embodiments of formula (A-1), (A-2) or (A-3), two R x or 2 Rs yThey form C3-C6 cycloalkyl or 3 to 6 heterocycloalkyl groups together with the atoms to which they are attached. In some embodiments, two Rs x or 2 Rs y They form a C3-C6 cycloalkyl group together with the atoms to which they are attached. In some embodiments, two Rs x or 2 Rs y They form 3 to 6-membered heterocycloalkyl groups together with the atoms to which they are attached.

[0137] In some embodiments of the formula (A-4), R x Each is independently hydrogen, halogen, -CN, -OH, -NH2, C1-C 10 alkyl, or C1-C 10 It is a haloalkyl. In some embodiments, R x Each independently consists of hydrogen, -OH, and C1-C 10 alkyl, or C1-C 10 It is a haloalkyl. In some embodiments, R x Each is independently hydrogen.

[0138] In some embodiments of formula (A-1), (A-2), (A-3), or (A-4), two R x They form C3-C6 cycloalkyl or 3 to 6 heterocycloalkyl groups together with the atoms to which they are attached. In some embodiments, two Rs x They form a C3-C6 cycloalkyl group together with the atoms to which they are attached. In some embodiments, two Rs x They form 3 to 6-membered heterocycloalkyl groups together with the atoms to which they are attached.

[0139] In some embodiments of formula (A-1), (A-2), or (A-3), two R y They form C3-C6 cycloalkyl or 3 to 6 heterocycloalkyl groups together with the atoms to which they are attached. In some embodiments, two Rs yThey form a C3-C6 cycloalkyl group together with the atoms to which they are attached. In some embodiments, two Rs y They form 3 to 6-membered heterocycloalkyl groups together with the atoms to which they are attached.

[0140] In some embodiments of chemical formula (A-1), (A-2), (A-3), or (A-4), j1 is 1. In some embodiments, j1 is 0.

[0141] In some embodiments, the DNA-binding moiety comprises the structure of formula (A-5) or a pharmaceutically acceptable salt thereof:

[0142]

[0143] Chemical formula (A-5),

[0144] In the above formula:

[0145] W 1 Silver is hydrogen, -C1-C6 haloalkyl, or -N=C(N(R 1e )2)2, where R 1e Each is independently a hydrogen or optionally substituted C1-C3 alkyl;

[0146] Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 Each is independently N or CH;

[0147] R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with;

[0148] R 3a and R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e and, in the above formula,

[0149] R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;

[0150] R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0151] 2 Rs 3a or 2 Rs 3b ...forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0152] One R 3a and one R 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0153] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)RZc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0154] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0155] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0156] m1 and n1 are each independently 0 or 1.

[0157] In some embodiments, the DNA-binding moiety comprises the structure of formula (A-6) or a pharmaceutically acceptable salt thereof:

[0158]

[0159] Chemical formula (A-6),

[0160] In the above formula:

[0161] W 1 Silver is hydrogen, -C1-C6 haloalkyl, or -N=C(N(R 1e )2)2, where R 1e Each is independently a hydrogen or optionally substituted C1-C3 alkyl;

[0162] Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 Each is independently N or CH;

[0163] R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with;

[0164] R 3a and R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e and, in the above formula,

[0165] R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;

[0166] R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0167] 2 Rs 3a or 2 Rs 3b...forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0168] One R 3a and one R 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0169] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0170] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0171] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0172] m1 and n1 are each independently 0 or 1.

[0173] In some embodiments, the DNA-binding moiety comprises the structure of formula (A-7) or a pharmaceutically acceptable salt thereof:

[0174]

[0175] Chemical formula (A-7),

[0176] In the above formula:

[0177] W 1 Silver is hydrogen, -C1-C6 haloalkyl, or -N=C(N(R 1e )2)2, where R 1e Each is independently a hydrogen or optionally substituted C1-C3 alkyl;

[0178] Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 Each is independently N or CH;

[0179] R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with;

[0180] R 3a and R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d, or -NHC(O)R 3e and, in the above formula,

[0181] R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;

[0182] R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0183] 2 Rs 3a or 2 Rs 3b ...forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0184] One R 3a and one R 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0185] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0186] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0187] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0188] m1 is 0 or 1.

[0189] In some embodiments, the DNA-binding moiety comprises the structure of formula (A-8) or a pharmaceutically acceptable salt thereof:

[0190]

[0191] Chemical formula (A-8),

[0192] In the above formula:

[0193] W 1 Silver is hydrogen, -C1-C6 haloalkyl, or -N=C(N(R 1e )2)2, where R 1e Each is independently a hydrogen or optionally substituted C1-C3 alkyl;

[0194] Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 Each is independently N or CH;

[0195] R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with;

[0196] R 3a and R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e and, in the above formula,

[0197] R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;

[0198] R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0199] 2 Rs 3a or 2 Rs 3b ...forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl with the atoms to which they are attached;

[0200] One R 3a and one R 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0201] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0202] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0203] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0204] In some embodiments of any one of chemical formulas (A-1) to (A-8), Y 2 , Y 4 , Y 7 , and Y 8 Each is independently N and Y 1 , Y 3 , and Y 6 Each is independently CH. In some embodiments, Y 2 , Y 4 , and Y 7 Each is independently N; and Y 1 and Y 3 Each is independently CH.

[0205] In some embodiments of any one of chemical formulas (A-1) to (A-8), Y 5 Each is independently CH. In some embodiments, Y 5 Each is independently N.

[0206] In some embodiments of any one of chemical formulas (A-1) to (A-8), Y 6 Each is independently CH. In some embodiments, Y 6 Each is independently N.

[0207] In some embodiments of any one of chemical formulas (A-1) to (A-8), Y 8 is CH. In some embodiments, Y 8 is N.

[0208] In some embodiments of the formula (A-1), W 1 Silver hydrogen, halogen, selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, NR 1e R 1f , -NR 1e C(O)R 1f , -NR 1e C(O)NR 1e R 1f , -C(O)NR 1e R 1f , -OC(O)NR 1e R 1f , or -NR 1e C(O)OR 1f is. In some embodiments, W 1 Silver hydrogen or optionally substituted C1-C 10 It is an alkyl. In some embodiments, W 1 -NR 1e C(O)R 1f , -NR 1e C(O)NR 1e R 1f , -C(O)NR 1e R 1f , -OC(O)NR 1e R 1f , or -NR 1e C(O)OR 1f am.

[0209] In some embodiments of the formula (A-1), W 1 -Z B -PO(OR 1e )2, -Z B -(CH2) p3 -PO(OR 1e ) 2. , or -Z B -(CH2) p3 -O-PO2(OR 1e )2 and, here Z B is O or N, and p3 is 1-10.

[0210] In some embodiments of any one of chemical formulas (A-1) to (A-8), W 1It is hydrogen or -N=C(N(R 1e )2)2, where R 1e Each is independently hydrogen or C1-C3 alkyl. In some embodiments, W 1 It is hydrogen or -N=C(N(R 1e )2)2, where R 1e Each is independently hydrogen or methyl.

[0211] In some embodiments of any one of chemical formulas (A-1) to (A-8), W 1 It is -CF3.

[0212] In some embodiments of any one of chemical formulas (A-1) to (A-8), W 1 It is hydrogen.

[0213] In some embodiments of the chemical formula (A-1), each of the AAs is a non-natural or natural amino acid.

[0214] In some embodiments of any one of chemical formulas (A-1) to (A-8), R 1e Each is independently hydrogen or C1-C 10 It is an alkyl. In some embodiments, R 1e Each is independently hydrogen or C1-C8 alkyl. In some embodiments, R 1e Each is independently hydrogen or a C1-C6 alkyl. In some embodiments, R 1e Each is independently hydrogen or C1-C3 alkyl. In some embodiments, R 1e Each is a C1-C3 alkyl. In some embodiments, R 1e Each is independently methyl. In some embodiments, R 1e Each is independently hydrogen.

[0215] In some embodiments of the formula (A-1), R 1f Each is independently hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Heteroalkyl, optionally substituted 5-membered heteroaryl, or AA 1-10is. In some embodiments, R 1f Each is independently hydrogen or optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 1f Each is independently a hydrogen or optionally substituted C1-C8 alkyl. In some embodiments, R 1f Each is independently a hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, R 1f Each is an independently optionally substituted C1-C6 alkyl. In some embodiments, R 1f Each is independently methyl. In some embodiments, R 1f Each is independently hydrogen. In some embodiments, R 1f is AA 1-10 is. In some embodiments, R 1f is AA 1-4 is. In some embodiments, R 1f is AA 1-3 am.

[0216] In some embodiments of any one of chemical formulas (A-1) to (A-7), m1 is 0. In some embodiments, m1 is 1.

[0217] In some embodiments of any one of chemical formulas (A-1), (A-2), (A-3), (A-5), or (A-6), n1 is 0. In some embodiments, n1 is 1.

[0218] In some embodiments, the DNA-binding moiety comprises the structure of formula (A-9) or a pharmaceutically acceptable salt thereof:

[0219]

[0220] Chemical formula (A-9),

[0221] In the above formula:

[0222] W 1 It is hydrogen;

[0223] R 2a , R 2b , R 2c, R 2d , R 2e , R 2g , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with;

[0224] R 3a and R 3b Each is independently hydrogen, -OH, -NH2, or C1-C6 alkyl;

[0225] 2 Rs 3a or 2 Rs 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0226] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10Heteroalkyl, C3-C 10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0227] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0228] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0229] In some embodiments, the DNA-binding moiety comprises the structure of formula (I) or a pharmaceutically acceptable salt thereof:

[0230]

[0231] Chemical formula (I),

[0232] In the above formula:

[0233] W 1 It is hydrogen;

[0234] R 2a , R 2c , R 2d , R 2e , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with;

[0235] R 3b Each is independently hydrogen, -NH2, or C1-C6 alkyl;

[0236] 2 Rs 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0237] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0238] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0239] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0240] In some embodiments, the DNA-binding moiety comprises the structure of the formula (IA) or a pharmaceutically acceptable salt thereof:

[0241]

[0242] Chemical formula (IA),

[0243] In the above formula:

[0244] W 1 It is hydrogen;

[0245] R 2a , R 2c , R 2d , R 2e , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with;

[0246] R 3a Each is independently hydrogen, -NH2, or C1-C6 alkyl;

[0247] 2 Rs 3a They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0248] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C10 alkyl, or C1-C 10 or haloalkyl;

[0249] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached, where

[0250] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0251] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0252] In some embodiments of the formula (IA), two R 3a They form C3-C6 cycloalkyl or 4 to 6 heterocycloalkyl groups together with the atoms to which they are attached. In some embodiments, two Rs 3a They form a C3-C6 cycloalkyl group together with the atoms to which they are attached. Two R 3a They form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl together with the atoms to which they are attached.

[0253] In some embodiments, the DNA-binding moiety of formula (IA) has the structure of formula (I-A') or a pharmaceutically acceptable salt thereof:

[0254]

[0255] Chemical formula (I-A').

[0256] In some embodiments of chemical formula (I) or (IA), R 2a , R 2c , R 2d , R 2e , or R 2h Each is an independently and selectively substituted C1-C 20 Alkyl, optionally substituted C1-C 20 haloalkyl, or optionally substituted C3-C8 cycloalkyl, each of which optionally has one or more R ZIt is replaced by. In some embodiments, R 2a , R 2c , R 2d , R 2e , or R 2h Each is an independently optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2a , R 2c , R 2d , R 2e , or R 2h Each is independently a monocyclic, spirocycloalkyl, or cross-linked C3-C8 cycloalkyl.

[0257] In some embodiments of chemical formula (I) or (IA), R 2a , R 2c , R 2d , R 2e , or R 2h One, two, or three of them are substituted. In some embodiments, R 2a , R 2c , R 2d , R 2e , or R 2h One or two of them are substituted. In some embodiments, R 2a , R 2c , R 2d , R 2e , or R 2h One of them is replaced.

[0258] In some embodiments of chemical formula (I) or (IA), R 2a , R 2c , R 2d , R 2e , or R 2h At least two of them are substituted. In some embodiments, R 2a , R 2c , R 2d , R 2e , or R 2h At least one of them is substituted.

[0259] In some embodiments of chemical formula (I) or (IA), R 2a , R 2c , R 2d, R 2e , or R 2h At least 2 of them are non-substituted C1-C 20 It is not an alkyl. In some embodiments, R 2a , R 2c , R 2d , R 2e , or R 2h At least one of them is a non-substituted C1-C 20 It is not an alkyl. In some embodiments, R 2a , R 2c , R 2d , R 2e , or R 2h At least two of them are not methyl. In some embodiments, R 2a , R 2c , R 2d , R 2e , or R 2h At least one of them is not methyl.

[0260] In some embodiments, the DNA-binding moiety comprises the structure of formula (Iaa) or a pharmaceutically acceptable salt thereof:

[0261]

[0262] Chemical formula (Iaa),

[0263] In the above formula:

[0264] W 1 It is hydrogen;

[0265] R 2a is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; and optionally one or more R Z Replaced with;

[0266] R 3b Each is independently hydrogen, -NH2, or C1-C6 alkyl;

[0267] 2 Rs 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0268] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0269] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0270] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0271] In some embodiments of the formula (Iaa), R 2a is an optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20haloalkyl, or optionally substituted C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced by. In some embodiments, R 2a is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2a is a monocyclic, spirocycloalkyl, or cross-linked C3-C8 cycloalkyl. In some embodiments, R 2a is non-substituted C1-C 20 It is not an alkyl. In some embodiments, R 2a is not methyl.

[0272] In some embodiments, the DNA-binding moiety comprises the structure of the formula (Ibb) or a pharmaceutically acceptable salt thereof:

[0273]

[0274] Chemical formula (Ibb),

[0275] In the above formula:

[0276] W 1 It is hydrogen;

[0277] R 2c is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; and optionally one or more R Z Replaced with;

[0278] R 3b Each is independently hydrogen, -NH2, or C1-C6 alkyl;

[0279] 2 Rs 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0280] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0281] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0282] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0283] In some embodiments of the chemical formula (Ibb), R 2c is an optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 haloalkyl, or optionally substituted C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced by. In some embodiments, R 2c is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2cis a monocyclic, spirocycloalkyl, or cross-linked C3-C8 cycloalkyl. In some embodiments, R 2c is non-substituted C1-C 20 It is not an alkyl. In some embodiments, R 2c is not methyl.

[0284] In some embodiments, the DNA-binding moiety comprises the structure of the formula (Icc) or a pharmaceutically acceptable salt thereof:

[0285]

[0286] Chemical formula (Icc),

[0287] In the above formula:

[0288] W 1 It is hydrogen;

[0289] R 2d is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; and optionally one or more R Z Replaced with;

[0290] R 3b Each is independently hydrogen, -NH2, or C1-C6 alkyl;

[0291] 2 Rs 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0292] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0293] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0294] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0295] In some embodiments of the chemical formula (Icc), R 2d is an optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 haloalkyl, or optionally substituted C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced by. In some embodiments, R 2d is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2d is a monocyclic, spirocycloalkyl, or cross-linked C3-C8 cycloalkyl. In some embodiments, R 2d is non-substituted C1-C 20 It is not an alkyl. In some embodiments, R 2d is not methyl.

[0296] In some embodiments, the DNA-binding moiety comprises the structure of the formula (Idd) or a pharmaceutically acceptable salt thereof:

[0297]

[0298] Chemical formula (Idd),

[0299] In the above formula:

[0300] W 1 It is hydrogen;

[0301] R 2e is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; and optionally one or more R Z Replaced with;

[0302] R 3b Each is independently hydrogen, -NH2, or C1-C6 alkyl;

[0303] 2 Rs 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0304] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc, -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0305] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0306] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0307] In some embodiments of the chemical formula (Idd), R 2e is an optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 haloalkyl, or optionally substituted C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced by. In some embodiments, R 2e is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2e is a monocyclic, spirocycloalkyl, or cross-linked C3-C8 cycloalkyl. In some embodiments, R 2e is non-substituted C1-C 20 It is not an alkyl. In some embodiments, R 2e is not methyl.

[0308] In some embodiments, the DNA-binding moiety comprises the structure of the formula (Iee) or a pharmaceutically acceptable salt thereof:

[0309]

[0310] Chemical formula (Iee),

[0311] In the above formula:

[0312] W 1 It is hydrogen;

[0313] R 2h is independently hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; and optionally one or more R Z Replaced with;

[0314] R 3b Each is independently hydrogen, -NH2, or C1-C6 alkyl;

[0315] 2 Rs 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0316] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; wherein, in the above formula,

[0317] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0318] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0319] In some embodiments of the chemical formula (Iee), R 2h is an optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 haloalkyl, or optionally substituted C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced by. In some embodiments, R 2h is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2h is a monocyclic, spirocycloalkyl, or cross-linked C3-C8 cycloalkyl. In some embodiments, R 2h is non-substituted C1-C 20 It is not an alkyl. In some embodiments, R 2h is not methyl.

[0320] In some embodiments, the DNA-binding moiety comprises the structure of formula (I') or a pharmaceutically acceptable salt thereof:

[0321]

[0322] Chemical formula (I'),

[0323] In the above formula:

[0324] W 1 It is hydrogen;

[0325] R 2a , R 2c , R 2e , and R 2h Each is an independently and selectively substituted C1-C20 alkyl, where each is optionally one or more R Z Replaced with;

[0326] R 2d is an optionally substituted C1-C 20 alkyl or optionally substituted C3-C 10 They are cycloalkyl, each of which optionally has one or more R Z Replaced with;

[0327] R 3b Each is independently hydrogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e and, here

[0328] R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;

[0329] R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0330] 2 Rs 3b They form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[0331] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0332] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached, where

[0333] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0334] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0335] However, R 2d is an optionally substituted C3-C 10 In the case of cycloalkyl, R 3b Each is hydrogen or; 2 R 3b If ga forms a C3-C6 cycloalkyl group, R 2d is an optionally substituted C1-C 20 It is an alkyl.

[0336] In some embodiments of the formula (I'), R 2d is an optionally substituted C3-C 10 It is cycloalkyl; R 3b Each is hydrogen.

[0337] In some embodiments of the formula (I'), R 2d is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl. In some embodiments, R 2d is one or more R Z It is a monocyclic C6-C8 cycloalkyl selectively substituted with , where R Z Each is independently a halogen, -OH, -OR Za , -NR Za R Zb , or C1-C6 alkyl. In some embodiments, R 2d Is , , , , , , , , , , , , , or am.

[0338] In some embodiments of formula (I'), 2 R 3b is formed with the atoms to which they are attached to form a C3-C6 cycloalkyl group; R 2d is an optionally substituted C1-C 20 It is an alkyl.

[0339] In some embodiments of formula (I'), 2 R 3b They form cyclopropyl together with the atoms to which they are attached.

[0340] In some embodiments of the formula (I'), R 2d is an unsubstituted C1-C8 alkyl. In some embodiments, R 2d is methyl, ethyl, isopropyl, n-butyl, isobutyl, pentyl, or hexyl. In some embodiments, R 2d is methyl, ethyl, or isopropyl. In some embodiments, R 2d is methyl. In some embodiments, R 2d is isopropyl.

[0341] In some embodiments of the formula (I'), R 2a , R 2c , R 2e , and R 2h Each is independently an unsubstituted C1-C8 alkyl. In some embodiments, R 2a , R 2c , R 2e , and R 2h Each is independently methyl, ethyl, or isopropyl.

[0342] In some embodiments, the DNA-binding moiety comprises the structure of formula (II) or a pharmaceutically acceptable salt thereof:

[0343]

[0344] Chemical formula (II),

[0345] In the above formula:

[0346] T A is -Q A -Q B and; here

[0347] Q A Is And;

[0348] Q B Is and; here

[0349] R 2j is an optionally substituted C1-C 20 It is alkyl, and optionally one or more R Z Replaced with;

[0350] R 2k is an optionally substituted C1-C 20 alkyl or optionally substituted C3-C 10 They are cycloalkyl, each of which optionally has one or more R Z Replaced with;

[0351] * is Q A to Q B It is the attachment point of;

[0352] ** is an attachment point for the oligomer linker;

[0353] W 1 It is hydrogen;

[0354] R 2c and R 2d Each is an independently and selectively substituted C1-C 20 Alkyl, optionally substituted, C3-C 10 Cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl, each of which optionally has one or more R Z Replaced with;

[0355] R 3b Each is hydrogen or C1-C6 alkyl;

[0356] 2 Rs 3b They form a C3-C6 cycloalkyl group together with the atoms to which they are attached;

[0357] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za RZb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0358] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached, where

[0359] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0360] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0361] In some embodiments of formula (II), R Z Each is independently a halogen, -OH, -OR Za , -NR Za R Zb , or C1-C6 alkyl.

[0362] In some embodiments of formula (II), R 2c is methyl, ethyl, isopropyl, , , or is. In some embodiments, R 2c is methyl, ethyl, or isopropyl. In some embodiments, R 2c is methyl. In some embodiments, R 2c is isopropyl.

[0363] In some embodiments, the DNA-binding moiety of formula (II) has the structure of formula (IIa) or a pharmaceutically acceptable salt thereof:

[0364]

[0365] Chemical formula (IIa).

[0366] In some embodiments of formula (II) or (IIa), R 2d is an optionally substituted C1-C 20 It is alkyl, and optionally one or more R Z It is replaced by. In some embodiments, R 2d is an optionally substituted C3-C 10 It is cycloalkyl, and optionally one or more R Z It is replaced by. In some embodiments, R 2d is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl, each of which is optionally substituted with one or more R Z It is replaced with, where R Z Each is independently a halogen, -OH, -OR Za , -NR Za R Zb , or C1-C6 alkyl.

[0367] In some embodiments of formula (II) or (IIa), R 2j is an optionally substituted C1-C 20 It is an alkyl. In some embodiments, R 2j is non-substituted C1-C 10 It is an alkyl. In some embodiments, R 2j is methyl, ethyl, isopropyl, , , or is. In some embodiments, R 2j is methyl, ethyl, or isopropyl. In some embodiments, R 2j is methyl. In some embodiments, R 2j is isopropyl.

[0368] In some embodiments of formula (II) or (IIa), R 2k is an optionally substituted C3-C 10 It is cycloalkyl, and optionally one or more R Z It is replaced by. In some embodiments, R 2kis an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl, each of which is optionally substituted with one or more R Z It is replaced with, where R Z Each is independently a halogen, -OH, -OR Za , -NR Za R Zb , or C1-C6 alkyl.

[0369] In some embodiments of formula (II) or (IIa), R 2k is an optionally substituted C1-C 10 It is an alkyl. In some embodiments of formula (II) or (IIa), R 2k is non-substituted C1-C 10 It is an alkyl. In some embodiments, R 2k is methyl, ethyl, isopropyl, , , or is. In some embodiments, R 2k is methyl, ethyl, or isopropyl. In some embodiments, R 2k is methyl. In some embodiments, R 2k is isopropyl.

[0370] In some embodiments of formula (II) or (IIa), R 2j is non-substituted C1-C 10 It is alkyl and R 2k is non-substituted C1-C 10 It is an alkyl. In some embodiments, R 2j is methyl and R 2k is methyl.

[0371] In some embodiments, the DNA-binding moiety comprises the structure of formula (III) or a pharmaceutically acceptable salt thereof:

[0372]

[0373] Chemical formula (III),

[0374] In the above formula:

[0375] TB -S 1 -Q L and; here

[0376] S 1 is -C(O)NH(CH2)2- and;

[0377] Q L silver and; here

[0378] R 2m is an optionally substituted C1-C 20 It is an alkyl, which optionally has one or more R Z Replaced with;

[0379] ** is an attachment point for the oligomer linker;

[0380] R 2c is an unsubstituted C1-C6 alkyl;

[0381] R 2d and R 2e Each is an independently and selectively substituted C1-C 20 Alkyl, optionally substituted, C3-C 10 Cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl, each of which optionally has one or more R Z Replaced with;

[0382] R 3b Each is hydrogen or C1-C6 alkyl;

[0383] 2 Rs 3b They form a C3-C6 cycloalkyl group together with the atoms to which they are attached;

[0384] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C10 or haloalkyl;

[0385] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached, where

[0386] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0387] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0388] In some embodiments of formula (III), R 2c is methyl, ethyl, or isopropyl. In some embodiments, R 2c is methyl. In some embodiments, R 2c is isopropyl.

[0389] In some embodiments, the DNA-binding moiety of formula (III) has the structure of formula (IIIa) or a pharmaceutically acceptable salt thereof:

[0390]

[0391] Chemical formula (IIIa).

[0392] In some embodiments of formula (III) or (IIIa), R 2d is an optionally substituted C1-C 20 It is alkyl, and optionally one or more R Z It is replaced by. In some embodiments, R 2d is an optionally substituted C3-C 10 It is cycloalkyl, and optionally one or more R Z It is replaced by. In some embodiments, R 2d is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl, each of which is optionally substituted with one or more R Z It is replaced with, where R Z Each is independently a halogen, -OH, -ORZa , -NR Za R Zb , or C1-C6 alkyl.

[0393] In some embodiments of formula (III) or (IIIa), R 2e is an optionally substituted C1-C 20 It is an alkyl. In some embodiments, R 2e is methyl, ethyl, or isopropyl. In some embodiments, R 2e is methyl. In some embodiments, R 2e is isopropyl.

[0394] In some embodiments of formula (III) or (IIIa), R 2m is an unsubstituted C1-C6 alkyl. In some embodiments, R 2m is methyl, ethyl, or isopropyl. In some embodiments, R 2m is methyl. In some embodiments, R 2m It is isopropyl.

[0395] In some embodiments, the DNA-binding moiety comprises the structure of formula (IV) or a pharmaceutically acceptable salt thereof:

[0396]

[0397] Chemical formula (IV),

[0398] In the above formula:

[0399] T C is -Q C -S 2 -Q D And;

[0400] T D is -Q C -S 2 -Q E and; here

[0401] S 2 Each is -NHC(O)(CH2)2- or -(CH2)2C(O)NH-;

[0402] Q C Each And;

[0403] Q D Is And;

[0404] Q E Is and; here

[0405] R 2n , R 2p , and R 2q Each is an independently and selectively substituted C1-C 20 alkyl, where each is optionally one or more R Z Replaced with;

[0406] ** is an attachment point for the oligomer linker;

[0407] R 2d is C3-C 10 It is a cycloalkyl, which optionally has one or more R Z Replaced with;

[0408] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0409] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached, where

[0410] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0411] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0412] In some embodiments of formula (IV), R 2n Each is independently an unsubstituted C1-C8 alkyl. In some embodiments, R 2n is methyl, ethyl, or isopropyl. In some embodiments, R 2n is methyl. In some embodiments, R 2n It is isopropyl.

[0413] In some embodiments of formula (IV), T C Is am.

[0414] In some embodiments of formula (IV), T D Is am.

[0415] In some embodiments of formula (IV), R 2p and R 2q is an independently and optionally substituted C1-C8 alkyl, each of which optionally has one or more R Z Replaced with; R Z Each is independently a halogen, -OH, -OR Za , or -NR Za R Zb am.

[0416] In some embodiments of formula (IV), R 2p Each is independently an unsubstituted C1-C8 alkyl. In some embodiments, R 2p is methyl, ethyl, or isopropyl. In some embodiments, R 2p is methyl. In some embodiments, R 2p is isopropyl.

[0417] In some embodiments of formula (IV), R 2q Each is independently an unsubstituted C1-C8 alkyl. In some embodiments, R 2q is methyl, ethyl, or isopropyl. In some embodiments, R 2q is methyl. In some embodiments, R 2q is isopropyl.

[0418] In some embodiments of formula (IV), R 2d is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl. In some embodiments, R 2d is an unsubstituted monocyclic C6-C8 cycloalkyl.

[0419] In some embodiments, the DNA-binding moiety of formula (IV) has the structure of formula (IVa) or a pharmaceutically acceptable salt thereof:

[0420]

[0421] Chemical formula (IVa),

[0422] In the above formula:

[0423] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 or haloalkyl;

[0424] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached;

[0425] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0426] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0427] pp is 0, 1, or 2.

[0428] In some embodiments of formula (IV) or (IVa), pp is 1 or 2. In some embodiments, pp is 0. In some embodiments, pp is 1. In some embodiments, pp is 2.

[0429] In some embodiments, the DNA-binding moiety comprises the structure of formula (V) or a pharmaceutically acceptable salt thereof:

[0430]

[0431] Chemical formula (V),

[0432] In the above formula:

[0433] T E is -Q M -Q N And;

[0434] T F -S 3 -Q P and; here

[0435] S 3 is -C(O)NH(CH2)2- and;

[0436] Q M silver And;

[0437] Q N silver And;

[0438] Q P Is and; here

[0439] R 2r , R 2rr , and R 2s Each is an independently and selectively substituted C1-C 20 alkyl, where each is optionally one or more R Z Replaced with;

[0440] * is Q M to Q N It is the attachment point of;

[0441] ** is an attachment point for the oligomer linker;

[0442] R2e is C3-C 10 It is a cycloalkyl, which optionally has one or more R Z Replaced with;

[0443] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0444] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached, where

[0445] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0446] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0447] In some embodiments of the formula (V), R 2e is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced by. In some embodiments, R 2e is an unsubstituted monocyclic C6-C8 cycloalkyl.

[0448] In some embodiments of the formula (V), R 2r , R 2rr , and R 2s is an independently and optionally substituted C1-C8 alkyl, each of which optionally has one or more R Z Replaced with; R ZEach is independently a halogen, -OH, -OR Za , or -NR Za R Zb am.

[0449] In some embodiments of the formula (V), R 2r , R 2rr , and R 2s is independently an unsubstituted C1-C8 alkyl.

[0450] In some embodiments of the formula (V), R 2r is methyl, ethyl, or isopropyl. In some embodiments, R 2r is methyl. In some embodiments, R 2r It is isopropyl.

[0451] In some embodiments of the formula (V), R 2rr is methyl, ethyl, or isopropyl. In some embodiments, R 2rr is methyl. In some embodiments, R 2rr It is isopropyl.

[0452] In some embodiments of the formula (V), R 2s is methyl, ethyl, or isopropyl. In some embodiments, R 2s is methyl. In some embodiments, R 2s is isopropyl.

[0453] In some embodiments, the DNA-binding moiety comprises the structure of formula (Va) or a pharmaceutically acceptable salt thereof:

[0454]

[0455] Chemical formula (Va),

[0456] In the above formula:

[0457] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc, -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 or haloalkyl;

[0458] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached;

[0459] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0460] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0461] qq is 0, 1, or 2.

[0462] In some embodiments of formula (V) or (Va), qq is 1 or 2. In some embodiments, qq is 0. In some embodiments, qq is 1. In some embodiments, qq is 2.

[0463] In some embodiments, the DNA-binding moiety comprises the structure of formula (VI) or a pharmaceutically acceptable salt thereof:

[0464]

[0465] Chemical formula (VI),

[0466] In the above formula:

[0467] T H is -Q F -S 4 -Q G and; here

[0468] S 4 is -NHC(O)(CH2)2- and;

[0469] Q F Is And;

[0470] Q G Is and; here

[0471] R 2u , and R 2t Each is an independently and selectively substituted C1-C 20 alkyl, where each is optionally one or more R Z Replaced with;

[0472] ** is an attachment point for the oligomer linker;

[0473] R 2a is C3-C 10 It is a cycloalkyl, which optionally has one or more R Z Replaced with;

[0474] R 3b Each is hydrogen or C1-C6 alkyl;

[0475] 2 Rs 3b They form a C3-C6 cycloalkyl group together with the atoms to which they are attached;

[0476] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0477] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached, where

[0478] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0479] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0480] In some embodiments of formula (VI), R 2a is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced by. In some embodiments, R 2a is an unsubstituted monocyclic C6-C8 cycloalkyl.

[0481] In some embodiments of formula (VI), R 2u and R 2t is an independently and optionally substituted C1-C8 alkyl, each of which optionally has one or more R Z Replaced with; R Z Each is independently a halogen, -OH, -OR Za , or -NR Za R Zb am.

[0482] In some embodiments of formula (VI), R 2u is an unsubstituted C1-C8 alkyl. In some embodiments, R 2u is methyl, ethyl, or isopropyl. In some embodiments, R 2u is methyl. In some embodiments, R 2u is isopropyl.

[0483] In some embodiments of formula (VI), R 2t is an unsubstituted C1-C8 alkyl. In some embodiments, R 2t is methyl, ethyl, or isopropyl. In some embodiments, R 2t is methyl. In some embodiments, R 2t is isopropyl.

[0484] In some embodiments, the DNA-binding moiety of formula (VI) has the structure of formula (VIa) or a pharmaceutically acceptable salt thereof:

[0485]

[0486] Chemical formula (VIa),

[0487] In the above formula:

[0488] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 or haloalkyl;

[0489] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached;

[0490] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0491] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0492] rr is 0, 1, or 2.

[0493] In some embodiments of formula (VI) or (VIa), rr is 1 or 2. In some embodiments, rr is 0. In some embodiments, rr is 1. In some embodiments, rr is 2.

[0494] In some embodiments, the DNA-binding moiety comprises the structure of formula (VII) or a pharmaceutically acceptable salt thereof:

[0495]

[0496] Chemical formula (VII),

[0497] In the above formula:

[0498] W 3 silver And;

[0499] TG is -Q F -S 5 -Q G and; here

[0500] S 5 is -NHC(O)(CH2)2- and;

[0501] Q F Is And;

[0502] Q G Is and; here

[0503] R 2a , R 2w , and R 2v Each is an independently and selectively substituted C1-C 20 alkyl, where each is optionally one or more R Z Replaced with;

[0504] ** is an attachment point for the oligomer linker;

[0505] R 2b is C3-C 10 It is a cycloalkyl, which optionally has one or more R Z Replaced with;

[0506] R 3b Each is hydrogen or C1-C6 alkyl;

[0507] 2 Rs 3b They form a C3-C6 cycloalkyl group together with the atoms to which they are attached;

[0508] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0509] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached, where

[0510] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0511] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0512] In some embodiments of formula (VII), R 2b is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced by. In some embodiments, R 2b is an unsubstituted monocyclic C6-C8 cycloalkyl.

[0513] In some embodiments of formula (VII), R 2a , R 2w , and R 2v is an independently and optionally substituted C1-C8 alkyl, each of which optionally has one or more R Z Replaced with; R Z Each is independently a halogen, -OH, -OR Za , or -NR Za R Zb am.

[0514] In some embodiments of formula (VII), R 2a is an unsubstituted C1-C8 alkyl. In some embodiments, R 2a is methyl, ethyl, or isopropyl. In some embodiments, R 2a is methyl. In some embodiments, R 2a is isopropyl.

[0515] In some embodiments of formula (VII), R 2w is an unsubstituted C1-C8 alkyl. In some embodiments, R 2wis methyl, ethyl, or isopropyl. In some embodiments, R 2w is methyl. In some embodiments, R 2w is isopropyl.

[0516] In some embodiments of formula (VII), R 2v is an unsubstituted C1-C8 alkyl. In some embodiments, R 2v is methyl, ethyl, or isopropyl. In some embodiments, R 2v is methyl. In some embodiments, R 2v is isopropyl.

[0517] In some embodiments, the DNA-binding moiety of formula (VII) has the structure of formula (VIIa) or a pharmaceutically acceptable salt thereof:

[0518]

[0519] Chemical formula (VIIa),

[0520] In the above formula:

[0521] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 or haloalkyl;

[0522] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached;

[0523] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0524] R Zcis an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0525] ss is 0, 1, or 2.

[0526] In some embodiments of formula (VII) or (VIIa), ss is 1 or 2. In some embodiments, ss is 0. In some embodiments, ss is 1. In some embodiments, ss is 2.

[0527] In some embodiments, the DNA-binding moiety comprises the structure of formula (VIII) or a pharmaceutically acceptable salt thereof:

[0528]

[0529] Chemical formula (VIII),

[0530] In the above formula:

[0531] T H Is And;

[0532] T J Is and; here

[0533] R 2y and R 2z Each is an independently and selectively substituted C1-C 20 alkyl, where each is optionally one or more R Z Replaced with;

[0534] ** is an attachment point for the oligomer linker;

[0535] R 2f is C3-C 10 It is a cycloalkyl, which optionally has one or more R Z Replaced with;

[0536] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NRZa R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0537] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached, where

[0538] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0539] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0540] In some embodiments of formula (VIII), R 2f is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced by. In some embodiments, R 2f is an unsubstituted monocyclic C6-C8 cycloalkyl.

[0541] In some embodiments of formula (VIII), R 2z and R 2y is an independently and optionally substituted C1-C8 alkyl, each of which optionally has one or more R Z Replaced with; R Z Each is independently a halogen, -OH, -OR Za , or -NR Za R Zb am.

[0542] In some embodiments of formula (VIII), R 2z is an unsubstituted C1-C8 alkyl. In some embodiments, R 2z is methyl, ethyl, or isopropyl. In some embodiments, R 2z is methyl. In some embodiments, R 2z is isopropyl.

[0543] In some embodiments of formula (VIII), R 2y is an unsubstituted C1-C8 alkyl. In some embodiments, R 2y is methyl, ethyl, or isopropyl. In some embodiments, R 2y is methyl. In some embodiments, R 2y is isopropyl.

[0544] In some embodiments, the DNA-binding moiety of formula (VIII) has the structure of formula (VIIIa) or a pharmaceutically acceptable salt thereof:

[0545]

[0546] Chemical formula (VIIIa),

[0547] In the above formula:

[0548] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 or haloalkyl;

[0549] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached;

[0550] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0551] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0552] tt is 0, 1, or 2.

[0553] In some embodiments of formula (VIII) or (VIIIa), ss is 1 or 2. In some embodiments, tt is 0. In some embodiments, tt is 1. In some embodiments, tt is 2.

[0554] In some embodiments, the DNA-binding moiety comprises the structure of formula (IX) or a pharmaceutically acceptable salt thereof:

[0555]

[0556] Chemical formula (IX),

[0557] In the above formula:

[0558] T K is -Q J -S 6 -Q K and; here

[0559] S 6 is -NHC(O)(CH2)2- or -(CH2)2C(O)NH-;

[0560] Q J Is And;

[0561] Q K Is and; here

[0562] R 2L and R 2X Each is an independently and selectively substituted C1-C 20 alkyl, where each is optionally one or more R Z Replaced with;

[0563] ** is the attachment point for the S group;

[0564] R 2h is C3-C 10 It is a cycloalkyl, which optionally has one or more R Z Replaced with;

[0565] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za RZb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 or haloalkyl;

[0566] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached, where

[0567] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0568] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0569] In some embodiments of formula (IX), R 2f is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced by. In some embodiments, R 2f is an unsubstituted monocyclic C6-C8 cycloalkyl.

[0570] In some embodiments of formula (IX), R 2x and R 2L is an independently and optionally substituted C1-C8 alkyl, each of which optionally has one or more R Z Replaced with; R Z Each is independently a halogen, -OH, -OR Za , or -NR Za R Zb am.

[0571] In some embodiments of formula (IX), R 2x is an unsubstituted C1-C8 alkyl. In some embodiments, R 2x is methyl, ethyl, or isopropyl. In some embodiments, R2x is methyl. In some embodiments, R 2x is isopropyl.

[0572] In some embodiments of formula (IX), R 2L is an unsubstituted C1-C8 alkyl. In some embodiments, R 2L is methyl, ethyl, or isopropyl. In some embodiments, R 2L is methyl. In some embodiments, R 2L is isopropyl.

[0573] In some embodiments, the DNA-binding moiety of formula (IX) has the structure of formula (IXa) or a pharmaceutically acceptable salt thereof.

[0574]

[0575] Chemical formula (IXa),

[0576] In the above formula:

[0577] R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 or haloalkyl;

[0578] 2 Rs Z They form a C3-C6 cycloalkyl group together with the atoms to which they are attached;

[0579] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG;

[0580] R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0581] uu is 0, 1, or 2.

[0582] In some embodiments of formula (IX) or (IXa), tt is 1 or 2. In some embodiments, tt is 0. In some embodiments, tt is 1. In some embodiments, tt is 2.

[0583] In some embodiments of any one of formulas (A-5) to (A-9), (I), (IA), (I-A'), or (Iaa), R 2a is hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with; in some embodiments, R 2a is an optionally substituted C1-C 10 It is an alkylamino. In some embodiments, R 2a is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2a is an optionally substituted C1-C 20 It is a heteroalkyl. In some embodiments, R 2a is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 2a is an optionally substituted C1-C 20It is a hydroxyalkyl. In some embodiments, R 2a is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2a is an independently and optionally substituted C3-C 10 It is a cycloalkyl or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R2a is hydrogen.

[0584] In some embodiments of any one of formulas (A-5) to (A-9), (I), (I'), (IA), (Iaa), or (VII), R 2a is an optionally substituted C1-C 20 It is an alkyl. In some embodiments, R 2a is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 2a is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2a is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2a is methyl. In some embodiments, R 2a is ethyl. In some embodiments, R 2a is isopropyl. In some embodiments, R 2a is butyl. In some embodiments, R 2a is pentyl. In some embodiments, R 2a is hexyl. In some embodiments, R 2a is heptyl. In some embodiments, R 2a is an optionally substituted C1-C 20 It is a haloalkyl. In some embodiments, R 2a is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2a is -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R2a is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2a Is , , , , , or am.

[0585] In some embodiments of any one of chemical formulas (A-5) to (A-9), R 2b is hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with; in some embodiments, R 2b is an optionally substituted C1-C 10 It is an alkylamino. In some embodiments, R 2b is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2b is an optionally substituted C1-C 20 It is a heteroalkyl. In some embodiments, R 2b is an optionally substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 2b is an optionally substituted C1-C 20 It is a hydroxyalkyl. In some embodiments, R 2bis an independently and optionally substituted C3-C 10 It is a cycloalkyl or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2b is a halogen.

[0586] In some embodiments of any one of chemical formulas (A-5) to (A-9), R 2b is an optionally substituted C1-C 20 It is an alkyl. In some embodiments, R 2b is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 2b is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2b is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2b is methyl. In some embodiments, R 2b is ethyl. In some embodiments, R 2b is isopropyl. In some embodiments, R 2b is butyl. In some embodiments, R 2b is pentyl. In some embodiments, R 2b is hexyl. In some embodiments, R 2b is heptyl. In some embodiments, R 2b is an optionally substituted C1-C 20 It is a haloalkyl. In some embodiments, R 2b is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2b is -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2b is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2b Is , , , , , or am.

[0587] In some embodiments of any one of chemical formulas (A-5) to (A-9), (I), (IA), (I-A'), or (Ibb), R 2c is hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with; in some embodiments, R 2c is an optionally substituted C1-C 10 It is an alkylamino. In some embodiments, R 2c is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2c is an optionally substituted C1-C 20 It is a heteroalkyl. In some embodiments, R 2c is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 2c is an optionally substituted C1-C 20 It is a hydroxyalkyl. In some embodiments, R 2c is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2c is an independently and optionally substituted C3-C10 It is a cycloalkyl or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2c is a halogen.

[0588] In some embodiments of any one of formulas (A-5) to (A-9), (I), (I'), (IA), (Ibb), or (II), R 2c is an optionally substituted C1-C 20 It is an alkyl. In some embodiments, R 2c is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 2c is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2c is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2c is methyl. In some embodiments, R 2c is ethyl. In some embodiments, R 2c is isopropyl. In some embodiments, R 2c is butyl. In some embodiments, R 2c is pentyl. In some embodiments, R 2c is hexyl. In some embodiments, R 2c is heptyl. In some embodiments, R 2c is an optionally substituted C1-C 20 It is a haloalkyl. In some embodiments, R 2c is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2c is -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2c is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2c Is , , , , , or am.

[0589] In some embodiments of any one of chemical formulas (A-5) to (A-9), (I), (I'), (IA), (I-A'), or (Ibb), R 2d is hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with; in some embodiments, R 2d is an optionally substituted C1-C 10 It is an alkylamino. In some embodiments, R 2d is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2d is an optionally substituted C1-C 20 It is a heteroalkyl. In some embodiments, R 2d is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 2d is an optionally substituted C1-C 20 It is a hydroxyalkyl. In some embodiments, R 2d is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2d is an independently and optionally substituted C3-C10 It is a cycloalkyl or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2d is a halogen.

[0590] In some embodiments of any one of formulas (A-1) to (A-9), (I), (I'), (IA), (Icc), (II), or (III), R 2d is an optionally substituted C1-C 20 It is an alkyl. In some embodiments, R 2a is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 2d is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2d is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2d is methyl. In some embodiments, R 2d is ethyl. In some embodiments, R 2d is isopropyl. In some embodiments, R 2d is butyl. In some embodiments, R 2d is pentyl. In some embodiments, R 2d is hexyl. In some embodiments, R 2d is heptyl. In some embodiments, R 2d is an optionally substituted C1-C 20 It is a haloalkyl. In some embodiments, R 2d is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2d is -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2d is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2d Is , , , , , or am.

[0591] In some embodiments of any one of chemical formulas (A-5) to (A-9), (I), (IA), (I-A'), or (Idd), R 2e is hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with; in some embodiments, R 2e is an optionally substituted C1-C 10 It is an alkylamino. In some embodiments, R 2e is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2e is an optionally substituted C1-C 20 It is a heteroalkyl. In some embodiments, R 2e is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 2e is an optionally substituted C1-C 20 It is a hydroxyalkyl. In some embodiments, R 2e is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2eis an independently and optionally substituted C3-C 10 It is a cycloalkyl or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2e is a halogen.

[0592] In some embodiments of any one of chemical formulas (A-5) to (A-9), (I), (I'), (IA), (I-A'), or (Idd), R 2e is an optionally substituted C1-C 20 It is an alkyl. In some embodiments, R 2e is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 2e is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2e is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2e is methyl. In some embodiments, R 2e is ethyl. In some embodiments, R 2e is isopropyl. In some embodiments, R 2e is butyl. In some embodiments, R 2e is pentyl. In some embodiments, R 2e is hexyl. In some embodiments, R 2e is heptyl. In some embodiments, R 2e is an optionally substituted C1-C 20 It is a haloalkyl. In some embodiments, R 2e is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2e is -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2e is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2e Is , , , , , or am.

[0593] In some embodiments of any one of chemical formulas (A-5), (A-6), or (A-7), R 2f is hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with; in some embodiments, R 2f is an optionally substituted C1-C 10 It is an alkylamino. In some embodiments, R 2f is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2f is an optionally substituted C1-C 20 It is a heteroalkyl. In some embodiments, R 2f is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 2f is an optionally substituted C1-C 20 It is a hydroxyalkyl. In some embodiments, R 2f is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2f is an independently and optionally substituted C3-C10 It is a cycloalkyl or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2f is a halogen.

[0594] In some embodiments of any one of chemical formulas (A-5), (A-6), to (A-7), R 2f is an optionally substituted C1-C 20 It is an alkyl. In some embodiments, R 2f is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 2f is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2f is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2f is methyl. In some embodiments, R 2f is ethyl. In some embodiments, R 2f is isopropyl. In some embodiments, R 2f is butyl. In some embodiments, R 2f is pentyl. In some embodiments, R 2f is hexyl. In some embodiments, R 2f is heptyl. In some embodiments, R 2f is an optionally substituted C1-C 20 It is a haloalkyl. In some embodiments, R 2f is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2f is -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2f is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2f Is , , , , , or am.

[0595] In some embodiments of any one of chemical formulas (A-5), (A-6), (A-8), or (A-9), R 2g is hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with; in some embodiments, R 2g is an optionally substituted C1-C 10 It is an alkylamino. In some embodiments, R 2g is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2g is an optionally substituted C1-C 20 It is a heteroalkyl. In some embodiments, R 2g is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 2g is an optionally substituted C1-C 20 It is a hydroxyalkyl. In some embodiments, R 2g is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2g is an independently and optionally substituted C3-C 10It is a cycloalkyl or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2g is hydrogen.

[0596] In some embodiments of any one of chemical formulas (A-5), (A-6), (A-8), or (A-9), R 2g is an optionally substituted C1-C 20 It is an alkyl. In some embodiments, R 2g is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 2g is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2g is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2a is methyl. In some embodiments, R 2g is ethyl. In some embodiments, R 2g is isopropyl. In some embodiments, R 2g is butyl. In some embodiments, R 2g is pentyl. In some embodiments, R 2g is hexyl. In some embodiments, R 2g is heptyl. In some embodiments, R 2g is an optionally substituted C1-C 20 It is a haloalkyl. In some embodiments, R 2g is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2g is -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2g is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2g Is , , , , , or am.

[0597] In some embodiments of any one of chemical formulas (A-5) to (A-9), (I), (IA), (I-A'), or (Iee), R 2h is hydrogen, optionally substituted C1-C20 alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with; in some embodiments, R 2h is an optionally substituted C1-C 10 It is an alkylamino. In some embodiments, R 2h is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2h is an optionally substituted C1-C 20 It is a heteroalkyl. In some embodiments, R 2h is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 2h is an optionally substituted C1-C 20 It is a hydroxyalkyl. In some embodiments, R 2h is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2h is an independently and optionally substituted C3-C 10It is a cycloalkyl or an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2h is a halogen.

[0598] In some embodiments of any one of chemical formulas (A-5) to (A-9), (I), (I'), (IA), (I-A'), or (Iee), R 2h is an optionally substituted C1-C 20 It is an alkyl. In some embodiments, R 2h is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 2h is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2h is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2h is methyl. In some embodiments, R 2h is ethyl. In some embodiments, R 2h is isopropyl. In some embodiments, R 2h is butyl. In some embodiments, R 2h is pentyl. In some embodiments, R 2h is hexyl. In some embodiments, R 2h is heptyl. In some embodiments, R 2h is an optionally substituted C1-C 20 It is a haloalkyl. In some embodiments, R 2h is an optionally substituted C1-C 10 It is a haloalkyl. In some embodiments, R 2h is -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2h is an optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 2h Is , , , , , or am.

[0599] In some embodiments of any one of formulas (A-5) to (A-9), (I), (IA), (I-A'), (Iaa), or (VI), R 2a is an optionally substituted C3-C 10 It is a cycloalkyl. In some embodiments, R 2a is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2a is an optionally substituted monocyclic, dicyclic, polycyclic, spirocyclic, or cross-linked cycloalkyl. In some embodiments, R 2a is an optionally substituted monocyclic cycloalkyl. In some embodiments, R 2a is an optionally substituted spirocyclic cycloalkyl. In some embodiments, R 2a is an optionally substituted cross-linked cycloalkyl. In some embodiments, R 2a is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2a is cyclopropyl. In some embodiments, R 2a is cyclobutyl. In some embodiments, R 2a is cyclopentyl. In some embodiments, R 2a is cyclohexyl. In some embodiments, R 2a is cyclohexyl. In some embodiments, R 2a Is , , , , , , , , , , , , , , or is. In some embodiments, R 2ais an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2a is an optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R 2a is a ternary, quaternary, pentary, or hexavalent heterocycloalkyl. In some embodiments, R 2a Is , , , , , , , , , or am.

[0600] In some embodiments of any one of formulas (A-5) to (A-9), or (VII), R 2b is an optionally substituted C3-C 10 It is a cycloalkyl. In some embodiments, R 2b is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2b is an optionally substituted monocyclic, dicyclic, polycyclic, spirocyclic, or cross-linked cycloalkyl. In some embodiments, R 2b is an optionally substituted monocyclic cycloalkyl. In some embodiments, R 2b is an optionally substituted spirocyclic cycloalkyl. In some embodiments, R 2b is an optionally substituted cross-linked cycloalkyl. In some embodiments, R 2b is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2b is cyclopropyl. In some embodiments, R 2b is cyclobutyl. In some embodiments, R 2b is cyclopentyl. In some embodiments, R 2b is cyclohexyl. In some embodiments, R 2b is cyclohexyl. In some embodiments, R 2b Is , , , , , , , , , , , , , , or is. In some embodiments, R 2b is an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2b is an optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R 2b is a ternary, quaternary, pentary, or hexavalent heterocycloalkyl. In some embodiments, R 2b Is , , , , , , , , , or am.

[0601] In some embodiments of any one of chemical formulas (A-5) to (A-9), (I), (I'), (IA), or (Ibb), R 2c is an optionally substituted C3-C 10 It is a cycloalkyl. In some embodiments, R 2c is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2c is an optionally substituted monocyclic, dicyclic, polycyclic, spirocyclic, or cross-linked cycloalkyl. In some embodiments, R 2c is an optionally substituted monocyclic cycloalkyl. In some embodiments, R 2c is an optionally substituted spirocyclic cycloalkyl. In some embodiments, R 2c is an optionally substituted cross-linked cycloalkyl. In some embodiments, R2c is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2c is cyclopropyl. In some embodiments, R 2c is cyclobutyl. In some embodiments, R 2c is cyclopentyl. In some embodiments, R 2c is cyclohexyl. In some embodiments, R 2c is cyclohexyl. In some embodiments, R 2c Is , , , , , , , , , , , , , , or is. In some embodiments, R 2c is an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2c is an optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R 2c is a ternary, quaternary, pentary, or hexavalent heterocycloalkyl. In some embodiments, R 2c Is , , , , , , , , , or am.

[0602] In some embodiments of any one of formulas (A-5) to (A-9), (I), (I'), (IA), (Icc), (II), (III), or (IV), R 2d is an optionally substituted C3-C 10 It is a cycloalkyl. In some embodiments, R2d is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2d is an optionally substituted monocyclic, dicyclic, polycyclic, spirocyclic, or cross-linked cycloalkyl. In some embodiments, R 2d is an optionally substituted monocyclic cycloalkyl. In some embodiments, R 2d is an optionally substituted spirocyclic cycloalkyl. In some embodiments, R 2d is an optionally substituted cross-linked cycloalkyl. In some embodiments, R 2d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2d is cyclopropyl. In some embodiments, R 2d is cyclobutyl. In some embodiments, R 2d is cyclopentyl. In some embodiments, R 2d is cyclohexyl. In some embodiments, R 2d is cyclohexyl. In some embodiments, R 2d Is , , , , , , , , , , , , , , or is. In some embodiments, R 2d is an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2d is an optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R 2d is a ternary, quaternary, pentary, or hexavalent heterocycloalkyl. In some embodiments, R 2d Is , , , , , , , , , or am.

[0603] In some embodiments of any one of chemical formulas (A-5) to (A-9), (I), (I'), (IA), (Idd), or (V), R 2e is an optionally substituted C3-C 10 It is a cycloalkyl. In some embodiments, R 2e is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2e is an optionally substituted monocyclic, dicyclic, polycyclic, spirocyclic, or cross-linked cycloalkyl. In some embodiments, R 2e is an optionally substituted monocyclic cycloalkyl. In some embodiments, R 2e is an optionally substituted spirocyclic cycloalkyl. In some embodiments, R 2e is an optionally substituted cross-linked cycloalkyl. In some embodiments, R 2e is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2e is cyclopropyl. In some embodiments, R 2e is cyclobutyl. In some embodiments, R 2e is cyclopentyl. In some embodiments, R 2e is cyclohexyl. In some embodiments, R 2e is cyclohexyl. In some embodiments, R 2e Is , , , , , , , , , , , , , , or is. In some embodiments, R 2e is an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2e is an optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R 2e is a ternary, quaternary, pentary, or hexavalent heterocycloalkyl. In some embodiments, R 2e Is , , , , , , , , , or am.

[0604] In some embodiments of any one of formulas (A-5) to (A-9), (I), (I'), (IA), or (VIII), R 2f is an optionally substituted C3-C 10 It is a cycloalkyl. In some embodiments, R 2f is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2f is an optionally substituted monocyclic, dicyclic, polycyclic, spirocyclic, or cross-linked cycloalkyl. In some embodiments, R 2f is an optionally substituted monocyclic cycloalkyl. In some embodiments, R 2f is an optionally substituted spirocyclic cycloalkyl. In some embodiments, R 2f is an optionally substituted cross-linked cycloalkyl. In some embodiments, R 2f is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2f is cyclopropyl. In some embodiments, R 2f is cyclobutyl. In some embodiments, R 2a is cyclopentyl. In some embodiments, R 2fis cyclohexyl. In some embodiments, R 2f is cyclohexyl. In some embodiments, R 2f Is , , , , , , , , , , , , , , or is. In some embodiments, R 2f is an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2f is an optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R 2f is a ternary, quaternary, pentary, or hexavalent heterocycloalkyl. In some embodiments, R 2f Is , , , , , , , , , or am.

[0605] In some embodiments of any one of formulas (A-5) to (A-9), (I), (IA), (I-A'), (Iee), or (IX), R 2h is an optionally substituted C3-C 10 It is a cycloalkyl. In some embodiments, R 2h is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2h is an optionally substituted monocyclic, dicyclic, polycyclic, spirocyclic, or cross-linked cycloalkyl. In some embodiments, R 2h is an optionally substituted monocyclic cycloalkyl. In some embodiments, R 2his an optionally substituted spirocyclic cycloalkyl. In some embodiments, R 2h is an optionally substituted cross-linked cycloalkyl. In some embodiments, R 2h is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2h is cyclopropyl. In some embodiments, R 2h is cyclobutyl. In some embodiments, R 2h is cyclopentyl. In some embodiments, R 2h is cyclohexyl. In some embodiments, R 2h is cyclohexyl. In some embodiments, R 2h Is , , , , , , , , , , , , , , or is. In some embodiments, R 2h is an optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, R 2h is an optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R 2h is a ternary, quaternary, pentary, or hexavalent heterocycloalkyl. In some embodiments, R 2h Is , , , , , , , , , or am.

[0606] In some embodiments of any one of formulas (A-2) to (A-9) or (IA), R 3aEach is independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d , or -NHC(O)R 3e and, here R 3c and R 3d Each is independently hydrogen, alkyl, or PEG; R 3e is an alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, R 3a Each independently -NR 3c R 3d is. In some embodiments, R 3a Each is -NH2. In some embodiments, R 3a Each independently -NHC(O)R 3e is. In some embodiments, R 3a Each is hydrogen.

[0607] In some embodiments of any one of formulas (A-2) to (A-9), (I), (I'), (Iaa), (Ibb), (Icc), (Idd), (Iee), (II), (III), (VI) or (VII), R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d , or -NHC(O)R 3e and, here R 3c and R 3d Each is independently hydrogen, alkyl, or PEG; R 3e is an alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, R 3b Each independently -NR 3c R 3d is. In some embodiments, R 3b Each is -NH2. In some embodiments, R 3b Each independently -NHC(O)R 3e is. In some embodiments, R 3b Each is hydrogen.

[0608] In some embodiments of any one of formulas (A-2) to (A-9), (I), (I'), (Iaa), (Ibb), (Icc), (Idd), (Iee), (II), (III), (VI), or (VII), R 3b Each is independently hydrogen, -NH2, or C1-C6 alkyl. In some embodiments, R 3b Each is independently hydrogen or -NH2. In some embodiments, R 3b Each is hydrogen.

[0609] In some embodiments of any one of formulas (A-2) to (A-9) or (IA), 2 R 3a They form optionally substituted C3-C6 cycloalkyl or 3 to 6 heterocycloalkyl groups together with the atoms to which they are attached. In some embodiments, two Rs 3a They form a C3-C6 cycloalkyl group together with the atoms to which they are attached. In some embodiments, two Rs 3a They form 4 to 6-membered heterocycloalkyl groups together with the atoms to which they are attached. In some embodiments, two Rs 3a They form a quaternary heterocycloalkyl with the atoms to which they are attached. In some embodiments, two Rs 3a They form a pentatonic heterocycloalkyl with the atoms to which they are attached. In some embodiments, two Rs 3a They form a hexacyclic heterocycloalkyl group together with the atoms to which they are attached. In some embodiments, two Rs 3a They form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl together with the atoms to which they are attached. In some embodiments, two R 3a They form cyclopropyl together with the atoms to which they are attached. In some embodiments, two R 3a They form cyclobutyl together with the atoms to which they are attached. In some embodiments, two R 3aThey form a cyclopentyl together with the atoms to which they are attached. In some embodiments, two Rs 3a They form a cyclohexyl together with the atoms to which they are attached.

[0610] In some embodiments of any one of formulas (A-2) to (A-9), (I), (I'), (Iaa), (Ibb), (Icc), (Idd), (Iee), (II), (III), (VI), or (VII), 2 R 3b They form optionally substituted C3-C6 cycloalkyl or 3 to 6 heterocycloalkyl groups together with the atoms to which they are attached. In some embodiments, two Rs 3b They form a C3-C6 cycloalkyl group together with the atoms to which they are attached. In some embodiments, two Rs 3b They form 4 to 6-membered heterocycloalkyl groups together with the atoms to which they are attached. In some embodiments, two Rs 3b They form a quaternary heterocycloalkyl with the atoms to which they are attached. In some embodiments, two Rs 3b They form a pentatonic heterocycloalkyl with the atoms to which they are attached. In some embodiments, two Rs 3b They form a hexacyclic heterocycloalkyl group together with the atoms to which they are attached. In some embodiments, two Rs 3b They form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl together with the atoms to which they are attached. In some embodiments, two R 3b They form cyclopropyl together with the atoms to which they are attached. In some embodiments, two R 3b They form cyclobutyl together with the atoms to which they are attached. In some embodiments, two R 3b They form a cyclopentyl together with the atoms to which they are attached. In some embodiments, two Rs 3b They form a cyclohexyl together with the atoms to which they are attached.

[0611] In some embodiments of the formula (A-2), one R 3a and one R 3b They form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl group together with the atoms to which they are attached. In some embodiments, one R 3a and one R 3b They form a C3-C6 cycloalkyl group together with the atoms to which they are attached. In some embodiments, one R 3a and one R 3b They form 4 to 6-membered heterocycloalkyl groups together with the atoms to which they are attached.

[0612] In some embodiments of any one of chemical formulas (A-2) to (A-9), R 3c and R 3d Each is independently hydrogen, alkyl, or PEG. In some embodiments, R 3c and R 3d Each independently hydrogen, C1-C 20 Alkyl, or PEG 1-20 is. In some embodiments, R 3c and R 3d Each is independently C1-C 20 It is an alkyl. In some embodiments, R 3c and R 3d Each is independently hydrogen.

[0613] In some embodiments of any one of chemical formulas (A-2) to (A-9), R 3e is an alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, R 3e is C1-C 20 Alkyl, PEG 1-20 , is a C3-C6 cycloalkyl, a 4 to 6-membered heterocycloalkyl, or a phenyl. In some embodiments, R 3e is C1-C 20 Alkyl or PEG 1-20 is. In some embodiments, R 3eis a C3-C6 cycloalkyl, a 4 to 6-membered heterocycloalkyl, or a phenyl. In some embodiments, R 3e is C1-C 20 It is an alkyl.

[0614] In some embodiments of any one of formulas (A-5 to (A-9), (I), (IA), (I-A'), (I'), (Iaa), (Ibb), (Icc), (Idd), (Iee), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), or (IXa), R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 It is cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl. In some embodiments, R Z Each independently -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NHC(O)R Zc , -NHC(O)OR Zc , -OC(O)NR Za R Zb , or optionally substituted 5 to 10-membered heteroaryls. In some embodiments, R ZEach independently -CN, -OH, -OR Za , -N3, or -NR Za R Zb is. In some embodiments, R Z Each independently -C(O)NR Za R Zb , -NHC(O)R Zc , or -OC(O)NR Za R Zb is. In some embodiments, R Z Each independently halogen, C1-C 10 alkyl, or C1-C 10 It is a haloalkyl. In some embodiments, R Z Each is independently a halogen. In some embodiments, R Z Each is independently C1-C 10 It is an alkyl. In some embodiments, R Z Each is independently C1-C 10 It is a haloalkyl.

[0615] In some embodiments of any one of formulas (A-5 to (A-9), (I), (IA), (I-A'), (I'), (Iaa), (Ibb), (Icc), (Idd), (Iee), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), or (IXa), R Z Each is independently a halogen, -OH, -OR Za , -NR Za R Zb , or C1-C6 alkyl. In some embodiments, R Z Each is independently -F, -OH, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3. In some embodiments, R Z Each is independently -F, -OH, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, RZ Each is independently -F or -OH. In some embodiments, R Z Each is independently -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3. In some embodiments, R Z Each is -F. In some embodiments, R Z is -OH.

[0616] In some embodiments of any one of formulas (A-5 to (A-9), (I), (IA), (I-A'), (I'), (Iaa), (Ibb), (Icc), (Idd), (Iee), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), or (IXa), R Za and R Zb Each is independently hydrogen, alkyl, or PEG. In some embodiments, R Za and R Zb Each independently hydrogen, C1-C 20 Alkyl, or PEG 1-20 is. In some embodiments, R Za and R Zb Each is independently C1-C 20 It is an alkyl. In some embodiments, R Za and R Zb Each is independently hydrogen.

[0617] In some embodiments of any one of formulas (A-5) to (A-9), (I), (IA), (I-A'), (I'), (Iaa), (Ibb), (Icc), (Idd), (Iee), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), or (IXa), RZc is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0618] In some embodiments, R Zc is an alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, R Zc is C1-C 20 Alkyl, PEG 1-20 , is a C3-C6 cycloalkyl, a 4 to 6-membered heterocycloalkyl, or a phenyl. In some embodiments, R Zc is C1-C 20 Alkyl or PEG 1-20 is. In some embodiments, R Zc is -C1-C 20 It is an alkyl.

[0619] The binding affinity between the polyamide and the target gene can be adjusted based on the composition of the polyamide. In some embodiments, the polyamide may bind to DNA with an affinity of about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, or less than about 50 nM. In some embodiments, the polyamide may bind to DNA with an affinity of less than about 300 nM. In some embodiments, the polyamide may bind to DNA with an affinity of less than about 200 nM. In some embodiments, the polyamide may bind to DNA with an affinity of about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, or more than about 1 nM. In some embodiments, polyamides can bind to DNA with an affinity in the range of about 1-600 nM, 10-500 nM, 20-500 nM, 50-400 nM, or 100-300 nM.

[0620] In some embodiments, the first end can bind to DNA with an affinity of less than 500 nM.

[0621] The binding affinity between polyamide and target DNA can be determined using a quantitative footprint titration experiment. The experiment involves measuring the dissociation constant Kd of the polyamide for the target sequence at 24°C or 37°C and using either standard polyamide analysis solution conditions or approximate intracellular solution conditions.

[0622] The binding affinity between a regulatory protein and a second-terminal ligand can be determined using an assay suitable for a specific protein. The experiment involves measuring the dissociation constant Kd of the ligand for the protein and using either standard protein assay solution conditions or approximate intracellular solution conditions.

[0623] Polyamides composed of a combination of pre-selected subunits can selectively bind to DNA in microspheres. In a hairpin structure, antiparallel pairs of two aromatic amino acids bind to the DNA sequence, and polyamide rings are specifically attached to each DNA base.

[0624] Second terminal - regulatory protein binding moiety

[0625] In some embodiments, the second end comprises a protein-binding moiety capable of binding to a regulatory molecule that regulates the expression of a gene having an extended nucleotide repeat sequence.

[0626] In some embodiments, the second end comprises a bromodomain binding moiety.

[0627] In some embodiments, the second end comprises a moiety capable of binding to a bromodomain and an extra terminal domain (BET) family member.

[0628] 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.

[0629] In some embodiments, the protein-binding moiety binds to CBP / p300, PCAF (P300 / CBP-associated factor), CECR2 (candidate cat eye syndrome chromosome region 2), BRPF (bromodomain and PHD finger-containing protein), ATAD2 / ATAD2B (chromatin remodeling protein), TRIM24 (trypatite motif-containing 24), BAZ2 (bromodomain adjacent to zinc finger), TAF1 (TBP-associated factor), BRD7 / 9, BPTF (bromodomain PHD finger transcription factor), SMARCA2 / 4, or PBRM1.

[0630] In some embodiments, the regulatory molecule is CBP / p300.

[0631] In some embodiments, the regulatory molecule is PCAF (P300 / CBP-associated factor).

[0632] In some embodiments, the regulatory molecule is CECR2 (candidate region 2 for cat eye syndrome).

[0633] In some embodiments, the regulatory molecule is BRPF (bromodomain and PHD finger-containing protein).

[0634] In some embodiments, the regulatory molecule is the ATAD2 or ATAD2B chromatin remodeling protein.

[0635] In some embodiments, the regulatory molecule is BAZ2 (a bromodomain adjacent to a zinc finger).

[0636] In some embodiments, the regulatory molecule is TAF1 (TBP-associated factor).

[0637] In some embodiments, the regulatory molecule is TRIM24 (tripatite motif-containing 24).

[0638] In some embodiments, the regulatory molecule is BRD7 / 9.

[0639] In some embodiments, the regulatory molecule is BPTF (bromodomain PHD finger transcription factor).

[0640] In some embodiments, the regulatory molecule is SMARCA2 / 4.

[0641] In some embodiments, the regulatory molecule is PBRM1.

[0642] In some embodiments, the regulatory molecule regulates the rearrangement of histones.

[0643] In some embodiments, the control molecule controls the glycosylation, phosphorylation, alkylation, or acylation of histones.

[0644] In some embodiments, the regulatory molecule is a transcription factor.

[0645] In some embodiments, the regulatory molecule is an RNA polymerase.

[0646] In some embodiments, the regulatory molecule is a moiety that regulates the activity of RNA polymerase.

[0647] In some embodiments, the recruitment moiety binds to the regulatory molecule but does not inhibit the activity of the regulatory molecule. In some embodiments, the recruitment moiety binds to the regulatory molecule and inhibits the activity of the regulatory molecule. In some embodiments, the recruitment moiety binds to the regulatory molecule and increases the activity of the regulatory molecule.

[0648] In some embodiments, the recruitment moiety binds to the active site of the regulatory molecule. In certain embodiments, the recruitment moiety binds to the regulatory site of the regulatory molecule.

[0649] The binding affinity between the regulatory protein and the second end can be adjusted based on the composition of the molecule or the type of protein. In some embodiments, the second end binds to the regulatory molecule with an affinity of about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, or less than about 50 nM. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 500 nM. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 400 nM. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 300 nM. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 250 nM. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 200 nM. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 150 nM. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 100 nM. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 50 nM.

[0650] In some embodiments, the second end comprises a diazine or diazepine ring, wherein the diazine or diazepine ring is fused with a C6-C10 aryl or 5- to 10 heteroaryl ring comprising one or more heteroatoms selected from S, N and O. In some embodiments, the second end comprises an optionally substituted dicyclic or tricyclic structure.

[0651] In some embodiments, the second end has a triazolodiazepine structure. In some embodiments, the second end has a thiazolodiazepine structure.

[0652] In some embodiments, the second end comprises the structure of formula (2-A) or a pharmaceutically acceptable salt thereof:

[0653]

[0654] Chemical formula (2-A),

[0655] In the above formula:

[0656] Ring A is an optionally substituted aryl or an optionally substituted 5 to 6-membered heteroaryl;

[0657] Ring B is an absent or optionally substituted 6-membered monocyclic aryl or heteroaryl;

[0658] D is C or N and;

[0659] E is O or N and;

[0660] Y A is -NH- or -O- and;

[0661] R 5 is hydrogen or C1-C6 alkyl;

[0662] R 6 It is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl;

[0663] R 7 Silver hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Selected from heteroalkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl;

[0664] R 7 -NR 7A R 7B and, here

[0665] R 7A and R 7B Each is independently hydrogen, optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 It is heteroalkyl;

[0666] x1 is an integer between 1 and 6.

[0667] In some embodiments, D is N and E is N. In some embodiments, D is C and E is O.

[0668] In some embodiments, the second end comprises the structure of formula (2-B) or a pharmaceutically acceptable salt thereof:

[0669]

[0670] Chemical formula (2-B),

[0671] In the above formula:

[0672] Ring A is an optionally substituted aryl or an optionally substituted 5 to 6-membered heteroaryl;

[0673] Ring B is an absent or optionally substituted 6-membered monocyclic aryl or heteroaryl;

[0674] Y A is -NH- or -O- and;

[0675] R 5 is hydrogen or C1-C6 alkyl;

[0676] R 6 It is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl;

[0677] R 7 Silver hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Selected from heteroalkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl;

[0678] R 7 -NR 7A R 7B and, here

[0679] R 7A and R 7B Each is independently hydrogen, optionally substituted C1-C 20alkyl, or optionally substituted C1-C 20 It is heteroalkyl;

[0680] x1 is an integer between 1 and 6.

[0681] 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 penteroaryl. 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.

[0682] In some embodiments, the second end comprises the structure of formula (2-C) or a pharmaceutically acceptable salt thereof:

[0683]

[0684] Chemical formula (2-C),

[0685] In the above formula:

[0686] Ring B is an absent or optionally substituted 6-membered monocyclic aryl or heteroaryl;

[0687] Y A is -NH- or -O- and;

[0688] R 5 is hydrogen or C1-C6 alkyl;

[0689] R 6 It is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl;

[0690] R 7 Silver hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20Selected from heteroalkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl;

[0691] R 7 -NR 7A R 7B and, here

[0692] R 7A and R 7B Each is independently hydrogen, optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 It is heteroalkyl;

[0693] R 8 and R 9 Each is independently hydrogen, -C(O)OR 8a , selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl;

[0694] R 8a is hydrogen, C1-C 20 alkyl, or C1-C 20 It is heteroalkyl;

[0695] x1 is an integer between 1 and 6.

[0696] In some embodiments, R 8 and R 9 Each is independently selected from optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments, R 8 and R 9 Each is independently selected from optionally substituted C1-C6 alkyls. In some embodiments, R 8 and R 9 Each is independently methyl, ethyl, or propyl. In some embodiments, R 8 and R 9 Each is independently methyl. In some embodiments, R 8 and R 9 Each is independently ethyl. In some embodiments, R 8 and R9 Each is an independent profile.

[0697] In some embodiments, the second end comprises the structure of formula (2-D) or a pharmaceutically acceptable salt thereof:

[0698]

[0699] Chemical formula (2-D),

[0700] In the above formula:

[0701] Ring B is an absent or optionally substituted 6-membered monocyclic aryl or heteroaryl;

[0702] Y A is -NH- or -O- and;

[0703] R 5 is hydrogen or C1-C6 alkyl;

[0704] R 6 It is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl;

[0705] R 7 Silver hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Selected from heteroalkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl;

[0706] R 7 -NR 7A R 7B and, here

[0707] R 7A and R 7B Each is independently hydrogen, optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 It is heteroalkyl;

[0708] R 10It is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl;

[0709] x1 is an integer between 1 and 6.

[0710] In some embodiments, R 5 is a C1-C6 alkyl. In some embodiments, R 5 is methyl or ethyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is hydrogen.

[0711] In some embodiments, R 7 is selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments, R 7 is a halogen. In some embodiments, R 7 is Br, Cl, or F. In some embodiments, R 7 is Cl. In some embodiments, R 7 is F. In some embodiments, R 7 is Br.

[0712] In some embodiments, R 7 -NR 7A R 7B and, here R 7A and R 7B Each is independently a hydrogen or optionally substituted C1-C6 alkyl.

[0713] In some embodiments, R 10 is selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R 10 is selected from optionally substituted C1-C6 alkyls. In some embodiments, R 10is methyl, ethyl, or propyl. In some embodiments, R 10 is methyl. In some embodiments, R 10 is optionally substituted C 1-6 It is a hydroxyalkyl. In some embodiments, R 10 is -OMe.

[0714] In some embodiments, R 6 is selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R 6 is an optionally substituted C1-C6 alkyl. In some embodiments, R 6 is methyl, ethyl, or propyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is a profile. In some embodiments, R 6 It is hydrogen.

[0715] In some embodiments, Y A is -NH-. In some embodiments, Y A is -O-.

[0716] In some embodiments, Y A is NH, and x1 is 1.

[0717] In some embodiments, x1 is an integer of 1-5, 1-4, 1-3, or 1-2. In some embodiments, x1 is 1. In some embodiments, x1 is 2.

[0718] In some embodiments, ring B is optionally substituted a 6-membered monocyclic aryl or heteroaryl, each of which is optionally substituted with an alkyl, amino, halogen, hydroxy, hydroxyalkyl, or PEG. In some embodiments, ring B is phenyl. In some embodiments, ring B is a 6-membered monocyclic heteroaryl. In some embodiments, ring B is pyridine or pyrimidine.

[0719] In some embodiments, ring B is absent.

[0720] In some embodiments, the second end comprises the structure of formula (2-E) or a pharmaceutically acceptable salt thereof:

[0721] Chemical formula (2-E).

[0722] In some embodiments, the second end comprises the structure of the formula (2-F) or a pharmaceutically acceptable salt thereof:

[0723] Chemical formula (2-F).

[0724] In some embodiments, the second end comprises the structure of the formula (2-G) or a pharmaceutically acceptable salt thereof:

[0725] Chemical formula (2-G).

[0726] In some embodiments, the second end comprises the structure of formula (3-A) or a pharmaceutically acceptable salt thereof:

[0727]

[0728] Chemical formula (3-A),

[0729] In the above formula:

[0730] Y B is -CH2NH-, -CH2O-, -NH-, or -O-;

[0731] R 11A and R 11B Each is independently a hydrogen or optionally substituted C1-C6 alkyl;

[0732] R 12 is hydrogen, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl;

[0733] R 14 and R 15Each is independently hydrogen, a halogen, -CN, -NO2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted C1-C6 hydroxyalkyl;

[0734] R 14 is -NR A R B And;

[0735] R 16 ... optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A , -SO2R A , or -NHSO2R A And;

[0736] R YA is hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted 5-6 member monocyclic aryl or heteroaryl;

[0737] R A and R B Each is independently hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 hydroxyalkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 4 to 6-membered heterocycloalkyl, or an optionally substituted 5 to 6-membered heteroaryl;

[0738] y1 is 1-3 and;

[0739] Here, the attachment to the linker is R 14 or R YA It is in.

[0740] In some embodiments, the second end comprises the structure of formula (3-B) or a pharmaceutically acceptable salt thereof:

[0741]

[0742] Chemical formula (3-B),

[0743] In the above formula:

[0744] Ring C is absent, optionally substituted 5 to 6-membered monocyclic or heteroaryl or 4 to 8-membered heterocycle;

[0745] Y B is -NH-, -CH2NH-, -CH2O-, or -O-;

[0746] R 11A and R 11B Each is independently a hydrogen or optionally substituted C1-C6 alkyl;

[0747] R 12 is hydrogen, optionally substituted C1-C6 alkyl, C(O)R A , or C(O)NR A R B and; here

[0748] R A and R B Each is independently hydrogen, an optionally substituted C1-C6 alkyl, or an optionally substituted C1-C6 heteroalkyl;

[0749] R 13 is hydrogen, a substituted aryl, a substituted heteroaryl, or a substituted oxydibenzene;

[0750] y2 is an integer between 0 and 2.

[0751] In some embodiments, the second end comprises the structure of formula (3-B1) or a pharmaceutically acceptable salt thereof:

[0752]

[0753] Chemical formula (3-B1),

[0754] In the above formula:

[0755] R 11A and R 11B Each is independently a hydrogen or optionally substituted C1-C6 alkyl;

[0756] R 13is hydrogen, a substituted aryl, a substituted heteroaryl, or a substituted oxydibenzene;

[0757] y2 is an integer between 0 and 2.

[0758] In some embodiments, y2 is 0. In some embodiments, y2 is 1. In some embodiments, y2 is 2.

[0759] In some embodiments, R 13 is a substituted aryl or a substituted heteroaryl. In some embodiments, R 13 It is hydrogen.

[0760] In some embodiments, R 13 is substituted oxydibenzene.

[0761] In some embodiments, R 13 silver and, here

[0762] R 14 and R 15 Each is independently hydrogen, a halogen, -CN, -NO2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted C1-C6 hydroxyalkyl;

[0763] R 14 is -NR A R B And;

[0764] R 16 ... optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A , -SO2R A , or -NHSO2R A And;

[0765] R A and R BEach is independently hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 hydroxyalkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 4 to 6-membered heterocycloalkyl, or an optionally substituted 5 to 6-membered heteroaryl;

[0766] y1 is 1-3.

[0767] In some embodiments, the second end comprises the structure of formula (3-C) or a pharmaceutically acceptable salt thereof:

[0768]

[0769] Chemical formula (3-C),

[0770] In the above formula:

[0771] Ring C is absent, optionally substituted 5 to 6-membered monocyclic or heteroaryl or 4 to 8-membered heterocycle;

[0772] Y B is -CH2NH-, -CH2O-, -NH-, or -O-;

[0773] R 11A and R 11B Each is independently a hydrogen or optionally substituted C1-C6 alkyl;

[0774] R 12 is hydrogen, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl;

[0775] R 14 and R 15 Each is independently hydrogen, a halogen, -CN, -NO2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted C1-C6 hydroxyalkyl;

[0776] R 14 is -NR A RB And;

[0777] R 16 ... optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A , -SO2R A , or -NHSO2R A And;

[0778] R A and R B Each is independently hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 hydroxyalkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 4 to 6-membered heterocycloalkyl, or an optionally substituted 5 to 6-membered heteroaryl;

[0779] y1 is an integer between 1 and 3.

[0780] In some embodiments, Y B is -NH-. In some embodiments, Y B is -CH2NH-. In some embodiments, Y B is -CH2O-. In some embodiments, Y B is -O-.

[0781] In some embodiments, ring C is optionally substituted a 5 or 6-membered monocyclic aryl or heteroaryl, each of which is optionally substituted with an alkyl, amino, halogen, hydroxy, hydroxyalkyl, or PEG.

[0782] . 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 pyrazol. In some embodiments, ring C is triazole, pyrrole, imidazole, oxazole, oxadiazole, thiazole, or thiadiazole. In some embodiments, ring C is triazole. In some embodiments, ring C is imidazole or pyrrole. In some embodiments, it is oxazole or oxadiazole. In some embodiments, ring C is thiazole or thiadiazole.

[0783] In some embodiments, ring C is absent.

[0784] In some embodiments, the second end comprises the structure of formula (3-D) or a pharmaceutically acceptable salt thereof:

[0785]

[0786] Chemical formula (3-D),

[0787] In the above formula:

[0788] R 11A and R 11B Each is independently a hydrogen or optionally substituted C1-C6 alkyl;

[0789] R 12 is hydrogen or optionally substituted C1-C6 alkyl;

[0790] R 15 Each is independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl;

[0791] R 16... optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A , -SO2R A , or -NHSO2R A And;

[0792] R A is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl;

[0793] y1 is an integer between 1 and 3.

[0794] In some embodiments, R 11A and R 11B Each is an independently optionally substituted C1-C6 alkyl. In some embodiments, R 11A and R 11B Each is independently methyl, ethyl, propyl, or tert-butyl. In some embodiments, R 11A and R 11B Each is independently methyl. In some embodiments, R 11A and R 11B Each is independently hydrogen.

[0795] In some embodiments, R 11A is a C1-C6 alkyl optionally substituted with a haloalkyl or phosphorus hydroxide. In some embodiments, R 11A is a C1-C6 alkyl substituted with -OP(O)(OH)2. In some embodiments, R 11A is an unsubstituted C1-C6 alkyl. In some embodiments, R 11A is methyl, ethyl, or tert-butyl. In some embodiments, R 11A is methyl. In some embodiments, R11A is hydrogen.

[0796] In some embodiments, R 12 is an optionally substituted C1-C6 alkyl. In some embodiments, R 12 is hydrogen.

[0797] In some embodiments, R 12 is C(O)R A or C(O)NR A R B is. In some embodiments, R 12 is C(O)NR A R B and, here R A and R B Each is independently a hydrogen or optionally substituted C1-C6 alkyl.

[0798] In some embodiments, R 14 and R 15 Each is independently hydrogen, -CN, or -NO2. In some embodiments, R 14 and R 15 Each is independently a halogen or optionally substituted C1-C6 alkyl. In some embodiments, R 14 and R 15 Each is independently Br, Cl, F, methyl, or ethyl. In some embodiments, R 14 and R 15 Each is independently F or methyl.

[0799] In some embodiments, R 16 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 hydroxyalkyl, each of which is optionally substituted with amido, alkyl, alkynyl, azido, amino, halogen, haloalkyl, hydroxy, nitro, oxo (=O), phosphorus hydroxide, or PEG.

[0800] In some embodiments, R 16is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R 16 is a C1-C6 alkyl or C1-C6 heteroalkyl, each of which is optionally substituted with -CN, -NH2, -N3, -OH, CF3, or -OP(O)(OH)2.

[0801] In some embodiments, R 16 -SO2R A and, here R A is a C1-C6 alkyl. In some embodiments, R 16 is -SO2Et. In some embodiments, R 16 It is -SO2Me.

[0802] In some embodiments, R 16 -NHSO2R A and, here R A is a C1-C6 alkyl. In some embodiments, R 16 is -NHSO2Et. In some embodiments, R 16 It is -NHSO2Me.

[0803] In some embodiments, y1 is 1. In some embodiments, y1 is 2. In some embodiments, y1 is 3.

[0804] In some embodiments, the second end comprises the structure of formula (3-E) or a pharmaceutically acceptable salt thereof:

[0805] Chemical formula (3-E).

[0806] In some embodiments, the second end comprises the structure of the formula (3-F) or a pharmaceutically acceptable salt thereof:

[0807] Chemical formula (3-F).

[0808] In some embodiments, the second end comprises the structure of formula (3-G) or formula (3-H), or a pharmaceutically acceptable salt thereof:

[0809] Chemical formula (3-G) or Chemical formula (3-H).

[0810] In some embodiments, the second end comprises the structure of formula (3-I) or a pharmaceutically acceptable salt thereof:

[0811] Chemical formula (3-I).

[0812] In some embodiments, the second end comprises the structure of formula (4-A) or a pharmaceutically acceptable salt thereof:

[0813]

[0814] Chemical formula (4-A),

[0815] In the above formula:

[0816] Ring D is absent, phenyl, or 5 to 6-membered heteroaryl;

[0817] X 9 and X 10 Each is independently C or N, where X 9 or X 10 One of them is N and;

[0818] L 2 is absent, optionally substituted alkylene, -O-, or -NR D -is, and here

[0819] R D is hydrogen or optionally substituted C1-C3 alkyl;

[0820] R 18 is an optionally substituted 5 to 6-membered heteroaryl;

[0821] R 19 is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4 to 7-membered heteroaryl;

[0822] R 20Each is independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl;

[0823] x3 is an integer between 1 and 3;

[0824] y4 is an integer between 1 and 4;

[0825] Here, the attachment to the linker is R 19 or R 20 It is in.

[0826] In some embodiments, attachment to the linker is R 19 It is in.

[0827] In some embodiments, attachment to the linker is R 20 It is in one of them.

[0828] In some embodiments, the second end comprises the structure of formula (4-B) or a pharmaceutically acceptable salt thereof:

[0829]

[0830] Chemical formula (4-B),

[0831] In the above formula:

[0832] Ring D is absent, optionally substituted phenyl, or optionally substituted 5 to 6-membered heteroaryl;

[0833] X 9 and X 10 Each is independently C or N, where X 9 or X 10 One of them is N and;

[0834] L 2 is absent, optionally substituted alkylene, -O-, or -NR D -is, and here

[0835] R D is hydrogen or optionally substituted C1-C3 alkyl;

[0836] R 18is an optionally substituted 5 to 6-membered heteroaryl;

[0837] R 19 is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4 to 7-membered heteroaryl;

[0838] x3 is an integer between 1 and 3.

[0839] In some embodiments, X 9 is N and; X 10 is C. In some embodiments, X 9 is C and; X 10 is N.

[0840] In some embodiments, the second end comprises the structure of the formula (4-C) or a pharmaceutically acceptable salt thereof:

[0841] Chemical formula (4-C).

[0842] 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.

[0843] In some embodiments, R 19 is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 19 is an optionally substituted 4 to 7-membered heteroaryl.

[0844] In some embodiments, the second end comprises the structure of formula (4-D) or a pharmaceutically acceptable salt thereof:

[0845]

[0846] Chemical formula (4-D),

[0847] In the above formula:

[0848] L 2 is an optionally substituted alkylene, -O-, or -NR D -is, and here

[0849] R D is hydrogen or optionally substituted C1-C3 alkyl;

[0850] R 18 is an optionally substituted 5 to 6-membered heteroaryl;

[0851] R 20 is hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl;

[0852] x3 is an integer between 1 and 3;

[0853] y4 is an integer between 1 and 4.

[0854] In some embodiments, L 2 is an optionally substituted alkylene. In some embodiments, L 2 is a C2-C4 alkylene and is optionally substituted with one or more C1-C3 alkyl groups. In some embodiments, L 2 is absent.

[0855] In some embodiments, L 2 is -NR D -is. In some embodiments, L 2 is -NH-.

[0856] In some embodiments, R 18 is an optionally substituted pentagonal heteroaryl. In some embodiments, R 18 is an optionally substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole. In some embodiments, R 18 It is an optionally substituted oxazole.

[0857] In some embodiments, R 20 is a halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl.

[0858] In some embodiments, x3 is 1. In some embodiments, x3 is 2. In some embodiments, x3 is 3.

[0859] 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.

[0860] In some embodiments, the second end comprises the structure of formula (4-E) or formula (4-F), or a pharmaceutically acceptable salt thereof:

[0861]

[0862] Chemical formula (4-E) or Chemical formula (4F).

[0863] In some embodiments, the second end comprises the structure of the formula (4-G) or a pharmaceutically acceptable salt thereof:

[0864] Chemical formula (4-G).

[0865] In some embodiments, the second end comprises the structure of formula (5-A) or a pharmaceutically acceptable salt thereof:

[0866]

[0867] Chemical formula (5-A),

[0868] In the above formula:

[0869] Ring E is absent, optionally substituted phenyl, or optionally substituted 5 to 6-membered heteroaryl;

[0870] X 11 is CH or N;

[0871] L 3 -NR E - or -CR E R E -is, and here

[0872] R E Each is independently a hydrogen or optionally substituted C1-C3 alkyl;

[0873] R 21 is a C1-C6 alkyl or C3-C6 cycloalkyl;

[0874] R 22 is a halogen, CN, NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl.

[0875] In some embodiments, ring E is absent. In some embodiments, ring E is optionally substituted phenyl. In some embodiments, ring E is optionally substituted 5 to 6-membered heteroaryl. In some embodiments, ring E is 5-membered heteroaryl. In some embodiments, ring E is 6-membered heteroaryl.

[0876] In some embodiments, X 11 is CH and L 3 -NR E -is. In some embodiments, X 11 is N and L 3 -CR E R E -am.

[0877] In some embodiments, R 21 is a C1-C6 alkyl. In some embodiments, R 21 It is methyl.

[0878] In some embodiments, R 22 is a halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R 22 is CN, F, Cl, Br, or methyl.

[0879] In some embodiments, the second end comprises the structure of formula (5-B) or formula (5-C), or a pharmaceutically acceptable salt thereof:

[0880] Chemical formula (5-B) or Chemical formula (5-C).

[0881] In some embodiments, the second end comprises the structure of formula (6-A) or a pharmaceutically acceptable salt thereof:

[0882]

[0883] Chemical formula (6-A),

[0884] In the above formula:

[0885] Ring G is an absent or optionally substituted C3-C6 cycloalkyl or an optionally substituted 4 to 6-membered heterocycloalkyl;

[0886] L 6 is -O- (optionally substituted alkylene);

[0887] R 28 is an optionally substituted 5 to 6-membered heteroaryl;

[0888] R 29 is an optionally substituted C1-C6 alkyl-(C6-C 10 aryl) or optionally substituted C1-C6 alkyl-(6 to 10-membered heteroaryl);

[0889] R 30 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 hydroxyalkyl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted 4 to 6 heterocycloalkyl.

[0890] In some embodiments, the second end comprises the structure of formula (7-A) or a pharmaceutically acceptable salt thereof:

[0891]

[0892] Chemical formula (7-A),

[0893] In the above formula:

[0894] A 3is -O-, -NH-, or -CH2-;

[0895] Z 2 is CH or N;

[0896] W is O or S and;

[0897] R 31 Each is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl;

[0898] 2 Rs 31 They form a selectively substituted C5-C8 cycloalkyl or a selectively substituted 5 to 8 heterocycloalkyl together with the atoms to which they are attached;

[0899] R 32 is hydrogen or optionally substituted C1-C 10 It is alkyl;

[0900] R 32a is hydrogen or optionally substituted C1-C 10 It is alkyl;

[0901] R 33 Silver hydrogen, halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl;

[0902] q6 is 0-4 and;

[0903] Here, the chemical formula (7-A) is R 32a or R 31 It is attached to the linker in one of them.

[0904] In some embodiments, Z 2 is CH. In some embodiments, Z 2 is N.

[0905] In some embodiments, the second end comprises the structure of formula (7-B) or a pharmaceutically acceptable salt thereof:

[0906]

[0907] Chemical formula (7-B),

[0908] In the above formula:

[0909] Ring F is an optionally substituted 5 to 6-membered heteroaryl;

[0910] A 3 is -O-, -NH-, or -CH2-;

[0911] Z 3 is CH or N;

[0912] W is O or S and;

[0913] R 31 Each consists of hydrogen, halogen, -OH, -CN, -NO2, -NH2, and optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C8-cycloalkyl, or optionally substituted 3- to 8-membered heterocycloalkyl;

[0914] 2 Rs 31 They form a selectively substituted C5-C8 cycloalkyl or a selectively substituted 5 to 8 heterocycloalkyl together with the atoms to which they are attached;

[0915] R 32 is hydrogen or optionally substituted C1-C 10 It is alkyl;

[0916] q6 is 1-4.

[0917] In some embodiments, A 3 is -O-. In some embodiments, A 3 is -NH-. In some embodiments, A 3 is -CH2-.

[0918] In some embodiments, Z 3 is CH. In some embodiments, Z 3 is N.

[0919] In some embodiments, W is O. In some embodiments, W is S.

[0920] In some embodiments, ring F is an optionally substituted 5-membered heteroaryl. In some embodiments, ring F is an optionally substituted 6-membered heteroaryl.

[0921] In some embodiments, R 31 Each is an independently and selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 31 Each is independently an optionally substituted C3-C8-cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R 31 Each is independently hydrogen, halogen, -OH, -CN, -NO2, or -NH2. In some embodiments, R 31 Each is hydrogen.

[0922] In some embodiments, R 32 is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 32 is methyl. In some embodiments, R 32 is hydrogen.

[0923] In some embodiments, R 32a is an optionally substituted C1-C 10It is an alkyl. In some embodiments, R 32a is hydrogen.

[0924] In some embodiments, R 33 is hydrogen, halogen, -OH, -CN, -NO2, or -NH2. In some embodiments, R 33 is an optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl.

[0925] In some embodiments, the formula (7-A) is R 32a It is attached to the linker at. In some embodiments, the formula (7-A) is R 31 It is attached to the linker in one of them.

[0926] In some embodiments, the second end comprises the structure of formula (7-C) or a pharmaceutically acceptable salt thereof:

[0927] Chemical formula (7-C).

[0928] In some embodiments, the second end comprises the structure of formula (7-D) or a pharmaceutically acceptable salt thereof:

[0929] Chemical formula (7-D).

[0930] In some embodiments, the second end comprises the structure of formula (7-E) or a pharmaceutically acceptable salt thereof:

[0931] Chemical formula (7-E).

[0932] In some embodiments, the second end comprises the structure of formula (8-A) or a pharmaceutically acceptable salt thereof:

[0933]

[0934] Chemical formula (8-A),

[0935] In the above formula:

[0936] Ring H is an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl;

[0937] Or ring H is And;

[0938] Z A is an absent or optionally substituted phenylformamide;

[0939] X 12 is CH or N;

[0940] R 34 is an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl;

[0941] R 34A is hydrogen, a halogen, or an optionally substituted C1-C3 alkyl;

[0942] R 35 Each is independently a halogen, optionally substituted C1-C 10 It is an alkyl, or optionally substituted 5 to 6-membered heteroaryl;

[0943] Here, the attachment to the linker is R 35 , Z A , or is in ring H.

[0944] In some embodiments, ring H is optionally substituted phenyl. In some embodiments, ring H is optionally substituted 6-membered heteroaryl.

[0945] In some embodiments, ring H is am.

[0946] In some embodiments, Z A is absent. In some embodiments, Z A is an optionally substituted phenylformamide. In some embodiments, Z A is -C(O)NH-phenyl.

[0947] In some embodiments, X 12 is CH. In some embodiments, X 12 is N.

[0948] In some embodiments, R34 is an optionally substituted phenyl. In some embodiments, R 34 is an optionally substituted 6-membered heteroaryl.

[0949] In some embodiments, R 34A is hydrogen or a halogen. In some embodiments, R 34A is an optionally substituted C1-C3 alkyl. In some embodiments, R 34A is methyl.

[0950] In some embodiments, the formula (8-A) is R 35 It is attached to the linker at. In some embodiments, the formula (8-A) is Z A It is attached to the linker. In some embodiments, formula (8-A) is attached to the linker in ring H.

[0951] In some embodiments, the second end comprises the structure of formula (8-B) or formula (8-C), or a pharmaceutically acceptable salt thereof:

[0952]

[0953] Chemical formula (8-B) or Chemical formula (8-C).

[0954] In some embodiments, the second end comprises the structure of formula (8-D) or a pharmaceutically acceptable salt thereof:

[0955] Chemical formula (8-D).

[0956] In some embodiments, the second end comprises the structure of formula (9-A) or a pharmaceutically acceptable salt thereof:

[0957] Chemical formula (9-A).

[0958] In some embodiments, the second end comprises the structure of formula (10-A) or formula (10-B), or a pharmaceutically acceptable salt thereof:

[0959] Chemical formula (10-A) or Chemical formula (10-B).

[0960] In some embodiments, the second end comprises the structure of formula (11-A) or a pharmaceutically acceptable salt thereof:

[0961] Chemical formula (11-A).

[0962] In some embodiments, the second end comprises the structure of formula (12-A) or a pharmaceutically acceptable salt thereof:

[0963]

[0964] Chemical formula (12-A),

[0965] In the above formula:

[0966] A 4 is -CR 40 R 40 - or -NR 40 -is; here R 40 Each is independently hydrogen or optionally substituted C1-C 10 It is alkyl;

[0967] R 36 is an optionally substituted 5 to 6-membered heteroaryl;

[0968] R 37 Each is independently hydrogen, a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl;

[0969] R 38 is an optionally substituted C1-C 10 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl;

[0970] R 39 is hydrogen, halogen, -OH, -CN, -NO2, -NH2, oxo (=O), =S, C1-C 10 haloalkyl, or C1-C 10 It is hydroxyalkyl;

[0971] p 11 is 1-4 and;

[0972] q1 and q2 are each independently 0-2;

[0973] Here, the linker is R 38 or R 40 It is attached to the chemical formula (12-A) in any one of them.

[0974] In some embodiments, R 36 is an optionally substituted pentagonal heteroaryl. In some embodiments, R 36 is an optionally substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole. In some embodiments, R 36 It is an optionally substituted oxazole.

[0975] In some embodiments, R 37 Each is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl. In some embodiments, R 37 Each is independently a halogen.

[0976] In some embodiments, R 38 is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 38 is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R 38 It is a 3 to 8-membered heterocycloalkyl.

[0977] In some embodiments, R 39 is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C 10 haloalkyl, or C1-C 10 It is a hydroxyalkyl. In some embodiments, R 39 is oxo or =S. In some embodiments, R 39 is an iodine. In some embodiments, R 39 is =S.

[0978] In some embodiments, A 4is -NR 40 is. In some embodiments, A 4 is -NH. In some embodiments, A 4 is -NCH3. In some embodiments, A 4 is -CR 40 R 40 is. In some embodiments, A 4 is -CH2-.

[0979] In some embodiments, R 40 Each is an independently and selectively substituted C1-C 10 It is an alkyl. In some embodiments, R 40 Each is independently hydrogen.

[0980] In some embodiments, p 11 is 3 or 4. In some embodiments, p 11 is 2. In some embodiments, p 11 It is 1.

[0981] In some embodiments, q1 is 1 and q2 is 1. In some embodiments, q1 is 2 and q2 is 0.

[0982] In some embodiments, the linker is R 38 It is attached to the formula (12-A) through. In some embodiments, the linker is R 40 It is attached to the chemical formula (12-A) through.

[0983] In some embodiments, the second end comprises formula (12-B) or formula (12-C), or a pharmaceutically acceptable salt thereof:

[0984] Chemical formula (12-B) or Chemical formula (12-C).

[0985] In some embodiments, the second end comprises formula (12-D) or formula (12-E), or a pharmaceutically acceptable salt thereof:

[0986] Chemical formula (12-D) or Chemical formula (12-E).

[0987] In some embodiments, the second end comprises the structure of formula (13-A) or a pharmaceutically acceptable salt thereof:

[0988]

[0989] Chemical formula (13-A),

[0990] In the above formula:

[0991] Ring J is an absent or optionally substituted 5 to 6-membered heteroaryl;

[0992] R 41 -C(O)R is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, -C(O)R 41a , -C(O)-, or -C(O)NR 41a R 41b and, here

[0993] R 41a and R 41b Each is an independently and selectively substituted C1-C 10 It is an alkyl or optionally substituted C3-C8 cycloalkyl;

[0994] R 42 is an optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 It is a haloalkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 3 to 8-membered heterocycloalkyl;

[0995] R 43 Silver hydrogen or optionally substituted C1-C 10 It is alkyl;

[0996] R 44 Each is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C10 Alkynyl, optionally substituted C3-C8-cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl;

[0997] R 43 and R 44 One of them forms a 5 to 8-membered heterocycloalkyl group that is selectively substituted together with the atoms to which they are attached;

[0998] p 12 is 1-4 and;

[0999] q3 is 0 or 1, and;

[1000] Here, the chemical formula (13-A) is the ring J, R 41 , or R 42 It connects to the linker.

[1001] In some embodiments, R 41 is an optionally substituted C1-C6 alkyl or an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 41 -C(O)R 41a is. In some embodiments, R 41 is -C(O)CH3 or -C(O)CH2CH3. In some embodiments, R 41 -C(O)-NR 41a R 41b am.

[1002] In some embodiments, R 41a is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 41a is an optionally substituted C3-C8 cycloalkyl.

[1003] In some embodiments, R 41b is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 41b is an optionally substituted C3-C8 cycloalkyl.

[1004] In some embodiments, R 42 is an optionally substituted C1-C 10 alkyl or optionally substituted C1-C10 It is a haloalkyl. In some embodiments, R 42 is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl. In some embodiments, R 42 is an optionally substituted 3- to 8-membered heterocycloalkyl ring.

[1005] In some embodiments, R 43 is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 43 It is hydrogen.

[1006] In some embodiments, R 44 Each is independently a halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 It is an alkynyl, an optionally substituted C3-C8-cycloalkyl, or an optionally substituted 3 to 8-membered heterocycle. In some embodiments, R 44 Each is independently a halogen or C1-C 10 It is a haloalkyl.

[1007] In some embodiments, R 43 and R 44 One of them forms a 5 to 8-membered heterocycloalkyl group that is optionally substituted together with the atom to which they are attached. In some embodiments, R 43 and R 44 One of them forms a 5, 6, 7, or 8-membered heterocycloalkyl group with the atom to which they are attached.

[1008] In some embodiments, p 12 is 3 or 4. In some embodiments, p 12 is 2. In some embodiments, p 12 is 1.

[1009] In some embodiments, q3 is 1. In some embodiments, q3 is 0.

[1010] In some embodiments, ring J is an optionally substituted pentagonal heteroaryl. In some embodiments, ring J is absent.

[1011] In some embodiments, the formula (13-A) is connected to the linker in ring J. In some embodiments, the formula (13-A) is R 41 It is connected to the linker at. In some embodiments, the formula (13-A) is R 42 It connects to the linker.

[1012] In some embodiments, the second end comprises the structure of formula (13-B) or a pharmaceutically acceptable salt thereof:

[1013] Chemical formula (13-B).

[1014] In some embodiments, the second end comprises the structure of formula (13-C1) or formula (13-C2), or a pharmaceutically acceptable salt thereof:

[1015] Chemical formula (13-C1) or

[1016] Chemical formula (13-C2).

[1017] In some embodiments, the second end comprises the structure of formula (13-D1) or formula (13-D2), or a pharmaceutically acceptable salt thereof:

[1018] Chemical formula (13-D1) or

[1019] Chemical formula (13-D2).

[1020] In some embodiments, the second end comprises the structure of formula (13-E) or a pharmaceutically acceptable salt thereof:

[1021] Chemical formula (13-E).

[1022] In some embodiments, the second end comprises the structure of formula (14-A) or a pharmaceutically acceptable salt thereof:

[1023]

[1024] Chemical formula (14-A),

[1025] In the above formula:

[1026] Ring K is a 5 to 6-membered heterocycloalkyl;

[1027] A 5 is absent, CH2, -NH-, or -O-;

[1028] L 4 is an alkylene or heteroalkylene;

[1029] R 45 Each is independently a halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 Heteroalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 It is an alkynyl, an optionally substituted C3-C8-cycloalkyl, or an optionally substituted 3 to 8-membered heterocycloalkyl;

[1030] R 46 Each is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 It is an alkynyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 3 to 8-membered heterocycloalkyl;

[1031] R 47 is an optionally substituted C1-C 10 Alkyl, -C(O)R 47a , or -C(O)-NR 47a R 47b and, here

[1032] R 47a and R 47b Each is an independently and selectively substituted C1-C 10 It is an alkyl or optionally substituted C3-C8 cycloalkyl;

[1033] q4 is 2-3 and;

[1034] q5 is 0-2 and;

[1035] Here, the chemical formula (14-A) is formed through ring K or R 45 It connects to the linker through one of them.

[1036] In some embodiments, A 5 is absent. In some embodiments, A 5 is -NH- or -O-. In some embodiments, A 5 is -NH-. In some embodiments, A 5 is -O-.

[1037] In some embodiments, L 4 is an alkylene. In some embodiments, in some embodiments, L 4 is a C1-C5 alkylene.

[1038] In some embodiments, L 4 is a heteroalkylene. In some embodiments, L 4 is a C1-C4 heteroalkylene. In some embodiments, L 4 is -O-CH2- or -O-CH2CH2-.

[1039] In some embodiments, R 45 Each is independently a halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10Haloalkyl, optionally substituted C1-C 10 Heteroalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 It is alkynyl. In some embodiments, R 45 Each is an independently and selectively substituted C1-C 10 alkyl or optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 45 Each is independently C1-C 10 It is a hydroxyalkyl. In some embodiments, R 45 Each is independently -OCH3 or -OCH2CH3.

[1040] In some embodiments, R 46 Each is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 46 Each is independently hydrogen.

[1041] In some embodiments, R 47 is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 47 -C(O)R 47a is. In some embodiments, R 47 is -C(O)CH3 or -C(O)CH2CH3. In some embodiments, -C(O)-NR 47a R 47b am.

[1042] In some embodiments, R 47a is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 47a is an optionally substituted C3-C8 cycloalkyl.

[1043] In some embodiments, R 47b is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 47b is an optionally substituted C3-C8 cycloalkyl.

[1044] In some embodiments, ring K is a hexacyclic heterocycloalkyl.

[1045] In some embodiments, q4 is 3. In some embodiments, q4 is 2.

[1046] In some embodiments, q5 is 2. In some embodiments, q5 is 1. In some embodiments, q5 is 0.

[1047] In some embodiments, the formula (14-A) is connected to a linker through ring K. In some embodiments, the formula (14-A) is R 45 It connects to the linker through one of them.

[1048] In some embodiments, the second end comprises the structure of formula (14-B) or formula (14-C), or a pharmaceutically acceptable salt thereof:

[1049] Chemical formula (14-B) or Chemical formula (14-C).

[1050] In some embodiments, the second end comprises the structure of formula (15-A) or a pharmaceutically acceptable salt thereof:

[1051]

[1052] Chemical formula (15-A),

[1053] In the above formula:

[1054] The ring L is an aryl or heteroaryl;

[1055] R 48 Each is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C 10 Alkyl, C1-C 10 haloalkyl, or C1-C 10 It is hydroxyalkyl;

[1056] R 49 and R 50 Each is independently hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 It is alkinyl;

[1057] R 51 Silver hydrogen, halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 It is alkinyl;

[1058] R 52 is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl;

[1059] p7 is 1-4.

[1060] In some embodiments, ring L is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, ring L is a heteroaryl. In some embodiments, ring L is a dicyclic heteroaryl comprising one, two, or three heteroatoms selected from N and O.

[1061] In some embodiments, the second end comprises the structure of formula (15-B) or a pharmaceutically acceptable salt thereof:

[1062]

[1063] Chemical formula (15-B),

[1064] In the above formula:

[1065] R 48 Each is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C 10 Alkyl, C1-C 10 haloalkyl, or C1-C 10 It is hydroxyalkyl;

[1066] R 49 and R 50 Each is independently hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 It is alkinyl;

[1067] R 51 Silver hydrogen, halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 It is alkinyl;

[1068] p7 is 1-4.

[1069] In some embodiments, the second end comprises the structure of formula (15-C) or a pharmaceutically acceptable salt thereof:

[1070]

[1071] Chemical formula (15-C),

[1072] In the above formula:

[1073] X is CR 48 or N and;

[1074] R 48 Each is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C 10 Alkyl, C1-C 10haloalkyl, or C1-C 10 It is hydroxyalkyl;

[1075] R 49 and R 50 Each is independently hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 It is alkinyl;

[1076] R 51 Silver hydrogen, halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 It is alkinyl;

[1077] R 53 Silver hydrogen or optionally substituted C1-C 10 It is alkyl;

[1078] p7 is 1-3.

[1079] In some embodiments, R 48 Silver, hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C 10 Alkyl, C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl.

[1080] In some embodiments, R 49 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 It is alkynyl. In some embodiments, R 49 is an optionally substituted C1-C10 It is an alkyl. In some embodiments, R 49 is methyl, ethyl, iso-propyl, or tert-butyl. In some embodiments, R 49 is hydrogen.

[1081] In some embodiments, R 50 Silver hydrogen, selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 It is alkynyl. In some embodiments, R 50 is an optionally substituted C1-C 10 alkyl or optionally substituted C2-C 10 It is an alkenyl. In some embodiments, R 50 It is hydrogen.

[1082] In some embodiments, R 51 Silver hydrogen, halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 It is alkinil.

[1083] In some embodiments, R 52 is hydrogen, halogen, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 52 is hydrogen.

[1084] In some embodiments, R 53 Silver hydrogen or optionally substituted C1-C 10 It is an alkyl. In some embodiments, R53 is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 53 is methyl, ethyl, iso-propyl, or tert-butyl. In some embodiments, R 53 It is hydrogen.

[1085] In some embodiments, p7 is 4. In some embodiments, p7 is 3. In some embodiments, p7 is 2. In some embodiments, p7 is 1.

[1086] In some embodiments, the second end comprises the structure of formula (15-D1), (15-D2), or (15-D3), or a pharmaceutically acceptable salt thereof:

[1087] Chemical formula (15-D1), Chemical formula (15-D2), or

[1088] Chemical formula (15-D3).

[1089] In some embodiments, the second end comprises the structure of formula (15-E1), (15-E2), or (15-E3), or a pharmaceutically acceptable salt thereof:

[1090] Chemical formula (15-E1) or Chemical formula (15-E2), or

[1091] Chemical formula (15-E3).

[1092] In some embodiments, the second end comprises the structure of formula (16-A) or a pharmaceutically acceptable salt thereof:

[1093]

[1094] Chemical formula (16-A),

[1095] In the above formula:

[1096] B 5 is -O-, -NH-, or S;

[1097] B6 is N or CH;

[1098] R 54 is an optionally substituted aryl or an optionally substituted heteroaryl;

[1099] R 55 Each is independently a halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl;

[1100] R 56 Silver hydrogen, selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl;

[1101] R 57 Silver halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl;

[1102] p9 is 1-3 and;

[1103] q7 is 0-2.

[1104] In some embodiments, B 5 is -O- or -S-. In some embodiments, B 5 is -O-. In some embodiments, B 5 is -S-.

[1105] In some embodiments, B 6 is N. In some embodiments, B 6 It is CH.

[1106] In some embodiments, R 54is an optionally substituted aryl. In some embodiments, R 54 is optionally one or more halogens, -CN, -NH2, -OH, C1-C 10 Alkyl, C1-C 10 haloalkyl, or C1-C 10 It is a phenyl substituted with a hydroxyalkyl group.

[1107] In some embodiments, R 55 Each is independently a halogen, -OH, -CN, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl.

[1108] In some embodiments, R 56 is an optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 56 is an optionally substituted C1-C 10 It is an alkyl.

[1109] In some embodiments, R 57 Silver halogens, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 It is an alkyl.

[1110] In some embodiments, p9 is 3. In some embodiments, p9 is 2. In some embodiments, p9 is 1.

[1111] In some embodiments, q7 is 2. In some embodiments, q7 is 1. In some embodiments, q7 is 0.

[1112] In some embodiments, the second end comprises the structure of formula (16-B) or a pharmaceutically acceptable salt thereof:

[1113] Chemical formula (16-B).

[1114] In some embodiments, the second end comprises the structure of formula (17-A) or a pharmaceutically acceptable salt thereof:

[1115]

[1116] Chemical formula (17-A),

[1117] In the above formula:

[1118] Ring M is an optionally substituted aryl or an optionally substituted heteroaryl;

[1119] The ring N is absent or is a 4 to 8-membered heterocycloalkyl;

[1120] A 6 is -O-, -NH-, or -CH2-;

[1121] R 58 Each is independently a halogen, -OH, -CN, -NO2, -NH2, C1-C 10 Alkyl, C1-C 10 haloalkyl, or C1-C 10 It is hydroxyalkyl;

[1122] R 59 is hydrogen, -OH, -NH2, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 hydroxyalkyl, or -NH-C1-C 10 It is alkyl;

[1123] R 60 Silver hydrogen or optionally substituted C1-C 10 It is alkyl;

[1124] p 10 is 1-4 and;

[1125] Here, the chemical formula (17-A) is R 59 It connects to the linker through.

[1126] In some embodiments, ring M is an aryl and optionally one or more halogens, CN, NH2, OH, C1-C 10 Alkyl, C1-C 10 haloalkyl, or C1-C10 It is substituted with a hydroxyalkyl group. In some embodiments, ring M is phenyl. In some embodiments, ring M is optionally a substituted hexavalent heteroaryl and optionally one or more halogens, CN, NH2, OH, C1-C 10 Alkyl, C1-C 10 haloalkyl, or C1-C 10 It is substituted with a hydroxyalkyl group. In some embodiments, ring M is optionally substituted pyridine.

[1127] In some embodiments, ring N is a 4 to 8-membered heterocycloalkyl. In some embodiments, ring N is a 4-membered heterocycloalkyl. In some embodiments, ring N is a 5-membered heterocycloalkyl. In some embodiments, ring N is a 6-membered heterocycloalkyl. In some embodiments, ring N is absent.

[1128] In some embodiments, A 6 is -O- or -NH-. In some embodiments, A 6 is -CH2-.

[1129] In some embodiments, R 58 Each is independently -OH, -NH2, C1-C 10 Alkyl, C1-C 10 haloalkyl, or C1-C 10 It is a hydroxyalkyl. In some embodiments, R 58 Each is independently C1-C 10 alkyl, or C1-C 10 It is a hydroxyalkyl. In some embodiments, R 58 Each is independently C1-C 10 It is a hydroxyalkyl.

[1130] In some embodiments, R 59 -OH, -NH2, C1-C 10 hydroxyalkyl, or -NH-C1-C 10 It is an alkyl. In some embodiments, R 59 is hydrogen.

[1131] In some embodiments, R60 is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 60 is methyl. In some embodiments, R 60 It is a halogen.

[1132] In some embodiments, p 10 is 3 or 4. In some embodiments, p 10 is 2. In some embodiments, p 10 It is 1.

[1133] In some embodiments, the second end comprises the structure of formula (17-B) or formula (17-C), or a pharmaceutically acceptable salt thereof:

[1134] Chemical formula (17-B) or Chemical formula (17-C).

[1135] In some embodiments, the second end comprises the structure of formula (18-A) or a pharmaceutically acceptable salt thereof:

[1136]

[1137] Chemical formula (18-A),

[1138] In the above formula:

[1139] B 7 is N or CH;

[1140] R 67 Silver hydrogen, halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl;

[1141] R 68 and R 69 Each is an independently selectively substituted 5-membered heteroaryl;

[1142] x5 and x6 are each independently 0-4.

[1143] In some embodiments, B 7 is N. In some embodiments, B 7 It is CH.

[1144] In some embodiments, R 67 Silver halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 67 It is a halogen, -OH, -CN, -NO2, -NH2, or -CH3.

[1145] In some embodiments, R 68 is an optionally substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole. In some embodiments, R 68 is pyrrole or pyrazole. In some embodiments, R 68 is pyrrole. In some embodiments, R 68 It is pyrazol.

[1146] In some embodiments, R 69 is an optionally substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole. In some embodiments, R 69 is pyrrole or pyrazole. In some embodiments, R 69 is pyrrole. In some embodiments, R 69 is pyrazol.

[1147] In some embodiments, x5 is 2 or 3. In some embodiments, x5 is 1. In some embodiments, x5 is 0.

[1148] In some embodiments, x6 is 3. In some embodiments, x6 is 2. In some embodiments, x6 is 1. In some embodiments, x6 is 0.

[1149] In some embodiments, the second end comprises the formula (18-B) or a pharmaceutically acceptable salt thereof:

[1150] Chemical formula (18-B).

[1151] In some embodiments, the second end comprises the formula (19-A) or a pharmaceutically acceptable salt thereof:

[1152] Chemical formula (19-A).

[1153] In some embodiments, the second end comprises the structure of formula (20-A) or a pharmaceutically acceptable salt thereof:

[1154]

[1155] Chemical formula (20-A),

[1156] In the above formula:

[1157] A 7 is -NHC(O)- or -NHS(O)2- and;

[1158] A 8 is -O- or -NH- and;

[1159] R 61 Each is independently hydrogen or C1-C6 alkyl;

[1160] R 62 Each is independently a halogen, -CN, -NO2, -OH, -OR 62a , -NR 62a R 62b , -C(O)R 62a , optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl; here

[1161] R 62a and R 62b Each is independently hydrogen or C1-C 10It is an alkyl, and here

[1162] R 63 Each independently -OR 63a , -NR 63a R 63b , optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl; here

[1163] R 63a and R 63b Each independently hydrogen, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 haloalkyl, or C1-C 10 It is hydroxyalkyl;

[1164] p 13 is 1-3 and;

[1165] p 14 is 1-3 and;

[1166] Here, the linker is R 62 One of or R 63 It is connected to the chemical formula (20-A) through one of them.

[1167] In some embodiments, A 7 is -NHC(O)-. In some embodiments, A 7 It is -NHS(O)2-.

[1168] In some embodiments, A 8 is -O-. In some embodiments, A 8 It is -NH-.

[1169] In some embodiments, R 61 Each is independently a C1-C6 alkyl. In some embodiments, R 61 Each is methyl. In some embodiments, R 61 Each is hydrogen.

[1170] In some embodiments, R 62Each is an independently and selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 62 Each is an independently and selectively substituted C1-C 10 It is an alkyl. In some embodiments, R 62 Each is an independently and selectively substituted C1-C 10 It is a haloalkyl. In some embodiments, R 62 Each is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 62 Each is an independently and selectively substituted C1-C 10 It is a hydroxyalkyl.

[1171] In some embodiments, R 63 Each is an independently and selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 63 Each is an independently and selectively substituted C1-C 10 It is an alkyl. In some embodiments, R 66 Each is an independently and selectively substituted C1-C 10 It is a haloalkyl. In some embodiments, R 63 Each is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 63 Each is an independently and selectively substituted C1-C 10 It is a hydroxyalkyl.

[1172] In some embodiments, p 13 is 1. In some embodiments, p 13is 2. In some embodiments, p 13 It is 3.

[1173] In some embodiments, p 14 is 1. In some embodiments, p 14 is 2. In some embodiments, p 14 is 3.

[1174] In some embodiments, the linker is R 62 It is connected to the chemical formula (20-A) through one of them. In some embodiments, the linker is R 63 It is connected to the chemical formula (20-A) through one of them.

[1175] In some embodiments, the second end comprises the structure of formula (20-B) or formula (20-C), or a pharmaceutically acceptable salt thereof:

[1176] Chemical formula (20-B) or

[1177] Chemical formula (20-C).

[1178] In some embodiments, the second end comprises the structure of formula (21-A) or a pharmaceutically acceptable salt thereof:

[1179]

[1180] Chemical formula (21-A),

[1181] In the above formula:

[1182] Ring Q is a C3-C8 cycloalkyl or a 4 to 8-membered heterocycloalkyl;

[1183] A 9 is -O-, -NH-, or -NHC(O)- and;

[1184] R 64 Each is independently hydrogen or C1-C6 alkyl;

[1185] R 65 Each is independently a halogen, -CN, -NO2, -OH, -OR 62a , -NR 62a R62b , optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl; here

[1186] R 62a and R 62b Each is independently hydrogen or C1-C 10 It is alkyl;

[1187] R 66 Each is independently a halogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl;

[1188] p 15 is 0-3 and;

[1189] p 16 is 1-3 and;

[1190] Here, the chemical formula (21-A) is R 65 One of or R 66 It connects to the linker in one of them.

[1191] In some embodiments, A 9 is -O-. In some embodiments, A 9 is -NH-. In some embodiments, A 9 is -NHC(O)-.

[1192] In some embodiments, ring Q is a C3-C8 cycloalkyl. In some embodiments, ring Q is a 4 to 8-membered heterocycloalkyl.

[1193] In some embodiments, R 64 Each is independently a C1-C6 alkyl. In some embodiments, R 64 Each is methyl. In some embodiments, R 64 Each is hydrogen.

[1194] In some embodiments, R 65 Each is an independently and selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 65 Each is an independently and selectively substituted C1-C 10 It is an alkyl. In some embodiments, R 65 Each is an independently and selectively substituted C1-C 10 It is a haloalkyl. In some embodiments, R 65 Each is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 65 Each is an independently and selectively substituted C1-C 10 It is a hydroxyalkyl.

[1195] In some embodiments, R 66 Each is an independently and selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is a hydroxyalkyl. In some embodiments, R 66 Each is an independently and selectively substituted C1-C 10 It is an alkyl. In some embodiments, R 66 Each is an independently and selectively substituted C1-C 10 It is a haloalkyl. In some embodiments, R 66 Each is an independently and selectively substituted C1-C 10 It is a heteroalkyl. In some embodiments, R 66 Each is an independently and selectively substituted C1-C 10 It is a hydroxyalkyl.

[1196] In some embodiments, p15 is 0. In some embodiments, p 15 is 1. In some embodiments, p 15 is 2. In some embodiments, p 15 is 3.

[1197] In some embodiments, p 16 is 1. In some embodiments, p 16 is 2. In some embodiments, p 16 It is 3.

[1198] In some embodiments, the formula (21-A) is R 65 It is connected to a linker in one of them. In some embodiments, the formula (21-A) is R 66 It connects to the linker in one of them.

[1199] In some embodiments, the second end comprises the structure of formula (21-B) or a pharmaceutically acceptable salt thereof:

[1200] Chemical formula (21-B).

[1201] In some embodiments, the second end comprises the structure of formula (22-A) or a pharmaceutically acceptable salt thereof:

[1202]

[1203] Chemical formula (22-A),

[1204] In the above formula:

[1205] R 67 It is hydrogen, -NH2, or -NHSO2CH3;

[1206] R 68 and R 69 Each is independently a halogen, -CN, -NO2, -OH, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl;

[1207] R 70 -S(O)R70a or -S(O)2R 70a and, here R 70a is hydrogen or C1-C 10 It is alkyl;

[1208] R 71 Silver, hydrogen, or C1-C 10 It is alkyl;

[1209] Here, the chemical formula (22-A) is R 67 or R 71 It is attached to the linker.

[1210] In some embodiments, R 67 is hydrogen. In some embodiments, R 67 It is -NH2 or -NHSO2CH3.

[1211] In some embodiments, R 68 and R 69 Each is an independently and selectively substituted C1-C 10 It is an alkyl. In some embodiments, R 68 and R 69 Each is methyl.

[1212] In some embodiments, R 70 -S(O)2R 70a is. In some embodiments, R 70 It is -S(O)2CH3.

[1213] In some embodiments, the formula (22-A) is R 67 It is attached to the linker at. In some embodiments, the formula (22-A) is R 71 It is attached to the linker.

[1214] In some embodiments, the second end comprises the structure of formula (22-B) or formula (22-C), or a pharmaceutically acceptable salt thereof:

[1215] Chemical formula (22-B) or Chemical formula (22-C).

[1216] In some embodiments, the second end comprises the structure of formula (23-A) or a pharmaceutically acceptable salt thereof:

[1217]

[1218] Chemical formula (23-A)

[1219] In the above formula:

[1220] B 9 -CH-CR B9 -, -N-, or NR B10 And;

[1221] B 10 is -N- or NR B10 and, here

[1222] R B9 is hydrogen or halogen; and R B10 is hydrogen;

[1223] R 72 is a halogen, -CN, -NO2, -OH, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl;

[1224] R 73 It is hydrogen;

[1225] Here, the chemical formula (23-A) is R B9 , R B10 , or R 73 It is attached to the linker.

[1226] In some embodiments, B 9 -CH-CR B9 - and, B 10 is -N-. In some embodiments, B 9 is -N- and B 10 NR B10 is. In some embodiments, B 9 is NR B10 and, B 10 is -N-.

[1227] In some embodiments, R72 is an optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 72 is methyl.

[1228] In some embodiments, the formula (23-A) is R B9 or R B10 It is attached to the linker at. In some embodiments, the formula (23-A) is R 73 It is attached to the linker.

[1229] In some embodiments, the second end comprises the structure of formula (23-B) or formula (23-C), or a pharmaceutically acceptable salt thereof:

[1230] Chemical formula (23-B), or

[1231] Chemical formula (23-C).

[1232] In some embodiments, the second end comprises the structure of formula (23-D) or formula (23-E), or a pharmaceutically acceptable salt thereof:

[1233] Chemical formula (23-D) or

[1234] Chemical formula (23-E).

[1235] In some embodiments, the second end comprises the structure of formula (24-A) or a pharmaceutically acceptable salt thereof:

[1236]

[1237] Chemical formula (24-A),

[1238] In the above formula:

[1239] R 74 is -CH2- (optionally substituted 5-membered heteroaryl) and;

[1240] R 75 is -O-(C1-C 10 Alkyl)-R 75a and; here R 75a is -C(O)O-alkyl and;

[1241] R 76 -OR 76a and, here R 76a is hydrogen or alkyl;

[1242] R 77 It is hydrogen or a halogen;

[1243] R 77a is hydrogen or C1-C 10 It is alkyl;

[1244] Here, the chemical formula (24-A) is R 75a or R 76a It is attached to the linker.

[1245] In some embodiments, R 75 is -O-(C1-C 10 It is alkyl)-C(O)O-alkyl. In some embodiments, R 75 is -O-(C1-C4alkyl)-C(O)O-C1-C4alkyl.

[1246] In some embodiments, R 76 is -OH. In some embodiments, R 76 is -OCH3. In some embodiments, R 76 It is -O-CH2CH3.

[1247] In some embodiments, R 77 is a halogen. In some embodiments, R 77 It is hydrogen.

[1248] In some embodiments, R 77a is hydrogen or methyl. In some embodiments, R 77a is methyl. In some embodiments, R 77a is hydrogen.

[1249] In some embodiments, the formula (24-A) is R 75a It is attached to the linker at. In some embodiments, the formula (24-A) is R 76a It is attached to the linker.

[1250] In some embodiments, the second end comprises the structure of formula (24-B) or formula (24-C), or a pharmaceutically acceptable salt thereof:

[1251] Chemical formula (24-B) or

[1252] Chemical formula (24-C).

[1253] In some embodiments, the second end comprises the structure of formula (25-A) or a pharmaceutically acceptable salt thereof:

[1254]

[1255] Chemical formula (25-A),

[1256] In the above formula:

[1257] B 12 is -NR 80a - or -C(R 80b )2-and;

[1258] R 78 Silver halogens, -CN, -NO2, -OH, or optionally substituted C1-C 10 It is alkyl;

[1259] R 79a and R 79b Each is independently a halogen, -CN, -NO2, -NH2, -N(CH3)2, or optionally a substituted C1-C 10 alkyl or;

[1260] R 79a and R 79b They form a 6-membered aryl together with the atoms to which they are attached;

[1261] R 80 Each is independently hydrogen, -O-C1-C3 alkyl, C1-C 10 alkyl, or C1-C 10 It is an alkoxy;

[1262] R 80a is a C1-C6 alkyl;

[1263] R 80bEach is independently hydrogen or C1-C6 alkyl;

[1264] r7 is 1, 2, or 3;

[1265] Here, the chemical formula (25-A) is R 80 It is attached to the linker in one of them.

[1266] In some embodiments, B 12 is -NR 80a -is. In some embodiments, B 12 is -C(R 80b )2-is.

[1267] In some embodiments, R 78 is -CN, -NO2, or -OH. In some embodiments, R 78 is -OH. In some embodiments, R 78 is a halogen. In some embodiments, R 78 is an optionally substituted C1-C 10 It is an alkyl.

[1268] In some embodiments, R 79a and R 79b Each is independently a halogen, -NH2, or -N(CH3)2.

[1269] In some embodiments, R 79a and R 79b They form a 6-membered aryl together with the atoms to which they are attached.

[1270] In some embodiments, R 80 Each is independently hydrogen. In some embodiments, R 80 C1-C 10 It is an alkyl. In some embodiments, R 80 Each is independently C1-C 10 It is an alkoxy. In some embodiments, R 80 Each is independently -OCH3.

[1271] In some embodiments, the second end comprises the structure of formula (25-B) or formula (25-C), or a pharmaceutically acceptable salt thereof:

[1272] Chemical formula (25-B) or

[1273] Chemical formula (25-C).

[1274] In some embodiments, the second end comprises the structure of formula (26-A) or a pharmaceutically acceptable salt thereof:

[1275]

[1276] Chemical formula (26-A),

[1277] In the above formula:

[1278] B 11 -O- or -NR 82 - and;

[1279] A 10 -NR 84 - or -NR 84 CH2- and;

[1280] R 81a and R 81b Each is independently C1-C 10 It is alkyl;

[1281] or R 81a and R 81b They combine together to form an oxo (=O);

[1282] R 82 is hydrogen or C1-C3 alkyl;

[1283] R 83 Each is independently a halogen, -CN, -NO2, -OH, -OR 83a , or optionally substituted C1-C 10 It is an alkyl; where R 83a is C1-C 10 It is alkyl;

[1284] R 84 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or phenyl;

[1285] R 85 is hydrogen or C1-C 10 It is alkyl;

[1286] r4 is 1, 2, or 3;

[1287] Here, the chemical formula (26-A) is R 83 It is attached to the linker in one of them.

[1288] In some embodiments, B 11 is -O-. In some embodiments, B 11 -NR 82 -is. In some embodiments, B 11 It is NCH3.

[1289] In some embodiments, A 10 -NR 84 -is. In some embodiments, A 10 -NR 84 CH2- is.

[1290] In some embodiments, R 81a and R 81b Each is methyl. In some embodiments, R 81a and R 81b They combine together to form an oxo (=O).

[1291] In some embodiments, R 83 Each independently -CN, -OH, -OR 83a , or optionally substituted C1-C 10 It is an alkyl. In some embodiments, R 83 Each independently -OH or -OR 83a am.

[1292] In some embodiments, R 84 is a C3-C6 cycloalkyl or phenyl. In some embodiments, R 84 is phenyl.

[1293] In some embodiments, R 85 is C1-C 10 It is an alkyl. In some embodiments, R 85 is methyl. In some embodiments, R 85 is hydrogen.

[1294] In some embodiments, the second end comprises the structure of formula (26-B) or formula (26-C), or a pharmaceutically acceptable salt thereof:

[1295] Chemical formula (26-B) or Chemical formula (26-C).

[1296] In some embodiments, the second end comprises the structure of formula (26-D) or formula (26-E), or a pharmaceutically acceptable salt thereof:

[1297] Chemical formula (26-D) or Chemical formula (26-E).

[1298] In some embodiments, the second end comprises the structure of formula (27-A) or a pharmaceutically acceptable salt thereof:

[1299] Chemical formula (27-A).

[1300] In some embodiments, the second end comprises the structure of formula (28-A) or a pharmaceutically acceptable salt thereof:

[1301]

[1302] Chemical formula (28-A),

[1303] In the above formula:

[1304] A 11 is a C1-C6 alkylene;

[1305] B 13 is N or CR 100 And;

[1306] R 97 is a C1-C6 alkyl;

[1307] R 98 It is a halogen;

[1308] R 99 is hydrogen, halogen, or optionally substituted C1-C 10 It is alkyl;

[1309] R 100-OR 100a or optionally substituted C1-C 10 It is an alkyl; where R 100a is hydrogen or C1-C 10 It is alkyl;

[1310] or R 99 and R 100 They form heterocycloalkyl groups together with the atoms to which they are attached.

[1311] In some embodiments, A 11 is a C1-C4 alkylene. In some embodiments, A 11 is -CH2CH2-.

[1312] In some embodiments, B 13 is N. In some embodiments, B 13 is CR 100 am.

[1313] In some embodiments, R 97 It is methyl.

[1314] In some embodiments, R 98 It is -Cl.

[1315] In some embodiments, R 100 -OR 100a is. In some embodiments, R 100 is an optionally substituted C1-C 10 It is an alkyl.

[1316] In some embodiments, R 99 and R 100 They form heterocycloalkyl groups together with the atoms to which they are attached.

[1317] In some embodiments, the second end comprises the structure of formula (28-B) or a pharmaceutically acceptable salt thereof:

[1318] Chemical formula (28-B).

[1319] In some embodiments, the second end comprises the structure of formula (28-C) or a pharmaceutically acceptable salt thereof:

[1320] Chemical formula (28-C).

[1321] In some embodiments, the second end comprises the structure of formula (29-A) or a pharmaceutically acceptable salt thereof:

[1322] Chemical formula (29-A).

[1323] In some embodiments, the second end comprises the structure of formula (30-A) or a pharmaceutically acceptable salt thereof:

[1324] Chemical formula (30-A).

[1325] In some embodiments, the second end comprises the structure of formula (31-A) or a pharmaceutically acceptable salt thereof:

[1326]

[1327] Chemical formula (31-A),

[1328] In the above formula:

[1329] R 94 is a halogen;

[1330] R 94a is hydrogen or C1-C3 alkyl;

[1331] R 95 is hydrogen, halogen, -OH, -OCH3, or optionally substituted C1-C 10 It is an alkyl.

[1332] In some embodiments, R 94 is -Cl.

[1333] In some embodiments, R 94a is a C1-C3 alkyl. In some embodiments, R 94a is methyl. In some embodiments, R 94a is hydrogen.

[1334] In some embodiments, R 95 is a halogen, -OH, -OCH3, or optionally substituted C1-C 10 It is an alkyl. In some embodiments, R95 is hydrogen.

[1335] In some embodiments, the second end comprises the structure of formula (31-B) or formula (31-C), or a pharmaceutically acceptable salt thereof:

[1336] Chemical formula (31-B) or Chemical formula (31-C).

[1337] In some embodiments, the second end comprises the structure of formula (32-A) or a pharmaceutically acceptable salt thereof:

[1338] Chemical formula (32-A).

[1339] In some embodiments, the second end comprises the structure of formula (33-A) or a pharmaceutically acceptable salt thereof:

[1340] Chemical formula (33-A).

[1341] In some embodiments, the second end comprises the structure of formula (34-A) or a pharmaceutically acceptable salt thereof:

[1342] Chemical formula (34-A).

[1343] In some embodiments, the second end comprises the structure of formula (35-A) or a pharmaceutically acceptable salt thereof:

[1344] Chemical formula (35-A).

[1345] In some embodiments, the second end comprises the structure of formula (36-A) or formula (36-B), or a pharmaceutically acceptable salt thereof:

[1346] Chemical formula (36-A) or

[1347] Chemical formula (36-B).

[1348] In some embodiments, the second end comprises the structure of formula (37-A) or a pharmaceutically acceptable salt thereof:

[1349]

[1350] Chemical formula (37-A),

[1351] In the above formula:

[1352] Ring T is a C5-C6 cycloalkyl, a 5 to 6-membered heterocycloalkyl, or a phenyl;

[1353] R 86 Each is independently a halogen, -CN, -NO2, -OH, -OR 86a , -N(R 86b )2, or optionally substituted C1-C 10 It is alkyl; here

[1354] R 86a Each is independently C1-C 10 It is alkyl;

[1355] R 86b Each is independently hydrogen or C1-C 10 It is alkyl;

[1356] R 87 is a C5-C6 cycloalkyl or phenyl;

[1357] R 88 Each is independently a halogen, -CN, -NO2, -OH, -OR 88a , -NR 88b R 88b , or optionally substituted C1-C 10 It is alkyl; here

[1358] R 88a Each is independently C1-C 10 It is alkyl;

[1359] R 88b Each is independently hydrogen or C1-C 10 It is alkyl;

[1360] R 89a and R 89b Each is independently hydrogen or C1-C 10It is alkyl;

[1361] or R 89a and R 89b They form a 5 to 6-membered heterocycloalkyl group together with the atoms to which they are attached;

[1362] R 96 It is hydrogen or -CH3;

[1363] r5 and r6 are each independently 0, 1, 2, or 3.

[1364] In some embodiments, ring T is a C5-C6 cycloalkyl. In some embodiments, ring T is a 5 to 6-membered heterocycloalkyl. In some embodiments, ring T is a phenyl.

[1365] In some embodiments, R 86 Each is independently a halogen, -OH, -OR 86a , or -N(R 86b )2. In some embodiments, R 86 Each is independently a halogen or -N(R 86b )2. In some embodiments, R 86 Each is independently -N(R 86b )2 is.

[1366] In some embodiments, R 87 is a C5-C6 cycloalkyl. In some embodiments, R 87 It is phenyl.

[1367] In some embodiments, R 89a and R 89b Each is independently C1-C 10 It is an alkyl. In some embodiments, R 89a and R 89b Each is hydrogen.

[1368] In some embodiments, R 89a and R 89b It is a 5 to 6-membered heterocycloalkyl along with the atoms to which they are attached.

[1369] In some embodiments, R 96 is -CH3. In some embodiments, R96 It is hydrogen.

[1370] In some embodiments, r5 and r6 are each independently 0, 1, or 2.

[1371] In some embodiments, the second end comprises the structure of formula (37-B) or formula (37-C), or a pharmaceutically acceptable salt thereof:

[1372] Chemical formula (37-B) or

[1373] Chemical formula (37-C).

[1374] In some embodiments, the second end is selected from the group consisting of the following:

[1375] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

[1376] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , or a pharmaceutically acceptable salt thereof.

[1377] In some embodiments, the second end is selected from the moiety described in Table 1, or a pharmaceutically acceptable salt thereof.

[1378] Exemplary combination moiety. structure Target CBP / P300 BET(BD1) PCAF CBP / P300 CBP / P300 CECR2 BPTF PCAF BRD7 / 9 TAF1 BRD7 / 9 BRPF ATAD2 / ATAD2B ATAD2 / ATAD2B TRIM24 TAF1 BET BET BET BET BET BET BET BRD4 BRD4 BET BRD4 BRD4 BRD4 BRD4 BRD4 BRDR; non-Kac BRD4 BRD4 BRD4 BRD4 BRD4 BRD4; CBP / P300

[1379] Oligomer Backbone - Linker Moiety

[1380] An oligomer backbone is a linker that connects the first and second ends and brings regulatory molecules close to target genes to regulate gene expression.

[1381] The length of the linker varies depending on the type of regulatory protein and 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.

[1382] In some embodiments, the oligomer backbone comprises 5 to 50 chain atoms.

[1383] In some embodiments, the oligomer backbone comprises a multimer having 2 to 50 spacing moiety, wherein

[1384] Each spacing moiety is independently -((CR 1b R 1b ) x -O) y -, -((CR 1b R 1b ) x -NR 1a ) y -, -((CR 1b R 1b ) x -CH=CH-(CR 1b R 1b ) x -O) y -, optionally substituted C1-C 12 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, selectively substituted C6-C 10 Arlylene, 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)NR 1a -, -NR 1a C(O)-, -C(O)-, -NR 1a -, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR 1a -, -NR 1a Selected from the group consisting of S(O)2-, and -P(O)OH-, and any combination thereof; where,

[1385] Each of x is independently 2-4 and;

[1386] Each of y is independently 1–10 and;

[1387] R 1aEach is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, -S(O)2-C1-C6 haloalkyl, -S(O)2-C1-C6 alkyl, -S(O)2-C3-C6 cycloalkyl, or -S(O)2N-(C1-C6 alkyl)2;

[1388] R 1b Each is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, optionally substituted alkylamide, optionally substituted haloalkyl, sulfonyl, optionally substituted thioalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.

[1389] In some embodiments, the oligomer backbone comprises a multimer having 2 to 50 spacing moietyes, wherein each spacing moiety is independently and optionally substituted C1-C 12 Alkyl, -((CH2) x -O) y -, -((CH2) x -NH) y It is selected from the group consisting of -, -O-, -C(O)NH-, -NH-, and any combination thereof.

[1390] In some embodiments, the oligomer backbone is -(T 1 -V 1 ) a -(T 2 -V 2 ) b -(T 3 -V 3 ) c -(T 4 -V 4 ) d -(T 5 -V 5 ) e - includes, here

[1391] a, b, c, d, and e are each independently 0 or 1, where the sum of a, b, c, d, and e is 1 to 5;

[1392] T 1 , T 2 , T 3 , T 4 and T 5 Each is independently an optionally substituted C1-C12 alkylene, an optionally substituted alkenylene, an optionally substituted alkynylene, (EA) w , (EDA) m , (PEG) n , (modified PEG) n , (AA) p , -(CR 2a OH) h -, optionally substituted C6-C 10 Selected from arylenes, optionally substituted C3-C7 cycloalkylenes, optionally substituted 5 to 10-membered heteroarylenes, optionally substituted 4 to 10-membered heterocycloalkylenes, acetal groups, disulfides, hydrazines, carbohydrates, beta-lactams, and esters,

[1393] (a) w is an integer from 1 to 20;

[1394] (b) m is an integer from 1 to 20;

[1395] (c) n is an integer from 1 to 30;

[1396] (d) p is an integer from 1 to 20;

[1397] (e) h is an integer from 1 to 12;

[1398] (f) EA has the following structure

[1399]

[1400] (g) EDA has the following structure:

[1401]

[1402] Here, each q is independently an integer from 1 to 6, each x is independently an integer from 1 to 4, and each r is independently 0 or 1;

[1403] (H) (PEG) n -(CR 1b R 1b -CR 1b R 1b -O) n -CR 1b R 1b - having the structure of;

[1404] (i) (Modified PEG) n (PEG) n At least one -(CR within 1b R 1b -CR 1b R 1b -O)-를 -(CH2-CR 1b =CR 1b -CH2-O)- or -(CR 1b R 1b -CR 1b R 1b Having a structure replaced with -S)-;

[1405] (j) AA is an amino acid residue;

[1406] (K) V 1 , V 2 , V 3 , V 4 and V 5 Each combines independently, C(O)-, -NR 1a -, -C(O)NR 1a -, -NR 1a C(O)-, -CONR 1a -C1-C4alkyl-, -NR 1a C(O)-C1-C4alkyl-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR 1a -, -NR 1a Selected from the group consisting of S(O)2- and -P(O)OH-;

[1407] (l) R 1aEach is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, -S(O)2-C1-C6 haloalkyl, -S(O)2-C1-C6 alkyl, -S(O)2-C3-C6 cycloalkyl, or -S(O)2N-(C1-C6 alkyl)2;

[1408] (m) R 1b Each is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, alkoxy, substituted alkoxy, amino, substituted amino, optionally substituted haloalkyl, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[1409] In some embodiments, a, b, c, d, and e are each independently 0 or 1, where the sum of a, b, c, d, and e is 1. In some embodiments, a, b, c, d, and e are each independently 0 or 1, where the sum of a, b, c, d, and e is 2. In some embodiments, a, b, c, d, and e are each independently 0 or 1, where the sum of a, b, c, d, and e is 3. In some embodiments, a, b, c, d, and e are each independently 0 or 1, where the sum of a, b, c, d, and e is 4. In some embodiments, a, b, c, d, and e are each independently 0 or 1, where the sum of a, b, c, d, and e is 5.

[1410] In some embodiments, n is 3-9. In some embodiments, n is 4-8. In some embodiments, n is 5 or 6.

[1411] In some embodiments, T 1 , T 2 , T3 , T 4 , and T 5 Each is independently C1-C 12 Alkyl, substituted C1-C 12 Alkyl, (EA) w , (EDA) m , (PEG) n , (modified PEG) n , (AA) p , -(CR 1b OH) h -, phenyl, substituted phenyl, piperidine-4-amino(P4A), para-amino-benzyloxycarbonyl (PABC), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy(PABO), meta-amino-benzyloxy(MABO), para-aminobenzyl, acetal group, disulfide, hydrazine, carbohydrate, beta-lactam, ester, (AA) p -MABC-(AA) p , (AA) p -MABO-(AA) p , (AA) p -PABO-(AA) p and (AA) p -PABC-(AA) p It is selected from. In some embodiments, piperidine-4-amino (P4A) is and, here R 1a is hydrogen or C1-C6 alkyl.

[1412] In some embodiments, T 1 , T 2 , T 3 , T 4 and T 5 Each independently (C1-C 12 )alkyl, substituted C1-C 12 Alkyl, (EA) w , (EDA) m , (PEG) n , (modified PEG) n , (AA) p ,-(CR 2a OH) h -, optionally substituted C6-C 10It is selected from arylenes, 4 to 10-membered heterocycloalkenes, and optionally substituted 5 to 10-membered heteroarylenes. In some embodiments, EA has the following structure:

[1413] ; and

[1414] EDA has the following structure:

[1415] .

[1416] In some embodiments, for EA and EDA, x is 2-3 and q is 1-3. In some embodiments, R 1a is hydrogen or C1-C6 alkyl.

[1417] In some embodiments, T 4 or T 5 is an optionally substituted C6-C 10 It is Arilen.

[1418] In some embodiments, T 4 or T 5 is phenylene or substituted phenylene. In some embodiments, T 4 or T 5 is phenylene or phenylene substituted with 1 to 3 substituents selected from C1-C6 alkyl, halogen, OH, or amine. In some embodiments, T 4 or T 5 is a 5 to 10-membered heteroarylene or a substituted heteroarylene. In some embodiments, T 4 or T 5 is a 4 to 10-membered heteroarylene or a substituted heteroarylene. In some embodiments, T 4 or T 5 is a heteroarylene or heterocyclene optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, halogen, OH, or amine.

[1419] In some embodiments, T 1 , T 2 , T 3 , T 4 and T 5and V 1 , V 2 , V 3 , V 4 and V 5 is the following Table 2 Selected from.

[1420] Exemplary linker unit. T 1 V 1 T 2 V 2 T 3 V 3 T 4 V 4 T 5 V 5 C1-C 12 alkylene C(O)NR 1a (EA) w CO (PEG) n NR 1a WHAT ---- ---- ---- ---- C1-C 12 alkylene C(O)NR 1a (EA) w CO (PEG) n O Arilen NR 1a WHAT ---- ---- C1-C 12 alkylene C(O)NR 1a (EA) w CO (PEG) n O Substituted arylene NR 1a WHAT ---- ---- C1-C 12 alkylene C(O)NR 1a (EA) w CO (PEG) n O NR 1a WHAT C1-C 12 alkyl Substituted arylene NR 1a WHAT C1-C 12 alkylene C(O)NR 1a (EA) w CO C1-C 12 alkyl NR 1a CO-C1-C4alkyl Substituted arylene No. 11 ---- ---- C1-C 12 alkylene C(O)NR 1a (EA) w CO (PEG) n O Substituted arylene --- ---- ---- (PEG) n C(O)NR 1a- C1-C4 alkyl ---- ---- ---- ---- ---- ---- ---- --- (EA) w CO C1-C 12 alkyl C(O)NR 1a- C1-C4 alkyl ---- ---- ---- ---- ---- --- C1-C 12 alkylene C(O)NR 1a (EA) w CO (PEG) n NR 1a CO-C1-C4alkyl ---- ---- ---- ---- (EA) w CO (PEG) n O phenyl NR 1a CO-C1-C4alkyl ---- ---- ---- ---- C1-C 12 alkylene C(O)NR 1a (PEG) n CO ---- ---- ---- ---- ---- --- C1-C 12 alkylene C(O)NR 1a (EA) w CO Modified (PEG) n O Arilen NR 1a WHAT ---- ---- (PEG) n (EA) w CO (PEG) n ---- ---- ---- ---- ---- ----

[1421] In some embodiments, the oligomer backbone is -N(R 1a )(CH2) x N(R 1a )(CH2) x Includes N-, where R 1a Each is independently selected from hydrogen or optionally substituted C1-C6 alkyl; each x is independently an integer in the range of 1-10.

[1422] In some embodiments, the oligomer backbone is -(CH2-C(O)N(R 1a )-(CH2) q -N(R 1a )-(CH2) q -N(R 1a )C(O)-(CH2) x -C(O)N(R 1a )-A-, -(CH2) x -C(O)N(R 1a )-(CH2CH2O) y (CH2 ) x -C(O)N(R 1a )-A-, or -C(O)N(R 1a )-(CH2) q -N(R 1a )-(CH2) q -N(R 1a )C(O)-(CH2) x Includes -A-; where each q is independently an integer from 2 to 10; each x is independently an integer from 1 to 6; and each A is independently a combined, optionally substituted C1-C 12 Alkyl, optionally substituted C6-C 10It is selected from arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5 to 10-membered heteroarylene, and optionally substituted 4 to 10-membered heterocycloalkylene. In some embodiments, A is spiro-cycloalkylene or spiro-heterocycloalkylene.

[1423] In some embodiments, the oligomer backbone is -(CH2CH2-O) x7 - or -(CH2CH2-O) x8 -A-(CH2CH2-O) x9 - including, where A is an optionally substituted 4 to 10-membered heterocycloalkylene or spirocyclene, and each x7, x8, and x9 is independently an integer from 1 to 15.

[1424] In some embodiments, the oligomer backbone is -NR 1a -(CH2CH2O) y (CH2) x - or - NR 1a -(CH2) q -C(O)NR 1a (CH2CH2O) y (CH2) x Includes -, where q is 2-10, x is 1-4, y is 1-50, and R 1a Each is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, -S(O)2-C1-C6 haloalkyl, -S(O)2-C1-C6 alkyl, -S(O)2-C3-C6 cycloalkyl, or -S(O)2N-(C1-C6 alkyl)2. In some embodiments, the oligomer backbone is -NR 1a -(CH2CH2O) y (CH2) x It includes. In some embodiments, the oligomer backbone is -NR 1a -(CH2) q -C(O)NR 1a (CH2CH2O) y (CH2) x Includes -

[1425] In some embodiments, the oligomer backbone is -(CH2CH2-O) x -, -(CH2CH2-O) x -(CH2CH2)-NH-, -NR 1a -(CH2CH2-O) x -, -NR 1a -(CH2CH2-O) x -(CH2CH2)-NR 1a -, -(CH2CH2-O) x -(CH2CH2)-NR 1a C(O)-, or -NR 1a -(CH2CH2-O) x -(CH2CH2)-NR 1a It contains C(O)-. In some embodiments, the oligomer backbone is -(CH2CH2-O) x -, -(CH2CH2-O) x -(CH2CH2)-NH-, -NH-(CH2CH2-O) x -, -NH-(CH2CH2-O) x -(CH2CH2)-NH-, -(CH2CH2-O) x -(CH2CH2)-NHC(O)-, or -NH-(CH2CH2-O) x It includes -(CH2CH2)-NHC(O)-. In some embodiments, the oligomer backbone is -NH-(CH2CH2-O) x - or -NH-(CH2CH2-O) x It includes -(CH2CH2)-NH-. In some embodiments, the oligomer backbone is -NH-(CH2CH2-O) x - includes. In some embodiments, the oligomer backbone is -NH-(CH2CH2-O) x It contains -(CH2CH2)-NH-

[1426] In some embodiments, the oligomer backbone comprises polyethylene glycol (PEG). In some embodiments, the oligomer backbone comprises 1 to 20 PEG units. In some embodiments, the oligomer backbone comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 PEG units.

[1427] In some embodiments, A is , , or It is selected from. In some embodiments, A is is. In some embodiments, A is is. In some embodiments, A is am.

[1428] In some embodiments, A comprises a moiety having the following structure, or a pharmaceutically acceptable salt thereof:

[1429]

[1430] In the above formula:

[1431] A 2 is absent or -C(O)- and;

[1432] R 27 is an optionally substituted C1-C 50 alkyl or optionally substituted C1-C 50 It is a heteroalkyl.

[1433] In some embodiments, A 2 is -C(O)-. In some embodiments, A 2 is absent.

[1434] In some embodiments, R 27 C1-C 50 It is an alkyl. In some embodiments, R 27 C1-C 40 It is an alkyl. In some embodiments, R 27 C1-C 30 It is an alkyl. In some embodiments, R 27 C1-C20 It is an alkyl. In some embodiments, R 27 C1-C 10 It is an alkyl. In some embodiments, R 27 C1-C 50 It is a heteroalkyl. In some embodiments, R 26 C1-C 40 It is a heteroalkyl. In some embodiments, R 27 C1-C 30 It is a heteroalkyl. In some embodiments, R 27 C1-C 20 It is a heteroalkyl. In some embodiments, R 27 C1-C 10 It is a heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG).

[1435] In some embodiments, the oligomer backbone comprises a moiety having the structure of formula (C-1) or a pharmaceutically acceptable salt thereof:

[1436]

[1437] Chemical formula (C-1),

[1438] In the above formula:

[1439] Ring P is absent, arylene, or heterocycloalkylene;

[1440] L 5 is absent, optionally substituted alkylene, or optionally substituted alkynylene;

[1441] B 1 and B 2 Each is independently CH or N;

[1442] s1 and s2 are each independently 0-3;

[1443] ** indicates attachment to the second end.

[1444] In some embodiments, ring P is absent. In some embodiments, ring P is a C4-C7 heterocycloalkylene.

[1445] In some embodiments, B 1 is N. In some embodiments, B 1 It is CH.

[1446] In some embodiments, B 2 is N. In some embodiments, B 2 is CH.

[1447] In some embodiments, L 5 is absent.

[1448] In some embodiments, L 5 is an alkylene or alkynylene.

[1449] In some embodiments, the oligomer backbone comprises a moiety having the structure of formula (C-2) or a pharmaceutically acceptable salt thereof:

[1450]

[1451] Chemical formula (C-2),

[1452] In the above formula:

[1453] L 5 is absent, optionally substituted alkylene, or optionally substituted alkynylene;

[1454] B 2 , B 3 and B 4 Each is independently N or CH.

[1455] In some embodiments, B 3 and B 4 Each is independently N or CH; B 2 is N.

[1456] In some embodiments, L 5 is a C1-C3 alkylene or a C1-C3 alkynylene. In some embodiments, L 5 is a C1-C3 alkylene. In some embodiments, L 5 is C1-C3 alkynylene. In some embodiments, L 5 -CH2-, -CH2CH2-, , or is. In some embodiments, L 5 is -CH2- or -CH2CH2-. In some embodiments, L 5 Is is. In some embodiments, L 5 Is am.

[1457] In some embodiments, L 5 is -(C R1G R 1G ) x10 -(alkylene)2-(CR 1G R 1G ) y10 - and; here x 10 and y 10 Each is independently 0 or 1; R 1G Each is hydrogen or C1-C3 alkyl.

[1458] In some embodiments, the oligomer backbone comprises a moiety having the structure of formula (C-3) or a pharmaceutically acceptable salt thereof:

[1459]

[1460] Chemical formula (C-3),

[1461] In the above formula:

[1462] s1 and s2 are each independently 0-3;

[1463] r1 is an integer between 1 and 3;

[1464] R 26 is an optionally substituted C1-C 20 Alkylene or optionally substituted C2-C 20 It is a heteroalkylene;

[1465] R 1G Each is independently hydrogen or C1-C3 alkyl;

[1466] ** indicates attachment to the second end.

[1467] In some embodiments, R 26 is an optionally substituted C1-C 20It is a heteroalkylene. In some embodiments, R 26 is PEG.

[1468] In some embodiments, R 1G Each is independently hydrogen. In some embodiments, R 1G is independently a C1-C3 alkyl. In some embodiments, the C1-C3 alkyl is methyl, ethyl, or propyl. In some embodiments, R 1G Each is independently methyl.

[1469] In some embodiments, s1 and s2 are each independently 0, 1, or 2. In some embodiments, s1 and s2 are each independently 0. In some embodiments, s1 and s2 are each independently 1.

[1470] In some embodiments, r1 is 1 or 2. In some embodiments, r1 is 1. In some embodiments, r1 is 2.

[1471] In some embodiments, the oligomer backbone comprises the following:

[1472] , , , , , , , , , , , , , , , or .

[1473] In some embodiments, the oligomer backbone is -C(O)-, -NR 1a -, -C(O)NR 1a -, -NR 1a C(O)-, -C(O)NR 1a C1-C4alkyl-, -NR 1a C(O)-C1-C4alkyl-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR1a -, -NR 1a S(O)2-, -P(O)OH-, -((CH2) x -O)-, -((CH2) y -NR 1a )-, optionally substituted C1-C 12 Alkylene, optionally substituted C2-C 10 Alkenylene, selectively substituted C2-C 10 alkynylene, selectively substituted C6-C 10 A group selected from arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5 to 10-membered heteroarylene, and optionally substituted 4 to 10-membered heterocycloalkylene is coupled to the first and / or second terminals, wherein each x is independently 1-4, each y is independently 1-4, and R 1a Each is independently a hydrogen or optionally substituted C1-C6 alkyl.

[1474] In some embodiments, the oligomer backbone is -O-, -C(O)-, -NR 1a -, C1-C 12 Alkyl, -C(O)NR 1a -, and -NR 1a The first terminal is coupled to a group selected from C(O)-. In some embodiments, the oligomer backbone is -O- or -NR 1a It is combined with the first terminal of the selected path from -.

[1475] In some embodiments, the oligomer backbone is -C(O)-, -NR 1a -, -C(O)NR 1a -, -NR 1a C(O)-, -((CH2) x -O)-, -((CH2) y -NR 1a )-, -O-, optionally substituted C1-C 12 Alkyl, optionally substituted C6-C 10A second terminal is bonded to a group selected from arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, and optionally substituted 4- to 10-membered heterocycloalkylene, wherein each x is independently 1-4, each y is independently 1-4, and R 1a Each is independently hydrogen, an optionally substituted C1-C6 alkyl, or an optionally substituted C1-C6 haloalkyl.

[1476] In some embodiments, the oligomer backbone is -O-, -C(O)-, -NR 1a -, C1-C 12 Alkyl, -C(O)NR 1a -, and -NR 1a The second end is coupled to a group selected from C(O)-. In some embodiments, the oligomer backbone is -O- or -NR 1a - is coupled to the second end with a group selected from. In some embodiments, the oligomer backbone is coupled to the second end with -O-. In some embodiments, the oligomer backbone is -NR 1a - is coupled to the second end. In some embodiments, the oligomer backbone is coupled to the second end with -NH-.

[1477] In some embodiments, R 1a Each is independently hydrogen, -CH3, -CF3, -CH2CF3, -SO2CH3, -SO2CH2CH3, -SO2CF3, -SO2N(CH3)2, or -SO2-cyclopropyl. In some embodiments, R 1a Each is independently hydrogen, -CH3, -CF3, or -CH2CF3. In some embodiments, R 1a Each is independently -SO2CH3, -SO2CH2CH3, or -SO2CF3. In some embodiments, R 1a Each is independently hydrogen. In some embodiments, R 1a Each is independently -CH3.

[1478] Any combination of the groups described above with respect to various variables is considered herein. Throughout the specification, groups and their substituents are selected by those skilled in the art to provide stable moiety and compounds.

[1479] In some embodiments, non-limiting examples of the transcription regulator compounds described herein are as follows Table 3 It is presented on the (next page).

[1480] [Table 3]

[1481] Compounds of the present disclosure.

[1482]

[1483]

[1484] How to use

[1485] In another embodiment, a method for reducing gene expression in a cell is provided herein, comprising contacting the cell with an effective amount of the molecule disclosed herein or a pharmaceutically acceptable salt thereof.

[1486] In some embodiments, the gene is huntingtin ( HTT ) is. In some embodiments, the gene is a mutant huntingtin.

[1487] In some embodiments, the expression of the gene is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or more.

[1488] In another embodiment, a method for treating Huntington's disease (HD) in a subject requiring this is provided herein, the method comprises administering to the subject a molecule described herein or a pharmaceutically acceptable salt thereof.

[1489] In another aspect, a method for treating Huntington's disease-like syndrome is provided herein.

[1490] In a subject requiring treatment, the method comprises administering to the subject the molecule described herein, or a pharmaceutically acceptable salt thereof.

[1491] In another embodiment, a method for treating juvenile Huntington's disease in a subject requiring such treatment is provided herein, said method comprising administering to the subject a molecule described herein or a pharmaceutically acceptable salt thereof.

[1492] In some embodiments, the method reduces one or more symptoms of Huntington's disease (HD).

[1493] In some embodiments, one or more symptoms are selected from chorea, cognitive decline, abnormal sexual desire, abnormal eye movement, abnormal sense of smell, aggression, agitation, anxiety, apathy, bradykinesia, psychokinesia, clumsiness, delusions, depression, difficulty walking, disinhibition, dystonia, gait imbalance, muscle weakness, hallucinations, hostility, hypokinesia, hypersensitivity, memory impairment, myoclonus, obsessive-compulsive behavior, poor fine motor coordination, seizures, dysarthria, staring, weight loss, abnormal cholesterol metabolism, abnormal cerebral white matter, alcoholism, Babinski sign, caudate nucleus atrophy, cerebral atrophy, asphyxiation, myoclonus, striatal degeneration, excessive daytime sleepiness, visuospatial cognitive impairment, inability to walk, insomnia, mutism, oropharyngeal dysphagia, rigidity, suicidal ideation, cerebellar atrophy, dementia, gait ataxia, gliosis, hyperreflexia, neuronal loss, or personality change.

[1494] Pharmaceutical composition and administration

[1495] The compounds described herein are administered to subjects in need of them, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents in pharmaceutical compositions, in accordance with standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[1496] In another aspect, a pharmaceutical composition is provided herein comprising the compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. The appropriate formulation depends on the selected route of administration. A summary of the pharmaceutical compositions described herein is provided, for example, in the literature [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; It can be found in Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, (NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999)], which is incorporated herein by reference to such disclosures.

[1497] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspenders, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration promoters, wetting agents, defoaming agents, antioxidants, preservatives, and any combination thereof.

[1498] The dosage of pharmaceutical preparations for treating the diseases or disorders described herein may vary depending on the subject's condition, such as the stage of the disease, the severity of symptoms resulting from the disease, and general health status, as well as age, sex, weight, and other factors apparent to a person skilled in the medical field. Pharmaceutical compositions may be administered in a manner appropriate for the disease to be treated, as determined by a person skilled in the medical field. In addition to the factors described above regarding the use of pharmaceutical preparations for treating the diseases or disorders described herein, the appropriate duration and frequency of administration of the pharmaceutical preparation may be determined or adjusted by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dosage of the preparation may generally be determined using experimental models and / or clinical trials. The optimal dosage may vary depending on the subject's body mass, weight, or blood volume. The use of the minimum dose sufficient to provide effective treatment is generally preferred. The design and execution of preclinical and clinical studies regarding the pharmaceutical preparations described herein, including when administered for prophylactic benefit, are within the scope of skill of a person skilled in the relevant field. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may differ, such as being lower than when any one agent is administered alone in monotherapy. In certain embodiments, the two combined pharmaceutical agents may act synergistically or additively, and any one agent may be used in a smaller amount than when administered alone. The amount of pharmaceutical agent that may be administered per day may be, for example, about 0.01 mg / kg to 100 mg / kg, for example, about 0.1 to 1 mg / kg, about 1 to 10 mg / kg, about 10 to 50 mg / kg, or about 50 to 100 mg / kg body weight. In other embodiments, the amount of pharmaceutical agent that may be administered per day is about 0.The dose is 0.1 mg / kg to 1000 mg / kg, about 100-500 mg / kg, or about 500-1000 mg / kg body weight. The optimal daily dose or per course of treatment may vary depending on the disease or disorder to be treated, and may also vary depending on the route of administration and therapeutic regimen.

[1499] definition

[1500] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art to which this invention pertains.

[1501] Unless otherwise required by context, throughout the following specification and claims, the word “comprise” and its variations “comprises” and “comprising” shall be interpreted in an open, inclusive sense, i.e., “comprising, but not limited thereto.” Furthermore, the headings provided herein are for convenience only and do not imply the scope or meaning of the claimed invention.

[1502] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include multiple referents unless explicitly indicated otherwise. Additionally, it should be noted that the term "or" is generally used to include "and / or" unless explicitly indicated otherwise.

[1503] Where a range of values ​​is disclosed and the notation “n1… to n2” or “between n1… and n2” is used, where n1 and n2 are numbers, unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integers or continuous between them, including the endpoint values. For example, the range “2 to 6 carbons” is intended to include 2, 3, 4, 5, and 6 carbons, as carbons are provided in integer units. For example, compared to the range “1 to 3 μM (micromoles)”, this is intended to include 1 μM, 3 μM, and everything in between at any number of significant digits (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[1504] The following terms, as used herein, have the following meanings unless otherwise specified:

[1505] "Okso" refers to =O.

[1506] "Carboxyl" refers to -COOH.

[1507] "Cyano" refers to -CN.

[1508] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups such as heptyl, octyl, etc. Whenever appearing herein, numerical ranges such as “C1-C6alkyl” or “C1-6alkyl” mean that the alkyl group may consist of one, two, three, four, five, or six carbon atoms, but the present definition also includes the appearance of the term “alkyl” where no numerical range is specified. In some embodiments, the alkyl is C1-C 10It is an alkyl. In some embodiments, the alkyl is a C1-C6 alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless otherwise specifically stated in the specification, the alkyl group may be optionally substituted, for example, an oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with an oxo, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with a halogen.

[1509] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon monoradical having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms, having one or more carbon-carbon double bonds. The group may be in a cis or trans form with respect to the double bond 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, etc. Whenever appearing herein, numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl" mean that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but the present definition also includes the appearance of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated in the specification, the alkenyl group may be optionally substituted, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. 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.

[1510] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethinyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever appearing herein, numerical ranges such as "C2-C6 alkynyl" or "C2-6 alkynyl" mean that the alkynyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but the present definition also includes the appearance of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated in the specification, the alkynyl group may be optionally substituted, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. 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.

[1511] "Alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, the alkylene group may be optionally substituted, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. 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 a halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with a halogen.

[1512] "Alkoxy" is R a As defined, the chemical formula -OR is an alkyl radical. a It refers to the radical. Unless otherwise specifically stated in the specification, the alkoxy group may be optionally substituted, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted with a halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or NO2. In some embodiments, the alkoxy is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with a halogen.

[1513] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system may contain only hydrogen and carbon and may contain 5 to 18 carbon atoms, wherein at least one of the rings of the ring system is aromatic, i.e., a cyclic delocalized (4n+2)π-electron system according to Hückel theory. The ring system from which the aryl group is derived includes, but is not limited to, groups such as benzene, fluorene, indan, indene, tetraline, and naphthalene. The aryl radical may be a monocyclic, dicyclic, tricyclic, or tetracyclic ring system, which may include a fused (where the aryl is bonded through the aromatic ring atom when fused with a cycloalkyl or heterocycloalkyl ring) or crosslinked ring system. In some embodiments, the aryl is a 6 to 10-membered aryl. In some embodiments, the aryl is a six-membered aryl (phenyl). The aryl radical includes, but is not limited to, aryl radicals derived from hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiaden, pyrene, and triphenylene. Unless otherwise specifically stated in the specification, the aryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the aryl is optionally substituted with a 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 a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with a halogen.

[1514] "Cycloalkyl" refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include a fused (where fused with an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or cross-linked ring system. In some embodiments, the cycloalkyl is fully saturated. Typical cycloalkyls have 3 to 15 carbon atoms (e.g., C3-C 15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), 3 to 10 carbon atoms (e.g., C3-C 10 Fully saturated cycloalkyl or C3-C 10Cycloalkyls comprising, but not limited to, cycloalkenyls having 3 to 8 carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is 3 to 10-membered fully saturated cycloalkyl or 3 to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is 3 to 6-membered fully saturated cycloalkyl or 3 to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, the 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, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with a halogen.

[1515] "Cycloalkenyl" refers to an unsaturated, non-aromatic monocyclic or polycyclic hydrocarbon radical composed solely of carbon and hydrogen atoms, comprising a fused or cross-linked ring system, preferably having 3 to 12 carbon atoms and containing at least one double bond. In certain embodiments, the cycloalkenyl comprises 3 to 10 carbon atoms. In other embodiments, the cycloalkenyl comprises 5 to 7 carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[1516] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[1517] As used herein, the terms “haloalkyl” or “haloalkane” mean an alkyl radical substituted by one or more halogen radicals as defined above, e.g., trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with one or more halogen radicals, each halogen can be selected independently, for example, 1-chloro,2-fluoroethane.

[1518] "Fluoroalkyl" refers to an alkyl radical substituted by one or more fluoro radicals as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc.

[1519] "Hydroxyalkyl" means an alkyl radical substituted by one or more hydroxyls as defined above. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[1520] "Aminoalkyl" means an alkyl radical substituted by one or more amines as defined above. In some embodiments, the alkyl is substituted by one amine. In some embodiments, the alkyl is substituted by one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[1521] "Heteroalkyl" means an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl group is attached to the carbon atoms of the heteroalkyl group to the rest of the molecule. In one embodiment, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists 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 a combination thereof, wherein the heteroalkyl group is attached to the carbon atoms of the heteroalkyl group to the rest of the molecule. Examples of such heteroalkyls are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated in the specification, the heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with a halogen.

[1522] "Heterocycloalkyl" refers to a 3 to 24 partially or fully saturated ring radical comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises 1 to 3 nitrogens. In some embodiments, the heterocycloalkyl comprises 1 or 2 nitrogens. In some embodiments, the heterocycloalkyl comprises 1 nitrogen. In some embodiments, the heterocycloalkyl comprises 1 nitrogen and 1 oxygen. Unless otherwise specifically stated in the specification, heterocycloalkyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused (wherein fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or cross-linked ring systems; nitrogen, carbon, or sulfur atoms of the heterocycloalkyl radical may be optionally oxidized; and nitrogen atoms may be optionally quaternized. Representative heterocycloalkyls are heterocycloalkyls having 2 to 15 carbon atoms (e.g., C2-C 15 Completely saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl), heterocycloalkyl having 2 to 10 carbon atoms (e.g., C2-C 10 Completely saturated heterocycloalkyl or C2-C 10Heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), heterocycloalkyl having 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), heterocycloalkyl having 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), heterocycloalkyl having 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or heterocycloalkyl having 2 to 4 carbon atoms (e.g., It includes, but is not limited to, C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl. Examples of such heterocycloalkyl radicals are aziridinyl, azetidinyl, oxetanil, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolininyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperadinyl, 2-oxopiperadinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomophorinyl, thiamophorinyl, 1-oxo-thiomophorinyl, 1,1-dioxo-thiomofolinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl are included, but not limited thereto. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycloalkyl has 2 to 10 carbons in the ring.When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not equal to the total number of atoms (including heteroatoms) constituting the heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3 to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4 to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5 to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4 to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 to 6-membered heterocycloalkenyl. Unless otherwise specifically stated in the specification, the heterocycloalkyl may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. 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 a halogen.

[1523] "Heteroaryl" refers to a 5 to 14-membered ring system radical comprising 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises 1 to 3 nitrogens. In some embodiments, the heteroaryl comprises 1 or 2 nitrogens. In some embodiments, the heteroaryl comprises 1 nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused (wherein when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or cross-linked ring system; the nitrogen, carbon, or sulfur atoms of the heteroaryl radical may be optionally oxidized; and the nitrogen atoms may be optionally quaternized. In some embodiments, the heteroaryl is a 5 to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5 to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azefinil, acrridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxephinil, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazoz[1,2-a]pyridinyl, carbazolyl, cinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, Isoindolyl, Indolinyl, Isoindolinyl, Isoquinolyl, Indoliginil, Isoxazolyl, Naphthiridinyl, Oxadiazollyl, 2-Oxozepinil, Oxazolyl, Oxiranil, 1-Oxidopyridinyl, 1-Oxidopyrimidinyl, 1-Oxidopyrazinyl, 1-Oxidopyridazinyl, 1-Phenyl-1H-Pyrrolyl, Fenazinyl, Fenothiazinyl, Fenoxazinyl, Phthalazinyl, Pteridinyl, Furinyl, Pyrrolyl, Pyrazolyl, Pyridinyl, Pyrazinyl, Pyrimidinyl, Pyridazinyl, Quinazolinyl, Quinoxalinyl, Quinolinyl, Quinuclidinyl, Isoquinolinyl, Tetrahydroquinolinyl, Thiazolyl, Thiadiazolyl, Triazolyl, Includes, but is not limited to, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in the specification, the heteroaryl may be optionally substituted, for example, a halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroaryl is optionally substituted with a 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 a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with a halogen.

[1524] 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 more nucleotides). The term "oligonucleotide repeat sequence" refers to a continuous extension of an oligonucleotide sequence.

[1525] The term “transcription” refers to the synthesis of RNA (i.e., ribonucleic acid) by DNA-directed RNA polymerase, as is well known in the art. The term “regulate transcription” refers to a change in transcription levels that can be measured by methods well known in the art, for example, by the analysis of the transcription product, mRNA. In certain embodiments, regulation is an increase in transcription. In other embodiments, regulation is a decrease in transcription.

[1526] The term "polyamide" refers to a polymer of connectable units chemically bonded by amide (i.e., CONH) bonds; optionally, the polyamide comprises a chemical probe conjugated thereto. Polyamides can be synthesized by the stepwise condensation of a carboxylic acid (COOH) and an amine (RR'NH) using methods known in the art. Alternatively, polyamides can be synthesized in vitro ( in vitro It can be formed using an enzymatic reaction or through fermentation using microorganisms.

[1527] The term “linkable unit” refers to straight-chain and branched-chain aliphatic functional groups (e.g., methylene, ethylene, propylene, butylene, etc.) containing methylimidazole, methylpyrrole, and optionally nitrogen substituents, and chemical derivatives thereof. The aliphatic functional groups of the linkable unit may be provided, for example, by the condensation of β-alanine or dimethylaminopropylamine during polyamide synthesis by methods well known in the art.

[1528] The term "linker" or "oligomer backbone" refers to a chain of at least 10 consecutive atoms. In certain embodiments, the linker comprises 20 or fewer non-hydrogen atoms. The terms linker and oligomer backbone may be used interchangeably. In some embodiments, the linker comprises 40 or fewer non-hydrogen atoms. In some embodiments, the linker comprises 60 or fewer non-hydrogen atoms. In certain embodiments, the linker comprises atoms selected from C, H, N, O, and S. In some embodiments, all non-hydrogen atoms are chemically bonded to two adjacent atoms of the linker, or to one adjacent atom of the linker and the end of the linker. In some embodiments, the linker forms an amide bond with at least one of two different groups to which it is attached. In certain embodiments, the linker forms an ester or ether bond with at least one of two different groups to which it is attached. In some embodiments, the linker forms a thioester or thioether bond with at least one of two other groups to which it is attached. In some embodiments, the linker forms a direct carbon-carbon bond with at least one of two other groups to which it is attached. In some embodiments, the linker forms an amine or amide bond with at least one of two other groups to which it is attached. In some embodiments, the linker comprises a -(CH2OCH2)- unit. In some embodiments, the linker comprises a -(CH(CH3)OCH2)- unit. In some embodiments, the linker is RN = C 1-4 Regarding alkyl (CH2NR N It includes a CH2 unit. In some embodiments, the linker includes an arylene, cycloalkylene, or heterocycloalkylene moiety.

[1529] The term "bond" refers to a covalent bond between two atoms, or between two moieties when the atoms connected by the bond are considered part of a larger substructure. Unless otherwise specified, bonds may be single, double, or triple. In molecular diagrams, a dashed line between two atoms indicates that an additional bond may or may not exist at that location.

[1530] As used herein, “optionally substituted” is a substituted group derived from an unsubstituted parent group in which one or more hydrogen atoms are exchanged for other atoms or groups. Unless otherwise indicated, when a group is considered "substituted" or "optionally substituted," this refers to a group of C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10-membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 member heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member Heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl(mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,It means being substituted with one or more substituents independently selected from C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Where a group is described as "optionally substituted," the group may be substituted with the said substituents.

[1531] The term “one or more” means that when referring to optional substituents, the target group is optionally substituted with one, two, three, or four substituents. In some embodiments, the target group is optionally substituted with one, two, or three substituents. In some embodiments, the target group is optionally substituted with one or two substituents. In some embodiments, the target group is optionally substituted with one substituent. In some embodiments, the target group is optionally substituted with two substituents.

[1532] Chemical substances having carbon-carbon double bonds or carbon-nitrogen double bonds Z - or E - It may exist in the form (or cis- or trans- form). Additionally, some chemicals may exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are all Z -, E - and is intended to include tautomeric forms as well.

[1533] The compounds disclosed herein are, in some embodiments, for example, 2 H, 3 H, 11 C, 13 C and / or 14It is used in various isotope-enriched forms enriched with a C content. In certain embodiments, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents No. 5,846,514 and No. 6,334,997. As described in U.S. Patents No. 5,846,514 and No. 6,334,997, deuteration can increase the duration of action of a drug by improving metabolic stability and / or efficacy.

[1534] Unless otherwise specified, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, hydrogen is replaced with deuterium or tritium, or carbon 13 C- or 14 Compounds having this structure, except that they are replaced with C-enriched carbon, are within the scope of this disclosure.

[1535] The compounds of the present disclosure optionally contain anomalous proportions of atomic isotopes in one or more atoms constituting such compounds. For example, the compounds are, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 It can be labeled with isotopes such as C). 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl,37 Cl, 79 Br, 81 Br, and 125 All isotopic substitutions using I are considered. Regardless of radioactivity, all isotopic variants of the compounds of the present invention are included within the scope of the present invention. In some embodiments, where isotopic variants are exemplified, the remaining atoms of the compound may optionally contain an anomalous proportion of atomic isotopes.

[1536] In certain embodiments, the compound disclosed herein is 1 Some or all of the H atoms 2 It is replaced by an H atom. Methods for synthesizing deuterium-containing compounds are known in the art and include the following synthesis methods only as non-limiting examples.

[1537] Deuterium-substituted compounds are synthesized using various methods as described in the following literature: [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].

[1538] Deuterated starting materials are readily available and can be applied to the synthesis methods described herein to provide for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[1539] In some embodiments, one or more substituent groups of the compounds disclosed herein contain deuterium in a proportion higher than the natural abundance of deuterium. In some embodiments of the compounds disclosed herein, one or more hydrogens are replaced by one or more deuteriums.

[1540] In some embodiments of the compounds disclosed herein, the abundance of deuterium in each substituent 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 the total number of hydrogen and deuterium.

[1541] The compounds of the present disclosure also include crystalline and amorphous forms of such compounds, pharmaceutically acceptable salts, and active metabolites of such compounds having the same type of activity, and include, for example, polymorphs, pseudo-polymorphs, solvates, hydrates, non-solvent polymorphs (including anhydrous), morphological polymorphs, and amorphous forms, as well as mixtures thereof.

[1542] The compounds described herein may exist in some cases as diastereomers, enantiomers, or other stereoisomers. Unless absolute stereochemistry is specified, the compounds presented herein include all diastereomers, enantiomers, and epimer forms, as well as suitable mixtures thereof. The separation of stereoisomers may be carried out by chromatography, by forming diastereomers and recrystallizing, or by chromatography, or any combination thereof. (Reference [Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981], incorporated herein by reference for the purposes of this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[1543] The terms "salt" or "pharmaceuticalally acceptable salt" refer to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids. Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvate, 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, etc. Pharmaceutically acceptable base addition salts may be formed with inorganic and organic bases. Inorganic bases from which salts may be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. 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, etc., specifically including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[1544] The phrase “pharmaceuticalally acceptable” refers to such compounds, substances, compositions, and / or formulations that are suitable within the scope of sound medical judgment for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, corresponding to a reasonable benefit-risk ratio.

[1545] As used herein, the phrases “pharmaceuticalally acceptable excipients” or “pharmaceutically acceptable carriers” mean pharmaceutically acceptable substances, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be “acceptable” in the sense that it is compatible with other components of the formulation and is not harmful to the patient. Some examples of substances that may 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 tragacanths; (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) Buffers 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 solution; and (21) Other non-toxic compatible materials used in pharmaceutical formulations.

[1546] "Effective dose" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses that is effective in producing a desired therapeutic effect.

[1547] As used herein, the terms “treat,” “treating,” or “treatment” include alleviating, reducing, or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, e.g., preventing the onset of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping symptoms of a disease or condition.

[1548] The term "patient" is generally synonymous with the term "object" and includes all mammals, including humans. Examples of patients include humans, livestock such as cattle, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[1549] The term "contacting" refers to bringing a compound (e.g., a transcription molecule of the present disclosure) close to a desired target gene. Contact may result in binding to the target moiety or causing a morphological change of the target moiety.

[1550] The methods and compositions described herein include the use of crystalline forms (also known as polymorphs) as well as amorphous forms. The compounds described herein may be in the form of pharmaceutically acceptable salts. Additionally, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of this disclosure. Furthermore, the compounds described herein may exist in non-solvent forms as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvented forms of the compounds presented herein are also considered to be disclosed herein.

[1551] Examples

[1552] The following examples are intended to illustrate various embodiments of the invention and are not intended to limit the invention in any way. These examples represent currently preferred embodiments together with the methods described herein, are illustrative, and are not intended to limit the scope of the invention. Modifications and other uses that fall within the spirit of the invention as defined by the claims will be known to those skilled in the art.

[1553] Compound synthesis

[1554] The compounds of the present disclosure may be prepared using the methods exemplified in the general synthesis schemes and experimental procedures described in detail below. The general synthesis schemes and experimental procedures are presented for illustrative purposes only and are not intended to be limiting. The starting materials used to prepare the compounds of the present disclosure may be commercially available or prepared using conventional methods known in the art.

[1555] Synthetic chemical transformations and methodologies useful for synthesizing the compounds described herein are known in the art, for example, in the literature [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 Includes the things described in (1995)].

[1556] List of abbreviations

[1557] Ac2O = Acetic anhydride; AcCl = Acetyl chloride; AcOH = Acetic acid; AIBN = Azobis-isobutyronitrile; aq = Aqueous solution; Boc = tert-Butyloxycarbonyl; Bu3SnH = Tributyltin Hydride; CD3OD = Deuterated Methanol; CDCl3 = Deuterated Chloroform; CDI = 1,1'-Carbonyldiimidazole; DBU = 1,8-Diazabicyclo[5.4.0]undec-7-en; DCM = Dichloromethane; DEAD = Diethyl Azodicarboxylate; DIBAL-H = Di-Iso-Butyl Aluminum Hydride; DIEA = DIPEA = N,N-Diisopropylethylamine; DMAP = 4-Dimethylaminopyridine; DMF = N,N-Dimethylformamide; DMSO-d6 = Deuterated Dimethyl Sulfoxide; DMSO = Dimethyl Sulfoxide; DPPA = Diphenylphosphoryl Azide; EDC.HCl = EDCI.HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = time; HATU = 2-(1H-7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate aluminum methanemate; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-PrOH = isopropanol; LAH = lithium aluminum hydride; LiHMDS = lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeI = methyl iodide; MeOH = methanol; MP-carbonate resin = macroporous triethylammonium methylpolystyrene carbonate resin; MsCl = mesyl chloride; MTBE = Methyl tertiary butyl ether; MW = Microwave irradiation; n-BuLi = n-butyllithium; NaHMDS = Sodium bis(trimethylsilyl)amide; NaOMe = Sodium methoxide; NaOtBu = Sodium t-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMI = 1-methylimidazole; NMP = N-methyl-2-pyrrolidone; OAc = Acetoxy; Pd(Ph3)4 = Tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2 = Bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; prep-HPLC = Preparative high-performance liquid chromatography; PyBop = (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; sat = saturated; ss = saturated solution; t-BuOH = tert-butanol; T3P = propylphosphonic anhydride; TBS = TBDMS =. tert -Butyldimethylsilyl; TBSCl = TBDMSCl = tert-Butyldimethylchlorosilane; TCFH = Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate; TEA = Et3N = Triethylamine; TFA = Trifluoroacetic acid; TFAA = Trifluoroacetic anhydride; THF = Tetrahydrofuran; Tol = Toluene; TsCl = Tosyl chloride; XPhos = 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[1558] Synthesis of representative polyamides

[1559] Example 1. Synthesis of 3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2-yl]formamido}propaneamido)imidazole-2-amido]pyrrole-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazole-2-yl]formamido}propaneamido)pyrrole-2-amido]imidazole-2-yl}formamido)propanoic acid

[1560] Reaction Equation 1.

[1561]

[1562] Step 1. Ethyl 2-(triphenyl-lambda5-phosphanylidene)acetate (19.98 g, 57.37 mmol, 1.00 equivalent) and benzoic acid (7.00 g, 57.37 mmol, 1.00 equivalent) were added to a stirred solution of (1-ethoxycyclopropoxy)trimethylsilane (10.00 g, 57.37 mmol, 1.00 equivalent) in toluene (100.00 mL), and the reaction mixture was stirred at 90°C for 2.0 hours. The solid was filtered, and the filtrate was used directly in the next step without further purification. LC / MS: Calculated mass. C7H 10 For O2: 126.07, Actual: 127.10 [M+H] + .

[1563] Step 2.CH3NO2 (4.01 mL, 74.83 mmol, 2.36 equivalents) and DBU (1.99 mL, 13.32 mmol, 0.42 equivalents) were added to a solution of crude ethyl 2-cyclopropylidene acetate at 0°C, and the reaction mixture was stirred at room temperature for 6.0 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / petroleum ether (1:8) to obtain ethyl 2-[1-(nitromethyl)cyclopropyl]acetate (3.00 g, 50.54%) as a pale yellow oil. LC / MS: Calculated mass. C8H 13 For NO4: 187.08, Actual: 188.20 [M+H] + .

[1564] Step 3. Pd / C (0.30 g, 10% w / w) and TFA (0.10 mL) were added at room temperature to a stirred mixture of ethyl 2-[1-(nitromethyl)cyclopropyl]acetate (3.00 g, 16.03 mmol, 1.00 equivalents) in EtOH (30.00 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 6.0 hours. The resulting mixture was filtered, and the filter cake was washed with EtOH (5 x 30 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with ethyl acetate / petroleum ether (1:1) to obtain ethyl 2-[1-(aminomethyl)cyclopropyl]acetate (1.50 g, 59.54%) as a pale yellow oil. LC / MS: Calculated mass. C8H 15 For NO2: 157.11, Actual: 158.15 [M+H] + .

[1565] Step 4.Saturated sodium bicarbonate (1.14 M in H2O, 20.95 mL, 23.88 mmol, 2.50 equivalents) and di-tert-butyl dicarbonate (3.13 g, 14.33 mmol, 1.50 equivalents) were added to a stirred mixture of ethyl 2-(1-(aminomethyl)cyclopropyl)acetate (1.50 g, 9.55 mmol, 1.00 equivalents) in H2O (15.00 mL), and the mixture was stirred at room temperature for 4.0 hours. The reaction mixture was filtered, diluted with water (30 mL), and extracted with EA (3 x 30 mL). The combined organic layer was washed with water (30 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1 / 1) to obtain ethyl 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)acetate (1.23 g, 50.20%) as a pale yellow oil. LC / MS: Calculated mass. C 13 H 23 For NO4: 257.16, Actual: 258.05 [M+H] + .

[1566] Step 5. LiOH (2 M in H2O, 11.96 mL, 23.93 mmol, 5.00 equivalents) was added to a stirred solution of ethyl 2-(1-{[(tert-butoxycarbonyl)amino]methyl}cyclopropyl)acetate (1.23 g, 4.79 mmol, 1.00 equivalents) in CH3OH (20.00 mL), and the mixture was stirred at room temperature for 2.0 hours. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL), and the mixture was acidified with 2 M HCl to a pH of 4–5. The resulting mixture was extracted with EA (3 x 30 mL), the combined organic layer was washed with brine (2 x 30 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain (1-{[(tert-butoxycarbonyl)amino]methyl}cyclopropyl)acetic acid (930.00 mg, 84.85%) as a white solid. LCMS: Calculated mass. C11 H 19 For NO4: 229.13, Actual: 252.00 [M+Na] + .

[1567] Step 6. TCFH (6.68 g, 23.82 mmol, 1.30 equivalents) and NMI (6.02 g, 73.28 mmol, 4.00 equivalents) were added to a stirred mixture of (1-{[(tert-butoxycarbonyl)amino]methyl}cyclopropyl)acetic acid (4.20 g, 18.32 mmol, 1.00 equivalents) and ethyl 4-amino...

Claims

Claim 1 A transcription regulator molecule having a first end, a second end, and an oligomeric backbone moiety, or a pharmaceutically acceptable salt thereof, wherein a) the first end comprises a DNA-binding moiety having the structure of formula (A-9); Chemical formula (A-9), in the above formula: W 1 Silver is hydrogen, -C1-C6 haloalkyl, or -N=C(N(R 1e )2)2 and R 1e Each is independently a hydrogen or optionally substituted C1-C3 alkyl; R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with;R 3a and R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e And, in the above equation, R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or 2 R 3a or 2 Rs 3b , together with the atoms to which they are attached, form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl; or one R 3a and one R 3b is formed with the atoms to which they are attached a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl; R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 It is cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; R Zc b) is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; c) the second end comprises a protein-binding moiety capable of binding to a regulatory molecule that regulates gene expression; and d) the oligomer backbone is a transcription regulator molecule, or a pharmaceutically acceptable salt thereof, connecting the first end and the second end. Claim 2 In paragraph 1, R 3a and R 3b Each is independently hydrogen or; two R 3a or 2 Rs 3b A molecule or a pharmaceutically acceptable salt thereof that forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl with the carbon atoms to which they are attached. Claim 3 In paragraph 1 or 2, R 3a and R 3b Each is hydrogen, a molecule, or a pharmaceutically acceptable salt thereof. Claim 4 In paragraph 1 or 2, 2 R 3a or they form a C3-C6 cycloalkyl group together with the atoms to which they are attached; R 3b Each is hydrogen, a molecule, or a pharmaceutically acceptable salt thereof. Claim 5 In paragraph 1 or 2, 2 R 3b is formed with the atoms to which they are attached to form a C3-C6 cycloalkyl group; R 3a Each is hydrogen, a molecule, or a pharmaceutically acceptable salt thereof. Claim 6 In any one of paragraphs 1 through 5, R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl, each of which optionally has one or more R Z A molecule or a pharmaceutically acceptable salt thereof that is substituted with Claim 7 In Paragraph 6, R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h Each is an independently and selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 A molecule or a pharmaceutically acceptable salt thereof that is a haloalkyl or an optionally substituted C3-C8 cycloalkyl. Claim 8 In any one of paragraphs 1 through 5, R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h Each is independently C1-C 10 An alkyl molecule or a pharmaceutically acceptable salt thereof. Claim 9 In any one of paragraphs 1 through 6, R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , or R 2h At least one of them is a non-substituted C1-C 10 A non-alkyl molecule or a pharmaceutically acceptable salt thereof. Claim 10 In Paragraph 9, R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , or R 2h At least one of the molecules or pharmaceutically acceptable salts thereof that is not methyl. Claim 11 In Paragraph 9, R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , or R 2h At least two of them are non-methyl molecules or pharmaceutically acceptable salts thereof. Claim 12 In claim 1, the DNA-binding moiety comprises the structure of chemical formula (I): Chemical formula (I), in the above formula: W 1 is hydrogen and;R 2a , R 2c , R 2d , R 2e , and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, selectively substituted C2-C 20 Heteroalkinyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C 10 It is a cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; each of which is optionally one or more R Z Replaced with;R 3b Each is independently hydrogen, halogen, C1-C6 alkyl, -OR 3c , -NR 3c R 3d , or -NHC(O)R 3e is, R 3c and R 3d Each is independently hydrogen, alkyl, or PEG;R 3e is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; or 2 R 3b is formed with the atoms to which they are attached a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl; R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl, C1-C 10 Haloalkyl, C1-C 10 Heteroalkyl, C3-C 10 It is cycloalkyl, 3 to 10-membered heterocycloalkyl, phenyl, or optionally 5 to 10-membered heteroaryl; R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl molecule, or a pharmaceutically acceptable salt thereof. Claim 13 In Paragraph 12, R 2a , R 2c , R 2d , R 2e , or R 2h Each is an independently and selectively substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 alkynyl, selectively substituted C1-C 20 Haloalkyl, optionally substituted C3-C 10 Cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl, each of which optionally has one or more R Z A molecule or a pharmaceutically acceptable salt thereof that is substituted with Claim 14 In Paragraph 12, R 2a , R 2c , R 2d , R 2e , or R 2h Each is an independently and selectively substituted C1-C 20 alkyl or optionally substituted C3-C 10 A molecule that is a cycloalkyl or a pharmaceutically acceptable salt thereof. Claim 15 In Paragraph 12, R 2a , R 2c , R 2d , R 2e , or R 2h Each is independently a monocyclic, spirocycloalkyl, or cross-linked C3-C 10 A molecule that is a cycloalkyl or a pharmaceutically acceptable salt thereof. Claim 16 In Paragraph 12, R 2a , R 2c , R 2d , R 2e , or R 2h One or two of them are independently and optionally substituted C3-C 10 It is a cycloalkyl or an optionally substituted 3 to 10-membered heterocycloalkyl; R 2a , R 2c , R 2d , R 2e , or R 2h The remainder are optionally substituted C1-C 20 An alkyl molecule or a pharmaceutically acceptable salt thereof. Claim 17 In Paragraph 16, R 2a , R 2c , R 2d , R 2e , or R 2h The remainder is non-substituted C1-C 10 An alkyl molecule or a pharmaceutically acceptable salt thereof. Claim 18 In any one of paragraphs 12 through 16, R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , C1-C 10 Alkyl, C1-C 10 A molecule or a pharmaceutically acceptable salt thereof that is a haloalkyl or C3-C6 cycloalkyl. Claim 19 In Paragraph 18, R Z A molecule or a pharmaceutically acceptable salt thereof, each of which is independently a halogen, -OH, -NH2, or C1-C6 alkyl. Claim 20 In Paragraph 12, R 2a , R 2c , R 2d , R 2e , or R 2h One or two of them are independently , , , , , , , , , , , , or Phosphorus, molecule, or pharmaceutically acceptable salt thereof. Claim 21 In Article 12 or Article 20, R 2a , R 2c , R 2d , R 2e , or R 2h The remainder is non-substituted C1-C 10 An alkyl molecule or a pharmaceutically acceptable salt thereof. Claim 22 In Paragraph 21, R 2a , R 2c , R 2d , R 2e , or R 2h The remainder are molecules or pharmaceutically acceptable salts thereof that are independently methyl, ethyl, or isopropyl. Claim 23 In Paragraph 21, R 2a , R 2c , R 2d , R 2e , or R 2h The remainder are, respectively, methyl, molecules, or pharmaceutically acceptable salts thereof. Claim 24 In any one of paragraphs 12 through 23, two R 3b A molecule or a pharmaceutically acceptable salt thereof that forms a C3-C6 cycloalkyl group together with the atoms to which they are attached. Claim 25 In paragraph 24, 2 Rs 3b A molecule or a pharmaceutically acceptable salt thereof that forms cyclopropyl together with the atoms to which they are attached. Claim 26 In any one of paragraphs 12 through 23, R 3b Each is hydrogen, a molecule, or a pharmaceutically acceptable salt thereof. Claim 27 A transcription regulator molecule having a first end, a second end, and an oligomeric backbone moiety, or a pharmaceutically acceptable salt thereof, wherein a) the first end comprises a DNA-binding moiety having the structure of formula (II); Chemical formula (II), in the above formula: T A is -Q A -Q B and;Q A Is Igo;Q B Is is;R 2j is an optionally substituted C1-C 20 It is alkyl, and optionally one or more R Z Replaced with;R 2k is an optionally substituted C1-C 20 alkyl or optionally substituted C3-C 10 They are cycloalkyl, each of which optionally has one or more R Z Replaced with; * is Q A to Q B is the attachment point of;** is the attachment point for the above oligomer linker; W 1 is hydrogen and;R 2c and R 2d Each is an independently and selectively substituted C1-C 20 Alkyl, optionally substituted, C3-C 10 Cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl, each of which optionally has one or more R Z Replaced with;R 3b Each is hydrogen or C1-C6 alkyl; and two R 3b is formed with the atoms to which they are attached to form a C3-C6 cycloalkyl group; R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 It is a haloalkyl or has two Rs Z forms a C3-C6 cycloalkyl group together with the atom(s) to which they are attached, and R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; R Zc a) is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; b) the second end comprises a protein-binding moiety capable of binding to a regulatory molecule that regulates gene expression; and c) the oligomer backbone is a transcription regulator molecule, or a pharmaceutically acceptable salt thereof, connecting the first end and the second end. Claim 28 In paragraph 27, R 3b Each is hydrogen, a molecule, or a pharmaceutically acceptable salt thereof. Claim 29 In paragraph 27, 2 Rs 3b A molecule or a pharmaceutically acceptable salt thereof that forms a C3-C6 cycloalkyl group together with the atoms to which they are attached. Claim 30 In paragraph 29, 2 Rs 3b A molecule or a pharmaceutically acceptable salt thereof that forms cyclopropyl together with the atoms to which they are attached. Claim 31 In any one of paragraphs 27 through 30, R 2c is an optionally substituted C1-C 20 It is alkyl, and optionally one or more R Z It is replaced with, and R Z Each is independently a halogen, -OH, -OR Za , -NR Za R Zb , or a molecule or a pharmaceutically acceptable salt thereof that is a C1-C6 alkyl. Claim 32 In Paragraph 31, R 2c is methyl, ethyl, isopropyl, , , or Phosphorus, molecule, or pharmaceutically acceptable salt thereof. Claim 33 In Paragraph 32, R 2c is a methyl, molecule, or pharmaceutically acceptable salt thereof. Claim 34 In paragraph 27, the first terminal of formula (II) is a molecule or a pharmaceutically acceptable salt thereof having the structure of formula (IIa): Chemical formula (IIa). Claim 35 In any one of paragraphs 27 through 34, R 2d is an optionally substituted C1-C 20 It is alkyl, and optionally one or more R Z A molecule or a pharmaceutically acceptable salt thereof that is substituted with Claim 36 In any one of paragraphs 27 through 34, R 2d is an optionally substituted C3-C 10 It is cycloalkyl, and optionally one or more R Z A molecule or a pharmaceutically acceptable salt thereof that is substituted with Claim 37 In Paragraph 36, R 2d is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl, each of which optionally has one or more R Z It is replaced with, and R Z Each is independently a halogen, -OH, -OR Za , -NR Za R Zb , or a molecule or a pharmaceutically acceptable salt thereof that is a C1-C6 alkyl. Claim 38 In any one of paragraphs 35 through 37, R Z A molecule or a pharmaceutically acceptable salt thereof, each of which is independently -F, -OH, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3. Claim 39 In any one of paragraphs 27 through 38, R 2j is non-substituted C1-C 10 An alkyl molecule or a pharmaceutically acceptable salt thereof. Claim 40 In any one of paragraphs 27 through 38, R 2j is optionally non-substituted C1-C 20 An alkyl molecule or a pharmaceutically acceptable salt thereof. Claim 41 In Paragraph 39, R 2c is methyl, ethyl, isopropyl, , , or Phosphorus, molecule, or pharmaceutically acceptable salt thereof. Claim 42 In any one of paragraphs 27 through 38, R 2j is non-substituted C1-C 10 It is alkyl, and R 2k is non-substituted C1-C 10 An alkyl molecule or a pharmaceutically acceptable salt thereof. Claim 43 In Paragraph 42, R 2j is methyl, and R 2k is a methyl, molecule, or pharmaceutically acceptable salt thereof. Claim 44 A transcription regulator molecule having a first end, a second end, and an oligomeric backbone moiety, or a pharmaceutically acceptable salt thereof, wherein a) the first end comprises a DNA-binding moiety having the structure of formula (III); Chemical formula (III), in the above formula: T B -S 1 -Q L Igo; S 1 is -C(O)NH(CH2)2- and; Q L silver is; R 2m is an optionally substituted C1-C 20 It is an alkyl group, which optionally has one or more R groups. Z It is replaced by;** is the attachment point for the above oligomer linker; and R 2c is an unsubstituted C1-C6 alkyl; R 2d and R 2e Each is an independently and selectively substituted C1-C 20 Alkyl, optionally substituted, C3-C 10 Cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl, each of which optionally has one or more R Z Replaced with;R 3b Each is hydrogen or C1-C6 alkyl; and 2 R 3b is formed with the atoms to which they are attached to form a C3-C6 cycloalkyl group; R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 It is a haloalkyl or; 2 R Z forms a C3-C6 cycloalkyl group together with the atoms to which they are attached, and R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; R Zc b) is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; c) the second end comprises a protein-binding moiety capable of binding to a regulatory molecule that regulates gene expression; and d) the oligomer backbone is a transcription regulator molecule, or a pharmaceutically acceptable salt thereof, connecting the first end and the second end. Claim 45 In Paragraph 44, R 3b Each is hydrogen, a molecule, or a pharmaceutically acceptable salt thereof. Claim 46 In paragraph 44, 2 Rs 3b A molecule or a pharmaceutically acceptable salt thereof that forms a C3-C6 cycloalkyl group together with the atoms to which they are attached. Claim 47 In paragraph 46, 2 Rs 3b A molecule or a pharmaceutically acceptable salt thereof that forms cyclopropyl together with the atoms to which they are attached. Claim 48 In any one of paragraphs 44 through 47, R 2c is a molecule or a pharmaceutically acceptable salt thereof that is methyl, ethyl, or isopropyl. Claim 49 In paragraph 44, the first terminal of formula (III) is a molecule or a pharmaceutically acceptable salt thereof having the structure of formula (IIIa): Chemical formula (IIIa). Claim 50 In any one of paragraphs 44 through 49, R 2d is an optionally substituted C1-C 20 It is alkyl, and optionally one or more R Z A molecule or a pharmaceutically acceptable salt thereof that is substituted with Claim 51 In any one of paragraphs 44 through 49, R 2d is an optionally substituted C3-C 10 It is cycloalkyl, and optionally one or more R Z A molecule or a pharmaceutically acceptable salt thereof that is substituted with Claim 52 In any one of paragraphs 44 through 51, R 2e is an optionally substituted C1-C 20 It is alkyl, and optionally one or more R Z A molecule or a pharmaceutically acceptable salt thereof that is substituted with Claim 53 In any one of paragraphs 50 through 52, R Z Each is independently a halogen, -OH, -OR Za , -NR Za R Zb , or a molecule or a pharmaceutically acceptable salt thereof that is a C1-C6 alkyl. Claim 54 In Paragraph 53, R Z A molecule or a pharmaceutically acceptable salt thereof, each of which is independently -F, -OH, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3. Claim 55 In Paragraph 52, R 2e is a molecule that is methyl, ethyl, or isopropyl. Claim 56 In any one of paragraphs 42 through 55, R 2m A molecule or a pharmaceutically acceptable salt thereof that is an unsubstituted C1-C6 alkyl. Claim 57 In Paragraph 56, R 2m A molecule or a pharmaceutically acceptable salt thereof that is methyl, ethyl, or isopropyl. Claim 58 A transcription regulator molecule having a first end, a second end, and an oligomeric backbone moiety, or a pharmaceutically acceptable salt thereof, wherein a) the first end comprises a DNA-binding moiety having the structure of formula (V); Chemical formula (V), in the above formula: T E is -Q M -Q N Igo;T F -S 3 -Q P is; S 3 is -C(O)NH(CH2)2- and;Q M silver Igo;Q N silver Igo;Q P Is is; R 2r , R 2rr , and R 2s Each is an independently and selectively substituted C1-C 20 alkyl, where each is optionally one or more R Z Replaced with; * is Q M to Q N is the attachment point of; ** is the attachment point for the above oligomer linker; R 2e is C3-C 10 It is a cycloalkyl, which optionally has one or more R Z Replaced with;R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 alkyl, or C1-C 10 It is a haloalkyl or; 2 R Z forms a C3-C6 cycloalkyl group together with the atoms to which they are attached, and R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; R Zc a) is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; b) the second end comprises a protein-binding moiety capable of binding to a regulatory molecule that regulates gene expression; and c) the oligomer backbone is a transcription regulator molecule, or a pharmaceutically acceptable salt thereof, connecting the first end and the second end. Claim 59 In paragraph 58, R 2r , R 2rr , and R 2s is an independently and optionally substituted C1-C8 alkyl, each of which optionally has one or more R Z It is replaced by; R Z Each is independently a halogen, -OH, -OR Za , or -NR Za R Zb Phosphorus, molecule, or pharmaceutically acceptable salt thereof. Claim 60 In paragraph 58, R 2r , R 2rr , and R 2s A molecule or a pharmaceutically acceptable salt thereof that is independently an unsubstituted C1-C8 alkyl. Claim 61 In any one of paragraphs 58 through 60, R 2e is an optionally substituted monocyclic, spirocyclic, or cross-linked C3-C8 cycloalkyl, each of which optionally has one or more R Z A molecule or a pharmaceutically acceptable salt thereof that is substituted with Claim 62 In Paragraph 61, R 2e is a molecule or a pharmaceutically acceptable salt thereof that is an unsubstituted monocyclic C6-C8 cycloalkyl. Claim 63 In paragraph 58, the first terminal comprises the structure of the chemical formula (Va): Chemical formula (Va), in the above formula: R Z Each is independently a halogen, -CN, -OH, -OR Za , -N3, -NR Za R Zb , -CO(O)R Zc , -C(O)OR Zc , -C(O)NR Za R Zb , -NR Za C(O)R Zc , C1-C 10 Alkyl, C1-C 10 It is a haloalkyl or; 2 R Z is formed with the atoms to which they are attached to form a C3-C6 cycloalkyl group; R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; R Zc is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; a molecule or a pharmaceutically acceptable salt thereof, where qq is 0, 1, or 2. Claim 64 In Paragraph 63, R Z Each is independently a halogen, -OH, -OR Za , -NR Za R Zb , or a molecule or a pharmaceutically acceptable salt thereof that is a C1-C6 alkyl. Claim 65 In Paragraph 64, R Z A molecule or a pharmaceutically acceptable salt thereof, each of which is independently -F, -OH, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3. Claim 66 In any one of paragraphs 63 through 65, qq is a molecule or a pharmaceutically acceptable salt thereof that is 1 or 2. Claim 67 In paragraph 63, qq is a molecule or a pharmaceutically acceptable salt thereof that is 0. Claim 68 In any one of claims 1 to 67, the first end is a molecule or a pharmaceutically acceptable salt thereof capable of binding to DNA with an affinity of less than 500 nM. Claim 69 A molecule or a pharmaceutically acceptable salt thereof, wherein the oligomer backbone is a linker having a length of less than about 50 angstroms, in any one of claims 1 to 67. Claim 70 A molecule or a pharmaceutically acceptable salt thereof, wherein the oligomer backbone is a linker having a length of about 10 to 60 Angstroms. Claim 71 In any one of claims 1 to 67, the oligomer backbone comprises a multimer having 2 to 50 spacing moiety, and each spacing moiety independently -((CR 1b R 1b ) x -O) y -, -((CR 1b R 1b ) x -NR 1a ) y -, -((CR 1b R 1b ) x -CH=CH-(CR 1b R 1b ) x -O) y -, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, selectively substituted C6-C 10 Arlylene, 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)NR 1a -, -NR 1a C(O)-, -C(O)-, -NR 1a -, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR 1a -, -NR 1a Selected from the group consisting of S(O)2-, and -P(O)OH-, and any combination thereof; x each is independently 2-4; y each is independently 1-10; and R 1a Each is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, -S(O)2-C1-C6 alkyl, -S(O)2-C1-C6 haloalkyl, -S(O)2-C3-C6 cycloalkyl, or -S(O)2N-(C1-C6 alkyl)2; R 1b A molecule or a pharmaceutically acceptable salt thereof, each of which is independently hydrogen, a halogen, an optionally substituted C1-C6 alkyl, or an optionally substituted C1-C6 haloalkyl. Claim 72 In claim 71, the oligomer backbone comprises a multimer having 2 to 50 spacing moiety, and each spacing moiety independently -((CH2) x -O) y -, -((CH2) x -NH) y A molecule or a pharmaceutically acceptable salt thereof selected from the group consisting of -, -O-, -C(O)NH-, -NH-, and any combination thereof. Claim 73 In Clause 71, the oligomer backbone is -NHC(O)((CH2) x -O) y -, -C(O)NH((CH2) x -O) y A molecule or a pharmaceutically acceptable salt thereof comprising a multimer having 2 to 50 spacing moiety selected from - Claim 74 A molecule or a pharmaceutically acceptable salt thereof, wherein the second end comprises a bromodomain binding moiety in any one of claims 1 to 73. Claim 75 A molecule or a pharmaceutically acceptable salt thereof, wherein, in any one of claims 1 to 73, the second end comprises a moiety capable of binding to a bromodomain and an extra terminal domain (BET) family member. Claim 76 In paragraph 75, the BET family member is a molecule or a pharmaceutically acceptable salt thereof which is BRD2, BRD3, BRD4, or BRDT. Claim 77 In any one of claims 1 to 73, the second end is a molecule, molecule, or pharmaceutically acceptable salt thereof that is a moiety capable of binding to CBP / p300, PCAF (P300 / CBP-associated factor), CECR2 (candidate cat eye syndrome chromosomal region 2), BRPF (bromodomain and PHD finger-containing protein), ATAD2 / ATAD2B (chromatin remodeling protein), TRIM24 (trypatite motif-containing 24), BAZ2 (bromodomain adjacent to zinc finger), TAF1 (TBP-associated factor), BRD7 / 9, BPTF (bromodomain PHD finger transcription factor), SMARCA2 / 4, or PBRM1. Claim 78 In paragraph 77, the molecule or pharmaceutically acceptable salt thereof, wherein the second end comprises a moiety capable of binding to a CBP / p300 binding moiety. Claim 79 In paragraph 77, the second terminal is a molecule or a pharmaceutically acceptable salt thereof that is a moiety capable of binding to a PCAF (P300 / CBP-associated factor) moiety. Claim 80 In any one of claims 1 to 73, the second end comprises the structure of the chemical formula (4-A): Chemical formula (4-A), wherein: ring D is absent, phenyl, or 5 to 6-membered heteroaryl; X 9 and X 10 Each is independently C or N, and X 9 or X 10 One of them is N and;L 2 is absent, optionally substituted alkylene, -O-, or -NR D -is, R D is hydrogen or optionally substituted C1-C3 alkyl; R 18 is an optionally substituted 5 to 6-membered heteroaryl; R 19 is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4 to 7-membered heteroaryl; R 20 Each is independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; x3 is an integer from 1 to 3; y4 is an integer from 1 to 4; and attachment to the linker is R 19 or R 20 A molecule or a pharmaceutically acceptable salt thereof located in. Claim 81 In claim 80, the second terminal comprises the structure of the chemical formula (4-B): Chemical formula (4-B), wherein: ring D is absent, optionally substituted phenyl, or optionally substituted 5 to 6-membered heteroaryl; X 9 and X 10 Each is independently C or N, and X 9 or X 10 One of them is N and;L 2 is absent, optionally substituted alkylene, -O-, or -NR D -is, R D is hydrogen or optionally substituted C1-C3 alkyl; R 18 is an optionally substituted 5 to 6-membered heteroaryl; R 19 is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4 to 7-membered heteroaryl; x3 is an integer from 1 to 3, a molecule or a pharmaceutically acceptable salt thereof. Claim 82 In claim 80, the second end comprises the structure of the chemical formula (4-D): Chemical formula (4-D), in the above formula: L 2 is an optionally substituted alkylene, -O-, or -NR D -is, R D is hydrogen or optionally substituted C1-C3 alkyl; R 18 is an optionally substituted 5 to 6-membered heteroaryl; R 20 A molecule or a pharmaceutically acceptable salt thereof, wherein is hydrogen, a halogen, -CN, -NO2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted C1-C6 hydroxyalkyl; x3 is an integer from 1 to 3; and y4 is an integer from 1 to 4. Claim 83 In any one of claims 1 to 73, the second end comprises the structure of the chemical formula (7-A): Chemical formula (7-A), in the above formula: A 3 is -O-, -NH-, or -CH2- and;Z 2 is CH or N; W is O or S; R 31 Each is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; or 2 R 31 ...bonds together with the atoms to which they are attached to form an optionally substituted C5-C8 cycloalkyl or an optionally substituted 5 to 8-membered heterocycloalkyl; R 32 is hydrogen or optionally substituted C1-C 10 It is alkyl and;R 32a is hydrogen or optionally substituted C1-C 10 It is alkyl and;R 33 Silver hydrogen, halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl; q6 is 0-4; and chemical formula (7-A) is R 32a or R 31 A molecule or a pharmaceutically acceptable salt thereof attached to the linker in one of the above. Claim 84 In any one of claims 1 to 73, the second terminal comprises the structure of the chemical formula (2-A): Chemical formula (2-A), wherein: ring A is an optionally substituted aryl or an optionally substituted 5- to 6-membered heteroaryl; ring B is absent or optionally substituted 6-membered monocyclic aryl or heteroaryl; D is C or N; E is O or N; Y A is -NH- or -O- and;R 5 is hydrogen or C1-C6 alkyl and R 6 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl; R 7 Silver hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Selected from heteroalkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl; R 7 -NR 7A R 7B is,R 7A and R 7B Each is independently hydrogen, optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 A molecule or a pharmaceutically acceptable salt thereof that is heteroalkyl and x1 is an integer from 1 to 6. Claim 85 In paragraph 84, the second terminal comprises the structure of the chemical formula (2-B): Chemical formula (2-B), wherein: ring A is an optionally substituted aryl or an optionally substituted 5- to 6-membered heteroaryl; ring B is absent or optionally substituted 6-membered monocyclic aryl or heteroaryl; Y A is -NH- or -O- and;R 5 is hydrogen or C1-C6 alkyl and R 6 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl; R 7 Silver hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Selected from heteroalkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl; R 7 -NR 7A R 7B is,R 7A and R 7B Each is independently hydrogen, optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 A molecule or a pharmaceutically acceptable salt thereof that is heteroalkyl and x1 is an integer from 1 to 6. Claim 86 In paragraph 84, the second terminal comprises the structure of the chemical formula (2-C): Chemical formula (2-C), wherein: ring B is an absent or optionally substituted 6-membered monocyclic aryl or heteroaryl; Y A is -NH- or -O- and;R 5 is hydrogen or C1-C6 alkyl and R 6 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl; R 7 Silver hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Selected from heteroalkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl; R 7 -NR 7A R 7B is,R 7A and R 7B Each is independently hydrogen, optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 It is heteroalkyl and;R 8 and R 9 Each is independently hydrogen, -C(O)OR 8a , selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; R 8a is hydrogen, C1-C 20 alkyl, or C1-C 20 A molecule or a pharmaceutically acceptable salt thereof that is heteroalkyl and x1 is an integer from 1 to 6. Claim 87 In claim 84, the second end of the chemical formula (2-A) has the structure of the chemical formula (2-D): Chemical formula (2-D), wherein: ring B is an absent or optionally substituted 6-membered monocyclic aryl or heteroaryl; Y A is -NH- or -O- and;R 5 is hydrogen or C1-C6 alkyl and R 6 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl; R 7 Silver hydrogen, halogen, -NO2, -CN, optionally substituted aryl, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Selected from heteroalkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C1-C6 hydroxyalkyl; R 7 -NR 7A R 7B is,R 7A and R 7B Each is independently hydrogen, optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 It is heteroalkyl; R 10 A molecule or a pharmaceutically acceptable salt thereof, wherein x1 is an integer from 1 to 6. Claim 88 In any one of claims 1 to 73, the second end comprises the structure of the chemical formula (3-A): Chemical formula (3-A), in the above formula: Y B is -CH2NH-, -CH2O-, -NH-, or -O- and;R 11A and R 11B Each is independently a hydrogen or optionally substituted C1-C6 alkyl; R 12 is hydrogen, a halogen, -OH, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted C1-C6 hydroxyalkyl; R 14 and R 15 Each is independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; R 14 is -NR A R B Igo;R 16 ... optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A , -SO2R A , or -NHSO2R A Igo;R YA is hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted 5-6 member monocyclic aryl or heteroaryl; R A and R B Each is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or optionally substituted 4 to 6-membered heteroalkyl; y1 is 1-3; and attachment to the linker is R 14 or R YA A molecule or a pharmaceutically acceptable salt thereof located in. Claim 89 In any one of claims 1 to 73, the second end comprises the structure of the chemical formula (3-B): Chemical formula (3-B), wherein: ring C is absent, optionally substituted 5 to 6-membered monocyclic aryl or heteroaryl or 4 to 8-membered heterocyclic; Y B is -NH-, -CH2NH-, -CH2O-, or -O- and; R 11A and R 11B Each is independently a hydrogen or optionally substituted C1-C6 alkyl; R 12 is hydrogen, optionally substituted C1-C6 alkyl, C(O)R A , or C(O)NR A R B is;R A and R B Each is independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 13 is hydrogen, a substituted aryl, a substituted heteroaryl, or a substituted oxydibenzene; and y2 is an integer from 0 to 2, a molecule or a pharmaceutically acceptable salt thereof. Claim 90 In claim 88, the second terminal comprises the structure of the chemical formula (3-C): Chemical formula (3-C), wherein: ring C is absent, optionally substituted 5 to 6-membered monocyclic aryl or heteroaryl or 4 to 8-membered heterocyclic; Y B is -CH2NH-, -CH2O-, -NH-, or -O- and;R 12 is hydrogen, a halogen, -OH, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted C1-C6 hydroxyalkyl; R 14 and R 15 Each is independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; R 14 is -NR A R B and; R 16 ... optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A , -SO2R A , or -NHSO2R A Igo;R A and R B Each is independently hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 hydroxyalkyl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted 4 to 6 heterocycloalkyl; and a molecule or a pharmaceutically acceptable salt thereof, wherein y1 is an integer from 1 to 3. Claim 91 In claim 88, the second end comprises the structure of the chemical formula (3-D): Chemical formula (3-D), in the above formula: R 11A and R 11B Each is independently a hydrogen or optionally substituted C1-C6 alkyl; R 12 is hydrogen or optionally substituted C1-C6 alkyl; R 15 Each is independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl;R 16 ... optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C1-C6 hydroxyalkyl, -S(O)(=NH)R A , -SO2R A , or -NHSO2R A Igo;R A is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, or optionally substituted 5 to 6-membered heteroaryl; and y1 is an integer from 1 to 3, a molecule or a pharmaceutically acceptable salt thereof. Claim 92 In any one of claims 1 to 73, the second end comprises the structure of the chemical formula (13-A): Chemical formula (13-A), wherein: ring J is absent or optionally substituted 5 to 6-membered heteroaryl; R 41 -C(O)R is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, -C(O)R 41a , -C(O)-, or -C(O)NR 41a R 41b is, R 41a and R 41b Each is an independently and selectively substituted C1-C 10 It is an alkyl or optionally substituted C3-C8 cycloalkyl; R 42 is an optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 It is a haloalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; R 43 Silver hydrogen or optionally substituted C1-C 10 It is alkyl; R 44 Each is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C8-cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; or R 43 and R 44 One of them forms a 5 to 8-membered heterocycloalkyl group that is selectively substituted together with the atoms to which they are attached; p 12 is 1-4; q3 is 0 or 1; and chemical formula (13-A) is ring J, R 41 or R 42 A molecule or a pharmaceutically acceptable salt thereof attached to the above linker. Claim 93 In any one of claims 1 to 73, the second end comprises the structure of the chemical formula (14-A): Chemical formula (14-A), wherein: ring K is a 5 to 6-membered heterocycloalkyl; A 5 is absent, CH2, -NH-, or -O-; L 4 is an alkylene or heteroalkylene; R 45 Each is independently a halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 Heteroalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C8-cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; R 46 Each is independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3 to 8-membered heterocycloalkyl; R 47 is an optionally substituted C1-C 10 Alkyl, -C(O)R 47a , or -C(O)-NR 47a R 47b is, R 47a and R 47b Each is an independently and selectively substituted C1-C 10 It is an alkyl or optionally substituted C3-C8 cycloalkyl; q4 is 2-3; q5 is 0-2; and formula (14-A) is formed through ring K or R 45 A molecule or a pharmaceutically acceptable salt thereof connected to the linker through one of the above. Claim 94 In any one of claims 1 to 73, the second end comprises the structure of the chemical formula (15-C): Chemical formula (15-C), in the above formula: X is CR 48 or N and;R 48 Each is hydrogen, halogen, -OH, -CN, -NO2, -NH2, C1-C 10 Alkyl, C1-C 10 haloalkyl, or C1-C 10 It is hydroxyalkyl and;R 49 and R 50 Each is independently hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 alkinyl and;R 51 Silver hydrogen, halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 hydroxyalkyl, optionally substituted C2-C 10 alkenyl, or optionally substituted C2-C 10 alkinyl and;R 53 Silver hydrogen or optionally substituted C1-C 10 A molecule or a pharmaceutically acceptable salt thereof that is alkyl and p7 is 1-3. Claim 95 In any one of claims 1 to 73, the second end comprises the structure of the chemical formula (16-A): Chemical formula (16-A), in the above formula: B 5 is -O-, -NH-, or S and;B 6 is N or CH and;R 54 is an optionally substituted aryl or an optionally substituted heteroaryl; R 55 Each is independently a halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Haloalkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl and;R 56 Silver hydrogen, selectively substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 It is hydroxyalkyl and;R 57 Silver halogens, -OH, -CN, -NO2, -NH2, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted C1-C 10 A molecule or a pharmaceutically acceptable salt thereof, which is hydroxyalkyl; p9 is 1-3; and q7 is 0-2. Claim 96 In any one of paragraphs 1 to 73, the second end is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or A molecule or a pharmaceutically acceptable salt thereof selected from the group consisting of , or a pharmaceutically acceptable salt thereof. Claim 97 As a molecule, , , , , , , , , , , , , , , , , , , , , , , , , , , or A molecule or a pharmaceutically acceptable salt thereof selected from. Claim 98 A pharmaceutical composition comprising a molecule according to any one of claims 1 to 97, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Claim 99 A method for reducing gene expression in a cell, wherein the method comprises contacting the cell with an effective amount of a molecule according to any one of claims 1 to 97, or a pharmaceutically acceptable salt thereof. Claim 100 In paragraph 99, the above gene is HTT Person, method. Claim 101 A method for treating Huntington's disease (HD) in a subject requiring treatment, wherein the method comprises administering to the subject a molecule according to any one of claims 1 to 97, or a pharmaceutically acceptable salt thereof. Claim 102 In paragraph 101, the above method is a method for reducing one or more symptoms of Huntington's disease. Claim 103 In paragraph 102, one or more of the above symptoms are selected from chorea, cognitive decline, abnormal sexual desire, abnormal eye movement, abnormal sense of smell, aggression, agitation, anxiety, apathy, bradykinesia, psychokinesia, clumsiness, delusions, depression, difficulty walking, disinhibition, dystonia, gait imbalance, muscle weakness, hallucinations, hostility, hypokinesia, irritability, memory impairment, myoclonus, obsessive-compulsive behavior, poor fine motor coordination, seizures, dysarthria, staring, weight loss, abnormal cholesterol metabolism, abnormal cerebral white matter, alcoholism, Babinski sign, caudate nucleus atrophy, cerebral atrophy, asphyxiation, myoclonus, striatal degeneration, excessive daytime sleepiness, visuospatial cognitive impairment, agitation, insomnia, mutism, oropharyngeal dysphagia, rigidity, suicidal ideation, cerebellar atrophy, dementia, gait ataxia, gliosis, hyperreflexia, neuronal loss, or personality change, method.

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