Methods and compounds for modulating huntington's disease

Abstract

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

Description

[0001] Cross-reference

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

[0003] This article discloses novel chimeric heterocyclic polyamide compounds and compositions, and their application as pharmaceutical agents for the treatment of diseases. Methods for modulating the expression of target genes containing CAG trinucleotide repeat sequences in subjects are also provided for the treatment of diseases such as Huntington's disease (HD). Background Technology

[0004] Huntington's disease (“HD”) was first identified as an autosomal dominant neurodegenerative disorder in the late 19th century. Symptoms of HD include a range of motor, cognitive, and psychiatric symptoms, typically appearing in adulthood. HD is associated with the presence of CAG trinucleotide repeats in the huntingtin gene (HTT), which encodes a protein called huntingtin. Subjects with more than approximately 36 trinucleotide repeats typically express symptoms of HD, with larger numbers of repeats associated with earlier onset of symptoms. The pathology stems from a cascade of steps: the production of poly-Q huntingtin, followed by the fragmentation of the elongated huntingtin into smaller peptides that bind together and accumulate in neurons. The effects of this cascade are most pronounced in the basal ganglia and cortex of the brain.

[0005] Huntington's disease-like syndrome (HDL2) refers to a range of symptoms similar to those of Huntington's disease, but lacking the characteristic mutations in the HTT gene. HDL2 is associated with approximately 40 or more CAG trinucleotide repeats in the junctophilin 3 (Jph3) gene. HDL2 is a genetic disorder observed in subjects with an African pedigree. The age of onset is negatively correlated with the number of CAG trinucleotide repeats. Symptoms of this syndrome include hypotonia and chorea (uncontrolled movements), mood disturbances, dysarthria, bradykinesia, difficulty absorbing new information, and indecisiveness. Life expectancy may range from several years to more than a decade after diagnosis. Current theory suggests that the pathology of the disease is caused by the formation of aggregates of polyglutamine protein encoded by the Jph3 gene in neuronal cells. However, there is also evidence of gain-of-function toxicity in the mRNA, indicating a possible dual pathological pathway.

[0006] In some embodiments, the mechanisms described above provide an opportunity for the effective treatment of diseases or conditions characterized by an excess number of CAG trinucleotide repeat sequences in the target gene. In some embodiments, the pathology of the disease or condition is attributed to the presence of mRNA containing an excess number of CAG trinucleotide repeat sequences. In some embodiments, the pathology of the disease or condition is attributed to the presence of translation products containing an excess number of glutamine amino acid residues. In some embodiments, the pathology of the disease or condition is attributed to loss of function of the translation product. In some embodiments, the pathology of the disease or condition is attributed to gain of function of the translation product. In some embodiments, the pathology of the disease or condition can be alleviated by increasing the transcription rate of the defective gene. In some embodiments, the pathology of the disease or condition can be alleviated by decreasing the transcription rate of the defective gene. Summary of the Invention

[0007] This disclosure utilizes regulatory molecules present in the cell nucleus that control gene expression. Eukaryotic cells provide several mechanisms for controlling gene replication, transcription, and / or translation. Regulatory molecules, generated by various intracellular biochemical mechanisms, regulate the various processes involved in the conversion of genetic information into cellular components. Several regulatory molecules are known to regulate mRNA production, and if targeted at a target gene (such as HTT), they will regulate the production of the target gene mRNA that causes diseases such as Huntington's disease or Huntington's disease-like syndromes, and thus reverse the progression of these diseases.

[0008] This document provides transcription regulator molecules for recruiting regulatory molecules to a location immediately adjacent to a target gene. In some embodiments, this document provides a transcription regulator molecule having a first end, a second end, and an oligomeric backbone portion, or a pharmaceutically acceptable salt thereof, wherein:

[0009] a) The first end contains a DNA-binding portion having the structure of formula (A-8):

[0010]

[0011] Equation (A-8),

[0012] in:

[0013] W 1 It is hydrogen, -C1-C6 haloalkyl or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or optionally substituted C1-C3 alkyl;

[0014] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Each can be either N or CH independently;

[0015] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups; each optionally substituted with one or more R Z replace;

[0016] Each R3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in

[0017] R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG;

[0018] R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0019] Or two Rs 3a Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0020] Or an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups; and

[0021] Each R Z Independent of 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 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0022] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0023] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0024] b) The second end contains a protein-binding portion capable of binding to regulatory molecules that regulate gene expression; and

[0025] c) The oligomeric backbone connects the first end and the second end.

[0026] In some embodiments, the DNA-binding moiety can selectively bind to a trinucleotide repeat sequence, such as HTT. Therefore, the recruitment moiety linked to the DNA-binding moiety will remain near the target gene; regulatory molecules will be recruited to the vicinity of the gene; and the regulatory molecules will regulate expression through direct interaction with the target gene, thus counteracting the production of the defective target gene. This mechanism can provide an effective treatment for HD caused by the expression of defective HTT, therefore correcting the expression of the defective target gene represents an effective method for treating these diseases.

[0027] The DNA-binding portion contains a polyamide segment that selectively binds to a target CAG sequence. Polyamides designed by, for example, Dervan (US Patents 9,630,950 and 8,524,899) and others, selectively bind to selected DNA sequences. These polyamides reside in the grooves of the double-helix DNA and interact with Watson-Crick base pairs through hydrogen bonds. Polyamides that selectively bind to specific DNA sequences can be designed by linking monoamide constructive blocks according to existing chemical rules. A constructive block is provided for each DNA base pair, wherein each constructive block is non-covalent and selectively binds to one of the following DNA base pairs: A / T, T / A, G / C, and C / G. According to this rule, trinucleotides bind to molecules having three amide units, i.e., triamides. Generally, these polyamides can be oriented in either direction of the DNA sequence.

[0028] In principle, longer DNA sequences can be targeted with higher specificity and / or higher affinity by combining a larger number of monoamide constructs into longer polyamide chains. Ideally, the binding affinity of the polyamide would simply equal the sum of the interactions of each individual monoamide / DNA base pair. However, in reality, due to the extremely rigid geometric mismatch between the polyamide and the DNA structure, the binding of longer polyamide sequences to longer DNA sequences is not as tight as expected based on a simple additive proportion. The geometric mismatch between longer polyamide sequences and longer DNA sequences induces unfavorable geometric strain that diminishes the originally expected binding affinity.

[0029] This disclosure provides transcription regulator molecules comprising a DNA-binding moiety (e.g., a polyamide containing polyamine subunits), said DNA-binding moiety being linked to a protein-binding moiety via a spacer (e.g., a linker portion or an oligomeric backbone). The spacer can mitigate the geometric strain that would otherwise reduce the binding affinity of a larger polyamide sequence.

[0030] However, it should be understood that in indicating particular embodiments, detailed descriptions and specific examples are provided only as illustrations, as various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description.

[0031] Incorporate by reference

[0032] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent, or patent application were specifically and individually instructed to be incorporated by reference. Where any publication, patent, or patent application incorporated by reference conflicts with any disclosure contained herein, this specification is intended to substitute for and / or give precedence to any such conflicting material. Detailed Implementation

[0033] This disclosure provides transcription regulator molecules comprising a DNA-binding moiety (e.g., a polyamide containing polyamine subunits), said DNA-binding moiety being linked to a protein-binding moiety via spacers (e.g., linker portions or oligomeric backbones). The spacers mitigate geometric strain that would otherwise reduce the binding affinity of larger polyamide sequences.

[0034] Treatment of subjects with these compounds modulates the expression of defective target genes, which in turn reduces the occurrence, severity, or frequency of symptoms associated with genetic diseases such as HD. The compounds described in this article recruit regulatory molecules to modulate the expression of defective target genes and effectively treat and alleviate disease-related symptoms.

[0035] Compounds - Transcription regulator molecules

[0036] The compounds disclosed herein are transcriptional regulator molecules. They possess useful activity in regulating the transcription of target genes (e.g., HTT) and can be used to treat or prevent diseases or conditions in which the target gene exerts its effective function. Therefore, broadly speaking, some embodiments also provide pharmaceutical compositions comprising one or more of the compounds disclosed herein and a pharmaceutically acceptable carrier, as well as methods for preparing and using said compounds and compositions.

[0037] In one aspect, this article provides a transcription regulator molecule having a first terminal, a second terminal, and a linker portion, wherein:

[0038] a) The first end contains a DNA-binding portion;

[0039] b) The second end contains a protein-binding portion capable of binding to regulatory molecules that regulate gene expression; and

[0040] c) The oligomeric backbone connects the first end and the second end.

[0041] First end - DNA binding region

[0042] The first end interacts with and binds to the gene, specifically the groove sequence. In one respect, the molecule disclosed herein provides a polyamide sequence.

[0043] In some embodiments, the DNA-binding portion comprises a polyamide selected from one or more of the following subunits:

[0044] (Py) (Im), (Th) (Pz) (Nt), (Tn), (Nh) (Fr), (Tp) (iNt) (beta or β), (gAB) (PyT) (ImT), (iIm), (ImBi) (PyBi) (Dp) , , , -NH-benzopyrazinyl-C(O)-, -NH-phenylene-C(O)-, -NH-pyridyl-C(O)-, -NH-piperidinyl-C(O)-, -NH-pyrimidinyl-C(O)-, -NH-anthrayl-C(O)-, -NH-quinolineyl-C(O)- and Each R' is independently hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Alkylamino; and Z is H, NH2, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkyl-NH2.

[0045] In some embodiments, the DNA-binding portion comprises a structure of formula (A-1), or a pharmaceutically acceptable salt thereof:

[0046]

[0047] Equation (A-1),

[0048] in:

[0049] Z 1 For non-existent, -O-, or -NH-;

[0050] W 1 Hydrogen, halogen, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated groups, -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, of which

[0051] Each R 1e Independently hydrogen or optionally substituted C1-C 10 alkyl;

[0052] Each R 1f Independently hydrogen, optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Heteroalkyl, AA p2 Alternatively, the substituted 5-membered heteroaryl group may be selected, wherein each AA is an amino acid and p2 is an integer from 1 to 10;

[0053] Z B It can be N or O;

[0054] p3 is 1 to 10;

[0055] W 2 Optionally substituted C1-C6 alkyl, -C(O)NR 1e R 1e or -C(O)NR 1e CH2CH2C(O)-, where each R 1e Independently hydrogen or optionally substituted C1-C10 alkyl;

[0056] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently N or CH;

[0057] Each X 1 X 2 X 3 X 4 X 5 X 6 X 7 and X 8 Independently for S, O or NR 2 ;

[0058] Each R 2 Independently hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, 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;

[0059] Each R 3 Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in

[0060] R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG;

[0061] R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0062] Or two Rs3 Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups;

[0063] Each R x and R y Independently hydrogen, halogen, -CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl; or

[0064] Two Rs x Or two Rs y Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups;

[0065] j1 is either 0 or 1;

[0066] m1 is 0 or 1;

[0067] n0 is 0 or 1; and

[0068] n1 is either 0 or 1;

[0069] p1 is 2 or 3, provided that Z is... 1 When Z is -O- or -NH-, p1 is 2, and when Z 1 When p1 does not exist, p1 is 3;

[0070] Among them W 1 or W 2 One of them is connected to the oligo main chain.

[0071] In some embodiments of equation (A-1), n0 is 1. In some embodiments, n0 is 0.

[0072] In some embodiments of formula (A-1), p1 is 3. In some embodiments, p1 is 2.

[0073] In some embodiments of formula (A-1), Z 1 It does not exist. In some embodiments, Z 1 For -O-. In some embodiments, Z 1 It is -NH-.

[0074] In some embodiments of formula (A-1), the DNA binding portion is via W 2 Connected to the oligomeric backbone. In some embodiments of formula (A-1), the DNA-binding portion is connected via W 1 Connect to the oligo main chain.

[0075] In some embodiments of formula (A-1), W 2 -C(O)NR 1e R 1e In some embodiments, W 2It is -C(O)NH-. In some embodiments, W 2 -C(O)NR 1e CH2CH2C(O)-. In some embodiments, W 2 It is -C(O)NHCH2CH2C(O)-.

[0076] In some embodiments of formula (A-1), W 2 The form is -C(O)NH(CH2)2C(O)-**, where the oligomeric backbone is connected at **. In some embodiments, W 2 It is -C(O)-NH-**, where the oligomeric backbone is connected at **.

[0077] In some embodiments of equation (A-1), each R 3 Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d or -NHC(O)R 3e , where R 3c and R 3d Each is independently hydrogen, alkyl, or PEG; and R 3e It is an alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl compound. In some embodiments, each R 3 Independently for -NR 3c R 3d In some embodiments, each R 3 Independently -NHC(O)R 3e In some embodiments, each R 3 It is hydrogen independently.

[0078] In some embodiments of equation (A-1), the two R 3 Together with the atoms they are attached to, they form optionally substituted C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups. In some embodiments, the two R groups... 3 Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups. In some embodiments, the two R groups... 3 Together with the atoms they are attached to, they form 4- to 6-membered heterocyclic alkyl groups. In some embodiments, the two R groups... 3 Together with the atoms they are attached to, they form a 4-membered heterocyclic alkyl group. In some embodiments, the two R groups... 3 Together with the atoms they are attached to, they form a 5-membered heterocyclic alkyl group. In some embodiments, the two R groups... 3 Together with the atoms they are attached to, they form a 6-membered heterocyclic alkyl group. In some embodiments, the two R groups... 3 Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. In some embodiments, the two R groups... 3Together with the atoms they are attached to, they form a cyclopropyl group. In some embodiments, the two R groups... 3 Together with the atoms they are attached to, they form a cyclobutyl group. In some embodiments, the two R groups... 3 Together with the atoms to which they are attached, they form a cyclopentyl group. In some embodiments, the two R groups... 3 Together with the atoms it is attached to, it forms a cyclohexyl group.

[0079] In some embodiments, the DNA-binding portion comprises the structure of formula (A-2), or a pharmaceutically acceptable salt thereof:

[0080]

[0081] Equation (A-2),

[0082] in:

[0083] W 1 It is hydrogen, -C1-C6 haloalkyl or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or optionally substituted C1-C3 alkyl;

[0084] Each X 1 X 2 X 3 X 4 X 5 X 6 X 7 and X 8 Independently for S, O or NR 2 ;

[0085] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Each can be either N or CH independently;

[0086] Each R 2 Independently hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20Halogenated alkyl groups, 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;

[0087] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in

[0088] R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG;

[0089] R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0090] Or two Rs 3a Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0091] Or an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups; and

[0092] Each R x and R y Independently hydrogen, halogen, -CN, -OH, -NH2, Cl-C 10 Alkyl or C1-C 10 Halogenated groups; or

[0093] Two Rs x Or two Rs y Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups;

[0094] j1 is 0 or 1; and

[0095] m1 and n1 are each independently 0 or 1.

[0096] In some embodiments, the DNA-binding portion comprises a structure of formula (A-3), or a pharmaceutically acceptable salt thereof:

[0097]

[0098] Equation (A-3),

[0099] in:

[0100] W 1 It is hydrogen, -C1-C6 haloalkyl or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or optionally substituted C1-C3 alkyl;

[0101] Each X 1 X 2 X 3 X 4 X 5 X 6 X 7 and X 8 Independently for S, O or NR 2 ;

[0102] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Each can be either N or CH independently;

[0103] Each R 2 Independently hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, 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;

[0104] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in

[0105] R 3cand R 3d Each can be independently hydrogen, alkyl, or PEG;

[0106] R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0107] Or two Rs 3a Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0108] Or an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0109] Each R x and R y Independently hydrogen, halogen, -CN, -OH, -NH2, Cl-C 10 Alkyl or C1-C 10 Halogenated groups; or

[0110] Two Rs x Or two Rs y Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups;

[0111] j1 is 0 or 1; and

[0112] m1 and n1 are each independently 0 or 1.

[0113] In some embodiments, the DNA-binding portion comprises a structure of formula (A-4), or a pharmaceutically acceptable salt thereof:

[0114]

[0115] Equation (A-4),

[0116] in:

[0117] W 1 It is hydrogen, -C1-C6 haloalkyl or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or optionally substituted C1-C3 alkyl;

[0118] Each X 1 X 2 X 3 X 4 X 5 X 7 and X 8 Independently for S, O or NR 2 ;

[0119] Y 1 Y 2 Y 3 Y 4 Y 5 Y 7 and Y 8 Each can be either N or CH independently;

[0120] Each R 2 Independently hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, 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;

[0121] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in

[0122] R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG;

[0123] R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0124] Or two Rs 3a Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0125] Or an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0126] Each R xIndependently hydrogen, halogen, -CN, -OH, -NH2, Cl-C 10 Alkyl or C1-C 10 Halogenated groups; or

[0127] Two Rs x Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups;

[0128] j1 is 0 or 1; and

[0129] m1 is either 0 or 1.

[0130] In some embodiments of formulas (A-1), (A-2), (A-3), or (A-4), each X 1 X 2 X 3 X 4 X 5 X 6 and X 7 Independently for -NR 2 In some embodiments, each X 1 X 2 X 3 X 4 X 5 X 6 X 7 and X 8 Independently O. In some embodiments, each X 1 X 2 X 3 X 4 X 5 X 6 X 7 and X 8 S stands independently.

[0131] In some embodiments of formulas (A-1), (A-2), (A-3), or (A-4), each R 2 Independently hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, each R 2 Independently hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, each R 2 Independently, the C1-C that can be arbitrarily replaced. 20 Alkylamino. In some embodiments, each R 2 Independently, the C1-C that can be arbitrarily replaced. 10 Alkylamino. In some embodiments, each R 2 Independently, the C1-C that can be arbitrarily replaced. 20 Haloalkyl. In some embodiments, each R 2 Independently, the C1-C that can be arbitrarily replaced. 10 Haloalkyl. In some embodiments, each R 2 Independently, the C1-C that can be arbitrarily replaced. 20 Heteroalkyl. In some embodiments, each R 2 Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, each R 2 Independently, the C1-C that can be arbitrarily replaced. 20 Hydroxyalkyl. In some embodiments, each R 2 Independently, the C1-C that can be arbitrarily replaced. 10 Hydroxyalkyl. In some embodiments, each R 2 Independently, C3-C can be arbitrarily replaced. 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, each R 2 Independently, C3-C can be arbitrarily replaced. 10 Cycloalkyl. In some embodiments, each R 2 Independently, each R is an optionally substituted 3- to 10-membered heterocyclic alkyl group. In some embodiments, each R 2 Independently, each R is an optionally substituted phenyl group. In some embodiments, each R 2 Independently, it is a 6-membered heteroaryl group that can be substituted.

[0132] In some embodiments of formulas (A-1), (A-2), (A-3), or (A-4), each R2 Independently, the C1-C that can be arbitrarily replaced. 20 Alkyl group. In some embodiments, each R 2 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl group. In some embodiments, each R 2 Independently, it is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octenyl. In some embodiments, each R 2 Independently, it is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octenyl. In some embodiments, each R 2 Methyl. In some embodiments, each R 2 Ethyl. In some embodiments, each R... 2 It is isopropyl. In some embodiments, each R... 2 For butyl. In some embodiments, each R 2 It is pentyl. In some embodiments, each R 2 For its own basis. In some embodiments, each R 2 For heptyl. In some embodiments, each R... 2 It is hydrogen.

[0133] In some embodiments of formula (A-1), (A-2), or (A-3), each R x and R y Independently hydrogen, halogen, -CN, -OH, -NH2, Cl-C 10 Alkyl or C1-C 10 Haloalkyl. In some embodiments, each R x and R y Independently hydrogen, -OH, C1-C 10 Alkyl or C1-C 10 Haloalkyl. In some embodiments, each R x and R y It is hydrogen independently.

[0134] In some embodiments of formula (A-1), (A-2), or (A-3), the two R x Or two Rs y Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups. In some embodiments, the two R... x Or two Rs y Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups. In some embodiments, the two R groups... x Or two Rs y Together with the atoms they are attached to, they form 3- to 6-membered heterocyclic alkyl groups.

[0135] In some embodiments of equation (A-4), each R x Independently hydrogen, halogen, -CN, -OH, -NH2, Cl-C 10 Alkyl or C1-C 10 Haloalkyl. In some embodiments, each R x Independently hydrogen, -OH, C1-C 10 Alkyl or C1-C 10 Haloalkyl. In some embodiments, each R x It is hydrogen independently.

[0136] In some embodiments of formulas (A-1), (A-2), (A-3), or (A-4), the two R x Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups. In some embodiments, the two R... x Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups. In some embodiments, the two R groups... x Together with the atoms they are attached to, they form 3- to 6-membered heterocyclic alkyl groups.

[0137] In some embodiments of formula (A-1), (A-2), or (A-3), the two R y Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups. In some embodiments, the two R... y Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups. In some embodiments, the two R groups... y Together with the atoms they are attached to, they form 3- to 6-membered heterocyclic alkyl groups.

[0138] In some embodiments of equations (A-1), (A-2), (A-3), or (A-4), j1 is 1. In some embodiments, j1 is 0.

[0139] In some embodiments, the DNA-binding portion comprises a structure of formula (A-5), or a pharmaceutically acceptable salt thereof:

[0140]

[0141] Equation (A-5),

[0142] in:

[0143] W 1 It is hydrogen, -C1-C6 haloalkyl or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or optionally substituted C1-C3 alkyl;

[0144] Y 1 Y 2Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Each can be either N or CH independently;

[0145] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups; each optionally substituted with one or more R Z replace;

[0146] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in

[0147] R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG;

[0148] R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0149] Or two Rs 3a Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0150] Or an R 3a And an R 3bTogether with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups; and

[0151] Each R Z Independent of 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 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0152] R Za and R Zb Each can be independently hydrogen, alkyl, haloalkyl, or PEG;

[0153] R Zc It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0154] m1 and n1 are each independently 0 or 1.

[0155] In some embodiments, the DNA-binding portion comprises a structure of formula (A-6), or a pharmaceutically acceptable salt thereof:

[0156]

[0157] Equation (A-6),

[0158] in:

[0159] W 1 It is hydrogen, -C1-C6 haloalkyl or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or optionally substituted C1-C3 alkyl;

[0160] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Each can be either N or CH independently;

[0161] Each R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups; each optionally substituted with one or more R Z replace;

[0162] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in

[0163] R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG;

[0164] R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0165] Or two Rs 3a Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0166] Or an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups; and

[0167] Each R Z Independent of 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, C1-C 10 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0168] R Za and R Zb Each can be independently hydrogen, alkyl, haloalkyl, or PEG;

[0169] R Zc It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0170] m1 and n1 are each independently 0 or 1.

[0171] In some embodiments, the DNA-binding portion comprises a structure of formula (A-7), or a pharmaceutically acceptable salt thereof:

[0172]

[0173] Equation (A-7),

[0174] in:

[0175] W 1 It is hydrogen, -C1-C6 haloalkyl or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or optionally substituted C1-C3 alkyl;

[0176] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Each can be either N or CH independently;

[0177] Each R 2a R 2b R 2c R 2d R 2e R 2f and R 2hIndependently hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups; each optionally substituted with one or more R Z replace;

[0178] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in

[0179] R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG;

[0180] R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0181] Or two Rs 3a Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0182] Or an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups; and

[0183] Each R Z Independent of 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 ZcC1-C 10 Alkyl, C1-C 10 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0184] R Za and R Zb Each can be independently hydrogen, alkyl, haloalkyl, or PEG;

[0185] R Zc It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0186] m1 is either 0 or 1.

[0187] In some embodiments, the DNA-binding portion comprises a structure of formula (A-8), or a pharmaceutically acceptable salt thereof:

[0188]

[0189] Equation (A-8),

[0190] in:

[0191] W 1 It is hydrogen, -C1-C6 haloalkyl or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or optionally substituted C1-C3 alkyl;

[0192] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Each can be either N or CH independently;

[0193] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups; each optionally substituted with one or more R Z replace;

[0194] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in

[0195] R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG;

[0196] R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0197] Or two Rs 3a Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0198] Or an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0199] Each R Z Independent of 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 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0200] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0201] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0202] In some embodiments of any of equations (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 represented by CH. In some embodiments, Y 2 Y 4 and Y 7 Each is independently N; and Y 1 and Y 3 Each is independently represented by CH.

[0203] In some embodiments of any of equations (A-1) to (A-8), each Y 5 Independently for CH. In some embodiments, each Y 5 Independently defined as N.

[0204] In some embodiments of any of equations (A-1) to (A-8), each Y 6 Independently for CH. In some embodiments, each Y 6 Independently defined as N.

[0205] In some embodiments of any of equations (A-1) to (A-8), Y 8 For CH. In some embodiments, Y 8 Let N be the number of elements in the array.

[0206] In some embodiments of formula (A-1), W 1 Hydrogen, halogen, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated groups, 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 -NR1e C(O)OR 1f In some embodiments, W 1 Hydrogen or optionally substituted C1-C 10 Alkyl group. In some embodiments, W 1 For -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 .

[0207] In some embodiments of 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, where Z B It is either O or N, and p3 is 1 to 10.

[0208] In some embodiments of any of equations (A-1) to (A-8), W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl. In some embodiments, W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e It can be hydrogen or methyl on its own.

[0209] In some embodiments of any of equations (A-1) to (A-8), W 1 It is -CF3.

[0210] In some embodiments of any of equations (A-1) to (A-8), W 1 It is hydrogen.

[0211] In some embodiments of formula (A-1), each AA is a non-natural or natural amino acid.

[0212] In some embodiments of any of equations (A-1) to (A-8), each R1e Independently hydrogen or C1-C 10 Alkyl group. In some embodiments, each R 1e Independently hydrogen or C1-C8 alkyl. In some embodiments, each R 1e Independently hydrogen or C1-C6 alkyl. In some embodiments, each R 1e Independently hydrogen or C1-C3 alkyl. In some embodiments, each R 1e It is a C1-C3 alkyl group. In some embodiments, each R 1e Independently methyl. In some embodiments, each R 1e It is hydrogen independently.

[0213] In some embodiments of equation (A-1), each R 1f Independently hydrogen, optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Heteroalkyl, optionally substituted 5-membered heteroaryl or AA 1-10 In some embodiments, each R 1f Independently hydrogen or optionally substituted C1-C 10 Alkyl group. In some embodiments, each R 1f Independently hydrogen or optionally substituted C1-C8 alkyl. In some embodiments, each R 1f Independently hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, each R 1f Independently, each R is an optional substituted C1-C6 alkyl group. In some embodiments, each R 1f Independently methyl. In some embodiments, each R 1f Independently hydrogen. In some embodiments, R 1f AA 1-10 In some embodiments, R 1f AA 1-4 In some embodiments, R 1f AA 1-3 .

[0214] In some embodiments of any of equations (A-1) to (A-7), m1 is 0. In some embodiments, m1 is 1.

[0215] In some embodiments of any of formulas (A-1), (A-2), (A-3), (A-5), or (A-6), n1 is 0. In some embodiments, n1 is 1.

[0216] In some embodiments, the DNA-binding portion comprises a structure of formula (A-9), or a pharmaceutically acceptable salt thereof:

[0217]

[0218] Equation (A-9),

[0219] in:

[0220] W 1 It is hydrogen;

[0221] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups; each optionally substituted with one or more R Z replace;

[0222] Each R 3a and R 3b It can be independently hydrogen, -OH, -NH2 or C1-C6 alkyl;

[0223] Or two Rs 3a Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0224] Each R Z Independent of 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 10Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0225] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0226] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0227] In some embodiments, the DNA-binding portion comprises a structure of formula (I), or a pharmaceutically acceptable salt thereof:

[0228]

[0229] Formula (I),

[0230] in:

[0231] W 1 It is hydrogen;

[0232] R 2a R 2c R 2d R 2e and R 2h Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups; each optionally substituted with one or more R Z replace;

[0233] Each R 3b Independently hydrogen, -NH2, or C1-C6 alkyl; or

[0234] Two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0235] Each R Z Independent of 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 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0236] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0237] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0238] In some embodiments, the DNA-binding portion includes a structure of formula (IA), or a pharmaceutically acceptable salt thereof:

[0239]

[0240] Formula (IA),

[0241] in:

[0242] W 1 It is hydrogen;

[0243] R 2a R 2c R 2d R 2e and R 2h Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups; each optionally substituted with one or more R Z replace;

[0244] Each R 3a Independently hydrogen, -NH2, or C1-C6 alkyl; or

[0245] Two Rs 3a Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups; and

[0246] Each R Z Independent of 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 Halogenated groups;

[0247] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which

[0248] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0249] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0250] In some embodiments of formula (IA), the two R 3a Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups. In some embodiments, the two R groups... 3a Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups. Two Rs 3a Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups.

[0251] In some embodiments, the DNA-binding portion of formula (IA) has the structure of formula (I-A'), or a pharmaceutically acceptable salt thereof:

[0252]

[0253] Formula (I-A').

[0254] In some embodiments of formula (I) or (IA), R 2a R 2c R 2d R 2e Or R 2h Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, optionally substituted C1-C 20 Halogenated alkyl groups or optionally substituted C3-C8 cycloalkyl groups, each optionally substituted with one or more R groups. Z Replacement. In some embodiments, R 2a R 2c R 2d R 2e Or R 2h Each is independently a optionally substituted C3-C8 cycloalkyl group. In some embodiments, R 2a R 2c R 2d R 2e Or R 2h Each can be independently a monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group.

[0255] In some embodiments of formula (I) or (IA), R 2a R 2c R 2d R 2e Or R 2h One, two, or all of them are replaced. In some embodiments, R 2a R 2c R 2d R 2e Or R 2h One or both of them are replaced. In some embodiments, R 2a R 2c R 2d R 2e Or R 2h One of them has been replaced.

[0256] In some embodiments of formula (I) or (IA), R 2a R 2c R 2d R 2e Or R 2h At least two of them are replaced. In some embodiments, R 2a R 2c R 2d R 2e Or R 2h At least one of them has been replaced.

[0257] In some embodiments of formula (I) or (IA), R 2a R 2c R 2d R 2e Or R 2h At least two of them are not unreplaced C1-C 20 Alkyl group. In some embodiments, R 2a R 2c R 2d R 2e Or R 2h At least one of them is not an unreplaced C1-C 20 Alkyl group. 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.

[0258] In some embodiments, the DNA-binding portion includes a structure of formula (Iaa), or a pharmaceutically acceptable salt thereof:

[0259]

[0260] Formula (Iaa),

[0261] in:

[0262] W 1 It is hydrogen;

[0263] R 2a Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; optionally substituted with one or more R Z replace;

[0264] Each R 3b Independently hydrogen, -NH2, or C1-C6 alkyl; or

[0265] Two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0266] Each R Z Independent of 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 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0267] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0268] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0269] In some embodiments of formula (Iaa), R 2a For the optional replacement of C1-C 20 Alkyl groups, optionally substituted C1-C 20 Halogenated alkyl groups or optionally substituted C3-C8 cycloalkyl groups, each optionally substituted with one or more R groups. Z Replacement. In some embodiments, R 2a The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2a It is a monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group. In some embodiments, R 2a Not for the unreplaced C1-C 20 Alkyl group. In some embodiments, R 2a It is not methyl.

[0270] In some embodiments, the DNA-binding portion includes a structure of formula (Ibb) or a pharmaceutically acceptable salt thereof:

[0271]

[0272] Formula (Ibb),

[0273] in:

[0274] W 1 It is hydrogen;

[0275] R 2c Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; optionally substituted with one or more R Z replace;

[0276] Each R 3b Independently hydrogen, -NH2, or C1-C6 alkyl; or

[0277] Two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0278] Each R Z Independent of 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 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0279] R Za and RZb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0280] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0281] In some embodiments of formula (Ibb), R 2c For the optional replacement of C1-C 20 Alkyl groups, optionally substituted C1-C 20 Halogenated alkyl groups or optionally substituted C3-C8 cycloalkyl groups, each optionally substituted with one or more R groups. Z Replacement. In some embodiments, R 2c The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2c It is a monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group. In some embodiments, R 2c Not for the unreplaced C1-C 20 Alkyl group. In some embodiments, R 2c It is not methyl.

[0282] In some embodiments, the DNA-binding portion includes a structure of formula (Icc), or a pharmaceutically acceptable salt thereof:

[0283]

[0284] Formula (Icc),

[0285] in:

[0286] W 1 It is hydrogen;

[0287] R 2d Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; optionally substituted with one or more R Z replace;

[0288] Each R3b Independently hydrogen, -NH2, or C1-C6 alkyl; or

[0289] Two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0290] Each R Z Independent of 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 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0291] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0292] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0293] In some embodiments of formula (Icc), R 2d For the optional replacement of C1-C 20 Alkyl groups, optionally substituted C1-C 20 Halogenated alkyl groups or optionally substituted C3-C8 cycloalkyl groups, each optionally substituted with one or more R groups. Z Replacement. In some embodiments, R 2d The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2d It is a monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group. In some embodiments, R 2d Not for the unreplaced C1-C 20 Alkyl group. In some embodiments, R 2d It is not methyl.

[0294] In some embodiments, the DNA-binding portion includes a structure of formula (Idd), or a pharmaceutically acceptable salt thereof:

[0295]

[0296] Formula (Idd),

[0297] in:

[0298] W 1 It is hydrogen;

[0299] R 2e Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; optionally substituted with one or more R Z replace;

[0300] Each R 3b Independently hydrogen, -NH2, or C1-C6 alkyl; or

[0301] Two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0302] Each R Z Independent of 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 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0303] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0304] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0305] In some embodiments of formula (Idd), R 2e For the optional replacement of C1-C 20 Alkyl groups, optionally substituted C1-C 20 Halogenated alkyl groups or optionally substituted C3-C8 cycloalkyl groups, each optionally substituted with one or more R groups. Z Replacement. In some embodiments, R 2e The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2e It is a monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group. In some embodiments, R 2e Not for the unreplaced C1-C 20 Alkyl group. In some embodiments, R 2e It is not methyl.

[0306] In some embodiments, the DNA-binding portion includes a structure of formula (Iee), or a pharmaceutically acceptable salt thereof:

[0307]

[0308] Formula (Iee),

[0309] in:

[0310] W 1 It is hydrogen;

[0311] R 2h Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; optionally substituted with one or more R Z replace;

[0312] Each R 3b Independently hydrogen, -NH2, or C1-C6 alkyl; or

[0313] Two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups;

[0314] Each R Z Independent of 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 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein

[0315] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0316] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0317] In some embodiments of formula (Iee), R 2h For the optional replacement of C1-C 20 Alkyl groups, optionally substituted C1-C 20 Halogenated alkyl groups or optionally substituted C3-C8 cycloalkyl groups, each optionally substituted with one or more R groups. Z Replacement. In some embodiments, R 2h The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2h It is a monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group. In some embodiments, R 2h Not for the unreplaced C1-C 20 Alkyl group. In some embodiments, R 2h It is not methyl.

[0318] In some embodiments, the DNA-binding portion comprises a structure of formula (I'), or a pharmaceutically acceptable salt thereof:

[0319]

[0320] Formula (I'),

[0321] in:

[0322] W 1 It is hydrogen;

[0323] R 2a R 2c R 2e and R 2h Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, each optionally containing one or more R Z replace;

[0324] R 2d For the optional replacement of C1-C 20 Alkyl or optionally substituted C3-C 10 cycloalkyl groups, each optionally bound by one or more R Z replace;

[0325] Each R 3b Independently hydrogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in

[0326] R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG;

[0327] R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0328] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups; and

[0329] Each R Z Independent of 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 Halogenated groups;

[0330] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which

[0331] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0332] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0333] The condition is when R 2d C3-C is arbitrarily replaced. 10 When cycloalkyl, then each R 3b For hydrogen; or when two Rs 3b When C3-C6 cycloalkyl groups are formed, then R 2d For the optional replacement of C1-C 20 alkyl.

[0334] In some embodiments of formula (I'), R 2d C3-C is arbitrarily replaced. 10 cycloalkyl; and each R 3b It is hydrogen.

[0335] In some embodiments of formula (I'), R 2d It can be an optionally substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group. In some embodiments, R 2d To be optionally used by one or more R Z Substituted monocyclic C6-C8 cycloalkyl groups, wherein each R Z Independent of halogen, -OH, -OR Za -NR Za R Zb Or C1-C6 alkyl. In some embodiments, R 2d for , , , , , , , , , , , , or .

[0336] In some embodiments of equation (I'), the two R 3b Together with the atoms it is attached to, it forms a C3-C6 cycloalkyl group; and R 2d For the optional replacement of C1-C 20 alkyl.

[0337] In some embodiments of equation (I'), the two R 3bTogether with the atoms it is attached to, it forms a cyclopropyl group.

[0338] In some embodiments of formula (I'), R 2d It is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2d It is methyl, ethyl, isopropyl, n-butyl, isobutyl, pentyl, or hexyl. In some embodiments, R 2d It is methyl, ethyl, or isopropyl. In some embodiments, R 2d methyl. In some embodiments, R 2d It is isopropyl.

[0339] In some embodiments of formula (I'), R 2a R 2c R 2e and R 2h Each is independently an unsubstituted C1-C8 alkyl group. In some embodiments, R 2a R 2c R 2e and R 2h Each can be methyl, ethyl, or isopropyl.

[0340] In some embodiments, the DNA-binding portion comprises a structure of formula (II), or a pharmaceutically acceptable salt thereof:

[0341]

[0342] Equation (II),

[0343] in:

[0344] T A For -Q A -Q B ;in

[0345] Q A for ;

[0346] Q B for ;in

[0347] R 2j For the optional replacement of C1-C 20 Alkyl groups, which are optionally composed of one or more R groups Z replace;

[0348] R 2k For the optional replacement of C1-C 20 Alkyl or optionally substituted C3-C 10 cycloalkyl groups, each optionally bound by one or more R Z replace;

[0349] *For Q A With Q B The connection point; and

[0350] **This is the connection point with the oligolinker;

[0351] W 1 It is hydrogen;

[0352] R 2c and R 2d Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z replace;

[0353] Each R 3b It is hydrogen or C1-C6 alkyl;

[0354] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0355] Each R Z Independent of 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 Halogenated groups;

[0356] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which

[0357] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0358] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0359] In some embodiments of equation (II), each R Z Independent of halogen, -OH, -OR Za -NR Za R Zb Or C1-C6 alkyl.

[0360] In some embodiments of formula (II), R 2c Methyl, ethyl, isopropyl, , or In some embodiments, R 2c It is methyl, ethyl, or isopropyl. In some embodiments, R 2c methyl. In some embodiments, R 2c It is isopropyl.

[0361] In some embodiments, the DNA-binding portion of formula (II) has the structure of formula (IIa), or a pharmaceutically acceptable salt thereof:

[0362]

[0363] Equation (IIa).

[0364] In some embodiments of formula (II) or (IIa), R 2d For the optional replacement of C1-C 20 Alkyl groups, which are optionally composed of one or more R groups Z Replacement. In some embodiments, R 2d C3-C is arbitrarily replaced. 10 cycloalkyl groups, optionally composed of one or more R groups Z Replacement. In some embodiments, R 2d The substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group is optionally substituted, each optionally being substituted by one or more R Z Replace, where each R Z Independent of halogen, -OH, -OR Za -NR Za R Zb Or C1-C6 alkyl.

[0365] In some embodiments of formula (II) or (IIa), R 2j For the optional replacement of C1-C 20 Alkyl group. In some embodiments, R 2j For the unreplaced C1-C 10 Alkyl group. In some embodiments, R 2j Methyl, ethyl, isopropyl, , or In some embodiments, R 2j It is methyl, ethyl, or isopropyl. In some embodiments, R 2j methyl. In some embodiments, R 2j It is isopropyl.

[0366] In some embodiments of formula (II) or (IIa), R 2k C3-C is arbitrarily replaced. 10 cycloalkyl groups, optionally composed of one or more R groups Z Replacement. In some embodiments, R 2k The substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group is optionally substituted, each optionally being substituted by one or more R Z Replace, where each R Z Independent of halogen, -OH, -OR Za -NR Za R Zb Or C1-C6 alkyl.

[0367] In some embodiments of formula (II) or (IIa), R 2k For the optional replacement of C1-C 10 Alkyl group. In some embodiments of formula (II) or (IIa), R 2k For the unreplaced C1-C 10 Alkyl group. In some embodiments, R 2k Methyl, ethyl, isopropyl, , or In some embodiments, R 2k It is methyl, ethyl, or isopropyl. In some embodiments, R 2k methyl. In some embodiments, R 2k It is isopropyl.

[0368] In some embodiments of formula (II) or (IIa), R 2j For the unreplaced C1-C 10 Alkyl and R 2k For the unreplaced C1-C 10 Alkyl group. In some embodiments, R 2j It is methyl and R 2k It is a methyl group.

[0369] In some embodiments, the DNA-binding portion comprises a structure of formula (III), or a pharmaceutically acceptable salt thereof:

[0370]

[0371] Equation (III),

[0372] in:

[0373] T B For -S 1 -Q L ;in

[0374] S 1 It is -C(O)NH(CH2)2-;

[0375] Q L for ;in

[0376] R 2m For the optional replacement of C1-C 20 Alkyl groups, which are optionally composed of one or more R groups Z Replace; and

[0377] **This is the connection point with the oligolinker;

[0378] R 2c It is an unsubstituted C1-C6 alkyl group;

[0379] R 2d and R 2e Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z replace;

[0380] Each R 3b It is hydrogen or C1-C6 alkyl;

[0381] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0382] Each R Z Independent of 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 Halogenated groups;

[0383] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which

[0384] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0385] R ZcIt can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0386] In some embodiments of formula (III), R 2c It is methyl, ethyl, or isopropyl. In some embodiments, R 2c methyl. In some embodiments, R 2c It is isopropyl.

[0387] In some embodiments, the DNA-binding portion of formula (III) has the structure of formula (IIIa), or a pharmaceutically acceptable salt thereof:

[0388]

[0389] Equation (IIIa).

[0390] In some embodiments of formula (III) or (IIIa), R 2d For the optional replacement of C1-C 20 Alkyl groups, which are optionally composed of one or more R groups Z Replacement. In some embodiments, R 2d C3-C is arbitrarily replaced. 10 cycloalkyl groups, optionally composed of one or more R groups Z Replacement. In some embodiments, R 2d The substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group is optionally substituted, each optionally being substituted by one or more R Z Replace, where each R Z Independent of halogen, -OH, -OR Za -NR Za R Zb Or C1-C6 alkyl.

[0391] In some embodiments of formula (III) or (IIIa), R 2e For the optional replacement of C1-C 20 Alkyl group. In some embodiments, R 2e It is methyl, ethyl, or isopropyl. In some embodiments, R 2e methyl. In some embodiments, R 2e It is isopropyl.

[0392] In some embodiments of formula (III) or (IIIa), R 2m It is an unsubstituted C1-C6 alkyl group. In some embodiments, R 2m It is methyl, ethyl, or isopropyl. In some embodiments, R 2m methyl. In some embodiments, R 2m It is isopropyl.

[0393] In some embodiments, the DNA-binding portion comprises a structure of formula (IV), or a pharmaceutically acceptable salt thereof:

[0394]

[0395] Formula (IV),

[0396] in:

[0397] T C For -Q C -S 2 -Q D ;

[0398] T D For -Q C -S 2 -Q E ;in

[0399] Each S 2 It is -NHC(O)(CH2)2- or -(CH2)2C(O)NH-;

[0400] Each Q C for ;

[0401] Q D for ;

[0402] Q E for ;in

[0403] R 2n R 2p and R 2q Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, each optionally containing one or more R Z Replace; and

[0404] **This is the connection point with the oligolinker;

[0405] R 2d To be optionally used by one or more R Z Replacement C3-C 10 cycloalkyl;

[0406] Each R Z Independent of halogen, -CN, -OH, -OR Za -N3, -NR Za R Zb -CO(O)R Zc -C(O)OR Zc -C(O)NR Za RZb -NR Za C(O)R Zc C1-C 10 Alkyl or C1-C 10 Halogenated groups;

[0407] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which

[0408] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0409] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0410] In some embodiments of equation (IV), each R 2n Independently, it is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2n It is methyl, ethyl, or isopropyl. In some embodiments, R 2n methyl. In some embodiments, R 2n It is isopropyl.

[0411] In some embodiments of formula (IV), T C for .

[0412] In some embodiments of formula (IV), T D for .

[0413] In some embodiments of formula (IV), R 2p and R 2q Independently, each of the optionally substituted C1-C8 alkyl groups is optionally substituted with one or more R groups. Z Replace; where each R Z Independent of halogen, -OH, -OR Za or -NR Za R Zb .

[0414] In some embodiments of equation (IV), each R 2p Independently, it is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2p It is methyl, ethyl, or isopropyl. In some embodiments, R 2p methyl. In some embodiments, R 2p It is isopropyl.

[0415] In some embodiments of equation (IV), each R 2qIndependently, it is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2q It is methyl, ethyl, or isopropyl. In some embodiments, R 2q methyl. In some embodiments, R 2q It is isopropyl.

[0416] In some embodiments of formula (IV), R 2d It can be an optionally substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group. In some embodiments, R 2d It is an unsubstituted monocyclic C6-C8 cycloalkyl group.

[0417] In some embodiments, the DNA-binding portion of formula (IV) has the structure of formula (IVa), or a pharmaceutically acceptable salt thereof:

[0418]

[0419] Formula (IVa),

[0420] in:

[0421] Each R Z Independent of 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 Halogenated groups;

[0422] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0423] R Za and R Zb Each can be independently hydrogen, alkyl, haloalkyl, or PEG;

[0424] R Zc It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0425] pp can be 0, 1, or 2.

[0426] 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.

[0427] In some embodiments, the DNA-binding portion comprises a structure of formula (V), or a pharmaceutically acceptable salt thereof:

[0428]

[0429] Equation (V),

[0430] in:

[0431] T E For -Q M -Q N ;

[0432] T F For -S 3 -Q P ;in

[0433] S 3 It is -C(O)NH(CH2)2-;

[0434] Q M for ;

[0435] Q N for ;

[0436] Q P for ;in

[0437] R 2r R 2rr and R 2s Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, each optionally containing one or more R Z replace;

[0438] *For Q M With Q N The connection point; and

[0439] **This is the connection point with the oligolinker;

[0440] R 2e To be optionally used by one or more R Z Replacement C3-C 10 cycloalkyl;

[0441] Each R Z Independent of 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 Halogenated groups;

[0442] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which

[0443] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0444] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0445] In some embodiments of formula (V), R 2e The substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group is optionally substituted, each optionally being substituted by one or more R Z Replacement. In some embodiments, R 2e It is an unsubstituted monocyclic C6-C8 cycloalkyl group.

[0446] In some embodiments of formula (V), R 2r R 2rr and R 2s Independently, each of the optionally substituted C1-C8 alkyl groups is optionally substituted with one or more R groups. Z Replace; where each R Z Independent of halogen, -OH, -OR Za or -NR Za R Zb .

[0447] In some embodiments of formula (V), R 2r R 2rr and R 2s It is an unsubstituted C1-C8 alkyl group.

[0448] In some embodiments of formula (V), R 2r It is methyl, ethyl, or isopropyl. In some embodiments, R 2r methyl. In some embodiments, R 2r It is isopropyl.

[0449] In some embodiments of formula (V), R 2rr It is methyl, ethyl, or isopropyl. In some embodiments, R 2rr methyl. In some embodiments, R 2rr It is isopropyl.

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

[0451] In some embodiments, the DNA-binding portion includes a structure of formula (Va), or a pharmaceutically acceptable salt thereof:

[0452]

[0453] Equation (Va),

[0454] in:

[0455] Each R Z Independent of 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 Halogenated groups;

[0456] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0457] R Za and R Zb Each can be independently hydrogen, alkyl, haloalkyl, or PEG;

[0458] R Zc It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0459] qq can be 0, 1, or 2.

[0460] 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.

[0461] In some embodiments, the DNA-binding portion includes the structure of formula (VI), or a pharmaceutically acceptable salt thereof:

[0462]

[0463] Formula (VI),

[0464] in:

[0465] T H For -Q F -S 4 -Q G ;in

[0466] S 4 It is -NHC(O)(CH2)2-;

[0467] Q F for ;

[0468] Q G for ;in

[0469] R 2u and R 2t Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, each optionally containing one or more R Z Replace; and

[0470] **This is the connection point with the oligolinker;

[0471] R 2a To be optionally used by one or more R Z Replacement C3-C 10 cycloalkyl;

[0472] Each R 3b It is hydrogen or C1-C6 alkyl;

[0473] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0474] Each R Z Independent of 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 Halogenated groups;

[0475] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which

[0476] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0477] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0478] In some embodiments of formula (VI), R 2a The substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group is optionally substituted, each optionally being substituted by one or more R Z Replacement. In some embodiments, R 2a It is an unsubstituted monocyclic C6-C8 cycloalkyl group.

[0479] In some embodiments of formula (VI), R 2u and R 2t Independently, each of the optionally substituted C1-C8 alkyl groups is optionally substituted with one or more R groups. Z Replace; where each R Z Independent of halogen, -OH, -OR Za or -NR Za R Zb .

[0480] In some embodiments of formula (VI), R 2u It is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2u It is methyl, ethyl, or isopropyl. In some embodiments, R 2u methyl. In some embodiments, R 2u It is isopropyl.

[0481] In some embodiments of formula (VI), R 2t It is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2t It is methyl, ethyl, or isopropyl. In some embodiments, R 2t methyl. In some embodiments, R 2t It is isopropyl.

[0482] In some embodiments, the DNA-binding portion of formula (VI) has the structure of formula (VIa), or a pharmaceutically acceptable salt thereof:

[0483]

[0484] Formula (VIa),

[0485] in:

[0486] Each R ZIndependent of 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 Halogenated groups;

[0487] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0488] R Za and R Zb Each can be independently hydrogen, alkyl, haloalkyl, or PEG;

[0489] R Zc It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0490] rr can be 0, 1, or 2.

[0491] 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.

[0492] In some embodiments, the DNA-binding portion comprises the structure of formula (VII), or a pharmaceutically acceptable salt thereof:

[0493]

[0494] Equation (VII),

[0495] in:

[0496] W 3 for ;

[0497] T G For -Q F -S 5 -Q G ;in

[0498] S 5 It is -NHC(O)(CH2)2-;

[0499] Q F for ;

[0500] QG for ;in

[0501] R 2a R 2w and R 2v Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, each optionally containing one or more R Z Replace; and

[0502] **This is the connection point with the oligolinker;

[0503] R 2b To be optionally used by one or more R Z Replacement C3-C 10 cycloalkyl;

[0504] Each R 3b It is hydrogen or C1-C6 alkyl;

[0505] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0506] Each R Z Independent of 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 Halogenated groups;

[0507] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which

[0508] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0509] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0510] In some embodiments of formula (VII), R 2b The substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group is optionally substituted, each optionally being substituted by one or more R Z Replacement. In some embodiments, R 2bIt is an unsubstituted monocyclic C6-C8 cycloalkyl group.

[0511] In some embodiments of formula (VII), R 2a R 2w and R 2v Independently, each of the optionally substituted C1-C8 alkyl groups is optionally substituted with one or more R groups. Z Replace; where each R Z Independent of halogen, -OH, -OR Za or -NR Za R Zb .

[0512] In some embodiments of formula (VII), R 2a It is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2a It is methyl, ethyl, or isopropyl. In some embodiments, R 2a methyl. In some embodiments, R 2a It is isopropyl.

[0513] In some embodiments of formula (VII), R 2w It is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2w It is methyl, ethyl, or isopropyl. In some embodiments, R 2w methyl. In some embodiments, R 2w It is isopropyl.

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

[0515] In some embodiments, the DNA-binding portion of formula (VII) has the structure of formula (VIIa), or a pharmaceutically acceptable salt thereof:

[0516]

[0517] Equation (VIIa),

[0518] in:

[0519] Each R Z Independent of 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 Halogenated groups;

[0520] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0521] R Za and R Zb Each can be independently hydrogen, alkyl, haloalkyl, or PEG;

[0522] R Zc It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0523] ss can be 0, 1, or 2.

[0524] 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.

[0525] In some embodiments, the DNA-binding portion includes the structure of formula (VIII), or a pharmaceutically acceptable salt thereof:

[0526]

[0527] Equation (VIII),

[0528] in:

[0529] T H for ;

[0530] T J for ;in

[0531] R 2y and R 2z Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, each optionally containing one or more R Z Replace; and

[0532] **This is the connection point with the oligolinker;

[0533] R 2f To be optionally used by one or more R Z Replacement C3-C 10 cycloalkyl;

[0534] Each R Z Independent of 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 Halogenated groups;

[0535] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which

[0536] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0537] R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0538] In some embodiments of formula (VIII), R 2f The substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group is optionally substituted, each optionally being substituted by one or more R Z Replacement. In some embodiments, R 2f It is an unsubstituted monocyclic C6-C8 cycloalkyl group.

[0539] In some embodiments of formula (VIII), R 2z and R 2y Independently, each of the optionally substituted C1-C8 alkyl groups is optionally substituted with one or more R groups. Z Replace; where each R Z Independent of halogen, -OH, -OR Za or -NR Za R Zb .

[0540] In some embodiments of formula (VIII), R 2z It is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2z It is methyl, ethyl, or isopropyl. In some embodiments, R 2z methyl. In some embodiments, R 2z It is isopropyl.

[0541] In some embodiments of formula (VIII), R2y It is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2y It is methyl, ethyl, or isopropyl. In some embodiments, R 2y methyl. In some embodiments, R 2y It is isopropyl.

[0542] In some embodiments, the DNA-binding portion of formula (VIII) has the structure of formula (VIIIa), or a pharmaceutically acceptable salt thereof:

[0543]

[0544] Equation (VIIIa),

[0545] in:

[0546] Each R Z Independent of 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 Halogenated groups;

[0547] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0548] R Za and R Zb Each can be independently hydrogen, alkyl, haloalkyl, or PEG;

[0549] R Zc It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0550] tt can be 0, 1, or 2.

[0551] In some embodiments of formula (VIII) or (VIIIa), tt is 1 or 2. In some embodiments, tt is 0. In some embodiments, tt is 1. In some embodiments, tt is 2.

[0552] In some embodiments, the DNA-binding portion includes the structure of formula (IX), or a pharmaceutically acceptable salt thereof:

[0553]

[0554] Equation (IX),

[0555] in:

[0556] T K For -Q J -S 6 -Q K ;in

[0557] S 6 It is -NHC(O)(CH2)2- or -(CH2)2C(O)NH-;

[0558] Q J for ;

[0559] Q K for ;in

[0560] R 2L and R 2X Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, each optionally containing one or more R Z Replace; and

[0561] **This is the connection point with the S group;

[0562] R 2h To be optionally used by one or more R Z Replacement C3-C 10 cycloalkyl;

[0563] Each R Z Independent of 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 Halogenated groups;

[0564] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which

[0565] R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and

[0566] RZc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

[0567] In some embodiments of formula (IX), R 2f The substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group is optionally substituted, each optionally being substituted by one or more R Z Replacement. In some embodiments, R 2f It is an unsubstituted monocyclic C6-C8 cycloalkyl group.

[0568] In some embodiments of formula (IX), R 2x and R 2L Independently, each of the optionally substituted C1-C8 alkyl groups is optionally substituted with one or more R groups. Z Replace; where each R Z Independent of halogen, -OH, -OR Za or -NR Za R Zb .

[0569] In some embodiments of formula (IX), R 2x It is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2x It is methyl, ethyl, or isopropyl. In some embodiments, R 2x methyl. In some embodiments, R 2x It is isopropyl.

[0570] In some embodiments of formula (IX), R 2L It is an unsubstituted C1-C8 alkyl group. In some embodiments, R 2L It is methyl, ethyl, or isopropyl. In some embodiments, R 2L methyl. In some embodiments, R 2L It is isopropyl.

[0571] In some embodiments, the DNA-binding portion of formula (IX) has the structure of formula (IXa), or a pharmaceutically acceptable salt thereof:

[0572]

[0573] Equation (IXa),

[0574] in:

[0575] Each R Z Independent of 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 Halogenated groups;

[0576] Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0577] R Za and R Zb Each can be independently hydrogen, alkyl, haloalkyl, or PEG;

[0578] R Zc It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0579] uu can be 0, 1, or 2.

[0580] 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.

[0581] In some embodiments of any of formulas (A-5) to (A-9), (I), (IA), (I-A'), or (Iaa), R 2a Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z Replacement. In some embodiments, R 2a For the optional replacement of C1-C 10 Alkylamino. In some embodiments, R 2a For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2a For the optional replacement of C1-C 20Heteroalkyl. In some embodiments, R 2a Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, R 2a For the optional replacement of C1-C 20 Hydroxyalkyl. In some embodiments, R 2a For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2a C3-C is arbitrarily replaced. 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, R 2a It is hydrogen.

[0582] In some embodiments of any of formulas (A-5) to (A-9), (I), (I'), (IA), (Iaa), or (VII), R 2a For the optional replacement of C1-C 20 Alkyl group. In some embodiments, R 2a For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 2a It is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2a It is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2a methyl. In some embodiments, R 2a It is ethyl. In some embodiments, R 2a It is isopropyl. In some embodiments, R... 2a It is butyl. In some embodiments, R 2a It is pentyl. In some embodiments, R 2a For its own basis. In some embodiments, R 2a It is heptyl. In some embodiments, R 2a For the optional replacement of C1-C 20 Haloalkyl. In some embodiments, R 2a For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2a For -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2a For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2a for , , , , or .

[0583] In some embodiments of any of equations (A-5) to (A-9), R 2b Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z Replacement. In some embodiments, R 2b For the optional replacement of C1-C 10 Alkylamino. In some embodiments, R 2b For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2b For the optional replacement of C1-C 20 Heteroalkyl. In some embodiments, R 2b For the optional replacement of C1-C 10 Heteroalkyl. In some embodiments, R 2b For the optional replacement of C1-C 20 Hydroxyalkyl. In some embodiments, R 2b C3-C is arbitrarily replaced. 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, R 2b It is hydrogen.

[0584] In some embodiments of any of equations (A-5) to (A-9), R 2b For the optional replacement of C1-C 20 Alkyl group. In some embodiments, R 2b For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 2b It is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2bIt is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2b methyl. In some embodiments, R 2b It is ethyl. In some embodiments, R 2b It is isopropyl. In some embodiments, R... 2b It is butyl. In some embodiments, R 2b It is pentyl. In some embodiments, R 2b For its own basis. In some embodiments, R 2b It is heptyl. In some embodiments, R 2b For the optional replacement of C1-C 20 Haloalkyl. In some embodiments, R 2b For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2b For -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2b For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2b for , , , , or .

[0585] In some embodiments of any of formulas (A-5) to (A-9), (I), (IA), (I-A'), or (Ibb), R 2c Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z Replacement. In some embodiments, R 2c For the optional replacement of C1-C 10 Alkylamino. In some embodiments, R2c For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2c For the optional replacement of C1-C 20 Heteroalkyl. In some embodiments, R 2c Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, R 2c For the optional replacement of C1-C 20 Hydroxyalkyl. In some embodiments, R 2c For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2c C3-C is arbitrarily replaced. 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, R 2c It is hydrogen.

[0586] In some embodiments of any of formulas (A-5) to (A-9), (I), (I'), (IA), (Ibb), or (II), R 2c For the optional replacement of C1-C 20 Alkyl group. In some embodiments, R 2c For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 2c It is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2c It is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2c methyl. In some embodiments, R 2c It is ethyl. In some embodiments, R 2c It is isopropyl. In some embodiments, R... 2c It is butyl. In some embodiments, R 2c It is pentyl. In some embodiments, R 2c For its own basis. In some embodiments, R 2c It is heptyl. In some embodiments, R 2c For the optional replacement of C1-C 20 Haloalkyl. In some embodiments, R 2c For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2c For -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2c For the optional replacement of C1-C 10Hydroxyalkyl. In some embodiments, R 2c for , , , , or .

[0587] In some embodiments of any of formulas (A-5) to (A-9), (I), (I'), (IA), (I-A'), or (Icc), R 2d Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z Replacement. In some embodiments, R 2d For the optional replacement of C1-C 10 Alkylamino. In some embodiments, R 2d For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2d For the optional replacement of C1-C 20 Heteroalkyl. In some embodiments, R 2d Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, R 2d For the optional replacement of C1-C 20 Hydroxyalkyl. In some embodiments, R 2d For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2d C3-C is arbitrarily replaced. 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, R 2d It is hydrogen.

[0588] In some embodiments of any of formulas (A-1) to (A-9), (I), (I'), (IA), (Icc), (II) or (III), R 2d For the optional replacement of C1-C 20 Alkyl group. In some embodiments, R 2a For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 2d It is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2d It is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2d methyl. In some embodiments, R 2d It is ethyl. In some embodiments, R 2d It is isopropyl. In some embodiments, R... 2d It is butyl. In some embodiments, R 2d It is pentyl. In some embodiments, R 2d For its own basis. In some embodiments, R 2d It is heptyl. In some embodiments, R 2d For the optional replacement of C1-C 20 Haloalkyl. In some embodiments, R 2d For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2d For -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2d For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2d for , , , , or .

[0589] In some embodiments of any of formulas (A-5) to (A-9), (I), (IA), (I-A'), or (Idd), R 2e Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z Replacement. In some embodiments, R 2e For the optional replacement of C1-C 10 Alkylamino. In some embodiments, R 2e For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2e For the optional replacement of C1-C 20 Heteroalkyl. In some embodiments, R 2e Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, R 2e For the optional replacement of C1-C 20 Hydroxyalkyl. In some embodiments, R 2e For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2e C3-C is arbitrarily replaced. 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, R 2e It is hydrogen.

[0590] In some embodiments of any of formulas (A-5) to (A-9), (I), (I'), (IA), (I-A'), or (Idd), R 2e For the optional replacement of C1-C 20 Alkyl group. In some embodiments, R 2e For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 2e It is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2e It is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2e methyl. In some embodiments, R 2e It is ethyl. In some embodiments, R 2e It is isopropyl. In some embodiments, R... 2e It is butyl. In some embodiments, R 2e It is pentyl. In some embodiments, R 2e For its own basis. In some embodiments, R2e It is heptyl. In some embodiments, R 2e For the optional replacement of C1-C 20 Haloalkyl. In some embodiments, R 2e For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2e For -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2e For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2e for , , , , or .

[0591] In some embodiments of any of formulas (A-5), (A-6), or (A-7), R 2f Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z Replacement. In some embodiments, R 2f For the optional replacement of C1-C 10 Alkylamino. In some embodiments, R 2f For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2f For the optional replacement of C1-C 20 Heteroalkyl. In some embodiments, R 2f Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, R 2f For the optional replacement of C1-C 20 Hydroxyalkyl. In some embodiments, R 2f For the optional replacement of C1-C10 Hydroxyalkyl. In some embodiments, R 2f C3-C is arbitrarily replaced. 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, R 2f It is hydrogen.

[0592] In some embodiments of any of formulas (A-5), (A-6), or (A-7), R 2f For the optional replacement of C1-C 20 Alkyl group. In some embodiments, R 2f For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 2f It is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2f It is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2f methyl. In some embodiments, R 2f It is ethyl. In some embodiments, R 2f It is isopropyl. In some embodiments, R... 2f It is butyl. In some embodiments, R 2f It is pentyl. In some embodiments, R 2f For its own basis. In some embodiments, R 2f It is heptyl. In some embodiments, R 2f For the optional replacement of C1-C 20 Haloalkyl. In some embodiments, R 2f For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2f For -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2f For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2f for , , , , or .

[0593] In some embodiments of any of formulas (A-5), (A-6), (A-8), or (A-9), R 2g Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z Replacement. In some embodiments, R 2g For the optional replacement of C1-C 10 Alkylamino. In some embodiments, R 2g For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2g For the optional replacement of C1-C 20 Heteroalkyl. In some embodiments, R 2g Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, R 2g For the optional replacement of C1-C 20 Hydroxyalkyl. In some embodiments, R 2g For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2g C3-C is arbitrarily replaced. 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, R 2g It is hydrogen.

[0594] In some embodiments of any of formulas (A-5), (A-6), (A-8), or (A-9), R 2g For the optional replacement of C1-C 20 Alkyl group. In some embodiments, R 2g For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 2g It is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2g It is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2a methyl. In some embodiments, R 2g It is ethyl. In some embodiments, R 2g It is isopropyl. In some embodiments, R...2g It is butyl. In some embodiments, R 2g It is pentyl. In some embodiments, R 2g For its own basis. In some embodiments, R 2g It is heptyl. In some embodiments, R 2g For the optional replacement of C1-C 20 Haloalkyl. In some embodiments, R 2g For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2g For -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2g For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2g for , , , , or .

[0595] In some embodiments of any of formulas (A-5) to (A-9), (I), (IA), (I-A'), or (Iee), R 2h Hydrogen, optionally substituted C1-C 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z Replacement. In some embodiments, R 2h For the optional replacement of C1-C 10 Alkylamino. In some embodiments, R 2h For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2h For the optional replacement of C1-C 20 Heteroalkyl. In some embodiments, R 2h Independently, the C1-C that can be arbitrarily replaced.10 Heteroalkyl. In some embodiments, R 2h For the optional replacement of C1-C 20 Hydroxyalkyl. In some embodiments, R 2h For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2h C3-C is arbitrarily replaced. 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, R 2h It is hydrogen.

[0596] In some embodiments of any of formulas (A-5) to (A-9), (I), (I'), (IA), (I-A'), or (Iee), R 2h For the optional replacement of C1-C 20 Alkyl group. In some embodiments, R 2h For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 2h It is methyl, ethyl, propyl, butyl, propyl, hexyl, heptyl, or octyl. In some embodiments, R 2h It is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-propyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 2h methyl. In some embodiments, R 2h It is ethyl. In some embodiments, R 2h It is isopropyl. In some embodiments, R... 2h It is butyl. In some embodiments, R 2h It is pentyl. In some embodiments, R 2h For its own basis. In some embodiments, R 2h It is heptyl. In some embodiments, R 2h For the optional replacement of C1-C 20 Haloalkyl. In some embodiments, R 2h For the optional replacement of C1-C 10 Haloalkyl. In some embodiments, R 2h For -CF3, -CH2CF3, or -CH2CH2CF3. In some embodiments, R 2h For the optional replacement of C1-C 10 Hydroxyalkyl. In some embodiments, R 2h for , , , , or .

[0597] In some embodiments of any of formulas (A-5) to (A-9), (I), (IA), (I-A'), (Iaa), or (VI), R 2a C3-C is arbitrarily replaced. 10 Cycloalkyl. In some embodiments, R 2a The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2a The substituted monocyclic, bicyclic, polycyclic, spirocyclic, or bridged cycloalkyl group is optionally substituted. In some embodiments, R 2a R is an optionally substituted monocyclic cycloalkyl group. In some embodiments, R 2a R is an optionally substituted spirocycloalkyl group. In some embodiments, R 2a The bridging cycloalkyl group can be optionally substituted. In some embodiments, R 2a It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2a It is cyclopropyl. In some embodiments, R 2a It is cyclobutyl. In some embodiments, R 2a It is cyclopentyl. In some embodiments, R 2a It is cyclohexyl. In some embodiments, R 2a It is cyclohexyl. In some embodiments, R 2a for , , , , , , , , , , , , , or In some embodiments, R 2a The substituted alkyl group is optionally a 3- to 10-membered heterocyclic alkyl group. In some embodiments, R 2a The substituted alkyl group is optionally a 3- to 8-membered heterocyclic alkyl group. In some embodiments, R 2a It is a ternary, quaternary, quinary, or 6-membered heterocyclic alkyl group. In some embodiments, R 2a for , , , , , , , , or .

[0598] In some embodiments of any of formulas (A-5) to (A-9) or (VII), R 2b C3-C is arbitrarily replaced. 10 Cycloalkyl. In some embodiments, R 2b The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2b The substituted monocyclic, bicyclic, polycyclic, spirocyclic, or bridged cycloalkyl group is optionally substituted. In some embodiments, R 2b R is an optionally substituted monocyclic cycloalkyl group. In some embodiments, R 2b R is an optionally substituted spirocycloalkyl group. In some embodiments, R 2b The bridging cycloalkyl group can be optionally substituted. In some embodiments, R 2b It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2b It is cyclopropyl. In some embodiments, R 2b It is cyclobutyl. In some embodiments, R 2b It is cyclopentyl. In some embodiments, R 2b It is cyclohexyl. In some embodiments, R 2b It is cyclohexyl. In some embodiments, R 2b for , , , , , , , , , , , , , or In some embodiments, R 2b The substituted alkyl group is optionally a 3- to 10-membered heterocyclic alkyl group. In some embodiments, R 2b The substituted alkyl group is optionally a 3- to 8-membered heterocyclic alkyl group. In some embodiments, R 2b It is a ternary, quaternary, quinary, or 6-membered heterocyclic alkyl group. In some embodiments, R 2b for , , , , , , , , or .

[0599] In some embodiments of any of formulas (A-5) to (A-9), (I), (I'), (IA), or (Ibb), R 2c C3-C is arbitrarily replaced. 10 Cycloalkyl. In some embodiments, R 2c The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2c The substituted monocyclic, bicyclic, polycyclic, spirocyclic, or bridged cycloalkyl group is optionally substituted. In some embodiments, R 2c R is an optionally substituted monocyclic cycloalkyl group. In some embodiments, R 2c R is an optionally substituted spirocycloalkyl group. In some embodiments, R 2c The bridging cycloalkyl group can be optionally substituted. In some embodiments, R 2c It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2c It is cyclopropyl. In some embodiments, R 2c It is cyclobutyl. In some embodiments, R 2c It is cyclopentyl. In some embodiments, R 2c It is cyclohexyl. In some embodiments, R 2c It is cyclohexyl. In some embodiments, R 2c for , , , , , , , , , , , , , or In some embodiments, R 2c The substituted alkyl group is optionally a 3- to 10-membered heterocyclic alkyl group. In some embodiments, R 2c The substituted alkyl group is optionally a 3- to 8-membered heterocyclic alkyl group. In some embodiments, R 2c It is a ternary, quaternary, quinary, or 6-membered heterocyclic alkyl group. In some embodiments, R 2c for , , , , , , , , or .

[0600] In some embodiments of any of formulas (A-5) to (A-9), (I), (I'), (IA), (Icc), (II), (III) or (IV), R 2d C3-C is arbitrarily replaced. 10 Cycloalkyl. In some embodiments, R 2d The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2d The substituted monocyclic, bicyclic, polycyclic, spirocyclic, or bridged cycloalkyl group is optionally substituted. In some embodiments, R 2d R is an optionally substituted monocyclic cycloalkyl group. In some embodiments, R 2d R is an optionally substituted spirocycloalkyl group. In some embodiments, R 2d The bridging cycloalkyl group can be optionally substituted. In some embodiments, R 2d It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2d It is cyclopropyl. In some embodiments, R 2d It is cyclobutyl. In some embodiments, R 2d It is cyclopentyl. In some embodiments, R 2d It is cyclohexyl. In some embodiments, R 2d It is cyclohexyl. In some embodiments, R 2d for , , , , , , , , , , , , , or In some embodiments, R 2d The substituted alkyl group is optionally a 3- to 10-membered heterocyclic alkyl group. In some embodiments, R 2d The substituted alkyl group is optionally a 3- to 8-membered heterocyclic alkyl group. In some embodiments, R 2d It is a ternary, quaternary, quinary, or 6-membered heterocyclic alkyl group. In some embodiments, R 2d for , , , , , , , , or .

[0601] In some embodiments of any of formulas (A-5) to (A-9), (I), (I'), (IA), (Idd), or (V), R 2e C3-C is arbitrarily replaced. 10 Cycloalkyl. In some embodiments, R 2e The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2e The substituted monocyclic, bicyclic, polycyclic, spirocyclic, or bridged cycloalkyl group is optionally substituted. In some embodiments, R 2e R is an optionally substituted monocyclic cycloalkyl group. In some embodiments, R 2e R is an optionally substituted spirocycloalkyl group. In some embodiments, R 2e The bridging cycloalkyl group can be optionally substituted. In some embodiments, R 2e It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2e It is cyclopropyl. In some embodiments, R 2e It is cyclobutyl. In some embodiments, R 2e It is cyclopentyl. In some embodiments, R 2e It is cyclohexyl. In some embodiments, R 2e It is cyclohexyl. In some embodiments, R 2e for , , , , , , , , , , , , , or In some embodiments, R 2e The substituted alkyl group is optionally a 3- to 10-membered heterocyclic alkyl group. In some embodiments, R 2e The substituted alkyl group is optionally a 3- to 8-membered heterocyclic alkyl group. In some embodiments, R 2e It is a ternary, quaternary, quinary, or 6-membered heterocyclic alkyl group. In some embodiments, R 2e for , , , , , , , , or .

[0602] In some embodiments of any of formulas (A-5) to (A-9), (I), (I'), (IA), or (VIII), R 2f C3-C is arbitrarily replaced. 10 Cycloalkyl. In some embodiments, R 2f The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2f The substituted monocyclic, bicyclic, polycyclic, spirocyclic, or bridged cycloalkyl group is optionally substituted. In some embodiments, R 2f R is an optionally substituted monocyclic cycloalkyl group. In some embodiments, R 2f R is an optionally substituted spirocycloalkyl group. In some embodiments, R 2f The bridging cycloalkyl group can be optionally substituted. In some embodiments, R 2f It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2f It is cyclopropyl. In some embodiments, R 2f It is cyclobutyl. In some embodiments, R 2a It is cyclopentyl. In some embodiments, R 2f It is cyclohexyl. In some embodiments, R 2f It is cyclohexyl. In some embodiments, R 2f for , , , , , , , , , , , , , or In some embodiments, R 2f The substituted alkyl group is optionally a 3- to 10-membered heterocyclic alkyl group. In some embodiments, R 2f The substituted alkyl group is optionally a 3- to 8-membered heterocyclic alkyl group. In some embodiments, R 2f It is a ternary, quaternary, quinary, or 6-membered heterocyclic alkyl group. In some embodiments, R 2f for , , , , , , , , or .

[0603] In some embodiments of any of formulas (A-5) to (A-9), (I), (IA), (I-A'), (Iee), or (IX), R 2h C3-C is arbitrarily replaced. 10 Cycloalkyl. In some embodiments, R 2h The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 2h The substituted monocyclic, bicyclic, polycyclic, spirocyclic, or bridged cycloalkyl group is optionally substituted. In some embodiments, R 2h R is an optionally substituted monocyclic cycloalkyl group. In some embodiments, R 2h R is an optionally substituted spirocycloalkyl group. In some embodiments, R 2h The bridging cycloalkyl group can be optionally substituted. In some embodiments, R 2h It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexyl. In some embodiments, R 2h It is cyclopropyl. In some embodiments, R 2h It is cyclobutyl. In some embodiments, R 2h It is cyclopentyl. In some embodiments, R 2h It is cyclohexyl. In some embodiments, R 2h It is cyclohexyl. In some embodiments, R 2h for , , , , , , , , , , , , , or In some embodiments, R 2h The substituted alkyl group is optionally a 3- to 10-membered heterocyclic alkyl group. In some embodiments, R 2h The substituted alkyl group is optionally a 3- to 8-membered heterocyclic alkyl group. In some embodiments, R 2h It is a ternary, quaternary, quinary, or 6-membered heterocyclic alkyl group. In some embodiments, R 2h for , , , , , , , , or .

[0604] In some embodiments of any of equations (A-2) to (A-9) or (IA), each R 3a Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d or -NHC(O)R 3e , where R 3c and R 3d Each is independently hydrogen, alkyl, or PEG; and R 3e It is an alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl compound. In some embodiments, each R 3a Independently for -NR 3c R 3d In some embodiments, each R 3a For -NH2. In some embodiments, each R 3a Independently -NHC(O)R 3e In some embodiments, each R 3a It is hydrogen.

[0605] In some embodiments of any of equations (A-2) to (A-9), (I), (I'), (Iaa), (Ibb), (Icc), (Idd), (Iee), (II), (III), (VI), or (VII), each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d or -NHC(O)R 3e , where R 3c and R 3d Each is independently hydrogen, alkyl, or PEG; and R 3e It is an alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl compound. In some embodiments, each R 3b Independently for -NR 3c R 3d In some embodiments, each R 3b For -NH2. In some embodiments, each R 3b Independently -NHC(O)R 3e In some embodiments, each R 3b It is hydrogen.

[0606] In some embodiments of any of equations (A-2) to (A-9), (I), (I'), (Iaa), (Ibb), (Icc), (Idd), (Iee), (II), (III), (VI), or (VII), each R 3b Independently hydrogen, -NH2, or C1-C6 alkyl. In some embodiments, each R 3bIndependently hydrogen or -NH2. In some embodiments, each R 3b It is hydrogen.

[0607] In some embodiments of any of equations (A-2) to (A-9) or (IA), the two R 3a Together with the atoms they are attached to, they form optionally substituted C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups. In some embodiments, the two R groups... 3a Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups. In some embodiments, the two R groups... 3a Together with the atoms they are attached to, they form 4- to 6-membered heterocyclic alkyl groups. In some embodiments, the two R groups... 3a Together with the atoms they are attached to, they form a 4-membered heterocyclic alkyl group. In some embodiments, the two R groups... 3a Together with the atoms they are attached to, they form a 5-membered heterocyclic alkyl group. In some embodiments, the two R groups... 3a Together with the atoms they are attached to, they form a 6-membered heterocyclic alkyl group. In some embodiments, the two R groups... 3a Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. In some embodiments, the two R groups... 3a Together with the atoms they are attached to, they form a cyclopropyl group. In some embodiments, the two R groups... 3a Together with the atoms they are attached to, they form a cyclobutyl group. In some embodiments, the two R groups... 3a Together with the atoms to which they are attached, they form a cyclopentyl group. In some embodiments, the two R groups... 3a Together with the atoms it is attached to, it forms a cyclohexyl group.

[0608] In some embodiments of any of equations (A-2) to (A-9), (I), (I'), (Iaa), (Ibb), (Icc), (Idd), (Iee), (II), (III), (VI), or (VII), the two R 3b Together with the atoms they are attached to, they form optionally substituted C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups. In some embodiments, the two R groups... 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups. In some embodiments, the two R groups... 3b Together with the atoms they are attached to, they form 4- to 6-membered heterocyclic alkyl groups. In some embodiments, the two R groups... 3b Together with the atoms they are attached to, they form a 4-membered heterocyclic alkyl group. In some embodiments, the two R groups... 3b Together with the atoms they are attached to, they form a 5-membered heterocyclic alkyl group. In some embodiments, the two R groups... 3b Together with the atoms they are attached to, they form a 6-membered heterocyclic alkyl group. In some embodiments, the two R groups... 3bTogether with the atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. In some embodiments, the two R groups... 3b Together with the atoms they are attached to, they form a cyclopropyl group. In some embodiments, the two R groups... 3b Together with the atoms they are attached to, they form a cyclobutyl group. In some embodiments, the two R groups... 3b Together with the atoms to which they are attached, they form a cyclopentyl group. In some embodiments, the two R groups... 3b Together with the atoms it is attached to, it forms a cyclohexyl group.

[0609] In some embodiments of equation (A-2), an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl. In some embodiments, an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups. In some embodiments, an R 3a And an R 3b Together with the atoms they are attached to, they form 4- to 6-membered heterocyclic alkyl groups.

[0610] In some embodiments of any of equations (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 is hydrogen, C1-C 20 Alkyl or PEG 1-20 In some embodiments, R 3c and R 3d Each independently is C1-C 20 Alkyl group. In some embodiments, R 3c and R 3d Each is hydrogen independently.

[0611] In some embodiments of any of equations (A-2) to (A-9), R 3e It is an alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl compound. In some embodiments, R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or phenyl. In some embodiments, R 3e For C1-C 20 Alkyl or PEG 1-20 In some embodiments, R 3e It is a C3-C6 cycloalkyl, a 4- to 6-membered heterocycloalkyl, or a phenyl. In some embodiments, R 3eFor C1-C 20 alkyl.

[0612] In some embodiments of any of equations (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), each R Z Independent of 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 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl. In some embodiments, each R Z 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, a 5- to 10-membered heteroaryl group may be substituted. In some embodiments, each R Z Independently CN, -OH, -OR Za -N3 or -NR Za R Zb In some embodiments, each R Z Independently -C(O)NR Za R Zb -NHC(O)R Zc or -OC(O)NR Za R ZbIn some embodiments, each R Z Independently halogen, C1-C 10 Alkyl or C1-C 10 Haloalkyl. In some embodiments, each R Z Independently halogenated. In some embodiments, each R Z Independently for C1-C 10 Alkyl group. In some embodiments, each R Z Independently for C1-C 10 Halogenated groups.

[0613] In some embodiments of any of equations (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), each R Z Independent of halogen, -OH, -OR Za -NR Za R Zb Or C1-C6 alkyl. In some embodiments, each R Z Independently -F, -OH, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3. In some embodiments, each R Z Independently -F, -OH, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each R Z Independently -F or -OH. In some embodiments, each R Z Independently -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3. In some embodiments, each R Z -F. In some embodiments, each R Z It is -OH.

[0614] In some embodiments of any of equations (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), each R Za and RZb Independently hydrogen, alkyl, or PEG. In some embodiments, each R Za and R Zb Independently hydrogen, C1-C 20 Alkyl or PEG 1-20 In some embodiments, each R Za and R Zb Independently for C1-C 20 Alkyl group. In some embodiments, each R Za and R Zb It is hydrogen independently.

[0615] In some embodiments of any of equations (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 Zc It is an alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl compound. In some embodiments, R Zc For C1-C 20 Alkyl, PEG 1-20 C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or phenyl. In some embodiments, R Zc For C1-C 20 Alkyl or PEG 1-20 In some embodiments, R Zc For C1-C 20 alkyl.

[0616] The binding affinity between the polyamide and the target gene can be tuned based on the composition of the polyamide. In some embodiments, the polyamide is capable of binding DNA with an affinity of less than about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, or about 50 nM. In some embodiments, the polyamide is capable of binding DNA with an affinity of less than about 300 nM. In some embodiments, the polyamide is capable of binding DNA with an affinity of less than about 200 nM. In some embodiments, the polyamide is capable of binding DNA with an affinity greater than about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, or about 1 nM. In some embodiments, the polyamide is capable of binding DNA with an affinity in the range of about 1 to 600 nM, 10 to 500 nM, 20 to 500 nM, 50 to 400 nM, or 100 to 300 nM.

[0617] In some embodiments, the first end is capable of binding DNA with an affinity of less than 500 nM.

[0618] The binding affinity between polyamide and target DNA can be determined using a quantitative footprint titration assay. The experiment involves measuring the dissociation constant K of the polyamide to the target sequence at 24°C or 37°C. d And use standard polyamide analytical solution conditions or approximate intracellular solution conditions.

[0619] The binding affinity between a regulatory protein and its ligand at the second terminal can be determined using an assay suitable for that specific protein. The experiment involves measuring the dissociation constant K of the protein's ligand. d And use standard protein analysis solution conditions or approximate intracellular solution conditions.

[0620] Polyamides containing preselected subunit combinations can selectively bind to DNA in small grooves. In their hairpin structure, two antiparallel pairs of aromatic amino acids bind to the DNA sequence, with the polyamide rings specifically stacked for each DNA base.

[0621] Second terminal regulatory protein binding region

[0622] In some embodiments, the second end includes a protein-binding portion capable of binding to a regulatory molecule that regulates the expression of a gene having an amplified nucleotide repeat sequence.

[0623] In some embodiments, the second end includes a bromodomain binding portion.

[0624] In some embodiments, the second end includes a portion capable of binding to members of the bromine domain and the additional terminal domain (BET) family.

[0625] 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.

[0626] In some embodiments, the protein-binding portion binds to CBP / p300, P300 / CBP-Associated Factor (PCAF), cat eye syndrome chromosome region candidate 2 (CECR2), bromodomain and PHD finger-containing protein (BRPF), ATAD2 / ATAD2B (chromatin remodeling protein), Tripartite motif-containing protein 24 (TRIM24), bromodomain adjacent to zinc finger (BAZ2), TAF1 (TBP-associated factor), BRD7 / 9, bromodomain PHD finger transcription factor (BPTF), SMARCA2 / 4, or PBRM1.

[0627] In some embodiments, the regulating molecule is CBP / p300.

[0628] In some embodiments, the regulatory molecule is PCAF (P300 / CBP related factor).

[0629] In some embodiments, the regulatory molecule is cat eyesyndrome chromosome region candidate 2 (CECR2).

[0630] In some embodiments, the regulatory molecule is a bromodomain and PHDfinger-containing protein (BRPF).

[0631] In some embodiments, the regulatory molecule is ATAD2 or ATAD2B chromatin remodeling protein.

[0632] In some embodiments, the regulating molecule is a bromodomain adjacent to the zinc finger (BAZ2).

[0633] In some embodiments, the regulatory molecule is TAF1 (TBP-related factor).

[0634] In some embodiments, the regulatory molecule is a tripartite motif-containing protein 24 (TRIM24).

[0635] In some embodiments, the regulating molecule is BRD7 / 9.

[0636] In some embodiments, the regulatory molecule is the bromodomain PHD finger transcription factor (BPTF).

[0637] In some embodiments, the regulating molecule is SMARCA2 / 4.

[0638] In some embodiments, the regulating molecule is PBRM1.

[0639] In some embodiments, the molecular regulation regulates histone rearrangements.

[0640] In some embodiments, the molecular regulation regulates the glycosylation, phosphorylation, alkylation, or acylation of histones.

[0641] In some embodiments, the regulatory molecule is a transcription factor.

[0642] In some embodiments, the regulatory molecule is an RNA polymerase.

[0643] In some embodiments, the regulatory molecule is the part that regulates the activity of RNA polymerase.

[0644] In some embodiments, the recruitment portion binds to the regulatory molecule without inhibiting its activity. In some embodiments, the recruitment portion binds to the regulatory molecule and inhibits its activity. In some embodiments, the recruitment portion binds to the regulatory molecule and increases its activity.

[0645] In some embodiments, the recruitment portion binds to the active site of the regulatory molecule. In some embodiments, the recruitment portion binds to the regulatory site of the regulatory molecule.

[0646] The binding affinity between the regulatory protein and the second terminal can be adjusted based on the composition of the molecule or the type of protein. In some embodiments, the second terminal binds to the regulatory molecule with an affinity of less than about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, or about 50 nM. In some embodiments, the second terminal binds to the regulatory molecule with an affinity of less than about 500 nM. In some embodiments, the second terminal binds to the regulatory molecule with an affinity of less than about 400 nM. In some embodiments, the second terminal binds to the regulatory molecule with an affinity of less than about 300 nM. In some embodiments, the second terminal binds to the regulatory molecule with an affinity of less than about 250 nM. In some embodiments, the second terminal binds to the regulatory molecule with an affinity of less than about 200 nM. In some embodiments, the second terminal binds to the regulatory molecule with an affinity of less than about 150 nM. In some embodiments, the second terminal 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.

[0647] In some embodiments, the second terminal comprises a diazine or diazapine ring, wherein the diazine or diazapine ring is C6-C ... 10 The aryl group or a 5- to 10-membered heteroaryl ring comprising one or more heteroatoms selected from S, N, and O is fused together. In some embodiments, the second end comprises an optionally substituted bicyclic or tricyclic structure.

[0648] In some embodiments, the second end has a triazolodiazepine structure. In some embodiments, the second end has a thiazodiazepine structure.

[0649] In some embodiments, the second terminal comprises a structure of formula (2-A), or a pharmaceutically acceptable salt thereof:

[0650]

[0651] Equation (2-A),

[0652] in:

[0653] Ring A is either a substituted aryl group or a substituted 5- to 6-membered heteroaryl group;

[0654] Ring B is a 6-membered monocyclic aryl or heteroaryl group that is absent or optionally substituted;

[0655] D is either C or N;

[0656] E is either O or N;

[0657] Y A It is -NH- or -O-;

[0658] R 5 It is hydrogen or C1-C6 alkyl;

[0659] R 6 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl;

[0660] R 7 Selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl group, optionally substituted C1-C 20 Alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl;

[0661] Or R 7 For -NR 7A R 7B ,in

[0662] R 7A and R 7B Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; and

[0663] x1 is an integer from 1 to 6.

[0664] In some embodiments, D is N and E is N. In some embodiments, D is C and E is O.

[0665] In some embodiments, the second end comprises a structure of formula (2-B), or a pharmaceutically acceptable salt thereof:

[0666]

[0667] Equation (2-B),

[0668] in:

[0669] Ring A is either a substituted aryl group or a substituted 5- to 6-membered heteroaryl group;

[0670] Ring B is a 6-membered monocyclic aryl or heteroaryl group that is absent or optionally substituted;

[0671] Y A It is -NH- or -O-;

[0672] R 5 It is hydrogen or C1-C6 alkyl;

[0673] R 6Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl;

[0674] R 7 Selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl group, optionally substituted C1-C 20 Alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl;

[0675] Or R 7 For -NR 7A R 7B ,in

[0676] R 7A and R 7B Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; and

[0677] x1 is an integer from 1 to 6.

[0678] In some embodiments, ring A is an optionally substituted aromatic ring. In some embodiments, ring A is an optionally substituted phenyl group. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl group. In some embodiments, ring A is an optionally substituted oxazolyl group. In some embodiments, ring A is an optionally substituted furanyl group. In some embodiments, ring A is an optionally substituted thiophene group.

[0679] In some embodiments, the second end comprises a structure of formula (2-C), or a pharmaceutically acceptable salt thereof:

[0680]

[0681] Equation (2-C),

[0682] in:

[0683] Ring B is a 6-membered monocyclic aryl or heteroaryl group that is absent or optionally substituted;

[0684] Y A It is -NH- or -O-;

[0685] R 5 It is hydrogen or C1-C6 alkyl;

[0686] R 6 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl;

[0687] R 7 Selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl group, optionally substituted C1-C 20 Alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl;

[0688] Or R 7 For -NR 7A R 7B ,in

[0689] R 7A and R 7B Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl;

[0690] R 8 and R 9 Each is independently selected from hydrogen, -C(O)OR 8a Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; and

[0691] R 8a Hydrogen, C1-C 20 Alkyl or C1-C 20 Heteroalkyl; and

[0692] x1 is an integer from 1 to 6.

[0693] 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 alkyl groups. 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 a methyl group. In some embodiments, R 8 and R 9 Each is independently ethyl. In some embodiments, R 8 and R 9 Each is independently propyl.

[0694] In some embodiments, the second end comprises a structure of formula (2-D), or a pharmaceutically acceptable salt thereof:

[0695]

[0696] Equation (2-D),

[0697] in:

[0698] Ring B is a 6-membered monocyclic aryl or heteroaryl group that is absent or optionally substituted;

[0699] Y A It is -NH- or -O-;

[0700] R 5 It is hydrogen or C1-C6 alkyl;

[0701] R 6 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl;

[0702] R 7 Selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl group, optionally substituted C1-C 20 Alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl;

[0703] Or R 7 For -NR 7A R 7B ,in

[0704] R 7A and R 7B Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl;

[0705] R 10 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; and

[0706] x1 is an integer from 1 to 6.

[0707] In some embodiments, R 5 It is a C1-C6 alkyl group. In some embodiments, R 5 It is methyl or ethyl. In some embodiments, R 5 methyl. In some embodiments, R 5 It is ethyl. In some embodiments, R 5 It is hydrogen.

[0708] In some embodiments, R7 Selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments, R 7 It is a halogen. In some embodiments, R 7 It is Br, Cl, or F. In some embodiments, R 7 For Cl. In some embodiments, R 7 For F. In some embodiments, R 7 It is Br.

[0709] In some embodiments, R 7 For -NR 7A R 7B , where R 7A and R 7B Each is independently hydrogen or optionally substituted C1-C6 alkyl.

[0710] In some embodiments, R 10 Selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R 10 Selected from optionally substituted C1-C6 alkyl groups. In some embodiments, R 10 It is methyl, ethyl, or propyl. In some embodiments, R 10 methyl. In some embodiments, R 10 C is arbitrarily replaced 1-6 Hydroxyalkyl. In some embodiments, R 10 For -OMe.

[0711] In some embodiments, R 6 Selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R 6 The alkyl group is optionally substituted (C1-C6 alkyl group). In some embodiments, R 6 It is methyl, ethyl, or propyl. In some embodiments, R 6 methyl. In some embodiments, R 6 It is ethyl. In some embodiments, R 6 It is propyl. In some embodiments, R 6 It is hydrogen.

[0712] In some embodiments, Y A For -NH-. In some embodiments, Y A It is -O-.

[0713] In some embodiments, Y A It is NH and x1 is 1.

[0714] In some embodiments, x1 is an integer from 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, x1 is 1. In some embodiments, x1 is 2.

[0715] In some embodiments, ring B is an optionally substituted 6-membered monocyclic aryl or heteroaryl group, each optionally substituted with an alkyl, amino, halogen, hydroxyl, hydroxyalkyl, or PEG. In some embodiments, ring B is phenyl. In some embodiments, ring B is a 6-membered monocyclic heteroaryl group. In some embodiments, ring B is pyridine or pyrimidine. In some embodiments, ring B is absent.

[0716] In some embodiments, the second end comprises a structure of formula (2-E), or a pharmaceutically acceptable salt thereof:

[0717] Equation (2-E).

[0718] In some embodiments, the second terminal comprises a structure of formula (2-F), or a pharmaceutically acceptable salt thereof:

[0719] Equation (2-F).

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

[0721] Equation (2-G).

[0722] In some embodiments, the second terminal comprises a structure of formula (3-A), or a pharmaceutically acceptable salt thereof:

[0723]

[0724] Equation (3-A),

[0725] in:

[0726] Y B It can be -CH2NH-, -CH2O-, -NH- or -O-;

[0727] R 11A and R 11B Each is independently hydrogen or optionally substituted C1-C6 alkyl;

[0728] R 12 It can be hydrogen, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl or optionally substituted C1-C6 hydroxyalkyl;

[0729] R 14 and R 15Each is independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl or optionally substituted C1-C6 hydroxyalkyl;

[0730] Or R 14 For -NR A R B ;

[0731] R 16 Optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 heteroalkyl, Optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 ynyl, Optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A -SO2R A or -NHSO2R A ;

[0732] R YA It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted 5- to 6-membered monocyclic aryl or heteroaryl;

[0733] Each R A and R B Independently, it 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

[0734] y1 ranges from 1 to 3;

[0735] The connection with the connector is in R 14 Or R YA Place.

[0736] In some embodiments, the second end comprises a structure of formula (3-B), or a pharmaceutically acceptable salt thereof:

[0737]

[0738] Equation (3-B),

[0739] in:

[0740] The ring C is absent or optionally substituted with a 5- to 6-membered monocyclic aryl or heteroaryl, or a 4- to 8-membered heterocycle;

[0741] Y B It can be -NH-, -CH2NH-, -CH2O-, or -O-;

[0742] R11A and R 11B Each is independently hydrogen or optionally substituted C1-C6 alkyl;

[0743] R 12 Hydrogen, optionally substituted C1-C6 alkyl, C(O)R A or C(O)NR A R B ;in

[0744] Each R A and R B Independently hydrogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl;

[0745] R 13 It is hydrogen, a substituted aryl group, a substituted heteroaryl group, or a substituted diphenyl ether; and

[0746] y2 is an integer from 0 to 2.

[0747] In some embodiments, the second end comprises a structure of formula (3-B1), or a pharmaceutically acceptable salt thereof:

[0748]

[0749] Equation (3-B1),

[0750] in:

[0751] R 11A and R 11B Each is independently hydrogen or optionally substituted C1-C6 alkyl;

[0752] R 13 It is hydrogen, a substituted aryl group, a substituted heteroaryl group, or a substituted diphenyl ether; and

[0753] y2 is an integer from 0 to 2.

[0754] In some embodiments, y2 is 0. In some embodiments, y2 is 1. In some embodiments, y2 is 2.

[0755] In some embodiments, R 13 It is a substituted aryl group or a substituted heteroaryl group. In some embodiments, R 13 It is hydrogen.

[0756] In some embodiments, R 13 The substituted diphenyl ether.

[0757] In some embodiments, R 13 for ,in

[0758] 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;

[0759] Or R 14 For -NR A R B ;

[0760] R 16 Optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 heteroalkyl, Optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 ynyl, Optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A -SO2R A or -NHSO2R A ;

[0761] Each R A and R B Independently, it 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

[0762] y1 ranges from 1 to 3.

[0763] In some embodiments, the second terminal comprises a structure of formula (3-C), or a pharmaceutically acceptable salt thereof:

[0764]

[0765] Equation (3-C),

[0766] in:

[0767] The ring C is absent or optionally substituted with a 5- to 6-membered monocyclic aryl or heteroaryl, or a 4- to 8-membered heterocycle;

[0768] Y B It can be -CH2NH-, -CH2O-, -NH- or -O-;

[0769] R 11A and R 11B Each is independently hydrogen or optionally substituted C1-C6 alkyl;

[0770] R 12It can be hydrogen, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl or optionally substituted C1-C6 hydroxyalkyl;

[0771] 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;

[0772] Or R 14 For -NR A R B ;

[0773] R 16 Optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 heteroalkyl, Optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 ynyl, Optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A -SO2R A or -NHSO2R A ;

[0774] Each R A and R B Independently, it 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

[0775] y1 is an integer from 1 to 3.

[0776] In some embodiments, Y B For -NH-. In some embodiments, Y B For -CH2NH-. In some embodiments, Y B For -CH2O-. In some embodiments, Y B It is -O-.

[0777] In some embodiments, the ring C is an optionally substituted 5- or 6-membered monocyclic aryl or heteroaryl group, each optionally substituted with an alkyl, amino, halogen, hydroxyl, hydroxyalkyl, or PEG.

[0778] In some embodiments, ring C is phenyl. In some embodiments, ring C is a 6-membered heteroaryl group. 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 group. In some embodiments, ring C is pyrazole. 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, oxazole or oxadiazole. In some embodiments, ring C is thiazole or thiadiazole.

[0779] In some embodiments, ring C is absent.

[0780] In some embodiments, the second end comprises a structure of formula (3-D), or a pharmaceutically acceptable salt thereof:

[0781]

[0782] Equation (3-D),

[0783] in:

[0784] R 11A and R 11B Each is independently hydrogen or optionally substituted C1-C6 alkyl;

[0785] R 12 It is hydrogen or optionally substituted C1-C6 alkyl;

[0786] Each R 15 Independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl or optionally substituted C1-C6 hydroxyalkyl;

[0787] R 16 Optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 heteroalkyl, Optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 ynyl, Optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A -SO2R A or -NHSO2R A ;

[0788] R A The substituted C1-C6 alkyl group, the substituted C1-C6 heteroalkyl group, the substituted C1-C6 haloalkyl group, the substituted C1-C6 hydroxyalkyl group, the substituted C3-C6 cycloalkyl group, the substituted 4- to 6-membered heterocycloalkyl group, or the substituted 5- to 6-membered heteroaryl group; and

[0789] y1 is an integer from 1 to 3.

[0790] In some embodiments, R 11A and R 11B Each is independently a C1-C6 alkyl group that can be optionally substituted. 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 a methyl group. In some embodiments, R 11A and R 11B Each is hydrogen independently.

[0791] In some embodiments, R 11A It is a C1-C6 alkyl group optionally substituted with a haloalkyl group or phosphorus hydroxide. In some embodiments, R 11A It is a C1-C6 alkyl group substituted with -OP(O)(OH)2. In some embodiments, R 11A It is an unsubstituted C1-C6 alkyl group. In some embodiments, R 11A It is methyl, ethyl, or tert-butyl. In some embodiments, R 11A methyl. In some embodiments, R 11A It is hydrogen.

[0792] In some embodiments, R 12 The alkyl group is optionally substituted (C1-C6 alkyl group). In some embodiments, R 12 It is hydrogen.

[0793] In some embodiments, R 12 For C(O)R A or C(O)NR A R B In some embodiments, R 12 For C(O)NR A R B , where R A and R B Each is independently hydrogen or optionally substituted C1-C6 alkyl.

[0794] 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 group. In some embodiments, R 14 and R 15Each is independently Br, Cl, F, methyl, or ethyl. In some embodiments, R 14 and R 15 Each can be either F or methyl.

[0795] In some embodiments, R 16 The C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 hydroxyalkyl are optionally substituted, each of which is optionally substituted with: amide, alkyl, alkynyl, azide, amino, halogen, haloalkyl, hydroxyl, nitro, oxo (=O), phosphorus hydroxide, or PEG.

[0796] In some embodiments, R 16 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R 16 It is a C1-C6 alkyl or C1-C6 heteroalkyl, each optionally substituted with -CN, -NH2, -N3, -OH, CF3 or -OP(O)(OH)2.

[0797] In some embodiments, R 16 -SO2R A , where R A It is a C1-C6 alkyl group. In some embodiments, R 16 For -SO2Et. In some embodiments, R 16 It is -SO2Me.

[0798] In some embodiments, R 16 -NHSO2R A , where R A It is a C1-C6 alkyl group. In some embodiments, R 16 For -NHSO2Et. In some embodiments, R 16 It is -NHSO2Me.

[0799] In some embodiments, y1 is 1. In some embodiments, y1 is 2. In some embodiments, y1 is 3.

[0800] In some embodiments, the second terminal comprises a structure of formula (3-E), or a pharmaceutically acceptable salt thereof:

[0801] Equation (3-E).

[0802] In some embodiments, the second terminal comprises a structure of formula (3-F), or a pharmaceutically acceptable salt thereof:

[0803] Equation (3-F).

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

[0805] Formula (3-G) or Equation (3-H).

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

[0807] Formula (3-I).

[0808] In some embodiments, the second terminal comprises a structure of formula (4-A), or a pharmaceutically acceptable salt thereof:

[0809]

[0810] Equation (4-A),

[0811] in;

[0812] Ring D is absent, phenyl, or a 5- to 6-membered heteroaryl group;

[0813] X 9 and X 10 Each is independently C or N, where X 9 or X 10 One of them is N;

[0814] L 2 The alkylene group that is absent or optionally substituted, or the -O- or -NR group. D -,in

[0815] R D It is hydrogen or optionally substituted C1-C3 alkyl;

[0816] R 18 The substituted 5- to 6-membered heteroaryl groups are selected;

[0817] R 19 It can be a C3-C8 cycloalkyl group that is optionally substituted or a 4- to 7-membered heteroaryl group that is optionally substituted;

[0818] Each R 20 Independently hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl or optionally substituted C1-C6 hydroxyalkyl;

[0819] x3 is an integer from 1 to 3; and

[0820] y4 is an integer from 1 to 4;

[0821] The connection with the connector is in R 19 Location or R 20 One of them.

[0822] In some embodiments, the connection with the connector is in R 19 Place.

[0823] In some embodiments, the connection with the connector is in R 20 One of them.

[0824] In some embodiments, the second end comprises a structure of formula (4-B), or a pharmaceutically acceptable salt thereof:

[0825]

[0826] Equation (4-B),

[0827] in:

[0828] Ring D is absent, optionally substituted phenyl, or optionally substituted 5- to 6-membered heteroaryl;

[0829] X 9 and X 10 Each is independently C or N, where X 9 or X 10 One of them is N;

[0830] L 2 The alkylene group that is absent or optionally substituted, or the -O- or -NR group. D -,in

[0831] R D It is hydrogen or optionally substituted C1-C3 alkyl;

[0832] R 18 The substituted 5- to 6-membered heteroaryl groups are selected;

[0833] R 19 The substituted C3-C8 cycloalkyl or the substituted 4- to 7-membered heteroaryl groups; and

[0834] x3 is an integer from 1 to 3.

[0835] In some embodiments, X 9 Let N be the number of elements; and X be the number of elements. 10 For C. In some embodiments, X 9 Let C be X; and X be X. 10 Let N be the number of elements in the array.

[0836] In some embodiments, the second terminal comprises a structure of formula (4-C), or a pharmaceutically acceptable salt thereof:

[0837] Equation (4-C).

[0838] 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.

[0839] In some embodiments, R 19 The substituted C3-C8 cycloalkyl group is optional. In some embodiments, R 19 The substituted 4- to 7-membered heteroaryl groups are selected.

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

[0841]

[0842] Equation (4-D),

[0843] in:

[0844] L 2 The substituted alkylene group, -O- or -NR can be substituted. D -,in

[0845] R D It is hydrogen or optionally substituted C1-C3 alkyl;

[0846] R 18 The substituted 5- to 6-membered heteroaryl groups are selected;

[0847] R 20 It can be hydrogen, halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl or optionally substituted C1-C6 hydroxyalkyl;

[0848] x3 is an integer from 1 to 3; and

[0849] y4 is an integer from 1 to 4.

[0850] In some embodiments, L 2 Optionally substituted alkylene groups. In some embodiments, L 2 C2-C4 alkylene groups optionally substituted with one or more C1-C3 alkyl groups. In some embodiments, L 2 It does not exist.

[0851] In some embodiments, L 2 For -NR D -. In some embodiments, L 2It is -NH-.

[0852] In some embodiments, R 18 The substituted 5-membered heteroaryl group is optionally used. In some embodiments, R 18 The substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole may be used. In some embodiments, R 18 The oxazole can be substituted by choice.

[0853] In some embodiments, R 20 It can be a halogen, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl.

[0854] In some embodiments, x3 is 1. In some embodiments, x3 is 2. In some embodiments, x3 is 3.

[0855] 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.

[0856] In some embodiments, the second terminal comprises a structure of formula (4-E) or formula (4-F), or a pharmaceutically acceptable salt thereof:

[0857] .

[0858] In some embodiments, the second terminal comprises a structure of formula (4-G), or a pharmaceutically acceptable salt thereof:

[0859] Equation (4-G).

[0860] In some embodiments, the second terminal comprises a structure of formula (5-A), or a pharmaceutically acceptable salt thereof:

[0861]

[0862] Equation (5-A),

[0863] in:

[0864] Ring E is a phenyl group that is absent or optionally substituted, or a 5- to 6-membered heteroaryl group that is optionally substituted.

[0865] X 11 For CH or N;

[0866] L 3 For -NR E -or-CR E R E -,in

[0867] Each R E Independently hydrogen or optionally substituted C1-C3 alkyl;

[0868] R 21 It is a C1-C6 alkyl or C3-C6 cycloalkyl; and

[0869] R 22 It can be a halogen, CN, NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl.

[0870] In some embodiments, ring E is absent. In some embodiments, ring E is an optionally substituted phenyl group. In some embodiments, ring E is an optionally substituted 5- or 6-membered heteroaryl group. In some embodiments, ring E is a 5-membered heteroaryl group. In some embodiments, ring E is a 6-membered heteroaryl group.

[0871] In some embodiments, X 11 For CH and L 3 For -NR E - In some embodiments, X 11 For N and L 3 For -CR E R E -

[0872] In some embodiments, R 21 It is a C1-C6 alkyl group. In some embodiments, R 21 It is a methyl group.

[0873] In some embodiments, R 22 It is a halogen, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 haloalkyl group, or an optionally substituted C1-C6 hydroxyalkyl group. In some embodiments, R 22 It can be CN, F, Cl, Br, or methyl.

[0874] In some embodiments, the second end comprises a structure of formula (5-B) or formula (5-C), or a pharmaceutically acceptable salt thereof:

[0875] Formula (5-B) or Equation (5-C).

[0876] In some embodiments, the second terminal comprises a structure of formula (6-A), or a pharmaceutically acceptable salt thereof:

[0877]

[0878] Equation (6-A),

[0879] in:

[0880] Ring G is a C3-C6 cycloalkyl group that is absent or optionally substituted, or a 4- to 6-membered heterocyclic alkyl group that is optionally substituted;

[0881] L 6 -O- (optionally substituted alkylene);

[0882] R 28 The substituted 5- to 6-membered heteroaryl groups are selected;

[0883] R 29 Optionally substituted C1-C6 alkyl-(C6-C 10 aryl) or optionally substituted C1-C6 alkyl-(6- to 10-membered heteroaryl); and

[0884] R 30 The substituted C1-C6 alkyl, the substituted C1-C6 haloalkyl, the substituted C1-C6 hydroxyalkyl, the substituted C3-C6 cycloalkyl, or the substituted 4- to 6-membered heterocyclic alkyl are optional.

[0885] In some embodiments, the second terminal comprises a structure of formula (7-A), or a pharmaceutically acceptable salt thereof:

[0886]

[0887] Equation (7-A),

[0888] in:

[0889] A 3 It can be -O-, -NH-, or -CH2-;

[0890] Z 2 For CH or N;

[0891] W represents O or S;

[0892] Each R 31 Independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkyne, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclic alkyl;

[0893] Or two Rs 31Together with the atoms to which they are attached, they can form optional substituted C5-C8 cycloalkyl groups or optional substituted 5- to 8-membered heterocycloalkyl groups;

[0894] R 32 Hydrogen or optionally substituted C1-C 10 alkyl;

[0895] R 32a Hydrogen or optionally substituted C1-C 10 alkyl;

[0896] R 33 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl; and

[0897] q6 ranges from 0 to 4;

[0898] Equation (7-A) is connected to R 32a Location or R 31 The connector at one of the points.

[0899] In some embodiments, Z 2 CH. In some embodiments, Z 2 Let N be the number of elements in the array.

[0900] In some embodiments, the second end comprises the structure of formula (7-B), or a pharmaceutically acceptable salt thereof:

[0901]

[0902] Equation (7-B),

[0903] in:

[0904] Ring F is a 5- to 6-membered heteroaryl group that can be optionally substituted;

[0905] A 3 It can be -O-, -NH-, or -CH2-;

[0906] Z 3 For CH or N;

[0907] W represents O or S;

[0908] Each R 31 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkyne, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclic alkyl;

[0909] Or two Rs 31 Together with the atoms to which they are attached, they can form optional substituted C5-C8 cycloalkyl groups or optional substituted 5- to 8-membered heterocycloalkyl groups;

[0910] R 32 Hydrogen or optionally substituted C1-C 10 Alkyl; and

[0911] q6 ranges from 1 to 4.

[0912] In some embodiments, A 3 For -O-. In some embodiments, A 3 For -NH-. In some embodiments, A 3 It is -CH2-.

[0913] In some embodiments, Z 3 CH. In some embodiments, Z 3 Let N be the number of elements in the array.

[0914] In some embodiments, W is O. In some embodiments, W is S.

[0915] In some embodiments, ring F is an optionally substituted 5-membered heteroaryl group. In some embodiments, ring F is an optionally substituted 6-membered heteroaryl group.

[0916] In some embodiments, each R 31 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl. In some embodiments, each R 31 Independently, it is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl. In some embodiments, each R 31 Independently, it is hydrogen, halogen, -OH, -CN, -NO2, or -NH2. In some embodiments, each R 31 It is hydrogen.

[0917] In some embodiments, R 32 For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 32 methyl. In some embodiments, R 32 It is hydrogen.

[0918] In some embodiments, R 32a For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 32a It is hydrogen.

[0919] In some embodiments, R 33 It can be hydrogen, halogen, -OH, -CN, -NO2, or -NH2. In some embodiments, R 33 For the optional replacement of C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl.

[0920] In some embodiments, formula (7-A) is connected to R 32a The connector at the location. In some embodiments, formula (7-A) is connected to the connector at R. 31 The connector at one of the points.

[0921] In some embodiments, the second end comprises a structure of formula (7-C), or a pharmaceutically acceptable salt thereof:

[0922] Equation (7-C).

[0923] In some embodiments, the second terminal comprises a structure of formula (7-D), or a pharmaceutically acceptable salt thereof:

[0924] Equation (7-D).

[0925] In some embodiments, the second terminal comprises a structure of formula (7-E), or a pharmaceutically acceptable salt thereof:

[0926] Equation (7-E).

[0927] In some embodiments, the second end comprises a structure of formula (8-A), or a pharmaceutically acceptable salt thereof:

[0928]

[0929] Equation (8-A),

[0930] in:

[0931] The ring H is either a substituted phenyl group or a substituted 6-membered heteroaryl group;

[0932] Or ring H is ;

[0933] Z A Phenylacetamide is either absent or optionally substituted;

[0934] X 12 For CH or N;

[0935] R 34 It can be an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl group;

[0936] R 34A It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; and

[0937] R 35 Independently halogenated, optionally substituted C1-C 10 Alkyl or optionally substituted 5- to 6-membered heteroaryl groups;

[0938] The connection with the connector is in R 35 Z A Or at point H on the ring.

[0939] In some embodiments, ring H is an optionally substituted phenyl group. In some embodiments, ring H is an optionally substituted 6-membered heteroaryl group.

[0940] In some embodiments, ring H is .

[0941] In some embodiments, Z A It does not exist. In some embodiments, Z A Z is an optional substituted phenylformamide. In some embodiments, Z A It is -C(O)NH-phenyl.

[0942] In some embodiments, X 12 For CH. In some embodiments, X 12 Let N be the number of elements in the array.

[0943] In some embodiments, R 34 The phenyl group is optionally substituted. In some embodiments, R 34 The substituted 6-membered heteroaryl group is selected.

[0944] In some embodiments, R 34A It is hydrogen or halogen. In some embodiments, R 34A The substituted C1-C3 alkyl group is optional. In some embodiments, R 34A It is a methyl group.

[0945] In some embodiments, formula (8-A) is connected to R 35 The connector at the location. In some embodiments, formula (8-A) is connected to the connector at Z. A The connector at the location. In some embodiments, formula (8-A) is connected to the connector at ring H.

[0946] In some embodiments, the second end comprises a structure of formula (8-B) or formula (8-C), or a pharmaceutically acceptable salt thereof:

[0947] .

[0948] In some embodiments, the second terminal comprises a structure of formula (8-D), or a pharmaceutically acceptable salt thereof:

[0949] Equation (8-D).

[0950] In some embodiments, the second terminal comprises a structure of formula (9-A), or a pharmaceutically acceptable salt thereof:

[0951] Equation (9-A).

[0952] In some embodiments, the second end comprises a structure of formula (10-A) or formula (10-B), or a pharmaceutically acceptable salt thereof:

[0953] Formula (10-A) or Equation (10-B).

[0954] In some embodiments, the second end comprises the structure of formula (11-A), or a pharmaceutically acceptable salt thereof:

[0955] Equation (11-A).

[0956] In some embodiments, the second end comprises a structure of formula (12-A), or a pharmaceutically acceptable salt thereof:

[0957]

[0958] Equation (12-A),

[0959] in:

[0960] A 4 For -CR 40 R 40 -or-NR 40 -; where each R 40 Independently hydrogen or optionally substituted C1-C 10 alkyl;

[0961] R 36 The substituted 5- to 6-membered heteroaryl groups are selected;

[0962] Each R 37 It is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl;

[0963] R 38 For the optional replacement of C1-C 10 Alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclic alkyl;

[0964] R 39 It can be hydrogen, halogen, -OH, -CN, -NO2, -NH2, oxo group (=O), =S, C1-C 10 Halogenated or C1-C 10 Hydroxyalkyl;

[0965] p 11 From 1 to 4; and

[0966] q1 and q2 are each independently between 0 and 2;

[0967] The connector is in R 38 Or R 40 Connect to equation (12-A).

[0968] In some embodiments, R 36 The substituted 5-membered heteroaryl group is optionally used. In some embodiments, R 36 The substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole may be used. In some embodiments, R 36 The oxazole can be substituted by choice.

[0969] In some embodiments, each R 37 Independently, it is a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments, each R 37 Halogens are independent of each other.

[0970] In some embodiments, R 38 For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 38 It is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocyclic alkyl. In some embodiments, R 38 It is a 3- to 8-membered heterocyclic alkyl group.

[0971] In some embodiments, R 39 It can be hydrogen, halogen, -OH, -CN, -NO2, -NH2, or Cl-C. 10 Halogenated or C1-C 10 Hydroxyalkyl. In some embodiments, R 39 It is an oxo group or =S. In some embodiments, R 39 It is an oxo group. In some embodiments, R 39 =S.

[0972] In some embodiments, A 4 For -NR 40 In some embodiments, A 4 For -NH. In some embodiments, A 4 For -NCH3. In some embodiments, A 4 For -CR 40 R 40 In some embodiments, A 4 It is -CH2-.

[0973] In some embodiments, each R 40 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl group. In some embodiments, each R 40 It is hydrogen independently.

[0974] In some embodiments, p 11 It is 3 or 4. In some embodiments, p 11 The value is 2. In some embodiments, p 11 The value is 1.

[0975] In some embodiments, q1 is 1 and q2 is 1. In some embodiments, q1 is 2 and q2 is 0.

[0976] In some embodiments, the connector is via R 38 Connect to equation (12-A). In some embodiments, the connector is via R 40 Connect to formula (12-A).

[0977] In some embodiments, the second end comprises formula (12-B) or formula (12-C), or a pharmaceutically acceptable salt thereof:

[0978] Formula (12-B) or Equation (12-C).

[0979] In some embodiments, the second terminal comprises formula (12-D) or formula (12-E), or a pharmaceutically acceptable salt thereof:

[0980] Formula (12-D) or Equation (12-E).

[0981] In some embodiments, the second end comprises the structure of formula (13-A), or a pharmaceutically acceptable salt thereof:

[0982]

[0983] Equation (13-A),

[0984] in:

[0985] Ring J is a 5- to 6-membered heteroaryl group that is absent or optionally substituted;

[0986] R 41 Optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, -C(O)R 41a -C(O)- or -C(O)NR 41a R 41b ,in

[0987] R 41a and R 41b Each of the C1-Cs can be arbitrarily replaced independently. 10 Alkyl or optionally substituted C3-C8 cycloalkyl;

[0988] R 42 For the optional replacement of C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclic alkyl;

[0989] R 43 Hydrogen or optionally substituted C1-C 10 alkyl;

[0990] Each R 44 Independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated, 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 heterocyclic alkyl; or

[0991] R 43 and R 44 One of them, together with the atoms to which it is attached, forms an optionally substituted 5- to 8-membered heterocyclic alkyl group;

[0992] p 12 From 1 to 4; and

[0993] q3 is either 0 or 1;

[0994] Equation (13-A) is connected to rings J and R. 41 Or R 42 Connector at the location.

[0995] In some embodiments, R 41It can be an optionally substituted C1-C6 alkyl or an optionally substituted C3-C8 cycloalkyl. In some embodiments, R 41 -C(O)R 41a In some embodiments, R 41 It is -C(O)CH3 or -C(O)CH2CH3. In some embodiments, R 41 -C(O)-NR 41a R 41b .

[0996] In some embodiments, R 41a For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 41a The C3-C8 cycloalkyl group can be optionally substituted.

[0997] In some embodiments, R 41b For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 41b The C3-C8 cycloalkyl group can be optionally substituted.

[0998] In some embodiments, R 42 For the optional replacement of C1-C 10 Alkyl or optionally substituted C1-C 10 Haloalkyl. In some embodiments, R 42 It is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocyclic alkyl. In some embodiments, R 42 The substituted 3- to 8-membered heterocyclic alkyl rings are optional.

[0999] In some embodiments, R 43 For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 43 It is hydrogen.

[1000] In some embodiments, each R 44 Independently halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated, 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 heterocycles. In some embodiments, each R 44 Independently halogenated or C1-C 10 Halogenated groups.

[1001] In some embodiments, R 43 and R 44 One of them, together with the atoms to which it is attached, forms an optionally substituted 5- to 8-membered heterocyclic alkyl group. In some embodiments, R 43 and R 44 One of them, together with the atoms it is attached to, forms a 5-membered, 6-membered, 7-membered, or 8-membered heterocyclic alkyl group.

[1002] In some embodiments, p 12 It is 3 or 4. In some embodiments, p 12 The value is 2. In some embodiments, p 12 The value is 1.

[1003] In some embodiments, q3 is 1. In some embodiments, q3 is 0.

[1004] In some embodiments, ring J is an optionally substituted 5-membered heteroaryl group. In some embodiments, ring J is absent.

[1005] In some embodiments, formula (13-A) is connected to the connector at ring J. In some embodiments, formula (13-A) is connected to R. 41 The connector at the location. In some embodiments, formula (13-A) is connected to the connector at R. 42 Connector at the location.

[1006] In some embodiments, the second end comprises the structure of formula (13-B), or a pharmaceutically acceptable salt thereof:

[1007] Equation (13-B).

[1008] In some embodiments, the second end comprises a structure of formula (13-C1) or formula (13-C2), or a pharmaceutically acceptable salt thereof:

[1009] Formula (13-C1) or

[1010] Equation (13-C2).

[1011] In some embodiments, the second end comprises a structure of formula (13-D1) or formula (13-D2), or a pharmaceutically acceptable salt thereof:

[1012] Equation (13-D1) or

[1013] Equation (13-D2).

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

[1015] Equation (13-E).

[1016] In some embodiments, the second end comprises the structure of formula (14-A), or a pharmaceutically acceptable salt thereof:

[1017]

[1018] Equation (14-A),

[1019] in:

[1020] Ring K is a 5- to 6-membered heterocyclic alkyl group;

[1021] A 5 For non-existent, CH2, -NH-, or -O-;

[1022] L 4 It is an alkylene or heteroalkylene;

[1023] Each R 45 Independently halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkyne, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclic alkyl;

[1024] Each R 46 Independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkyne, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclic alkyl;

[1025] R 47 For the optional replacement of C1-C 10 Alkyl, -C(O)R 47a or -C(O)-NR 47a R47b ,in

[1026] R 47a and R 47b Each of the C1-Cs can be arbitrarily replaced independently. 10 Alkyl or optionally substituted C3-C8 cycloalkyl;

[1027] q4 is 2 to 3; and

[1028] q5 is between 0 and 2;

[1029] Equation (14-A) passes through ring K or through R. 45 One of them is connected to the connector.

[1030] In some embodiments, A 5 It does not exist. In some embodiments, A 5 It is -NH- or -O-. In some embodiments, A 5 For -NH-. In some embodiments, A 5 It is -O-.

[1031] In some embodiments, L 4 It is an alkylene group. In some embodiments, L 4 It is a C1-C5 alkylene group.

[1032] In some embodiments, L 4 It is a heteroalkylene group. In some embodiments, L 4 It is a C1-C4 heteroalkylene group. In some embodiments, L 4 It is -O-CH2- or -O-CH2CH2-.

[1033] In some embodiments, each R 45 Independently halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 Alkynyl group. In some embodiments, each R 45 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl or optionally substituted C1-C 10 Hydroxyalkyl. In some embodiments, each R 45 Independently for C1-C 10 Hydroxyalkyl. In some embodiments, each R45 It can be -OCH3 or -OCH2CH3 independently.

[1034] In some embodiments, each R 46 Independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl. In some embodiments, each R 46 It is hydrogen independently.

[1035] In some embodiments, R 47 For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 47 -C(O)R 47a In some embodiments, R 47 It is -C(O)CH3 or -C(O)CH2CH3. In some embodiments, -C(O)-NR 47a R 47b .

[1036] In some embodiments, R 47a For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 47a The C3-C8 cycloalkyl group can be optionally substituted.

[1037] In some embodiments, R 47b For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 47b The C3-C8 cycloalkyl group can be optionally substituted.

[1038] In some embodiments, ring K is a 6-membered heterocyclic alkyl group.

[1039] In some embodiments, q4 is 3. In some embodiments, q4 is 2.

[1040] In some embodiments, q5 is 2. In some embodiments, q5 is 1. In some embodiments, q5 is 0.

[1041] In some embodiments, equation (14-A) is connected to the connector via ring K. In some embodiments, equation (14-A) is connected via R. 45 One of them is connected to the connector.

[1042] In some embodiments, the second end comprises a structure of formula (14-B) or formula (14-C), or a pharmaceutically acceptable salt thereof:

[1043] Formula (14-B) or Formula (14-C).

[1044] In some embodiments, the second end comprises a structure of formula (15-A), or a pharmaceutically acceptable salt thereof:

[1045]

[1046] Equation (15-A),

[1047] in:

[1048] The ring L is aryl or heteroaryl;

[1049] Each R 48 It can be hydrogen, halogen, -OH, -CN, -NO2, -NH2, or Cl-C. 10 Alkyl, C1-C 10 Halogenated or C1-C 10 Hydroxyalkyl;

[1050] R 49 and R 50 Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 10 Alkyl groups, optionally substituted C1-C 10 Halogenated groups, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 alkynyl group;

[1051] R 51 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 alkynyl group;

[1052] R 52 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl; and

[1053] p7 is from 1 to 4.

[1054] In some embodiments, ring L is an aryl group. In some embodiments, the aryl group is a phenyl group. In some embodiments, ring L is a heteroaryl group. In some embodiments, ring L is a bicyclic heteroaryl group comprising one, two, or three heteroatoms selected from N and O.

[1055] In some embodiments, the second end comprises a structure of formula (15-B), or a pharmaceutically acceptable salt thereof:

[1056]

[1057] Equation (15-B),

[1058] in:

[1059] Each R 48 It can be hydrogen, halogen, -OH, -CN, -NO2, -NH2, or Cl-C. 10 Alkyl, C1-C 10 Halogenated or C1-C 10 Hydroxyalkyl;

[1060] R 49 and R 50 Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 10 Alkyl groups, optionally substituted C1-C 10 Halogenated groups, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 alkynyl group;

[1061] R 51 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 acetylenic group; and

[1062] p7 is from 1 to 4.

[1063] In some embodiments, the second end comprises a structure of formula (15-C), or a pharmaceutically acceptable salt thereof:

[1064]

[1065] Formula (15-C),

[1066] in:

[1067] X is CR 48 Or N;

[1068] Each R 48 It can be hydrogen, halogen, -OH, -CN, -NO2, -NH2, or Cl-C. 10 Alkyl, C1-C 10 Halogenated or C1-C 10 Hydroxyalkyl;

[1069] R 49 and R 50 Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 10 Alkyl groups, optionally substituted C1-C 10 Halogenated groups, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 alkynyl group;

[1070] R 51 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 alkynyl group;

[1071] R 53 Hydrogen or optionally substituted C1-C 10 Alkyl; and

[1072] p7 is 1 to 3.

[1073] In some embodiments, each R 48 It can be hydrogen, halogen, -OH, -CN, -NO2, -NH2, or Cl-C. 10 Alkyl, C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl.

[1074] In some embodiments, R 49 Hydrogen, optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated groups, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 Alkynyl group. In some embodiments, R 49 For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 49 It is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R 49 It is hydrogen.

[1075] In some embodiments, R 50 Hydrogen, optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated groups, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 Alkynyl group. In some embodiments, R 50 For the optional replacement of C1-C 10 Alkyl or optionally substituted C2-C 10 Alkenyl. In some embodiments, R 50 It is hydrogen.

[1076] In some embodiments, R 51 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 Alkyne group.

[1077] In some embodiments, R 52 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl. In some embodiments, R 52 It is hydrogen.

[1078] In some embodiments, R 53 Hydrogen or optionally substituted C1-C 10 Alkyl group. In some embodiments, R 53 For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 53 It is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R 53 It is hydrogen.

[1079] In some embodiments, p7 is 4. In some embodiments, p7 is 3. In some embodiments, p7 is 2. In some embodiments, p7 is 1.

[1080] In some embodiments, the second terminal comprises a structure of formula (15-D1), (15-D2), or (15-D3), or a pharmaceutically acceptable salt thereof:

[1081] Equation (15-D1), Formula (15-D2) or

[1082] Equation (15-D3).

[1083] In some embodiments, the second terminal comprises a structure of formula (15-E1), (15-E2), or (15-E3), or a pharmaceutically acceptable salt thereof:

[1084] Formula (15-E1) Formula (15-E2) or

[1085] Equation (15-E3).

[1086] In some embodiments, the second end comprises a structure of formula (16-A), or a pharmaceutically acceptable salt thereof:

[1087]

[1088] Equation (16-A),

[1089] in:

[1090] B 5 It can be -O-, -NH-, or S;

[1091] B 6 For N or CH;

[1092] R 54 The aryl group can be substituted or the heteroaryl group can be substituted.

[1093] Each R 55 Independently halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl;

[1094] R 56 Hydrogen, optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl;

[1095] R 57 Halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl;

[1096] p9 is 1 to 3; and

[1097] q7 is between 0 and 2.

[1098] In some embodiments, B 5 For -O- or -S-. In some embodiments, B 5 For -O-. In some embodiments, B 5 For -S-.

[1099] In some embodiments, B 6 For N. In some embodiments, B 6 For CH.

[1100] In some embodiments, R 54 The aryl group is optionally substituted. In some embodiments, R 54 It is a phenyl group, optionally bonded by one or more halogens, -CN, -NH2, -OH, C1-C 10 Alkyl, C1-C 10 Halogenated or C1-C 10 Hydroxyalkyl substitution.

[1101] In some embodiments, each R 55 Independently halogen, -OH, -CN, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl.

[1102] In some embodiments, R 56 For the optional replacement of C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl. In some embodiments, R 56 For the optional replacement of C1-C 10 alkyl.

[1103] In some embodiments, R 57 It is a halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C. 10 alkyl.

[1104] In some embodiments, p9 is 3. In some embodiments, p9 is 2. In some embodiments, p9 is 1.

[1105] In some embodiments, q7 is 2. In some embodiments, q7 is 1. In some embodiments, q7 is 0.

[1106] In some embodiments, the second end comprises a structure of formula (16-B), or a pharmaceutically acceptable salt thereof:

[1107] Equation (16-B).

[1108] In some embodiments, the second end comprises the structure of formula (17-A), or a pharmaceutically acceptable salt thereof:

[1109]

[1110] Equation (17-A),

[1111] in:

[1112] Ring M is either an aryl group that is optionally substituted or a heteroaryl group that is optionally substituted;

[1113] The ring N is absent or is a 4- to 8-membered heterocyclic alkyl group;

[1114] A 6 It can be -O-, -NH-, or -CH2-;

[1115] Each R 58 Independently halogen, -OH, -CN, -NO2, -NH2, Cl-C 10 Alkyl, C1-C 10 Halogenated or C1-C 10 Hydroxyalkyl;

[1116] R 59 For hydrogen, -OH, -NH2, Cl-C 10 Alkyl, C1-C 10 Halogenated, C1-C 10 hydroxyalkyl or -NH-C1-C 10 alkyl;

[1117] R 60 Hydrogen or optionally substituted C1-C 10 Alkyl; and

[1118] p 10 The range is 1 to 4;

[1119] Equation (17-A) is passed through R 59 Connect to the connector.

[1120] In some embodiments, ring M is an aryl group, optionally dilated by one or more halogens, CN, NH2, OH, C1-C. 10 Alkyl, C1-C10 Halogenated or C1-C 10 Hydroxyalkyl substituted. In some embodiments, ring M is phenyl. In some embodiments, ring M is an optionally substituted 6-membered heteroaryl group, optionally substituted with one or more halogens, CN, NH2, OH, C1-C 10 Alkyl, C1-C 10 Halogenated or C1-C 10 Hydroxyalkyl substitution. In some embodiments, ring M is optionally substituted pyridine.

[1121] In some embodiments, ring N is a 4- to 8-membered heterocyclic alkyl group. In some embodiments, ring N is a 4-membered heterocyclic alkyl group. In some embodiments, ring N is a 5-membered heterocyclic alkyl group. In some embodiments, ring N is a 6-membered heterocyclic alkyl group. In some embodiments, ring N is absent.

[1122] In some embodiments, A 6 It is -O- or -NH-. In some embodiments, A 6 It is -CH2-.

[1123] In some embodiments, each R 58 Independently -OH, -NH2, Cl-C 10 Alkyl, C1-C 10 Halogenated or C1-C 10 Hydroxyalkyl. In some embodiments, each R 58 Independently for C1-C 10 Alkyl or C1-C 10 Hydroxyalkyl. In some embodiments, each R 58 Independently for C1-C 10 Hydroxyalkyl.

[1124] In some embodiments, R 59 -OH, -NH2, Cl-C 10 hydroxyalkyl or -NH-C1-C 10 Alkyl group. In some embodiments, R 59 It is hydrogen.

[1125] In some embodiments, R 60 For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 60 methyl. In some embodiments, R 60 It is hydrogen.

[1126] In some embodiments, p 10 It is 3 or 4. In some embodiments, p 10 The value is 2. In some embodiments, p 10 The value is 1.

[1127] In some embodiments, the second end comprises a structure of formula (17-B) or formula (17-C), or a pharmaceutically acceptable salt thereof:

[1128] Formula (17-B) or Equation (17-C).

[1129] In some embodiments, the second end comprises a structure of formula (18-A), or a pharmaceutically acceptable salt thereof:

[1130]

[1131] Equation (18-A),

[1132] in:

[1133] B 7 For N or CH;

[1134] R 67 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl;

[1135] R 68 and R 69 Each is independently a substituted 5-membered heteroaryl group; and

[1136] x5 and x6 are each independently between 0 and 4.

[1137] In some embodiments, B 7 For N. In some embodiments, B 7 For CH.

[1138] In some embodiments, R 67 Halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl, C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl. In some embodiments, R 67 It can be a halogen, -OH, -CN, -NO2, -NH2, or -CH3.

[1139] In some embodiments, R 68 The substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole may be used. In some embodiments, R 68It is pyrrole or pyrazole. In some embodiments, R 68 It is pyrrole. In some embodiments, R 68 It is pyrazole.

[1140] In some embodiments, R 69 The substituted oxazole, oxadiazole, thiazole, thiadiazole, pyrrole, or pyrazole may be used. In some embodiments, R 69 It is pyrrole or pyrazole. In some embodiments, R 69 It is pyrrole. In some embodiments, R 69 It is pyrazole.

[1141] In some embodiments, x5 is 2 or 3. In some embodiments, x5 is 1. In some embodiments, x5 is 0.

[1142] In some embodiments, x6 is 3. In some embodiments, x6 is 2. In some embodiments, x6 is 1. In some embodiments, x6 is 0.

[1143] In some embodiments, the second terminal comprises formula (18-B), or a pharmaceutically acceptable salt thereof:

[1144] Equation (18-B).

[1145] In some embodiments, the second terminal comprises formula (19-A), or a pharmaceutically acceptable salt thereof:

[1146] Equation (19-A).

[1147] In some embodiments, the second end comprises a structure of formula (20-A), or a pharmaceutically acceptable salt thereof:

[1148]

[1149] Equation (20-A),

[1150] in:

[1151] A 7 It is -NHC(O)- or -NHS(O)2-;

[1152] A 8 It can be -O- or -NH-;

[1153] Each R 61 Independently hydrogen or C1-C6 alkyl;

[1154] Each R 62 Independently halogen, -CN, -NO2, -OH, -OR 62a -NR 62a R62b -C(O)R 62a Optional replacement of C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl; wherein

[1155] Each R 62a and R 62b Independently hydrogen or C1-C 10 Alkyl, wherein

[1156] Each R 63 Independently for -OR 63a -NR 63a R 63b Optional replacement of C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl; wherein

[1157] Each R 63a and R 63b Independently hydrogen, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Halogenated or C1-C 10 Hydroxyalkyl;

[1158] p 13 1 to 3; and

[1159] p 14 The range is 1 to 3;

[1160] The connector is connected via R 62 One of them or R 63 One of them is connected to equation (20-A).

[1161] In some embodiments, A 7 It is -NHC(O)-. In some embodiments, A 7 It is -NHS(O)2-.

[1162] In some embodiments, A 8 For -O-. In some embodiments, A 8 It is -NH-.

[1163] In some embodiments, each R 61 Independently C1-C6 alkyl. In some embodiments, each R61 Methyl. In some embodiments, each R 61 It is hydrogen.

[1164] In some embodiments, each R 62 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl. In some embodiments, each R 62 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl group. In some embodiments, each R 62 Independently, the C1-C that can be arbitrarily replaced. 10 Haloalkyl. In some embodiments, each R 62 Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, each R 62 Independently, the C1-C that can be arbitrarily replaced. 10 Hydroxyalkyl.

[1165] In some embodiments, each R 63 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl. In some embodiments, each R 63 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl group. In some embodiments, each R 66 Independently, the C1-C that can be arbitrarily replaced. 10 Haloalkyl. In some embodiments, each R 63 Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, each R 63 Independently, the C1-C that can be arbitrarily replaced. 10 Hydroxyalkyl.

[1166] In some embodiments, p 13 The value is 1. In some embodiments, p 13 The value is 2. In some embodiments, p 13 The value is 3.

[1167] In some embodiments, p 14 The value is 1. In some embodiments, p 14 The value is 2. In some embodiments, p14 The value is 3.

[1168] In some embodiments, the connector is via R 62 One of them is connected to equation (20-A). In some embodiments, the connector is connected via R 63 One of them is connected to equation (20-A).

[1169] In some embodiments, the second end comprises a structure of formula (20-B) or formula (20-C), or a pharmaceutically acceptable salt thereof:

[1170] Formula (20-B) or

[1171] Formula (20-C).

[1172] In some embodiments, the second end comprises the structure of formula (21-A), or a pharmaceutically acceptable salt thereof:

[1173]

[1174] Equation (21-A),

[1175] in:

[1176] Ring Q is a C3-C8 cycloalkyl or a 4- to 8-membered heterocyclic alkyl;

[1177] A 9 It can be -O-, -NH-, or -NHC(O)-;

[1178] Each R 64 Independently hydrogen or C1-C6 alkyl;

[1179] Each R 65 Independently halogen, -CN, -NO2, -OH, -OR 62a -NR 62a R 62b Optional replacement of C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl; wherein

[1180] Each R 62a and R 62b Independently hydrogen or C1-C 10 alkyl;

[1181] Each R 66 Independently halogenated, optionally substituted C1-C 10Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl;

[1182] p 15 0 to 3; and

[1183] p 16 The range is 1 to 3;

[1184] Equation (21-A) is connected to R 65 One of them or R 66 The connector at one of the points.

[1185] In some embodiments, A 9 For -O-. In some embodiments, A 9 For -NH-. In some embodiments, A 9 It is -NHC(O)-.

[1186] In some embodiments, ring Q is a C3-C8 cycloalkyl group. In some embodiments, ring Q is a 4- to 8-membered heterocyclic alkyl group.

[1187] In some embodiments, each R 64 Independently C1-C6 alkyl. In some embodiments, each R 64 Methyl. In some embodiments, each R 64 It is hydrogen.

[1188] In some embodiments, each R 65 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl. In some embodiments, each R 65 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl group. In some embodiments, each R 65 Independently, the C1-C that can be arbitrarily replaced. 10 Haloalkyl. In some embodiments, each R 65 Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, each R 65 Independently, the C1-C that can be arbitrarily replaced. 10 Hydroxyalkyl.

[1189] In some embodiments, each R 66 Independently, the C1-C that can be arbitrarily replaced.10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl. In some embodiments, each R 66 Independently, the C1-C that can be arbitrarily replaced. 10 Alkyl group. In some embodiments, each R 66 Independently, the C1-C that can be arbitrarily replaced. 10 Haloalkyl. In some embodiments, each R 66 Independently, the C1-C that can be arbitrarily replaced. 10 Heteroalkyl. In some embodiments, each R 66 Independently, the C1-C that can be arbitrarily replaced. 10 Hydroxyalkyl.

[1190] In some embodiments, p 15 It is 0. In some embodiments, p 15 The value is 1. In some embodiments, p 15 The value is 2. In some embodiments, p 15 The value is 3.

[1191] In some embodiments, p 16 The value is 1. In some embodiments, p 16 The value is 2. In some embodiments, p 16 The value is 3.

[1192] In some embodiments, formula (21-A) is connected to R 65 The connector at one of the locations. In some embodiments, formula (21-A) is connected to R. 66 The connector at one of the points.

[1193] In some embodiments, the second end comprises the structure of formula (21-B), or a pharmaceutically acceptable salt thereof:

[1194] Equation (21-B).

[1195] In some embodiments, the second end comprises the structure of formula (22-A), or a pharmaceutically acceptable salt thereof:

[1196]

[1197] Equation (22-A),

[1198] in:

[1199] R 67 It can be hydrogen, -NH2, or -NHSO2CH3;

[1200] R 68 and R 69 Each is independently a halogen, -CN, -NO2, -OH, or an optional substituted C1-C. 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl;

[1201] R 70 -S(O)R 70a or -S(O)2R 70a , where R 70a It is hydrogen or C1-C 10 Alkyl; and

[1202] R 71 It is hydrogen or C1-C 10 alkyl;

[1203] Equation (22-A) is connected to R 67 Or R 71 Connector at the location.

[1204] In some embodiments, R 67 It is hydrogen. In some embodiments, R is... 67 It is -NH2 or -NHSO2CH3.

[1205] In some embodiments, R 68 and R 69 Each of the C1-Cs can be arbitrarily replaced independently. 10 Alkyl group. In some embodiments, R 68 and R 69 Each is a methyl group.

[1206] In some embodiments, R 70 is -S(O)2R 70a In some embodiments, R 70 It is -S(O)2CH3.

[1207] In some embodiments, formula (22-A) is connected to R 67 The connector at the location. In some embodiments, formula (22-A) is connected to the connector at R. 71 Connector at the location.

[1208] In some embodiments, the second end comprises a structure of formula (22-B) or formula (22-C), or a pharmaceutically acceptable salt thereof:

[1209] Equation (22-B) or Equation (22-C).

[1210] In some embodiments, the second end comprises the structure of formula (23-A), or a pharmaceutically acceptable salt thereof:

[1211]

[1212] Equation (23-A)

[1213] in:

[1214] B 9 -CH-CR B9 -、-N- or NR B10 ;

[1215] B 10 -N- or NR B10 ,in

[1216] R B9 It is hydrogen or halogen; and R B10 It is hydrogen;

[1217] R 72 Halogen, -CN, -NO2, -OH, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl; and

[1218] R 73 It is hydrogen;

[1219] Equation (23-A) is connected to R B9 R B10 Or R 73 Connector at the location.

[1220] In some embodiments, B 9 -CH-CR B9 -and B 10 For -N-. In some embodiments, B 9 For -N- and B 10 For NR B10 In some embodiments, B 9 For NR B10 And B 10 It is -N-.

[1221] In some embodiments, R 72 For the optional replacement of C1-C 10 Alkyl group. In some embodiments, R 72 It is a methyl group.

[1222] In some embodiments, formula (23-A) is connected to R B9 Or R B10The connector at the location. In some embodiments, formula (23-A) is connected to the connector at R. 73 Connector at the location.

[1223] In some embodiments, the second end comprises a structure of formula (23-B) or formula (23-C), or a pharmaceutically acceptable salt thereof:

[1224] Equation (23-B) or

[1225] Equation (23-C).

[1226] In some embodiments, the second end comprises a structure of formula (23-D) or formula (23-E), or a pharmaceutically acceptable salt thereof:

[1227] Equation (23-D) or

[1228] Equation (23-E).

[1229] In some embodiments, the second end comprises the structure of formula (24-A), or a pharmaceutically acceptable salt thereof:

[1230]

[1231] Equation (24-A),

[1232] in:

[1233] R 74 -CH2- (optionally substituted 5-membered heteroaryl);

[1234] R 75 -O-(C1-C) 10 alkyl)-R 75a ;where R 75a It is a -C(O)O-alkyl;

[1235] R 76 For -OR 76a , where R 76a It is hydrogen or alkyl;

[1236] R 77 It is hydrogen or halogen; and

[1237] R 77a It is hydrogen or C1-C 10 alkyl;

[1238] Equation (24-A) is connected to R 75a Or R 76a Connector at the location.

[1239] In some embodiments, R 75 -O-(C1-C) 10 Alkyl)-C(O)O-alkyl. In some embodiments, R 75 It is -O-(C1-C4 alkyl)-C(O)O-C1-C4 alkyl.

[1240] In some embodiments, R 76 It is -OH. In some embodiments, R 76 For -OCH3. In some embodiments, R 76 It is -O-CH2CH3.

[1241] In some embodiments, R 77 It is a halogen. In some embodiments, R 77 It is hydrogen.

[1242] In some embodiments, R 77a It is hydrogen or methyl. In some embodiments, R 77a methyl. In some embodiments, R 77a It is hydrogen.

[1243] In some embodiments, formula (24-A) is connected to R 75a The connector at the location. In some embodiments, formula (24-A) is connected to the connector at R. 76a Connector at the location.

[1244] In some embodiments, the second end comprises a structure of formula (24-B) or formula (24-C), or a pharmaceutically acceptable salt thereof:

[1245] Formula (24-B) or

[1246] Equation (24-C).

[1247] In some embodiments, the second end comprises a structure of formula (25-A), or a pharmaceutically acceptable salt thereof:

[1248]

[1249] Equation (25-A),

[1250] in:

[1251] B 12 For -NR 80a -or-C(R) 80b )2-;

[1252] R 78 It is a halogen, -CN, -NO2, -OH, or optionally substituted C1-C. 10 alkyl;

[1253] R 79a and R 79b Each is independently a halogen, -CN, -NO2, -NH2, -N(CH3)2, or optionally substituted C1-C. 10 alkyl;

[1254] Or R 79a and R 79b Together with the atoms they are attached to, they form a 6-membered aryl group;

[1255] Each R 80 Independently hydrogen, -O-C1-C3 alkyl, C1-C 10 Alkyl or C1-C 10 Alkoxy;

[1256] R 80a It is a C1-C6 alkyl group;

[1257] Each R 80b Independently hydrogen or C1-C6 alkyl; and

[1258] r7 is 1, 2, or 3;

[1259] Equation (25-A) is connected to R 80 The connector at one of the points.

[1260] In some embodiments, B 12 For -NR 80a -. In some embodiments, B 12 -C(R) 80b )2-.

[1261] In some embodiments, R 78 It can be -CN, -NO2, or -OH. In some embodiments, R 78 It is -OH. In some embodiments, R 78 It is a halogen. In some embodiments, R 78 For the optional replacement of C1-C 10 alkyl.

[1262] In some embodiments, R 79a and R 79b Each can be independently a halogen, -NH2, or -N(CH3)2.

[1263] In some embodiments, R 79a and R 79b Together with the atoms they are attached to, they form a 6-membered aryl group.

[1264] In some embodiments, each R 80 Independently hydrogen. In some embodiments, each R80 Independently for C1-C 10 Alkyl group. In some embodiments, each R 80 Independently for C1-C 10 Alkyl groups. In some embodiments, each R 80 Independently -OCH3.

[1265] In some embodiments, the second end comprises a structure of formula (25-B) or formula (25-C), or a pharmaceutically acceptable salt thereof:

[1266] Formula (25-B) or

[1267] Formula (25-C).

[1268] In some embodiments, the second end comprises the structure of formula (26-A), or a pharmaceutically acceptable salt thereof:

[1269]

[1270] Equation (26-A),

[1271] in:

[1272] B 11 -O- or -NR 82 -;

[1273] A 10 For -NR 84 -or-NR 84 CH2-;

[1274] R 81a and R 81b Each independently is C1-C 10 alkyl;

[1275] Or R 81a and R 81b They combine to form an oxygen group (=O);

[1276] R 82 It is hydrogen or C1-C3 alkyl;

[1277] Each R 83 Independently halogen, -CN, -NO2, -OH, -OR 83a Or optionally, the C1-C that is replaced 10 Alkyl; wherein R 83a For C1-C 10 alkyl;

[1278] R 84 It is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or phenyl;

[1279] R 85 It is hydrogen or C1-C 10 Alkyl; and

[1280] r4 is 1, 2, or 3;

[1281] Equation (26-A) is connected to R 83 The connector at one of the points.

[1282] In some embodiments, B 11 For -O-. In some embodiments, B 11 For -NR 82 -. In some embodiments, B 11 It is NCH3.

[1283] In some embodiments, A 10 For -NR 84 - In some embodiments, A 10 For -NR 84 CH2-.

[1284] In some embodiments, R 81a and R 81b Each is a methyl group. In some embodiments, R 81a and R 81b They combine to form an oxo group (=O).

[1285] In some embodiments, each R 83 Independently -CN, -OH, -OR 83a Or optionally, the C1-C that is replaced 10 Alkyl group. In some embodiments, each R 83 Independently -OH or -OR 83a .

[1286] In some embodiments, R 84 It is a C3-C6 cycloalkyl or phenyl. In some embodiments, R 84 It is a phenyl group.

[1287] In some embodiments, R 85 For C1-C 10 Alkyl group. In some embodiments, R 85 methyl. In some embodiments, R 85 It is hydrogen.

[1288] In some embodiments, the second end comprises a structure of formula (26-B) or formula (26-C), or a pharmaceutically acceptable salt thereof:

[1289] Formula (26-B) or Equation (26-C).

[1290] In some embodiments, the second end comprises a structure of formula (26-D) or formula (26-E), or a pharmaceutically acceptable salt thereof:

[1291] Formula (26-D) or Equation (26-E).

[1292] In some embodiments, the second end comprises the structure of formula (27-A), or a pharmaceutically acceptable salt thereof:

[1293] Equation (27-A).

[1294] In some embodiments, the second end comprises the structure of formula (28-A), or a pharmaceutically acceptable salt thereof:

[1295]

[1296] Equation (28-A),

[1297] in:

[1298] A 11 It is a C1-C6 alkylene group;

[1299] B 13 For N or CR 100 ;

[1300] R 97 It is a C1-C6 alkyl group;

[1301] R 98 It is a halogen;

[1302] R 99 Hydrogen, halogen, or optionally substituted C1-C 10 Alkyl; and

[1303] R 100 For -OR 100a Or optionally, the C1-C that is replaced 10 Alkyl; wherein R 100a It is hydrogen or C1-C 10 alkyl;

[1304] Or R 99 and R 100 Together with the atoms to which it is attached, it forms a heterocyclic alkyl group.

[1305] In some embodiments, A 11 It is a C1-C4 alkylene group. In some embodiments, A 11 It is -CH2CH2-.

[1306] In some embodiments, B 13 For N. In some embodiments, B 13 For CR 100 .

[1307] In some embodiments, R 97 It is a methyl group.

[1308] In some embodiments, R 98 It is -Cl.

[1309] In some embodiments, R 100 For -OR 100a In some embodiments, R 100 For the optional replacement of C1-C 10 alkyl.

[1310] In some embodiments, R 99 and R 100 Together with the atoms to which it is attached, it forms a heterocyclic alkyl group.

[1311] In some embodiments, the second end comprises the structure of formula (28-B), or a pharmaceutically acceptable salt thereof:

[1312] Equation (28-B).

[1313] In some embodiments, the second end comprises a structure of formula (28-C), or a pharmaceutically acceptable salt thereof:

[1314] Equation (28-C).

[1315] In some embodiments, the second end comprises the structure of formula (29-A), or a pharmaceutically acceptable salt thereof:

[1316] Equation (29-A).

[1317] In some embodiments, the second end comprises a structure of formula (30-A), or a pharmaceutically acceptable salt thereof:

[1318] Equation (30-A).

[1319] In some embodiments, the second end comprises the structure of formula (31-A), or a pharmaceutically acceptable salt thereof:

[1320]

[1321] Equation (31-A),

[1322] in:

[1323] R 94 It is a halogen;

[1324] R 94a It is hydrogen or C1-C3 alkyl; and

[1325] R 95 It is hydrogen, halogen, -OH, -OCH3, or optionally substituted C1-C. 10 alkyl.

[1326] In some embodiments, R 94 It is -Cl.

[1327] In some embodiments, R 94a It is a C1-C3 alkyl group. In some embodiments, R 94a methyl. In some embodiments, R 94a It is hydrogen.

[1328] In some embodiments, R 95 Halogen, -OH, -OCH3, or optionally substituted C1-C 10 Alkyl group. In some embodiments, R 95 It is hydrogen.

[1329] In some embodiments, the second end comprises a structure of formula (31-B) or formula (31-C), or a pharmaceutically acceptable salt thereof:

[1330] Formula (31-B) or Equation (31-C).

[1331] In some embodiments, the second end comprises the structure of formula (32-A), or a pharmaceutically acceptable salt thereof:

[1332] Equation (32-A).

[1333] In some embodiments, the second end comprises the structure of formula (33-A), or a pharmaceutically acceptable salt thereof:

[1334] Equation (33-A).

[1335] In some embodiments, the second end comprises the structure of formula (34-A), or a pharmaceutically acceptable salt thereof:

[1336] Equation (34-A).

[1337] In some embodiments, the second end comprises a structure of formula (35-A), or a pharmaceutically acceptable salt thereof:

[1338] Equation (35-A).

[1339] In some embodiments, the second end comprises a structure of formula (36-B) or formula (36-A), or a pharmaceutically acceptable salt thereof:

[1340] Formula (36-A) or

[1341] Equation (36-B).

[1342] In some embodiments, the second end comprises the structure of formula (37-A), or a pharmaceutically acceptable salt thereof:

[1343]

[1344] Equation (37-A),

[1345] in:

[1346] The ring T is a C5-C6 cycloalkyl, a 5- to 6-membered heterocycloalkyl, or a phenyl;

[1347] Each R 86 Independently halogen, -CN, -NO2, -OH, -OR 86a -N(R) 86b )2 or optionally, the C1-C that is replaced 10 Alkyl; wherein

[1348] Each R 86a Independently for C1-C 10 alkyl;

[1349] Each R 86b Independently hydrogen or C1-C 10 alkyl;

[1350] R 87 It is a C5-C6 cycloalkyl or phenyl group;

[1351] Each R 88 Independently halogen, -CN, -NO2, -OH, -OR 88a -NR 88b R 88b Or optionally, the C1-C that is replaced 10 Alkyl; wherein

[1352] Each R 88a Independently for C1-C 10 alkyl;

[1353] Each R 88b Independently hydrogen or C1-C 10 alkyl;

[1354] R89a and R 89b Each is independently hydrogen or C1-C 10 alkyl;

[1355] Or R 89a and R 89b Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic alkyl groups;

[1356] R 96 It is hydrogen or -CH3; and

[1357] r5 and r6 are each independently 0, 1, 2 or 3.

[1358] In some embodiments, ring T is a C5-C6 cycloalkyl group. In some embodiments, ring T is a 5- or 6-membered heterocycloalkyl group. In some embodiments, ring T is a phenyl group.

[1359] In some embodiments, each R 86 Independent of halogen, -OH, -OR 86a or -N(R) 86b )2. In some embodiments, each R 86 Independently halogenated or -N(R) 86b )2. In some embodiments, each R 86 Independently for -N(R) 86b )2.

[1360] In some embodiments, R 87 It is a C5-C6 cycloalkyl group. In some embodiments, R 87 It is a phenyl group.

[1361] In some embodiments, R 89a and R 89b Each independently is C1-C 10 Alkyl group. In some embodiments, R 89a and R 89b Each is hydrogen.

[1362] In some embodiments, R 89a and R 89b Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic alkyl groups.

[1363] In some embodiments, R 96 For -CH3. In some embodiments, R 96 It is hydrogen.

[1364] In some embodiments, r5 and r6 are each independently 0, 1, or 2.

[1365] In some embodiments, the second end comprises a structure of formula (37-B) or formula (37-C), or a pharmaceutically acceptable salt thereof:

[1366] Formula (37-B) or

[1367] Equation (37-C).

[1368] In some embodiments, the second end is selected from the group consisting of:

[1369] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

[1370] In some embodiments, the second end is selected from the portions described in Table 1, or a pharmaceutically acceptable salt thereof.

[1371] Table 1. Exemplary combination portion.

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379] Oligomeric Main Chain - Connector Sub-part

[1380] The oligomeric backbone is a linker that connects the first and second ends and brings the regulatory molecule close to the target gene to regulate gene expression.

[1381] The length of the linker depends on the type of regulatory protein and the target gene. In some embodiments, the linker length is less than about 50 angstroms. In some embodiments, the linker length is about 20 to 30 angstroms.

[1382] In some embodiments, the oligomeric backbone comprises 5 to 50 chain atoms.

[1383] In some embodiments, the oligomeric backbone comprises a polymer having 2 to 50 spacer portions, wherein

[1384] Each interval is independently selected from the following groups: -((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 - Optional replacement of C1-C 12 Alkyl groups, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkyne group, optionally substituted C6-C 10 arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5- to 10-membered heteroalkylene, optionally substituted 4- to 10-membered heteroalkylene, 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 S(O)2- and -P(O)OH-, and any combination thereof; where

[1385] Each x is independently between 2 and 4;

[1386] Each y is independently between 1 and 10;

[1387] Each R 1a Independently, it is 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; and

[1388] Each R 1b Independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, optionally substituted alkylamide, optionally substituted haloalkyl, sulfonyl, optionally substituted thioalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclic.

[1389] In some embodiments, the oligomeric backbone comprises a polymer having 2 to 50 spacer portions, wherein each spacer portion is independently selected from the group consisting of: optionally substituted C1-C 12 Alkyl group, -((CH2) x -O) y -、-((CH2) x -NH) y -, -O-, -C(O)NH-, -NH- and any combination thereof.

[1390] In some embodiments, the oligo-chain includes -(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 -,in

[1391] a, b, c, d, and e are each independently 0 or 1, and the sum of a, b, c, d, and e is between 1 and 5;

[1392] T 1 T 2 T 3 T 4 and T 5 Each is independently selected from the arbitrarily substituted C1-C. 12 Alkylene, optionally substituted alkenylene, optionally substituted ynylene, (EA) w (EDA) m (PEG) n (Modified PEG) n (AA) p 、-(CR 2a OH) h - Optional replacement of C6-C 10 arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5- to 10-membered heteroalkylene, optionally substituted 4- to 10-membered heteroalkylene, acetal, disulfide, hydrazine, carbohydrate, β-lactam and ester,

[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] , where each q is an integer from 1 to 6 independently, each x is an integer from 1 to 4 independently, and each r is 0 or 1 independently;

[1402] (h)(PEG) n With -(CR 1b R 1b -CR 1b R 1b -O) n -CR 1b R 1b - structure;

[1403] (i) (Modified PEG) n With -(CH2-CR 1b =CR 1b -CH2-O)- or -(CR 1b R 1b -CR 1b R 1b -S)-substitution (PEG) n At least one of -(CR) 1b R 1b -CR 1b R 1b The structure of -O)-;

[1404] (j)AA represents an amino acid residue;

[1405] (k)V 1 V 2 V 3 V 4 and V 5 Each is independently selected from the following groups: bond, C(O)-, -NR 1a -、-C(O)NR 1a -、-NR 1a C(O)-、-CONR 1a -C1-C4 alkyl-, -NR 1aC(O)-C1-C4 alkyl-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR 1a -、-NR 1a S(O)2- and -P(O)OH-;

[1406] (l) Each R 1a Independently, it is 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; and

[1407] (m) Each R 1b It 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, heterocyclic and substituted heterocyclic.

[1408] 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.

[1409] In some embodiments, n is 3 to 9. In some embodiments, n is 4 to 8. In some embodiments, n is 5 or 6.

[1410] In some embodiments, T 1 T 2 T 3 and T 4 And T 5 Each was independently selected from C 1- C 12 Alkyl, substituted C1-C 12 Alkyl group, (EA) w (EDA) m(PEG) n (Modified PEG) n (AA) p 、-(CR 1b OH) h - Phenyl, substituted phenyl, piperidine-4-amino (P4A), p-amino-benzoxycarbonyl (PABC), m-amino-benzoxycarbonyl (MABC), p-amino-benzoxy (PABO), m-amino-benzoxy (MABO), p-aminobenzylmethyl, acetal, disulfide, hydrazine, carbohydrate, β-lactam, ester, (AA) p -MABC-(AA) p (AA) p -MABO-(AA) p (AA) p -PABO-(AA) p and (AA) p -PABC-(AA) p In some embodiments, piperidine-4-amino (P4A) is , where R 1a It is hydrogen or C1-C6 alkyl.

[1411] In some embodiments, T 1 T 2 T 3 T 4 and T 5 Each is independently selected from (C1-C) 12 )alkyl, substituted C1-C 12 Alkyl group, (EA) w (EDA) m (PEG) n (Modified PEG) n (AA) p 、-(CR 2a OH) h - Optional replacement of C6-C 10 Arylidene, 4- to 10-membered heterocyclic alkene, or optionally substituted 5- to 10-membered heterolidene. In some embodiments, EA has the following structure:

[1412] ;and

[1413] EDA has the following structure:

[1414] .

[1415] In some embodiments, for EA and EDA, x is 2 to 3 and q is 1 to 3. In some embodiments, R 1aIt is hydrogen or C1-C6 alkyl.

[1416] In some embodiments, T 4 or T 5 C6-C is arbitrarily replaced. 10 Alpha-aryl.

[1417] In some embodiments, T 4 or T 5 It is a phenylene or a substituted phenylene. In some embodiments, T 4 or T 5 It is a phenylene or a phenylene substituted with one to three substituents selected from C1-C6 alkyl, halogen, OH, or amine. In some embodiments, T 4 or T 5 It is a 5- to 10-membered heteroaryl group or a substituted heteroaryl group. In some embodiments, T 4 or T 5 It is a 4- to 10-membered heterocyclic sub-heterocyclic group or a substituted heterocyclic sub-heterocyclic group. In some embodiments, T 4 or T 5 It is a heteroaryl group or a heteroaryl group optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, halogen, OH or amine.

[1418] In some embodiments, T 1 T 2 T 3 T 4 and T 5 and V 1 V 2 V 3 V 4 and V 5 Selected from Table 2 below.

[1419] Table 2. Exemplary connection subunits.

[1420]

[1421] In some embodiments, the oligomeric main chain includes -N(R) 1a (CH2) x N(R 1a (CH2) x N-, where each R 1a The x is independently selected from hydrogen or optionally substituted C1-C6 alkyl groups; and each x is independently an integer in the range of 1 to 10.

[1422] In some embodiments, the oligomeric backbone comprises -(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 -A-; where each q is an independent integer from 2 to 10; each x is an independent integer from 1 to 6; and each A is independently selected from the key, arbitrarily substituted C1-C 12 Alkyl groups, optionally substituted C6-C 10 The arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5- to 10-membered heteroalkylene, and optionally substituted 4- to 10-membered heteroalkylene. In some embodiments, A is a spirocycloalkylene or spiroheteroalkylene.

[1423] In some embodiments, the oligomeric backbone comprises -(CH2CH2-O). x7 -or-(CH2CH2-O) x8 -A-(CH2CH2-O) x9 - where A is an optional substituted 4- to 10-membered heterocyclic alkylene or spirocyclic alkene, and each x7, x8 and x9 is an integer from 1 to 15 independently.

[1424] In some embodiments, the oligo-chain includes -NR 1a -(CH2CH2O) y (CH2) x -or-NR 1a -(CH2) q -C(O)NR 1a (CH2CH2O) y (CH2) x - where q is 2 to 10, x is 1 to 4, y is 1 to 50, and each R 1a Independently, it is 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 oligomeric backbone comprises -NR1a -(CH2CH2O) y (CH2) x In some embodiments, the oligo-chain includes -NR 1a -(CH2) q -C(O)NR 1a (CH2CH2O) y (CH2) x -

[1425] In some embodiments, the oligomeric backbone comprises -(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 C(O)-. In some embodiments, the oligomeric backbone comprises -(CH2CH2-O). x -、-(CH2CH2-O) x -(CH2CH2)-NH-, -NH-(CH2CH2-O) x -、-NH-(CH2CH2-O) x -(CH2CH2)-NH-, -(CH2CH2-O) x -(CH2CH2)-NHC(O)- or -NH-(CH2CH2-O) x -(CH2CH2)-NHC(O)-. In some embodiments, the oligomeric backbone comprises -NH-(CH2CH2-O). x -or -NH-(CH2CH2-O) x -(CH2CH2)-NH-. In some embodiments, the oligomeric backbone comprises -NH-(CH2CH2-O). x - In some embodiments, the oligomeric backbone comprises -NH-(CH2CH2-O). x -(CH2CH2)-NH-.

[1426] In some embodiments, the oligomeric backbone comprises polyethylene glycol (PEG). In some embodiments, the oligomeric backbone comprises 1 to 20 PEG units. In some embodiments, the oligomeric backbone comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 PEG units.

[1427] In some embodiments, A is selected from , or In some embodiments, A is In some embodiments, A is In some embodiments, A is .

[1428] In some embodiments, A comprises a portion having the following structure, or a pharmaceutically acceptable salt thereof:

[1429]

[1430] in:

[1431] A 2 For non-existent or -C(O)-; and

[1432] R 27 For the optional replacement of C1-C 50 Alkyl or optionally substituted C1-C 50 Heteroalkyl groups.

[1433] In some embodiments, A 2 For -C(O)-. In some embodiments, A 2 It does not exist.

[1434] In some embodiments, R 27 For C1-C 50 Alkyl group. In some embodiments, R 27 For C1-C 40 Alkyl group. In some embodiments, R 27 For C1-C 30 Alkyl group. In some embodiments, R 27 For C1-C 20 Alkyl group. In some embodiments, R 27 For C1-C 10 Alkyl group. In some embodiments, R 27 For C1-C 50 Heteroalkyl. In some embodiments, R 26 For C1-C 40 Heteroalkyl. In some embodiments, R 27 For C1-C 30Heteroalkyl. In some embodiments, R 27 For C1-C 20 Heteroalkyl. In some embodiments, R 27 For C1-C 10 Heteroalkyl groups. In some embodiments, the heteroalkyl group is polyethylene glycol (PEG).

[1435] In some embodiments, the oligomeric backbone comprises a portion having a structure of formula (C-1), or a pharmaceutically acceptable salt thereof:

[1436]

[1437] Equation (C-1),

[1438] in:

[1439] Cycle P is absent, arylene, or heterocyclic alkyl;

[1440] L 5 The alkylene group is absent, optionally substituted, or optionally substituted with an alkylene group;

[1441] B 1 and B 2 Each can be independently CH or N;

[1442] s1 and s2 are each independently between 0 and 3; and

[1443] ** indicates the connection to the second end.

[1444] In some embodiments, ring P is absent. In some embodiments, ring P is a C4-C7 heterocyclic alkyl group.

[1445] In some embodiments, B 1 For N. In some embodiments, B 1 For CH.

[1446] In some embodiments, B 2 For N. In some embodiments, B 2 For CH.

[1447] In some embodiments, L 5 It does not exist.

[1448] In some embodiments, L 5 It is an alkylene or ynylene group.

[1449] In some embodiments, the oligomeric backbone comprises a portion having a structure of formula (C-2), or a pharmaceutically acceptable salt thereof:

[1450]

[1451] Equation (C-2),

[1452] in:

[1453] L 5 The alkylene group is absent, optionally substituted, or optionally substituted with an alkylene group; and

[1454] B 2 B 3 and B 4 Each can be either N or CH independently.

[1455] In some embodiments, B 3 and B 4 Each of them is independently N or CH; and B 2 Let N be the number of elements in the array.

[1456] In some embodiments, L 5 It is a C1-C3 alkylene or C1-C3 ynylene. In some embodiments, L 5 It is a C1-C3 alkylene group. In some embodiments, L 5 It is a C1-C3 acetylenic group. In some embodiments, L 5 -CH2-, -CH2CH2-, or In some embodiments, L 5 It is -CH2- or -CH2CH2-. In some embodiments, L 5 for In some embodiments, L 5 for .

[1457] In some embodiments, L 5 For -(C R1G R 1G ) x10 -(alkylene)2-(CR) 1G R 1G ) y10 -; where x 10 and y 10 Each is independently 0 or 1; and each R 1G It is hydrogen or C1-C3 alkyl.

[1458] In some embodiments, the oligomeric backbone comprises a portion having a structure of formula (C-3), or a pharmaceutically acceptable salt thereof:

[1459]

[1460] Equation (C-3),

[1461] in:

[1462] s1 and s2 are each independently between 0 and 3;

[1463] r1 is an integer from 1 to 3;

[1464] R 26 For the optional replacement of C1-C 20 Alkylene or optionally substituted C2-C 20 Heteroalkyl;

[1465] Each R 1G Independently hydrogen or C1-C3 alkyl; and

[1466] ** indicates the connection to the second end.

[1467] In some embodiments, R 26 For the optional replacement of C1-C 20 Heteroalkylene. In some embodiments, R 26 It is PEG.

[1468] In some embodiments, each R 1G Independently hydrogen. In some embodiments, R 1G Independently, it is a C1-C3 alkyl group. In some embodiments, the C1-C3 alkyl group is methyl, ethyl, or propyl. In some embodiments, each R 1G It is methyl on its own.

[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 oligopoly main chain includes:

[1472] , , , , , , , , , , , , , or .

[1473] In some embodiments, the oligomeric backbone is coupled to a first end and / or a second end having a group selected from: -C(O)-, -NR 1a -、-C(O)NR 1a -、-NR 1a C(O)-、-C(O)NR 1a C1-C4 alkyl-,-NR 1a C(O)-C1-C4 alkyl-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR 1a -、-NR 1a S(O)2-, -P(O)OH-, -((CH2) x -O)-、-((CH2) y -NR 1a - Optional replacement of C1-C 12 Alkylene, optionally substituted C2-C 10 alkenyl groups, optionally substituted C2-C 10 Ethyne group, optionally substituted C6-C 10 arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5- to 10-membered heteroalkylene and optionally substituted 4- to 10-membered heteroalkylene, wherein each x is independently 1 to 4, each y is independently 1 to 4, and each R 1a It is independently hydrogen or optionally substituted C1-C6 alkyl.

[1474] In some embodiments, the oligomeric backbone is coupled to a first end having a group selected from: -O-, -C(O)-, -NR 1a -、C1-C 12 Alkyl, -C(O)NR 1a -and-NR 1a C(O)-. In some embodiments, the oligomeric backbone has a component selected from -O- or -NR-. 1a - The first end of the group is attached.

[1475] In some embodiments, the oligomeric backbone is coupled to a second end having a group selected from: -C(O)-, -NR 1a -、-C(O)NR 1a -、-NR 1a C(O)-、-((CH2) x -O)-、-((CH2) y -NR 1a -, -O-, optional C1-C to be replaced 12 Alkyl groups, optionally substituted C6-C 10arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5- to 10-membered heteroalkylene and optionally substituted 4- to 10-membered heteroalkylene, wherein each x is independently 1 to 4, each y is independently 1 to 4, and each R 1a Independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 haloalkyl.

[1476] In some embodiments, the oligomeric backbone is coupled to a second end having a group selected from: -O-, -C(O)-, -NR 1a -、C1-C 12 Alkyl, -C(O)NR 1a -and-NR 1a C(O)-. In some embodiments, the oligomeric backbone has a component selected from -O- or -NR-. 1a - The second end of the oligomeric backbone is attached to the -O- group. In some embodiments, the oligomeric backbone is attached to the second end having -O-. In some embodiments, the oligomeric backbone is attached to the second end having -NR 1a -The second end is joined. In some embodiments, the oligomeric backbone is joined to a second end having -NH-.

[1477] In some embodiments, each R 1a Independently, it is hydrogen, -CH3, -CF3, -CH2CF3, -SO2CH3, -SO2CH2CH3, -SO2CF3, -SO2N(CH3)2, or -SO2-cyclopropyl. In some embodiments, each R 1a Independently hydrogen, -CH3, -CF3, or -CH2CF3. In some embodiments, each R 1a Independently -SO2CH3, -SO2CH2CH3, or -SO2CF3. In some embodiments, each R 1a Independently hydrogen. In some embodiments, each R 1a Independently -CH3.

[1478] This document covers any combination of groups described above with respect to various variables. Throughout this specification, groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[1479] In some embodiments, non-limiting examples of transcription regulator compounds described herein are presented in Table 3 below (next page).

[1480]

[1481]

[1482]

[1483]

[1484]

[1485]

[1486]

[1487]

[1488]

[1489]

[1490]

[1491]

[1492]

[1493]

[1494]

[1495]

[1496]

[1497]

[1498]

[1499]

[1500]

[1501]

[1502]

[1503]

[1504]

[1505]

[1506]

[1507]

[1508]

[1509]

[1510]

[1511]

[1512]

[1513]

[1514]

[1515]

[1516]

[1517]

[1518]

[1519]

[1520]

[1521]

[1522]

[1523]

[1524]

[1525]

[1526]

[1527]

[1528]

[1529]

[1530]

[1531]

[1532]

[1533]

[1534]

[1535]

[1536]

[1537]

[1538]

[1539]

[1540]

[1541]

[1542]

[1543]

[1544]

[1545]

[1546]

[1547]

[1548]

[1549]

[1550]

[1551]

[1552]

[1553]

[1554]

[1555]

[1556]

[1557]

[1558]

[1559]

[1560]

[1561]

[1562]

[1563]

[1564]

[1565]

[1566]

[1567]

[1568]

[1569]

[1570]

[1571]

[1572]

[1573]

[1574]

[1575]

[1576]

[1577]

[1578]

[1579]

[1580]

[1581]

[1582]

[1583]

[1584]

[1585]

[1586]

[1587]

[1588]

[1589]

[1590]

[1591]

[1592]

[1593]

[1594]

[1595]

[1596]

[1597]

[1598]

[1599]

[1600]

[1601]

[1602]

[1603]

[1604]

[1605]

[1606]

[1607]

[1608]

[1609]

[1610]

[1611] How to use

[1612] On the other hand, this document provides a method for reducing gene expression in cells, the method comprising contacting the cells with an effective amount of a molecule disclosed herein or a pharmaceutically acceptable salt thereof.

[1613] In some embodiments, the gene is the Huntington protein (HTT). In some embodiments, the gene is a mutant Huntington protein.

[1614] In some embodiments, gene expression 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.

[1615] On the other hand, this article provides a method for treating Huntington's disease (HD) in a subject in need, the method comprising administering to the subject the molecules described herein or pharmaceutically acceptable salts thereof.

[1616] On the other hand, this article provides a method for treating Huntington's disease-like syndrome in a subject in need, the method comprising administering to the subject the molecules described herein or pharmaceutically acceptable salts thereof.

[1617] On the other hand, this article provides a method for treating adolescent Huntington's disease in subjects in need, the method comprising administering to the subject the molecules described herein or pharmaceutically acceptable salts thereof.

[1618] In some embodiments, the method alleviates one or more symptoms of Huntington's disease (HD).

[1619] In some embodiments, one or more symptoms are selected from chorea, cognitive decline, sexual dysfunction, eye movement disorders, olfactory disorders, aggression, irritability, anxiety, apathy, bradykinesia, slowed thinking, clumsiness, delusions, depression, gait disorder, inhibition disorder, lack of tension, gait instability, muscle weakness, hallucinations, hostility, impaired motor function, irritability, memory impairment, myoclonus, compulsive behaviors, poor fine motor coordination, epilepsy, speech difficulties, staring, weight loss, abnormal cholesterol metabolism, abnormal white matter, alcoholism, Babinski sign, caudate nucleus atrophy, cerebral atrophy, asphyxia, clonic disorders, striatal degeneration, excessive daytime sleepiness, impaired visuospatial cognitive function, inability to walk, insomnia, mutism, oropharyngeal dysphagia, rigidity, suicidal ideation, cerebellar atrophy, dementia, gating ataxia, glioma, hyperreflexia, neuronal loss, or personality changes.

[1620] Pharmaceutical composition and administration

[1621] The compounds described herein are administered to subjects in need, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in the form of pharmaceutical compositions, in accordance with standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[1622] On the other hand, this document provides pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are 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. Appropriate formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, (NY, 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the contents of which are incorporated herein by reference.

[1623] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, defoamers, antioxidants, preservatives, and any combination thereof.

[1624] The dosage of the pharmaceutical agents described herein for treating diseases or conditions may be determined based on the subject's condition, namely the stage of the disease, the severity of symptoms caused by the disease, general health status, and age, sex, and weight, and other factors obvious to a medical professional. The pharmaceutical composition may be administered in a manner appropriate to the disease being treated, as determined by a medical professional. In addition to the factors described herein and above regarding the use of pharmaceutical agents for treating diseases or conditions, the appropriate duration and frequency of administration of the pharmaceutical agent 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. Optimal dosage of the agent may generally be determined using experimental models and / or clinical trials. Optimal dosage may be determined based on the subject's body mass, weight, or blood volume. Generally, the minimum dose sufficient to provide an effective therapy is preferred. The design and execution of preclinical and clinical studies of the pharmaceutical agents described herein (including when administered for prophylactic benefit) are entirely within the scope of the skill of a person skilled in the art. When two or more pharmaceutical agents are administered to treat a disease or condition, the optimal dosage of each agent may differ, such as being less than the dosage of any single agent administered alone as a monotherapy. In certain specific embodiments, the combination of two pharmaceutical agents can act synergistically or additively, and either agent can be used in a smaller amount than when administered alone. The daily dose of the pharmaceutical agent can be, for example, between about 0.01 mg / kg and 100 mg / kg, such as between about 0.1 and 1 mg / kg, between about 1 and 10 mg / kg, between about 10 and 50 mg / kg, or between about 50 and 100 mg / kg body weight. In other embodiments, the daily dose of the pharmaceutical agent can be between about 0.01 mg / kg and 1000 mg / kg, between about 100 and 500 mg / kg, or between about 500 and 1000 mg / kg body weight. The optimal daily dose or dose per treatment cycle may vary depending on the disease or condition being treated and may also vary with the route of administration and treatment regimen.

[1625] definition

[1626] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[1627] Unless the context otherwise requires, throughout this specification and in the following claims, the word “comprise” and its variations, such as “comprises” and “comprising”, shall be considered to have an open-ended, inclusive meaning, i.e., “including but not limited to”. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[1628] As used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include the plural references. It should also be noted that unless the context clearly indicates otherwise, the term “or” is generally used to mean “and / or.”

[1629] When 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, this notation is intended to include the numbers themselves and the range between them, unless otherwise specified. This range may be integers or consecutive and includes endpoints. As an example, the range “2 to 6 carbons” is intended to include two, three, four, five, and six carbons because carbon appears in integer units. As an example, the range “1 to 3 µM (micromolars)” (which is intended to include all values ​​between 1 µM and 3 µM) is compared to any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

[1630] Unless otherwise indicated, the following terms have the following meanings as used herein:

[1631] "O" refers to =O.

[1632] "Carboxyl group" refers to -COOH.

[1633] "Cyano" refers to -CN.

[1634] "alkyl" refers to a straight-chain or branched monovalent group of a saturated hydrocarbon having one to ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and similar groups. Whenever it appears herein, numerical ranges such as “C1-C6 alkyl” or “C1-6 alkyl” mean that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term “alkyl” where no numerical range is specified. In some embodiments, the alkyl group is C1-C6. 10Alkyl group. In some embodiments, the alkyl group is C1-C6 alkyl. In some embodiments, the alkyl group is C1-C5 alkyl. In some embodiments, the alkyl group is C1-C4 alkyl. In some embodiments, the alkyl group is C1-C3 alkyl. Unless otherwise specifically stated in this specification, the alkyl group may optionally be substituted with, for example, an oxo group, halogen, amino group, nitrile group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and similar groups. In some embodiments, the alkyl group may optionally be substituted with an oxo group, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group may optionally be substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group may optionally be substituted with a halogen.

[1635] "Alkenyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in a cis or trans configuration around the double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and similar groups. Whenever it appears 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 definition of this invention also covers the presence of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkenyl group may optionally be substituted with, for example, an oxo group, halogen, amino group, nitrile group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and similar groups. In some embodiments, the alkenyl group may optionally be substituted with an oxo group, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group may optionally be substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group may optionally be substituted with a halogen.

[1636] "Alynyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and similar groups. Whenever it appears herein, numerical ranges such as "C2-C6 alkynyl" or "C2-6 alkynyl" mean that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkynyl group may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the alkynyl group is optionally substituted with an oxo group, a halogen, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[1637] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically stated in this specification, alkylene may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, alkylene may optionally be substituted with oxo, halogen, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene may optionally be substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene may optionally be substituted with halogen.

[1638] "Alkoxy" refers to an alkoxy group with the formula -OR a The group, wherein R a Alkyl groups are defined alkyl groups. Unless otherwise specifically stated in this specification, alkoxy groups may optionally be substituted with, for example, oxo groups, halogens, amino groups, nitriles, hydroxyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and similar groups. In some embodiments, alkoxy groups are optionally substituted with halogens, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkoxy groups are optionally substituted with halogens, -CN, -OH, or -OMe. In some embodiments, alkoxy groups are optionally substituted with halogens.

[1639] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a self-ring carbon atom. An aromatic monocyclic or polycyclic aromatic hydrocarbon ring system may contain only hydrogen and carbon and five to eighteen carbon atoms, wherein at least one of the rings in the ring system is aromatic, i.e., according to Hückel theory, it contains a cyclic, non-localized (4n+2) π-electron system. Ring systems that derive aryl groups include, but are not limited to, groups such as benzene, fluorene, dihydroindene, indene, tetrahydronaphthalene, and naphthalene. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded by aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6-membered to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracene, naphthyl, phenanthrene, anthracene, azulene, benzene, chrysene, fluorene, s-dicyclopentadienzobenzene, s-dicyclopentadienzobenzene, dihydroindene, indene, naphthalene, fen, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated in this specification, aryl groups may optionally be substituted, for example, with halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and similar groups. In some embodiments, aryl groups are optionally substituted with halogens, methyl groups, ethyl groups, -N3, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with a halogen.

[1640] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbon ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl group is bonded by non-aromatic ring atoms), helical, or bridged ring systems. In some embodiments, the cycloalkyl group is fully saturated. Representative cycloalkyl groups include, but are not limited to, those having three to fifteen carbon atoms (e.g., C3-C4). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), three to ten carbon atoms (e.g., C3-C) 10 Fully saturated cycloalkyl or C3-C 10Cycloalkyl groups are 3- to 10-membered fully saturated cycloalkyl groups or 3- to 6-membered cycloalkenyl groups. In some embodiments, the cycloalkyl group is 5- to 6-membered fully saturated cycloalkyl groups or 5- to 6-membered cycloalkenyl groups. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, 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, as well as 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in this specification, cycloalkyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the cycloalkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, -N3, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[1641] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having three to twelve carbon atoms and containing at least one double bond. In some embodiments, the cycloalkenyl group contains three to ten carbon atoms. In other embodiments, the cycloalkenyl group contains five to seven carbon atoms. The cycloalkenyl group can be linked to the rest of the molecule via a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[1642] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[1643] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above, substituted with one or more halogen groups such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and similar groups. In some embodiments, the alkyl portion of the fluoroalkyl group may optionally be further substituted. Examples of halogen-substituted alkanes (“haloalkanes”) include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., chloroform, 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 alkanes (or substituted alkanes) with halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen group, each halogen can be chosen independently, for example, 1-chloro,2-fluoroethane.

[1644] "Fluoroalkyl" means an alkyl group as defined above that is substituted with one or more fluorinated groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl and similar groups.

[1645] "Hydroxyalkyl" means an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[1646] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[1647] "Heteroalkyl" means an alkyl group in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated in this specification, heteroalkyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl groups are optionally substituted with halogens.

[1648] "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and one to eight heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises one to three nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one or two nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom and one oxygen atom. Unless otherwise specifically stated in this specification, the heterocyclic alkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl is bonded by non-aromatic ring atoms), helical, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclic alkyl may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, those having two to fifteen carbon atoms (e.g., C2-C). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, two to ten carbon atoms (e.g., C2-C) 10Fully saturated heterocyclic alkyl or C2-C 10Heterocyclic alkyl groups consisting of two to eight carbon atoms (e.g., C2-C8 fully saturated heterocyclic alkyl or C2-C8 heterocyclic alkyl), two to seven carbon atoms (e.g., C2-C7 fully saturated heterocyclic alkyl or C2-C7 heterocyclic alkyl), two to six carbon atoms (e.g., C2-C6 fully saturated heterocyclic alkyl or C2-C6 heterocyclic alkyl), two to five carbon atoms (e.g., C2-C5 fully saturated heterocyclic alkyl or C2-C5 heterocyclic alkyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocyclic alkyl or C2-C4 heterocyclic alkyl). Examples of such heterocyclic alkyl groups include, but are not limited to, azirrocyclopropane, azirrocyclobutane, oxacyclobutane, dioxopentane, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrroliyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, and pyrroliyl. The terms heterocyclic alkyl, pyrazolyl, quininecycloalkyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl are also included. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl, the number of carbon atoms in the heterocyclic alkyl is not the same as the total number of atoms constituting the heterocyclic alkyl (i.e., the skeletal atoms of the heterocyclic alkyl ring), including heteroatoms. In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkenyl group. Unless otherwise specifically stated in this specification, the heterocyclic alkyl group may optionally be substituted with, for example, an oxo group, halogen, amino group, nitrile group, nitro group, hydroxyl group, alkyl group, alkenyl group, alkynyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocyclic alkyl group, heteroaryl group and similar groups as described below.In some embodiments, the heterocyclic alkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, a -CN group, a -C(O)OH group, a C(O)OMe group, a -CF3 group, a -OH group, a -OMe group, a -NH2 group, or a -NO2 group. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen, a methyl group, an ethyl group, a -CN group, a -CF3 group, a -OH group, or a -OMe group. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[1649] "Heteroaryl" refers to a 5- to 14-membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group comprises one to three nitrogen atoms. In some embodiments, a heteroaryl group comprises one or two nitrogen atoms. In some embodiments, a heteroaryl group comprises one nitrogen atom. A heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl group is bonded by aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, a heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, a heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, a heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azirphonyl, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, and benzo[b][1,4] Dioxaneheptenyl, 1,4-benzodioxane, benzonaphthylfuranyl, benzooxazolyl, benzodioxanepentenyl, benzodioxanehexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cenylyl, dibenzofuranyl, dibenzothienyl, furanyl, furanoneyl, isothiazolyl, imidazoyl, indazoleyl, indoleyl, indazoleyl, isoindoleyl, indolinyl, isoindoleyl Dolinyl, isoquinolinyl, indoleazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxo-azizoyl, oxazolyl, epoxyethyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in this specification, heteroaryl groups may optionally be substituted with, for example, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and similar groups.In some embodiments, the heteroaryl group 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 group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[1650] The term "oligonucleotide sequence" refers to multiple nucleic acids having a defined sequence and length (e.g., 2, 3, 4, 5, 6, or even more nucleotides). The term "oligonucleotide repeat sequence" refers to the sequential amplification of an oligonucleotide sequence.

[1651] The term "transcription," as well known in the art, refers to the synthesis of RNA (i.e., ribonucleic acid) by a DNA-directed RNA polymerase. The term "regulation of transcription" refers to changes in the amount of transcription, which can be measured by methods well known in the art (e.g., analysis of the transcription product mRNA). In some embodiments, regulation is an increase in transcription. In other embodiments, regulation is a decrease in transcription.

[1652] The term "polyamide" refers to a polymer of linkable units chemically bonded by amide (i.e., CONH) bonds; optionally, the polyamide includes a chemical probe bound thereto. Polyamides can be synthesized by stepwise condensation of carboxylic acids (COOH) and amines (RR'NH) using methods known in the art. Alternatively, polyamides can be formed in vitro using enzymatic reactions or by employing microbial fermentation.

[1653] The term "linkable unit" refers to methylimidazolium, methylpyrrole, and straight-chain and branched aliphatic functional groups (e.g., methylene, ethylene, propylene, butylene, and similar groups), and their chemical derivatives, optionally containing nitrogen-substituted groups. The aliphatic functional groups of the linkable unit can be provided, for example, by condensing β-alanine or dimethylaminopropylamine using methods well known in the art during the synthesis of polyamides.

[1654] The term "linker" or "oligomeric backbone" refers to a chain of at least 10 consecutive atoms. In some embodiments, the linker contains no more than 20 non-hydrogen atoms. The terms linker and oligomeric backbone are used interchangeably. In some embodiments, the linker contains no more than 40 non-hydrogen atoms. In some embodiments, the linker contains no more than 60 non-hydrogen atoms. In some embodiments, the linker contains atoms selected from C, H, N, O, and S. In some embodiments, each non-hydrogen atom is chemically bonded to two adjacent atoms in the linker, or to one adjacent atom in the linker and the end of the linker. In some embodiments, the linker forms an amide bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms an ester bond or an ether bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms a thioester bond or a thioether bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms a direct carbon-carbon bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms an amine bond or an amide bond with at least one of the two other groups to which it is attached. In some embodiments, the linker includes -(CH2OCH2)- units. In some embodiments, the linker includes -(CH(CH3)OCH2)- units. In some embodiments, the linker includes -(CH2NR)- units. N CH2) unit, where R N = C 1-4 Alkyl group. In some embodiments, the linker comprises an arylene, cycloalkyl, or heteroalkyl moiety.

[1655] The term "bond" refers to a covalent bond between two atoms, or, when the atoms connected by a bond are considered part of a larger substructure, a covalent bond between two parts. Unless otherwise specified, a bond can be a single, double, or triple bond. The dashed line between two atoms in a molecular diagram indicates whether an additional bond may or may not be present at that location.

[1656] As used herein, “optionally substituted” is derived from a substituted group of an unsubstituted parent group, wherein one or more hydrogen atoms are replaced by another atom or group. Unless otherwise indicated, when a group is considered “substituted” or “optionally substituted,” it means that the group is substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocycloyl (optionally substituted by a halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclo-C1-C6 alkyl (optionally substituted by a halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1- C6 haloalkoxy substituted), 3- to 10-membered heterocyclic groups (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclic-C1-C6 alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkyl and C1-C6 haloalkoxy). -C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy substituted), 5- to 10-membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6)alkyl (i.e., ether), Aryloxy, thiohydro (mercapto), halogen (C1-C6) alkyl (e.g., -CF3), halogen (C1-C6) alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino (C1-C6) alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, acyl, cyano, isocyano, thiocyano, isothiocyano, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," the group may be substituted with the above substituents.

[1657] The term "one or more" when referring to optional substituents means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[1658] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z or E forms (or cis or trans forms). Furthermore, some chemical entities can exist in various tautomeric forms. Unless otherwise stated, the compounds described herein are intended to include all Z, E, and tautomeric forms.

[1659] In some embodiments, the compounds disclosed herein are enriched with different isotopes (e.g., rich in...). 2 H, 3 H, 11 C 13 C and / or 14 Used in form C). In one particular embodiment, the compound is deuterated at at least one position. These deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thus increasing the duration of drug action.

[1660] Unless otherwise stated, the compounds described herein are intended to include compounds differing only in the presence of one or more isotopically enriched atoms. For example, compounds other than those with hydrogen replaced by deuterium or tritium, or carbon replaced by... 13 C or 14 Compounds having the structure of this invention, other than carbon replacement enriched by C, are within the scope of this disclosure.

[1661] The compounds disclosed herein optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting these compounds. For example, the compounds may contain isotopes such as deuterium (… 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Marker. By 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 Isotopic substitutions are included. All isotopic variants of the compounds of the present invention (whether or not radioactive) are covered within the scope of the present invention. In some embodiments, when describing isotopic variants, the remaining atoms of the compound may optionally contain non-natural portions of atomic isotopes.

[1662] In some embodiments, some or all of the compounds disclosed herein 1 H atom 2 H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art, and include the following synthetic methods as examples only.

[1663] Deuterated compounds were synthesized using various methods such as those described below: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [in: Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; 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.

[1664] Deuterated starting materials are readily available and can be synthesized using the methods described herein to provide deuterated compounds. A wide range of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[1665] In some embodiments of the compounds disclosed herein, one or more of the substituents contain a percentage of deuterium higher than the natural abundance of deuterium. In some embodiments of the compounds disclosed herein, one or more hydrogen atoms are substituted with one or more deuterium atoms.

[1666] In some embodiments of the compounds disclosed herein, the deuterium abundance of each of the substituents is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total amount of hydrogen and deuterium.

[1667] The compounds disclosed herein also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvable polymorphs (including anhydrous forms), configurational polymorphs and amorphous forms of the compounds, and mixtures thereof.

[1668] In some cases, the compounds described herein may exist as diastereomers, enantiomers, or other stereoisomers. When absolute stereochemistry is not specified, the compounds presented herein include all diastereomers, enantiomers, and epimers, and suitable mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, this disclosure is incorporated herein by reference). Stereoisomers may also be obtained by stereoselective synthesis.

[1669] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from various organic and inorganic relative ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and similar inorganic acids. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and similar organic acids. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and similar inorganic bases. Organic bases that can be derivatized include, for example, primary amines, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins and similar organic bases, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[1670] The phrase “pharmaceutically acceptable” is used herein to refer to compounds, materials, compositions, and / or dosage forms that, to a reasonable extent of medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[1671] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” and harmless to the patient in relation to compatibility with the other components of the formulation. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered astragalus gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil and cottonseed oil. Oils, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, 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) isotropic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic and compatible substances used in pharmaceutical formulations.

[1672] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses, which is sufficient to produce the desired therapeutic effect.

[1673] As used herein, the terms “treat,” “treating,” or “treatment” include relieving, alleviating, or improving at least one symptom of a disease or condition; preventing other symptoms; suppressing a disease or condition, such as curbing its progression; reducing a disease or condition; causing a disease or condition to subside; alleviating symptoms caused by a disease or condition; or stopping the symptoms of a disease or condition.

[1674] The term "patient" is generally synonymous with the term "subject" 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.

[1675] The term "contact" refers to bringing a compound (such as the transcriptional regulator molecule of this disclosure) into close proximity to a desired target gene. Contact can induce binding to the target moiety or cause a conformational change in the target moiety.

[1676] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be in pharmaceutically acceptable salt forms. In some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. Additionally, the compounds described herein may be present in both non-solubilized and solubilized forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solubilized forms of the compounds presented herein are also considered to be disclosed herein.

[1677] Example

[1678] The following examples are given for the purpose of illustrating various embodiments of the invention and are not intended to limit the invention in any way. The examples of the invention and the methods described herein represent preferred embodiments and are exemplary and not intended to limit the scope of the invention. Variations and other uses known to those skilled in the art will be covered within the spirit and scope of the invention, as defined by the scope of the claims.

[1679] Compound Synthesis

[1680] The compounds disclosed herein can be prepared using the methods described in the general synthetic procedures and experimental procedures detailed below. The general synthetic procedures and experimental procedures are provided for illustrative purposes and are not intended to be limiting. Starting materials used to prepare the compounds of this disclosure are commercially available or can be prepared using conventional methods known in the art.

[1681] The synthetic chemical transformations and methods used to synthesize the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd edition (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[1682] List of abbreviations

[1683] Ac₂O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous solution; Boc = tert-butoxycarbonyl; Bu₃SnH = hydrogenated tributyltin; CD₃OD = deuterated methanol; CDCl₃ = deuterated chloroform; CDI = 1,1'-carbonyldiimidazole; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = hydrogenated di-isobutylaluminum; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO-d₆ = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenyl azidophosphate; EDC.HCl = EDCI.HCl = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = hours; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate methylammonium; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-PrOH = isopropanol; LAH = lithium aluminum hydride; LiHMDS = bis(trimethylsilyl)aminolithium; MeCN = acetonitrile; MeI = iodomethane; MeOH = methanol; MP-carbonate resin = macroporous triethylammonium methyl polystyrene carbonate resin; MsCl = methanesulfonyl chloride; MTBE = methyl tert-butyl ether; MW = microwave radiation; n-BuLi = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)aminobis; NaOMe = sodium methoxide; NaOtBu =Sodium tert-butoxide; NBS =N-bromosuccinimide; NCS =N-chlorodiimide; NMI =1-methylimidazolium; NMP =N-methyl-2-pyrrolidone; OAc =acetoxy; Pd(Ph3)4 =tetra(triphenylphosphine)palladium(0); Pd2(dba)3 =tris(diphenylmethylacetone)dipalladium(0); PdCl2(PPh3)2 =bis(triphenylphosphine)palladium(II) chloride; PG =protecting group; preparative HPLC = preparative high performance liquid chromatography; PyBop = (benzotriazol-1-yloxy)tripyrrolidinephosphonium hexafluorophosphate; Pyr =pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; sat.=Saturated; ss =Saturated solution; t-BuOH =T-Butanol; T3P =Propylphosphonic anhydride; TBS = TBDMS =T-Butyldimethylsilyl; TBSCl = TBDMSCl =T-Butyldimethylchlorosilane; TCFH =Chloro-N,N,N',N'-Tetramethylfluorourea hexafluorophosphate; TEA = Et3N =Triethylamine; TFA =Trifluoroacetic acid; TFAA =Trifluoroacetic anhydride; THF =Tetrahydrofuran; Tol =Toluene; TsCl =Toluenesulfonyl chloride; XPhos =2-Dicyclohexylphosphino-2',4',6'-Triisopropylbiphenyl.

[1684] Synthesis of representative polyamides

[1685] Example 1. 3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(2-{1-[ ...methyl-4 4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acyl) [amino]pyrrolo-2-yl]formamide)methyl]cyclopropyl]acetamido]imidazol-2-yl]formamide]propionamide)pyrrolo ...propionamide)pyrrolo-2-yl]propionamide)pyrrolo-2-yl]propionamide)pyrrolo-2- Synthesis of [[irazol-2-acylamino]imidazol-2-yl]formamide)propionic acid

[1686] Process 1.

[1687]

[1688] Step 1. Add ethyl 2-(triphenyl-λ5-phosphine) (19.98 g, 57.37 mmol, 1.00 equivalent) and benzoic acid (7.00 g, 57.37 mmol, 1.00 equivalent) to a stirred solution of (1-ethoxycyclopropoxy)trimethylsilane (10.00 g, 57.37 mmol, 1.00 equivalent) in toluene (100.00 mL), and stir the reaction mixture at 90 °C for 2.0 h. Filter off the solids; the filtrate can be used directly in the next step without further purification. LC / MS: C7H 10 Calculated mass of O2: 126.07, Experimental value: 127.10 [M+H] + .

[1689] 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 the crude product, 2-cyclopropylene ethyl acetate, at 0 °C, and the reaction mixture was stirred at room temperature for 6.0 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (1:8), to give 2-[1-(nitromethyl)cyclopropyl]ethyl acetate (3.00 g, 50.54%) as a pale yellow oil. LC / MS: C8H 13 Calculated mass of NO4: 187.08, Experimental mass: 188.20 [M+H] + .

[1690] Step 3. At room temperature, Pd / C (0.30 g, 10% w / w) and TFA (0.10 mL) were added to a stirred mixture of ethyl 2-[1-(nitromethyl)cyclopropyl]acetate (3.00 g, 16.03 mmol, 1.00 equivalent) in EtOH (30.00 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 6.0 h. The resulting mixture was filtered and the filter cake was washed with EtOH (5 × 30 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (1:1) elution to give ethyl 2-[1-(aminomethyl)cyclopropyl]acetate (1.50 g, 59.54%) as a pale yellow oil. LC / MS: C8H 15 Calculated mass of NO2: 157.11, Experimental value: 158.15 [M+H] + .

[1691] Step 4. Saturated sodium bicarbonate (1.14 M in H2O, 20.95 mL, 23.88 mmol, 2.50 equivalent) and di-tert-butyl dicarbonate (3.13 g, 14.33 mmol, 1.50 equivalent) were added to a stirred mixture of ethyl 2-(1-(aminomethyl)cyclopropyl)acetate (1.50 g, 9.55 mmol, 1.00 equivalent) in H2O (15.00 mL), and the mixture was stirred at room temperature for 4.0 h. The reaction mixture was filtered, diluted with water (30 mL), and extracted with EA (3 × 30 mL). The combined organic layers were washed with water (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1 / 1) elution to give ethyl 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)acetate (1.23 g, 50.20%) as a pale yellow oil. LC / MS: C 13 H 23 Calculated mass of NO4: 257.16, Experimental value: 258.05 [M+H] + .

[1692] Step 5. LiOH (2 M in H2O, 11.96 mL, 23.93 mmol, 5.00 equivalent) was added to a stirred solution of 2-(1-{[(tert-butoxycarbonyl)amino]methyl}cyclopropyl)acetic acid (1.23 g, 4.79 mmol, 1.00 equivalent) in CH3OH (20.00 mL), and the mixture was stirred at room te...

Claims

1. A transcription regulator molecule having a first terminal, a second terminal, and an oligomeric backbone, or a pharmaceutically acceptable salt thereof, wherein: a) The first end includes a DNA-binding portion having the structure of formula (A-9): Equation (A-9), in: W 1 It is hydrogen, -C1-C6 haloalkyl or -N=C(N(R) 1e )2)2, where each R 1e Independently 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, and the C1-C atoms can be optionally substituted. 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups; each optionally substituted with one or more R Z replace; Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG; R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; Or two Rs 3a Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups; Or an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups; Each R Z Independent of 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 group, C1-C 10 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; b) The second end includes a protein-binding portion capable of binding to regulatory molecules that regulate gene expression; and c) The oligomeric backbone connects the first end and the second end.

2. The molecule according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 3a and R 3b Independently hydrogen; or two Rs 3a Or two Rs 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl.

3. The molecule according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R 3a and each R 3b It is hydrogen.

4. The molecule or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein two R... 3a Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups; and each R 3b It is hydrogen.

5. The molecule or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein two R... 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups; and each R 3a It is hydrogen.

6. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z replace.

7. The molecule according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each of the C1-Cs can be arbitrarily replaced independently. 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl or optionally substituted C3-C8 cycloalkyl.

8. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each independently is C1-C 10 alkyl.

9. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 2a R 2b R 2c R 2d R 2e R 2g Or R 2h At least one of them is not an unreplaced C1-C 10 alkyl.

10. The molecule of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 2c R 2d R 2e R 2g Or R 2h At least one of them is not methyl.

11. The molecule of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 2c R 2d R 2e R 2g Or R 2h At least two of them are not methyl.

12. The molecule of claim 1 or a pharmaceutically acceptable salt thereof, wherein the DNA-binding portion comprises the structure of formula (I): Formula (I), in: W 1 It is hydrogen; R 2a R 2c R 2d R 2e and R 2h Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Heteroalkyl groups, optionally substituted C2-C 20 Heterene groups, optionally substituted C2-C 20 Heterynyl group, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups; each optionally substituted with one or more R Z replace; Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -OR 3c -NR 3c R 3d or -NHC(O)R 3e ,in R 3c and R 3d Each can be independently hydrogen, alkyl, or PEG; R 3e It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups; Each R Z Independent of 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 group, C1-C 10 Halogenated, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or optionally 5- to 10-membered heteroaryl; wherein R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl.

13. The molecule of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2c R 2d R 2e Or R 2h Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Halogenated groups, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z replace.

14. The molecule of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2c R 2d R 2e Or R 2h Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl or optionally substituted C3-C 10 Cycloalkyl.

15. The molecule of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2c R 2d R 2e Or R 2h Each is independently a monocyclic, spirocyclic, or bridged C3-C alkyl group. 10 Cycloalkyl.

16. The molecule of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2c R 2d R 2e Or R 2h One or both of them are independently optional C3-C that can be replaced. 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl; and R 2a R 2c R 2d R 2e Or R 2h The remainder are the C1-C that are arbitrarily replaced. 20 alkyl.

17. The molecule of claim 16 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2c R 2d R 2e Or R 2h The remainder are unsubstituted C1-C 10 alkyl.

18. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 12 to 16, wherein each R Z Independent of halogen, -CN, -OH, -OR Za -N3, -NR Za R Zb C1-C 10 Alkyl, C1-C 10 Halogenated alkyl or C3-C6 cycloalkyl.

19. The molecule of claim 18 or a pharmaceutically acceptable salt thereof, wherein each R Z It can be independently a halogen, -OH, -NH2 or C1-C6 alkyl group.

20. The molecule of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2c R 2d R 2e Or R 2h One or both of them independently , , , , , , , , , , , or .

21. The molecule or a pharmaceutically acceptable salt thereof according to claim 12 or 20, wherein R 2a R 2c R 2d R 2e Or R 2h The remainder are unsubstituted C1-C 10 alkyl.

22. The molecule of claim 21 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2c R 2d R 2e Or R 2h The others are independently methyl, ethyl, or isopropyl.

23. The molecule of claim 21 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2c R 2d R 2e Or R 2h The rest are each methyl.

24. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 12 to 23, wherein the two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups.

25. The molecule of claim 24 or a pharmaceutically acceptable salt thereof, wherein the two Rs 3b Together with the atoms it is attached to, it forms a cyclopropyl group.

26. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 12 to 23, wherein each R 3b It is hydrogen.

27. A transcription regulator molecule having a first terminal, a second terminal, and an oligomeric backbone, or a pharmaceutically acceptable salt thereof, wherein: a) The first end includes a DNA-binding portion having the structure of formula (II): Equation (II), in: T A For -Q A -Q B ;in Q A for ; Q B for ;in R 2j For the optional replacement of C1-C 20 Alkyl groups, which are optionally composed of one or more R groups Z replace; R 2k For the optional replacement of C1-C 20 Alkyl or optionally substituted C3-C 10 cycloalkyl groups, each optionally bound by one or more R Z replace; *For Q A With Q B The connection point; **This is the connection point with the oligolinker; W 1 It is hydrogen; R 2c and R 2d Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z replace; Each R 3b It is hydrogen or C1-C6 alkyl; Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups; Each R Z Independent of 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 Halogenated groups; Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; b) The second end includes a protein-binding portion capable of binding to regulatory molecules that regulate gene expression; and c) The oligomeric backbone connects the first end and the second end.

28. The molecule of claim 27 or a pharmaceutically acceptable salt thereof, wherein each R 3b It is hydrogen.

29. The molecule of claim 27 or a pharmaceutically acceptable salt thereof, wherein the two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups.

30. The molecule of claim 29 or a pharmaceutically acceptable salt thereof, wherein the two Rs 3b Together with the atoms it is attached to, it forms a cyclopropyl group.

31. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 27 to 30, wherein R 2c For the optional replacement of C1-C 20 Alkyl groups, which are optionally composed of one or more R groups Z Replace, where each R Z Independent of halogen, -OH, -OR Za -NR Za R Zb Or C1-C6 alkyl.

32. The molecule of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 2c Methyl, ethyl, isopropyl, , or .

33. The molecule of claim 32 or a pharmaceutically acceptable salt thereof, wherein R 2c It is a methyl group.

34. The molecule of claim 27 or a pharmaceutically acceptable salt thereof, wherein the first end of formula (II) has the structure of formula (IIa): Equation (IIa).

35. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 27 to 34, wherein R 2d For the optional replacement of C1-C 20 Alkyl groups, which are optionally composed of one or more R groups Z replace.

36. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 27 to 34, wherein R 2d C3-C is arbitrarily replaced. 10 cycloalkyl groups, optionally composed of one or more R groups Z replace.

37. The molecule of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 2d The substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group is optionally substituted, each optionally being substituted by one or more R Z Replace, where each R Z Independent of halogen, -OH, -OR Za -NR Za R Zb Or C1-C6 alkyl.

38. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 35 to 37, wherein each R Z It can be -F, -OH, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2 or -C(CH3)3 independently.

39. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 27 to 38, wherein R 2j For the unreplaced C1-C 10 alkyl.

40. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 27 to 38, wherein R 2j For the optional replacement of C1-C 20 alkyl.

41. The molecule of claim 39 or a pharmaceutically acceptable salt thereof, wherein R 2c Methyl, ethyl, isopropyl, , or .

42. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 27 to 38, wherein R 2j For the unreplaced C1-C 10 Alkyl and R 2k For the unreplaced C1-C 10 alkyl.

43. The molecule of claim 42 or a pharmaceutically acceptable salt thereof, wherein R 2j It is methyl and R 2k It is a methyl group.

44. A transcription regulator molecule having a first terminal, a second terminal, and an oligomeric backbone, or a pharmaceutically acceptable salt thereof, wherein: a) The first end includes a DNA-binding portion having the structure of formula (III): Equation (III), in: T B For -S 1 -Q L ; S 1 It is -C(O)NH(CH2)2-; where Q L for ;in R 2m For the optional replacement of C1-C 20 Alkyl groups, which are optionally composed of one or more R groups Z replace; **This is the connection point with the oligolinker; R 2c It is an unsubstituted C1-C6 alkyl group; R 2d and R 2e Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, optionally substituted C3-C 10 Cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl groups, each optionally substituted with one or more R Z replace; Each R 3b It is hydrogen or C1-C6 alkyl; Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups; Each R Z Independent of 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 Halogenated groups; Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; b) The second end includes a protein-binding portion capable of binding to regulatory molecules that regulate gene expression; and c) The oligomeric backbone connects the first end and the second end.

45. The molecule of claim 44 or a pharmaceutically acceptable salt thereof, wherein each R 3b It is hydrogen.

46. ​​The molecule of claim 44 or a pharmaceutically acceptable salt thereof, wherein the two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups.

47. The molecule of claim 46 or a pharmaceutically acceptable salt thereof, wherein the two Rs 3b Together with the atoms it is attached to, it forms a cyclopropyl group.

48. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 44 to 47, wherein R 2c It can be methyl, ethyl, or isopropyl.

49. The molecule according to claim 44 or a pharmaceutically acceptable salt thereof, wherein the first end of formula (III) has the structure of formula (IIIa): Equation (IIIa).

50. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 44 to 49, wherein R 2d For the optional replacement of C1-C 20 Alkyl groups, which are optionally composed of one or more R groups Z replace.

51. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 44 to 49, wherein R 2d C3-C is arbitrarily replaced. 10 cycloalkyl groups, optionally composed of one or more R groups Z replace.

52. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 44 to 51, wherein R 2e For the optional replacement of C1-C 20 Alkyl groups, which are optionally composed of one or more R groups Z replace.

53. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 52, wherein each R Z Independent of halogen, -OH, -OR Za -NR Za R Zb Or C1-C6 alkyl.

54. The molecule of claim 53 or a pharmaceutically acceptable salt thereof, wherein each R Z It can be -F, -OH, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2 or -C(CH3)3 independently.

55. The molecule according to claim 52, wherein R 2e It can be methyl, ethyl, or isopropyl.

56. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 42 to 55, wherein R 2m It is an unsubstituted C1-C6 alkyl group.

57. The molecule of claim 56 or a pharmaceutically acceptable salt thereof, wherein R 2m It can be methyl, ethyl, or isopropyl.

58. A transcription regulator molecule having a first terminal, a second terminal, and an oligomeric backbone, or a pharmaceutically acceptable salt thereof, wherein: a) The first end includes a DNA-binding portion having the structure of formula (V): Equation (V), in: T E For -Q M -Q N ; T F For -S 3 -Q P ;in S 3 It is -C(O)NH(CH2)2-; Q M for ; Q N for ; Q P for ;in R 2r R 2rr and R 2s Each of the C1-Cs can be arbitrarily replaced independently. 20 Alkyl groups, each optionally containing one or more R Z replace; *For Q M With Q N The connection point; and **This is the connection point with the oligolinker; R 2e To be optionally used by one or more R Z Replacement C3-C 10 cycloalkyl; Each R Z Independent of 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 Halogenated groups; Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups, in which R Za and R Zb Each is independently hydrogen, alkyl, haloalkyl, or PEG; and R Zc It can be alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; b) The second end includes a protein-binding portion capable of binding to regulatory molecules that regulate gene expression; and c) The oligomeric backbone connects the first end and the second end.

59. The molecule of claim 58 or a pharmaceutically acceptable salt thereof, wherein R 2r R 2rr and R 2s Independently, each of the optionally substituted C1-C8 alkyl groups is optionally substituted with one or more R groups. Z Replace; where each R Z Independent of halogen, -OH, -OR Za or -NR Za R Zb .

60. The molecule of claim 58 or a pharmaceutically acceptable salt thereof, wherein R 2r R 2rr and R 2s It is an unsubstituted C1-C8 alkyl group.

61. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 58 to 60, wherein R 2e The substituted monocyclic, spirocyclic, or bridged C3-C8 cycloalkyl group is optionally substituted, each optionally being substituted by one or more R Z replace.

62. The molecule of claim 61 or a pharmaceutically acceptable salt thereof, wherein R 2e It is an unsubstituted monocyclic C6-C8 cycloalkyl group.

63. The molecule of claim 58 or a pharmaceutically acceptable salt thereof, wherein the first terminal comprises the structure of formula (Va): Equation (Va), in: Each R Z Independent of 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 Halogenated groups; Or two Rs Z Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups; R Za and R Zb Each can be independently hydrogen, alkyl, haloalkyl, or PEG; R Zc It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and qq can be 0, 1, or 2.

64. The molecule of claim 63 or a pharmaceutically acceptable salt thereof, wherein each R Z Independent of halogen, -OH, -OR Za -NR Za R Zb Or C1-C6 alkyl.

65. The molecule of claim 64 or a pharmaceutically acceptable salt thereof, wherein each R Z It can be -F, -OH, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2 or -C(CH3)3 independently.

66. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 63 to 65, wherein qq is 1 or 2.

67. The molecule of claim 63 or a pharmaceutically acceptable salt thereof, wherein qq is 0.

68. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 67, wherein the first end is capable of binding the DNA with an affinity of less than 500 nM.

69. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 67, wherein the oligomeric backbone is a linker with a length of less than about 50 angstroms.

70. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 67, wherein the oligomeric backbone is a linker of about 10 to 60 angstroms in length.

71. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 67, wherein the oligomeric backbone comprises a polymer having 2 to 50 spacer portions, wherein Each interval is independently selected from the following groups: -((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 - Optional replacement of C1-C 10 Alkyl groups, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkyne group, optionally substituted C6-C 10 arylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 5- to 10-membered heteroalkylene, optionally substituted 4- to 10-membered heteroalkylene, 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 S(O)2- and -P(O)OH-, and any combination thereof; where Each x is independently between 2 and 4; Each y is independently between 1 and 10; Each R 1a Independently, it is 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; and Each R 1b Independently hydrogen, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 haloalkyl.

72. The molecule of claim 71 or a pharmaceutically acceptable salt thereof, wherein the oligomeric backbone comprises a polymer having 2 to 50 spacer portions, wherein each spacer portion is independently selected from the group consisting of: -((CH2) x -O) y -、-((CH2) x -NH) y -, -O-, -C(O)NH-, -NH- and any combination thereof.

73. The molecule of claim 71 or a pharmaceutically acceptable salt thereof, wherein the oligomeric backbone comprises having 2 to 50 groups selected from -NHC(O)((CH2)). x -O) y -、-C(O)NH((CH2) x -O) y - The polymer in the spacer portion.

74. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises a bromodomain binding portion.

75. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises a portion capable of binding to a member of the bromine domain and the additional terminal domain (BET) family.

76. The molecule of claim 75 or a pharmaceutically acceptable salt thereof, wherein the BET family member is BRD2, BRD3, BRD4 or BRDT.

77. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end is capable of binding the following moieties: CBP / p300, P300 / CBP-Associated Factor (PCAF), cat eye syndrome chromosome region candidate 2 (CECR2), bromodomain and PHD finger-containing protein (BRPF), ATAD2 / ATAD2B (chromatin remodeling protein), Tripartitemotif-containing protein 24 (TRIM24), bromodomain adjacent to Zincfinger (BAZ2), TAF1 (TBP-associated factor), BRD7 / 9, bromodomain PHDFinger transcription factor (BPTF), SMARCA2 / 4, or PBRM1.

78. The molecule of claim 77 or a pharmaceutically acceptable salt thereof, wherein the second end comprises a portion capable of binding to the CBP / p300 binding portion.

79. The molecule of claim 77 or a pharmaceutically acceptable salt thereof, wherein the second end is a portion capable of binding to the PCAF (P300 / CBP related factor) portion.

80. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises the structure of formula (4-A): Equation (4-A), in: Ring D is absent, phenyl, or a 5- to 6-membered heteroaryl group; X 9 and X 10 Each is independently C or N, where X 9 or X 10 One of them is N; L 2 For non-existent, optionally substituted alkylene groups, -O- or -NR D -, where R D It is hydrogen or optionally substituted C1-C3 alkyl; R 18 The substituted 5- to 6-membered heteroaryl groups are selected; R 19 It can be a C3-C8 cycloalkyl group that is optionally substituted or a 4- to 7-membered heteroaryl group that is optionally substituted; Each R 20 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; and y4 is an integer from 1 to 4; The connection with the connector is in R 19 Location or R 20 One of them.

81. The molecule of claim 80 or a pharmaceutically acceptable salt thereof, wherein the second end comprises a structure of formula (4-B): Equation (4-B), in: 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, where X 9 or X 10 One of them is N; L 2 For non-existent, optionally substituted alkylene groups, -O- or -NR D -, where R D It is hydrogen or optionally substituted C1-C3 alkyl; R 18 The substituted 5- to 6-membered heteroaryl groups are selected; R 19 The substituted C3-C8 cycloalkyl or the substituted 4- to 7-membered heteroaryl groups; and x3 is an integer from 1 to 3.

82. The molecule of claim 80 or a pharmaceutically acceptable salt thereof, wherein the second end comprises a structure of formula (4-D): Equation (4-D), in: L 2 The substituted alkylene group can be either -O- or -NR. D -, where R D It is hydrogen or optionally substituted C1-C3 alkyl; R 18 The substituted 5- to 6-membered heteroaryl groups are selected; R 20 It can be 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; and y4 is an integer from 1 to 4.

83. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises the structure of formula (7-A): Equation (7-A), in: A 3 It can be -O-, -NH-, or -CH2-; Z 2 For CH or N; W represents O or S; Each R 31 Independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkyne, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclic alkyl; Or two Rs 31 It bonds with the atoms to which it is attached to form an optionally substituted C5-C8 cycloalkyl or an optionally substituted 5- to 8-membered heterocycloalkyl. R 32 Hydrogen or optionally substituted C1-C 10 alkyl; R 32a Hydrogen or optionally substituted C1-C 10 alkyl; R 33 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl; and q6 ranges from 0 to 4; Equation (7-A) is connected to R 32a Location or R 31 The connector at one of the points.

84. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises the structure of formula (2-A): Equation (2-A), in: Ring A is either a substituted aryl group or a substituted 5- to 6-membered heteroaryl group; Ring B is a 6-membered monocyclic aryl or heteroaryl group that is absent or optionally substituted; D is either C or N; E is either O or N; Y A It is -NH- or -O-; R 5 It is hydrogen or C1-C6 alkyl; R 6 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl; R 7 Selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl group, optionally substituted C1-C 20 Alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl; Or R 7 For -NR 7A R 7B ,in R 7A and R 7B Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; and x1 is an integer from 1 to 6.

85. The molecule of claim 84 or a pharmaceutically acceptable salt thereof, wherein the second end comprises a structure of formula (2-B): Equation (2-B), in: Ring A is either a substituted aryl group or a substituted 5- to 6-membered heteroaryl group; Ring B is a 6-membered monocyclic aryl or heteroaryl group that is absent or optionally substituted; Y A It is -NH- or -O-; R 5 It is hydrogen or C1-C6 alkyl; R 6 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl; R 7 Selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl group, optionally substituted C1-C 20 Alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl; Or R 7 For -NR 7A R 7B ,in R 7A and R 7B Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; and x1 is an integer from 1 to 6.

86. The molecule of claim 84 or a pharmaceutically acceptable salt thereof, wherein the second end comprises a structure of formula (2-C): Equation (2-C), in: Ring B is a 6-membered monocyclic aryl or heteroaryl group that is absent or optionally substituted; Y A It is -NH- or -O-; R 5 It is hydrogen or C1-C6 alkyl; R 6 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl; R 7 Selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl group, optionally substituted C1-C 20 Alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl; Or R 7 For -NR 7A R 7B ,in R 7A and R 7B Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; R 8 and R 9 Each is independently selected from hydrogen, -C(O)OR 8a Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; and R 8a Hydrogen, C1-C 20 Alkyl or C1-C 20 Heteroalkyl; and x1 is an integer from 1 to 6.

87. The molecule according to claim 84 or a pharmaceutically acceptable salt thereof, wherein the second end of formula (2-A) has the structure of formula (2-D): Equation (2-D), in: Ring B is a 6-membered monocyclic aryl or heteroaryl group that is absent or optionally substituted; Y A It is -NH- or -O-; R 5 It is hydrogen or C1-C6 alkyl; R 6 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl; R 7 Selected from hydrogen, halogen, -NO2, -CN, optionally substituted aryl group, optionally substituted C1-C 20 Alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C6 haloalkyl and optionally substituted C1-C6 hydroxyalkyl; Or R 7 For -NR 7A R 7B ,in R 7A and R 7B Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; R 10 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; and x1 is an integer from 1 to 6.

88. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises a structure of formula (3-A): Equation (3-A), in: Y B It can be -CH2NH-, -CH2O-, -NH- or -O-; R 11A and R 11B Each is independently hydrogen or optionally substituted C1-C6 alkyl; R 12 It can be hydrogen, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl or 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; Or R 14 For -NR A R B ; R 16 Optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 heteroalkyl, Optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 ynyl, Optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A -SO2R A or -NHSO2R A ; R YA It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted 5- to 6-membered monocyclic aryl or heteroaryl; Each R A and R B Independently, it 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, 4- to 6-membered heterocycloalkyl, or optionally substituted 4- to 6-membered heteroalkyl; and y1 ranges from 1 to 3; The connection with the connector is in R 14 Or R YA Place.

89. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises the structure of formula (3-B): Equation (3-B), in: The ring C is absent or optionally substituted with a 5- to 6-membered monocyclic aryl or heteroaryl, or a 4- to 8-membered heterocycle; Y B It can be -NH-, -CH2NH-, -CH2O-, or -O-; R 11A and R 11B Each is independently hydrogen or optionally substituted C1-C6 alkyl; R 12 Hydrogen, optionally substituted C1-C6 alkyl, C(O)R A or C(O)NR A R B ;in Each R A and R B Independently hydrogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; R 13 It is hydrogen, a substituted aryl group, a substituted heteroaryl group, or a substituted diphenyl ether; and y2 is an integer from 0 to 2.

90. The molecule of claim 88 or a pharmaceutically acceptable salt thereof, wherein the second end comprises a structure of formula (3-C): Equation (3-C), in: The ring C is absent or optionally substituted with a 5- to 6-membered monocyclic aryl or heteroaryl, or a 4- to 8-membered heterocycle; Y B It can be -CH2NH-, -CH2O-, -NH- or -O-; R 12 It can be hydrogen, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl or 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; Or R 14 For -NR A R B ; R 16 Optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 heteroalkyl, Optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 ynyl, Optionally substituted C1-C6 hydroxyalkyl, -S(O)(=NH)R A -SO2R A or -NHSO2R A ; Each R A and R B Independently, it 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, or optionally substituted 4- to 6-membered heterocyclic alkyl; and y1 is an integer from 1 to 3.

91. The molecule of claim 88 or a pharmaceutically acceptable salt thereof, wherein the second end comprises a structure of formula (3-D): Equation (3-D), in: R 11A and R 11B Each is independently hydrogen or optionally substituted C1-C6 alkyl; R 12 It is hydrogen or optionally substituted C1-C6 alkyl; Each R 15 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 ynyl, C1-C6 hydroxyalkyl, -S(O)(=NH)R A -SO2R A or -NHSO2R A ; R A The substituted C1-C6 alkyl group, the substituted C1-C6 heteroalkyl group, the substituted C1-C6 haloalkyl group, the substituted C1-C6 hydroxyalkyl group, the substituted C3-C6 cycloalkyl group, the substituted 4- to 6-membered heterocycloalkyl group, or the substituted 5- to 6-membered heteroaryl group; and y1 is an integer from 1 to 3.

92. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises the structure of formula (13-A): Equation (13-A), in: Ring J is a 5- to 6-membered heteroaryl group that is absent or optionally substituted; R 41 Optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, -C(O)R 41a -C(O)- or -C(O)NR 41a R 41b ,in R 41a and R 41b Each of the C1-Cs can be arbitrarily replaced independently. 10 Alkyl or optionally substituted C3-C8 cycloalkyl; R 42 For the optional replacement of C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclic alkyl; R 43 Hydrogen or optionally substituted C1-C 10 alkyl; Each R 44 Independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated, 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 heterocyclic alkyl; or R 43 and R 44 One of them, together with the atoms to which it is attached, forms an optionally substituted 5- to 8-membered heterocyclic alkyl group; p 12 From 1 to 4; and q3 is either 0 or 1; Equation (13-A) is connected to rings J and R. 41 Or R 42 Connector at the location.

93. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises the structure of formula (14-A): Equation (14-A), in: Ring K is a 5- to 6-membered heterocyclic alkyl group; A 5 For non-existent, CH2, -NH-, or -O-; L 4 It is an alkylene or heteroalkylene; Each R 45 Independently halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkyne, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclic alkyl; Each R 46 Independently hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkyne, optionally substituted C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocyclic alkyl; R 47 For the optional replacement of C1-C 10 Alkyl, -C(O)R 47a or -C(O)-NR 47a R 47b ,in R 47a and R 47b Each of the C1-Cs can be arbitrarily replaced independently. 10 Alkyl or optionally substituted C3-C8 cycloalkyl; q4 is 2 to 3; and q5 is between 0 and 2; The formula (14-A) is obtained by passing through ring K or through R. 45 One of them is connected to the connector.

94. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises a structure of formula (15-C): Formula (15-C), in: X is CR 48 Or N; Each R 48 It can be hydrogen, halogen, -OH, -CN, -NO2, -NH2, or Cl-C. 10 Alkyl, C1-C 10 Halogenated or C1-C 10 Hydroxyalkyl; R 49 and R 50 Each is independently hydrogen, and the C1-C atoms can be optionally substituted. 10 Alkyl groups, optionally substituted C1-C 10 Halogenated groups, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 alkynyl group; R 51 Hydrogen, halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C2-C 10 Alkenyl or optionally substituted C2-C 10 alkynyl group; R 53 Hydrogen or optionally substituted C1-C 10 Alkyl; and p7 is 1 to 3.

95. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end comprises the structure of formula (16-A): Equation (16-A), in: B 5 It can be -O-, -NH-, or S; B 6 For N or CH; R 54 The aryl group can be substituted or the heteroaryl group can be substituted. Each R 55 Independently halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Hydroxyalkyl; R 56 Hydrogen, optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl; R 57 Halogen, -OH, -CN, -NO2, -NH2, or optionally substituted C1-C 10 Alkyl groups, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Hydroxyalkyl; p9 is 1 to 3; and q7 is between 0 and 2.

96. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73, wherein the second end is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , Or its pharmaceutically acceptable salt.

97. A molecule selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or ， Or its pharmaceutically acceptable salt.

98. A pharmaceutical composition comprising a molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 97, and a pharmaceutically acceptable excipient.

99. A method for reducing gene expression in a cell, the method comprising 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.

100. The method of claim 99, wherein the gene is HTT.

101. A method for treating Huntington's disease (HD) in a subject in need, the method comprising administering to the subject a molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 97.

102. The method of claim 101, wherein the method alleviates one or more symptoms of Huntington's disease.

103. The method according to claim 102, wherein the one or more symptoms are selected from chorea, cognitive decline, abnormal libido, abnormal eye movement, abnormal sense of smell, aggression, irritability, anxiety, apathy, bradykinesia, slow thinking, clumsiness, delusions, depression, dyskinesia, dysinusia, hypotonia, gait instability, muscle weakness, hallucinations, hostility, impaired motor function, irritability, memory impairment, myoclonus, compulsive behaviors, poor fine motor coordination, epilepsy, speech difficulties, staring, weight loss, abnormal cholesterol metabolism, abnormal white matter, alcoholism, Babinski sign, caudate nucleus atrophy, cerebral atrophy, asphyxia, clonic seizures, striatal degeneration, excessive daytime sleepiness, impaired visuospatial cognitive function, inability to walk, insomnia, mutism, oropharyngeal dysphagia, rigidity, suicidal ideation, cerebellar atrophy, dementia, gating ataxia, glioma, hyperreflexia, neuronal loss, or personality changes.

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