Methods and compounds for modulating inherited genetic diseases

Abstract

The present disclosure relates to transcriptional modulating molecular compounds, compositions, and methods for treating DM1 and FECD.

Description

[0001] Cross-references

[0002] This application claims the benefits of U.S. Provisional Application No. 63 / 564,707, filed March 13, 2024, and U.S. Provisional Application No. 63 / 607,832, filed December 8, 2023, which are hereby incorporated in their entirety. Technical Field

[0003] This article discloses heterocyclic polyamide compounds and compositions, as well as their use as pharmaceutical agents for the treatment of myotonic dystrophy type 1 (“DM1”), Fuchs’ endothelial dystrophy (“Fuchs’ endothelial corneal dystrophy”; “FECD”). Background Technology

[0004] This disclosure relates to the treatment of hereditary diseases characterized by excessive mRNA production.

[0005] Myotonic dystrophy (“DM”) is a member of a group of diseases called muscular dystrophy, affecting approximately 1 in 8,000 people. DM is the most common form of muscular dystrophy in adults, with most cases diagnosed after age 20. DM is characterized by persistent muscle contractions and is associated with several symptoms, including muscle symptoms and cataracts, as well as cardiac and respiratory symptoms, all of which typically appear later in the disease's progression. While symptoms can be improved with treatment, there is currently no cure to stop or reverse the progression of DM. Respiratory failure and cardiac arrhythmias are the most common causes of death in patients with DM.

[0006] The most severe form of DM is myotonic dystrophy type 1 (“DM1”). DM1 is an autosomal dominant genetic disorder caused by mutations in the dmpk gene. This gene encodes the myotonic dystrophy protein kinase (MDPK) protein, also known as myotonic protein kinase. MDPK proteins can be found in muscle, heart, and nerve tissue.

[0007] DM1 is induced by transcription of a defective dmpk gene in DM1 individuals. Typically, this gene contains a 3' untranslated region with 5–37 CTG trinucleotide repeats. In the DM1 genotype, the number of these trinucleotide repeats expands to 50 to over 3,000, with the majority having over 1,000 CTG repeats. This number of trinucleotide repeats tends to increase in offspring, leading to earlier age of onset. Furthermore, the number of these trinucleotide repeats has been observed to increase throughout the lifetime of the individual, possibly due to abnormal DNA repair.

[0008] The progression of DM1 is attributed to the “RNA toxicity” of dmpk mRNA with an extended CTG region. This mRNA forms aggregates with certain proteins, and these aggregates interfere with normal cellular function. The binding of defective mRNA to bleblin may be a mechanism leading to DM1 symptoms, especially since bleblin activity is essential for normal muscle development in flies.

[0009] Fauci's endothelial dystrophy, or Fauci's corneal endothelial dystrophy (“FECD”), is a non-inflammatory, sporadic, or autosomal dominant dystrophy involving the corneal endothelium. Due to Fauci's dystrophy, the cornea begins to swell, leading to glare, halos, and decreased vision. The damage to the cornea caused by Fauci's endothelial dystrophy can be very severe, even leading to corneal blindness. Fauci's dystrophy is classified into early-onset (first decade) and late-onset (fourth to fifth decades), the latter being more prevalent in women. Early-onset Fauci's dystrophy involves the type 8 collagen α2 chain. Late-onset Fauci's dystrophy is characterized by involvement of transcription factor 4 (TCF4), transcription factor 8 (TCF8), ATP / GTP-binding protein-like protein 1 (AGBL1), lipoxygenase homeodomain 1 (LOXHD1), solute carrier family 4 member 11 (SLC4A11) genes, and transgrowth factor-β inducible protein, as well as aggregates. Summary of the Invention

[0010] In one respect, this article provides a transcriptional regulatory molecule having the structure of formula (I) or a pharmaceutically acceptable salt thereof:

[0011] ,

[0012] in:

[0013] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently CH or N;

[0014] W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0015] L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl;

[0016] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0017] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in

[0018] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0019] R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0020] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0021] Each R2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0022] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,

[0023] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl;

[0024] 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; wherein

[0025] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0026] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0027] Each R 5 Independent of halogen, -CN, -OH, -OR5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0028] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0029] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0030] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0031] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0032] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

[0033] In some embodiments, the transcriptional regulatory molecules are selected from Table 1, or pharmaceutically acceptable salts thereof.

[0034] On the other hand, this article provides a pharmaceutical composition comprising the transcriptional regulatory molecule disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0035] On the other hand, this article provides a method for treating Fauci's endothelial dystrophy or Fauci's corneal endothelial dystrophy (FECD) in a subject of need, the method comprising administering to the subject an effective amount of the transcriptional regulatory molecule disclosed herein or a pharmaceutically acceptable salt thereof.

[0036] On the other hand, this article provides a method for treating type 1 myotonic dystrophy (DM1) in a subject of need, the method comprising administering to the subject an effective amount of the transcriptional regulatory molecule disclosed herein or a pharmaceutically acceptable salt thereof.

[0037] However, it should be understood that in indicating particular embodiments, detailed descriptions and specific examples are provided by way of illustration only, as various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from the detailed description herein.

[0038] Incorporate by reference

[0039] 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. Detailed Implementation

[0040] This article discloses transcriptional regulatory molecules and methods for treating DM1 and FECD.

[0041] Compounds - Transcription Regulatory Molecules

[0042] In one respect, this article provides a transcriptional regulatory molecule having the structure of formula (A-1) or a pharmaceutically acceptable salt thereof:

[0043] ,

[0044] in:

[0045] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently CH or N;

[0046] W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0047] W 2 C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; or W 2 -LZR 4 ;in

[0048] L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl;

[0049] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0050] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in

[0051] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0052] R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 12-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0053] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0054] R W Hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; or

[0055] W 2 and R W Together with the nitrogen atom to which it is attached, it forms optionally substituted 4- to 10-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0056] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0057] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,

[0058] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl;

[0059] 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; wherein

[0060] R 3c and R3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0061] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0062] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0063] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0064] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0065] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0066] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0067] R6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0068] Each R 7 It can be hydrogen, halogen, -OH or C1-C3 alkyl independently;

[0069] n1 and n2 are each independently 0 or 1;

[0070] n3 is 1 or 2;

[0071] m1 is 0, 1, 2, or 3; and

[0072] n0 is either 0 or 1, where neither n0 nor m1 is 0.

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

[0074] In some embodiments of equation (A-1), n2 is 1. In some embodiments of equation (A-1), n2 is 0.

[0075] In some embodiments of equation (A-1), n3 is 1. In some embodiments of equation (A-1), n3 is 0.

[0076] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (A-2) or a pharmaceutically acceptable salt thereof:

[0077] ,

[0078] in:

[0079] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently CH or N;

[0080] W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0081] W 2 C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20Heteroalkyl; or W 2 -LZR 4 ;in

[0082] L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl;

[0083] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0084] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in

[0085] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0086] R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0087] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0088] R W Hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; or

[0089] W 2 and R W Together with the nitrogen atom to which it is attached, it forms optionally substituted 4- to 10-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0090] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0091] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,

[0092] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl;

[0093] 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; wherein

[0094] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0095] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0096] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0097] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0098] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0099] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0100] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0101] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0102] Each R 7 Independently hydrogen, halogen, -OH, or C1-C3 alkyl; and

[0103] n1 and m1 are each independently 0 or 1.

[0104] In some embodiments of formula (A-1) or (A-2), W 2 C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl. In some embodiments of formula (A-1) or (A-2), W 2 C1-C is optionally substituted 10 Alkyl or optionally substituted C1-C 10 Heteroalkyl. In some embodiments of formula (A-1) or (A-2), W 2 C1-C is optionally substituted 10 Alkyl group. In some embodiments of formula (A-1) or (A-2), W 2 C1-C is optionally substituted 10 Heteroalkyl groups.

[0105] In some embodiments of formula (A-1) or (A-2), W 2 -LZR 4 .

[0106] In some embodiments of formula (A-1) or (A-2), R W C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl. In some embodiments of formula (A-1) or (A-2), R W C1-C is optionally substituted 10 Alkyl or optionally substituted C1-C 10 Heteroalkyl. In some embodiments of formula (A-1) or (A-2), R W C1-C is optionally substituted 10 Alkyl group. In some embodiments of formula (A-1) or (A-2), R W C1-C is optionally substituted 10 Heteroalkyl. In some embodiments of formula (A-1) or (A-2), R W It is hydrogen.

[0107] In some embodiments of formula (A-1) or (A-2), W 2 and R WTogether with the nitrogen atom to which it is attached, it forms optionally substituted 4- to 10-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 Replacement. In some embodiments of formula (A-1) or (A-2), W 2 and R W Together with the nitrogen atom to which it is attached, it forms an optionally substituted 4- to 6-membered heterocyclic alkyl group. In some embodiments of formula (A-1) or (A-2), W 2 and R W Together with the nitrogen atom to which it is attached, it forms an optionally substituted 4-membered heterocyclic alkyl group. In some embodiments of formula (A-1) or (A-2), W 2 and R W Together with the nitrogen atom to which it is attached, it forms an optionally substituted 5-membered heterocyclic alkyl group. In some embodiments of formula (A-1) or (A-2), W 2 and R W Together with the nitrogen atom to which it is attached, it forms an optionally substituted 6-membered heterocyclic alkyl group.

[0108] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (A-3) or a pharmaceutically acceptable salt thereof:

[0109] ,

[0110] in:

[0111] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently CH or N;

[0112] W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0113] L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl;

[0114] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0115] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR4b or -NR 4a R 4b ;in

[0116] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0117] R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0118] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0119] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0120] Each R 3a and R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,or

[0121] Two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; or

[0122] 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; wherein

[0123] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0124] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0125] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0126] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0127] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0128] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0129] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0130] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl; and

[0131] n1 and m1 are each independently 0 or 1.

[0132] In some embodiments of formula (A-1), (A-2), or (A-3), n1 is 1. In some embodiments of formula (A-1), (A-2), or (A-3), n1 is 0.

[0133] In some embodiments of formula (A-1), m1 is 1, 2, or 3. In some embodiments of formula (A-1), m1 is 1 or 2. In some embodiments of formulas (A-1), (A-2), or (A-3), m1 is 0 or 1. In some embodiments of formulas (A-1), (A-2), or (A-3), m1 is 0. In some embodiments of formulas (A-1), (A-2), or (A-3), m1 is 1.

[0134] In some embodiments, this document provides a transcriptional regulatory molecule having the structure of formula (I) or a pharmaceutically acceptable salt thereof:

[0135] ,

[0136] in:

[0137] Each Y 1 Y 2 Y 3 Y 4 Y 6 Y 7 and Y 8 Independently CH or N;

[0138] W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0139] L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl;

[0140] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0141] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in

[0142] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0143] R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0144] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 10-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0145] Each R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

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

[0147] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; or

[0148] 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; wherein

[0149] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0150] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0151] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0152] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0153] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0154] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0155] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0156] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

[0157] In some embodiments of formulas (A-1), (A-2), (A-3), or (I), Y 1 CH. In some embodiments of formula (A-1), (A-2), (A-3) or (I), Y 1 Let N be the number of elements in the array.

[0158] In some embodiments of formulas (A-1), (A-2), (A-3), or (I), Y 2 CH. In some embodiments of formula (A-1), (A-2), (A-3) or (I), Y 2 Let N be the number of elements in the array.

[0159] In some embodiments of formulas (A-1), (A-2), (A-3), or (I), Y 3 CH. In some embodiments of formula (A-1), (A-2), (A-3) or (I), Y 3 Let N be the number of elements in the array.

[0160] In some embodiments of formulas (A-1), (A-2), (A-3), or (I), Y 4 CH. In some embodiments of formula (A-1), (A-2), (A-3) or (I), Y 4 Let N be the number of elements in the array.

[0161] In some embodiments of formula (A-1), (A-2) or (A-3), each Y 5 Independently CH. In some embodiments of formula (A-1), (A-2), or (A-3), each Y 5 N stands independently.

[0162] In some embodiments of formulas (A-1), (A-2), (A-3), or (I), each Y 6 CH. In some embodiments of formula (A-1), (A-2), (A-3) or (I), each Y 6 N stands independently.

[0163] In some embodiments of formulas (A-1), (A-2), (A-3), or (I), Y 7 CH. In some embodiments of formula (A-1), (A-2), (A-3) or (I), Y 7 Let N be the number of elements in the array.

[0164] In some embodiments of formulas (A-1), (A-2), (A-3), or (I), Y 8 CH. In some embodiments of formula (A-1), (A-2), (A-3) or (I), Y 8 Let N be the number of elements in the array.

[0165] In some embodiments of formulas (A-1), (A-2), (A-3), or (I), Y 2 Y 4 Y 7 and Y 8 Each is N, and Y 1 Y 3 and Y 6 Each is CH.

[0166] In some embodiments of formulas (A-1), (A-2), (A-3), or (I), Y 1 Y 2 Y 3 and Y 8 Each is N, and Y 4 Y 6 and Y 7 Each is CH.

[0167] In some embodiments, this document provides a transcriptional regulatory molecule having the structure of formula (II) or a pharmaceutically acceptable salt thereof:

[0168] ,

[0169] in:

[0170] W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0171] L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl;

[0172] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0173] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in

[0174] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5replace;

[0175] R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0176] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0177] Each R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0178] Each R 3a and R 3b Independently hydrogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R3e ,

[0179] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; or

[0180] 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; wherein

[0181] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0182] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0183] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0184] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0185] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0186] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0187] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0188] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

[0189] In some embodiments, this document provides a transcriptional regulatory molecule having the structure of formula (III) or a pharmaceutically acceptable salt thereof:

[0190] ,

[0191] in:

[0192] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0193] L is C1-C 20 Alkylene or C2-C 20 Heteroalkyl;

[0194] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0195] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in

[0196] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0197] R 4bHydrogen, 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0198] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0199] Each R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0200] Each R 3b Independently hydrogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,

[0201] Or two Rs 3bTogether with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein

[0202] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0203] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0204] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0205] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0206] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0207] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0208] R 6a and R 6bEach independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0209] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

[0210] In some embodiments, this document provides a transcriptional regulatory molecule having a structure of formula (IIIa) or a pharmaceutically acceptable salt thereof:

[0211] ,

[0212] in:

[0213] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0214] L does not exist; it is 1-C. 20 Alkylene or C2-C 20 Heteroalkyl;

[0215] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0216] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in

[0217] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0218] R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0219] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0220] Each R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0221] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0222] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20;

[0223] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0224] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0225] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0226] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

[0227] In some embodiments of formulas (I), (II), (III) or (IIIa), R 2a R 2b R 2c R 2d R 2e R 2g Or R 2h At least one of them is not an unsubstituted C1-C 20 Alkyl group. In some embodiments of formula (I), (II), (III), or (IIIa), R 2a R 2b R 2c R 2d R 2e R 2g Or R 2h At least one of them is not methyl.

[0228] In some embodiments, this document provides a transcriptional regulatory molecule having a structure of formula (IV) or a pharmaceutically acceptable salt thereof:

[0229] ,

[0230] in:

[0231] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0232] L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl;

[0233] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0234] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in

[0235] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0236] R 4b Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0237] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0238] Each R 2a R 2c R 2d R 2e and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0239] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,

[0240] 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, wherein

[0241] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0242] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0243] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5bOptionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0244] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0245] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0246] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0247] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0248] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

[0249] In some embodiments, this document provides a transcriptional regulatory molecule having a structure of formula (IVa) or a pharmaceutically acceptable salt thereof:

[0250] ,

[0251] in:

[0252] W 1 For hydrogen or -N=C(N(R) 1e)2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0253] L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl;

[0254] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0255] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in

[0256] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0257] R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0258] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0259] Each R 2a R 2c R 2d R 2e and R 2hIndependently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0260] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0261] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0262] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0263] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0264] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0265] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

[0266] On the other hand, this article provides a transcriptional regulatory molecule having a structure of formula (V) or a pharmaceutically acceptable salt thereof:

[0267] ,

[0268] in:

[0269] W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0270] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0271] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocyclic alkyl or -NR 4a R 4b ;in

[0272] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0273] R 4b Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0274] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0275] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Halogenated or optionally substituted PEG 1-20 Each of them may choose to pass through one or more R 6 replace;

[0276] Each R 3b It is hydrogen;

[0277] 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;

[0278] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0279] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0280] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0281] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b-CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0282] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0283] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl; and

[0284] x is between 0 and 10.

[0285] In some embodiments of formula (V), R 2a R 2b R 2c R 2d R 2e R 2g or R 2h At least one of them is not an unsubstituted C1-C 20 Alkyl group. In some embodiments of formula (V), R 2a R 2b R 2c R 2d R 2e R 2g or R 2h At least one of them is not methyl.

[0286] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (VI) or a pharmaceutically acceptable salt thereof:

[0287] ,

[0288] in:

[0289] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0290] R 2a R2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may optionally pass through one or more R 6 replace;

[0291] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0292] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0293] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0294] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0295] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c-NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0296] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0297] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl; and

[0298] x1 is 0-6.

[0299] In some embodiments of formula (VI), x1 is 0-6. In some embodiments of formula (VI), x1 is 0-3. In some embodiments of formula (VI), x1 is 1, 2, or 3. In some embodiments of formula (VI), x1 is 0. In some embodiments of formula (VI), x1 is 1. In some embodiments of formula (VI), x1 is 2. In some embodiments of formula (VI), x1 is 3. In some embodiments of formula (VI), x1 is 4. In some embodiments of formula (VI), x1 is 5. In some embodiments of formula (VI), x1 is 6.

[0300] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (VII) or a pharmaceutically acceptable salt thereof:

[0301] ,

[0302] in:

[0303] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0304] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0305] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0306] Or two Rs 3b Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0307] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0308] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0309] R 4 ª and R 4b Each is independently a C1-C3 alkyl or PEG. 1-10 ;

[0310] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0311] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0312] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl; and

[0313] x is an integer between 0 and 10.

[0314] In some embodiments of formula (VII), R 4 ª and R 4b Each is independently a C1-C3 alkyl group. In some embodiments of formula (VII), R 4 ª and R 4b Each is -CH3. In some embodiments of formula (VII), R 4 ª and R 4b Each independently for PEG 1-10 .

[0315] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (VIII) or a pharmaceutically acceptable salt thereof:

[0316] ,

[0317] in:

[0318] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0319] B 2 For NR 10a or CHR 12 ;in

[0320] R 10a It is hydrogen or C1-C3 alkyl;

[0321] R 12 Optionally substituted 4- to 6-membered heterocyclic alkyl groups or ;

[0322] R 12a Optionally substituted 4- to 6-membered heterocyclic alkyl groups;

[0323] R 2a R 2bR 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted PEG 1-50 Each of them may choose to pass through one or more R 6 replace;

[0324] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0325] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0326] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0327] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0328] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c-NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0329] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0330] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0331] Each R 11 It can be independently a halogen, -CN, -OH, -N3 or C1-C6 haloalkyl;

[0332] p6 is 0, 1, 2, 3, or 4; and

[0333] q1 and q2 are each independently 0, 1 or 2.

[0334] In some embodiments of formula (VIII), B 2 For NR 10a In some embodiments of formula (VIII), CHR 12 .

[0335] In some embodiments of formula (VIII), R 12 It is optionally a substituted 4- to 6-membered heterocyclic alkyl group. In some embodiments of formula (VIII), R 12 for In some embodiments of formula (VIII), R 12 for .

[0336] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (VIIIa) or a pharmaceutically acceptable salt thereof:

[0337] ,

[0338] in:

[0339] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0340] R 2a R 2b R2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0341] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;or

[0342] Two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0343] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0344] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0345] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0346] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0347] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl

[0348] B 3 For N or CH;

[0349] R 10b It is hydrogen or C1-C3 alkyl; and

[0350] q3 and q4 are each independently 0, 1 or 2.

[0351] In some embodiments of formula (VIIIa), B 3 For N. In some embodiments of equation (VIIIa), B 3 For CH.

[0352] In some embodiments of formula (VIIIa), R 10b It is a C1-C3 alkyl group. In some embodiments of formula (VIIIa), R 10b R is methyl. In some embodiments of formula (VIIIa), R 10b It is hydrogen.

[0353] In some embodiments of equation (VIIIa), q3 and q4 are both 0. In some embodiments of equation (VIIIa), q3 and q4 are both 1.

[0354] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (VIIIb) or a pharmaceutically acceptable salt thereof:

[0355] ,

[0356] in:

[0357] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0358] R 2a R2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0359] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0360] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0361] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0362] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0363] Each R 6 Independently -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -C(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c-NHC(O)OR 6c or -OC(O)NR 6a R 6b ;in

[0364] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0365] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0366] R 10a It is hydrogen or C1-C3 alkyl;

[0367] Each R 11 It can be independently a halogen, -CN, -OH, -N3 or C1-C6 haloalkyl;

[0368] p6 is 0, 1, 2, 3 or 4;

[0369] q1 and q2 are each independently 0, 1, or 2; and

[0370] x is an integer between 0 and 10.

[0371] In some embodiments of formula (VIII) or (VIIIb), R 10a It is a C1-C3 alkyl group. In some embodiments of formula (VIII) or (VIIIb), R 10a It is methyl or ethyl. In some embodiments of formula (VIII) or (VIIIb), R 10a It is methyl. In some embodiments of formula (VIII) or (VIIIb), R 10a It is hydrogen.

[0372] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (VIIIc) or a pharmaceutically acceptable salt thereof:

[0373] ,

[0374] in:

[0375] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0376] R 2a R 2b R2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0377] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0378] Or two Rs 3b Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0379] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0380] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0381] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0382] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0383] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0384] Each R 11 It can be independently a halogen, -CN, -OH, -N3 or C1-C6 haloalkyl;

[0385] B 4 It can be O or CH2;

[0386] p6 is 0, 1, 2, 3 or 4;

[0387] q1 and q2 are each independently 0, 1, or 2; and

[0388] x is an integer between 0 and 10.

[0389] In some embodiments of formula (VIIIc), B 4 For O. In some embodiments of formula (VIIIc), B 4 It is CH2.

[0390] In some embodiments of formulas (VIII), (VIIIa), (VIIIb), or (VIIIc), p6 is 1 or 2. In some embodiments of formulas (VIII), (VIIIa), (VIIIb), or (VIIIc), p6 is 0. In some embodiments of formulas (VIII), (VIIIa), (VIIIb), or (VIIIc), p6 is 1. In some embodiments of formulas (VIII), (VIIIa), (VIIIb), or (VIIIc), p6 is 2.

[0391] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (VIIId) or a pharmaceutically acceptable salt thereof:

[0392] ,

[0393] in:

[0394] W 1 For hydrogen or -N=C(N(R)1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0395] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0396] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0397] Or two Rs 3b Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0398] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0399] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0400] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0401] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0402] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0403] Each R 11 It can be independently a halogen, -CN, -OH, -N3 or C1-C6 haloalkyl;

[0404] p5 is 1, 2, 3, or 4;

[0405] q5 is 0, 1, 2, or 3; and

[0406] x is an integer from 0 to 10;

[0407] In some embodiments of formula (VIIId), p5 is 1 or 2. In some embodiments of formula (VIIId), p5 is 1 and R 11 It is a halogen or a C1-C6 haloalkyl group. In some embodiments of formula (VIIId), p5 is 2 and R 11 It is a halogen or a C1-C6 haloalkyl group. In some embodiments of formula (VIIId), p5 is 1 and R 5 For -F or -CF3.

[0408] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (IX) or a pharmaceutically acceptable salt thereof:

[0409] ,

[0410] in:

[0411] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0412] B 5 For NR 10c Or O; where

[0413] R 10c It is hydrogen or C1-C3 alkyl;

[0414] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0415] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0416] Or two Rs 3b Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0417] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0418] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0419] Each R 6 Independent of halogen, -CN, -OH, -OR6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0420] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0421] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl; and

[0422] q1, q2, q3 and q4 are each independently 0, 1 or 2.

[0423] In some embodiments of formula (IX), B 5 For NR 10c In some embodiments of formula (IX), B 5 For NCH3. In some embodiments of formula (IX), B 5 For -NH-. In some embodiments of formula (IX), B 5 It is -O-.

[0424] In some embodiments of equations (VIII), (VIIIb), (VIIIc), or (IX), q1 and q2 are each 0. In some embodiments of equations (VIII), (VIIIb), (VIIIc), or (IX), q1 and q2 are each 1. In some embodiments of equations (VIII), (VIIIb), (VIIIc), or (IX), q1 is 1 and q2 is 0.

[0425] In some embodiments of formula (VIIIa) or (IX), q3 and q4 are both 0. In some embodiments of formula (VIIIa) or (IX), q3 and q4 are both 1. In some embodiments of formula (VIIIa) or (IX), q3 is 1 and q4 is 0.

[0426] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (X) or a pharmaceutically acceptable salt thereof:

[0427] ,

[0428] in:

[0429] W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0430] L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl;

[0431] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0432] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in

[0433] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0434] R 4b Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl, optionally substituted C2-C 20 Alkyne group, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0435] R 4a and R 4bTogether with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0436] Each R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0437] Each R 3a and R 3b Independently hydrogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,

[0438] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl;

[0439] 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; wherein

[0440] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0441] R 3e For C1-C 20 Alkyl, PEG 1-20C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0442] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0443] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0444] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0445] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0446] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0447] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

[0448] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (XI) or a pharmaceutically acceptable salt thereof:

[0449] ,

[0450] in:

[0451] W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0452] Z does not exist; it is either -C(O)- or -C(=NH)-.

[0453] R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl or -NR 4a R 4b ;in

[0454] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0455] R 4b Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0456] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0457] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, C1-C20 Heteroalkyl, optionally substituted C1-C 20 Halogenated or optionally substituted PEG 1-20 Each of them may choose to pass through one or more R 6 replace;

[0458] Each R 3b It is hydrogen;

[0459] 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;

[0460] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which

[0461] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0462] Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl;

[0463] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0464] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG1-20 ;

[0465] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl; and

[0466] x is between 0 and 10.

[0467] In some embodiments of formula (V), (X), or (XI), R 2a R 2b R 2c R 2d R 2e R 2g Or R 2h At least one of them is not an unsubstituted C1-C 20 Alkyl group. In some embodiments of formula (V), (X), or (XI), R 2a R 2b R 2c R 2d R 2e R 2g Or R 2h At least one of them is not methyl.

[0468] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (XII) or a pharmaceutically acceptable salt thereof:

[0469] ,

[0470] in:

[0471] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0472] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0473] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0474] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0475] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0476] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0477] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0478] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0479] R 6c For C1-C 20 Alkyl, PEG 1-20C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl; and

[0480] x1 is 0-6.

[0481] In some embodiments of formula (XII), x1 is 0-6. In some embodiments of formula (XII), x1 is 0-3. In some embodiments of formula (XII), x1 is 1, 2, or 3. In some embodiments of formula (XI), x1 is 0. In some embodiments of formula (XII), x1 is 1. In some embodiments of formula (XII), x1 is 2. In some embodiments of formula (XII), x1 is 3. In some embodiments of formula (XII), x1 is 4. In some embodiments of formula (XII), x1 is 5. In some embodiments of formula (XII), x1 is 6.

[0482] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (XIII) or a pharmaceutically acceptable salt thereof:

[0483] ,

[0484] in:

[0485] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0486] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0487] Each R 3bIndependently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0488] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0489] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0490] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0491] R 4 ª and R 4b Each is independently a C1-C3 alkyl or PEG. 1-10 ;

[0492] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0493] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0494] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl; and

[0495] x is an integer between 0 and 10.

[0496] In some embodiments of formula (XIII), R 4 ª and R 4b Each is independently a C1-C3 alkyl group. In some embodiments of formula (XIII), R 4 ª and R 4b Each is -CH3. In some embodiments of formula (XIII), R 4 ª and R 4b Each independently for PEG 1-10 .

[0497] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (XIV) or a pharmaceutically acceptable salt thereof:

[0498] ,

[0499] in:

[0500] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0501] B 2 For NR 10a or CHR 12 ;in

[0502] R 10a It is hydrogen or C1-C3 alkyl;

[0503] R 12 Optionally substituted 4- to 6-membered heterocyclic alkyl groups or ;

[0504] R 12a Optionally substituted 4- to 6-membered heterocyclic alkyl groups;

[0505] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted PEG 1-50 Each of them may choose to pass through one or more R 6 replace;

[0506] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0507] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0508] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0509] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0510] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0511] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0512] R 6c For C1-C 20Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0513] Each R 11 It can be independently a halogen, -CN, -OH, -N3 or C1-C6 haloalkyl;

[0514] p6 is 0, 1, 2, 3, or 4; and

[0515] q1 and q2 are each independently 0, 1 or 2.

[0516] In some embodiments of formula (XIV), B 2 For NR 10a In some embodiments of formula (XIV), CHR 12 .

[0517] In some embodiments of formula (XIV), R 12 It is optionally a substituted 4- to 6-membered heterocyclic alkyl group. In some embodiments of formula (XIV), R 12 for In some embodiments of formula (XIV), R 12 for .

[0518] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (XIVa) or a pharmaceutically acceptable salt thereof:

[0519] ,

[0520] in:

[0521] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0522] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0523] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;or

[0524] Two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0525] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0526] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0527] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0528] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0529] R 6c For C1-C 20 Alkyl, PEG 1-20C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl

[0530] B 3 For N or CH;

[0531] R 10b It is hydrogen or C1-C3 alkyl; and

[0532] q3 and q4 are each independently 0, 1 or 2.

[0533] In some embodiments of formula (XIVa), B 3 For N. In some embodiments of formula (XIVa), B 3 For CH.

[0534] In some embodiments of formula (XIVa), R 10b It is a C1-C3 alkyl group. In some embodiments of formula (XIVa), R 10b R is methyl. In some embodiments of formula (XIVa), R 10b It is hydrogen.

[0535] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (XIVb) or a pharmaceutically acceptable salt thereof:

[0536] ,

[0537] in:

[0538] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0539] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG.1-50 Each of them may choose to pass through one or more R 6 replace;

[0540] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0541] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0542] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0543] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0544] Each R 6 Independently -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -C(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c or -OC(O)NR 6a R 6b ;in

[0545] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0546] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0547] R 10a It is hydrogen or C1-C3 alkyl;

[0548] Each R 11 It can be independently a halogen, -CN, -OH, -N3 or C1-C6 haloalkyl;

[0549] p6 is 0, 1, 2, 3 or 4;

[0550] q1 and q2 are each independently 0, 1, or 2; and

[0551] x is an integer between 0 and 10.

[0552] In some embodiments of formula (XIV) or (XIVb), R 10a It is a C1-C3 alkyl group. In some embodiments of formula (XIV) or (XIVb), R 10a It is methyl or ethyl. In some embodiments of formula (XIV) or (XIVb), R 10a It is methyl. In some embodiments of formula (XIV) or (XIVb), R 10a It is hydrogen.

[0553] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (XIVc) or a pharmaceutically acceptable salt thereof:

[0554] ,

[0555] in:

[0556] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0557] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50Each of them may choose to pass through one or more R 6 replace;

[0558] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0559] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0560] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0561] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0562] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0563] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0564] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0565] Each R 11It can be independently a halogen, -CN, -OH, -N3 or C1-C6 haloalkyl;

[0566] B 4 It can be O or CH2;

[0567] p6 is 0, 1, 2, 3 or 4;

[0568] q1 and q2 are each independently 0, 1, or 2; and

[0569] x is an integer between 0 and 10.

[0570] In some embodiments of formula (XIVc), B 4 For O. In some embodiments of formula (XIVc), B 4 It is CH2.

[0571] In some embodiments of formulas (XIV), (XIVa), (XIVb), or (XIVc), p6 is 1 or 2. In some embodiments of formulas (XIV), (XIVa), (XIVb), or (XIVc), p6 is 0. In some embodiments of formulas (XIV), (XIVa), (XIVb), or (XIVc), p6 is 1. In some embodiments of formulas (XIV), (XIVa), (XIVb), or (XIVc), p6 is 2.

[0572] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (XIVd) or a pharmaceutically acceptable salt thereof:

[0573] ,

[0574] in:

[0575] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0576] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0577] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0578] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0579] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0580] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0581] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0582] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0583] R 6c For C1-C20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0584] Each R 11 It can be independently a halogen, -CN, -OH, -N3 or C1-C6 haloalkyl;

[0585] p5 is 1, 2, 3, or 4;

[0586] q5 is 0, 1, 2, or 3; and

[0587] x is an integer between 0 and 10.

[0588] In some embodiments of formula (XIVd), p5 is 1 or 2. In some embodiments of formula (XIVd), p5 is 1 and R 11 It is a halogen or a C1-C6 haloalkyl group. In some embodiments of formula (XIVd), p5 is 2 and R 11 It is a halogen or a C1-C6 haloalkyl group. In some embodiments of formula (XIVd), p5 is 1 and R 5 For -F or -CF3.

[0589] On the other hand, this article provides a transcriptional regulatory molecule having the structure of formula (XV) or a pharmaceutically acceptable salt thereof:

[0590] ,

[0591] in:

[0592] W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl;

[0593] B 5 For NR 10c Or O; where

[0594] R 10c It is hydrogen or C1-C3 alkyl;

[0595] R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C50 Heteroalkyl, optionally substituted C2-C 50 Heterene, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace;

[0596] Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ;

[0597] Or two Rs 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl; wherein

[0598] R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ;

[0599] R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl;

[0600] Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein

[0601] R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;

[0602] R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl; and

[0603] q1, q2, q3 and q4 are each independently 0, 1 or 2.

[0604] In some embodiments of formula (XV), B 5 For NR 10c In some embodiments of formula (XV), B 5 For NCH3. In some embodiments of formula (XV), B 5 For -NH-. In some embodiments of formula (XV), B 5 It is -O-.

[0605] In some embodiments of formulas (XIV), (XIVb), (XIVc), or (XV), q1 and q2 are each 0. In some embodiments of formulas (XIV), (XIVb), (XIVc), or (XV), q1 and q2 are each 1. In some embodiments of formulas (XIV), (XIVb), (XIVc), or (XV), q1 is 1 and q2 is 0.

[0606] In some embodiments of formula (XIVa) or (XV), q3 and q4 are both 0. In some embodiments of formula (XIVa) or (XV), q3 and q4 are both 1. In some embodiments of formula (XIVa) or (XV), q3 is 1 and q4 is 0.

[0607] In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 1-10. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 1-8. In some embodiments of formula (V), x is 1-6. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 1, 2, 3, 4, or 5. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 1, 2, 3, or 4. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 0. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 1. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 2. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 3. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 4. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 5. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 6. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 7.In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 8. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 9. In some embodiments of formulas (V), (VII), (VIIIb), (VIIIc), (VIIId), (XI), (XIII), (XIVb), (XIVc), or (XIVd), x is 10.

[0608] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-20 Each of them may choose to pass through one or more R 6 replace.

[0609] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R2h Independently, it is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocyclic alkyl, wherein the cycloalkyl or heterocyclic alkyl is monocyclic, bridged, or spirocyclic cycloalkyl or heterocyclic alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently, it is an optionally substituted C3-C8 cycloalkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each independently , , or .

[0610] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each independently represents the optionally substituted C1-C 20 Alkyl, C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Halogenated or optionally substituted PEG 1-20 Each of them may choose to pass through one or more R 6 Replacement. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each independently for PEG 1-20 In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2hEach independently represents the optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Halogenated alkyl groups; each optionally derived from one or more R 6 Replacement. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each independently serves as an optional route via one or more R 6 Replacement C1-C 20 Alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each independently is C1-C 20 Alkyl haloide. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2hEach is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclohexyl, -CF3, or -CH2CF3. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently methyl, ethyl, propyl, hexyl, cyclohexyl, -CF3, or -CH2CF3. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently methyl, ethyl, propyl, cyclohexyl, or -CH2CF3. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2hEach is a methyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is propyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is a cyclohexyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is -CH2CF3.

[0611] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g Or R 2h At least one of them is not an unsubstituted C1-C 20 Alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 2a R 2b R 2c R 2d R 2e R 2g Or R 2h At least one of them is not methyl.

[0612] In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C3-C6 cycloalkyl groups, or optionally substituted PEGs 1-20 Each of them may choose to pass through one or more R 6 Replacement. In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e and R 2h Each independently represents the optionally substituted C1-C 20Alkyl or optionally substituted C1-C 20 Halogenated alkyl groups; each optionally derived from one or more R 6 Replacement. In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e and R 2h Each independently serves as an optional route via one or more R 6 Replacement C1-C 20 Alkyl group. In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e and R 2h Each is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclohexyl, -CF3, or -CH2CF3. In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e and R 2h Each is independently methyl, ethyl, propyl, cyclohexyl, or -CH2CF3. In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e and R 2h Each is independently methyl, ethyl, propyl, or -CH2CF3. In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e and R 2h Each is a methyl group. In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e and R 2h Each is propyl. In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e and R 2h Each is -CH2CF3. In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e and R 2h Each is a cyclohexanediol.

[0613] In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e Or R 2h At least one of them is not an unsubstituted C1-C 20 Alkyl group. In some embodiments of formula (IV) or (IVa), R 2a R 2c R 2d R 2e Or R 2h At least one of them is not methyl.

[0614] In some embodiments of formula (A-1), (A-2) or (A-3), R 2f Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-20 Each of them may choose to pass through one or more R 6 Replacement. In some embodiments of formula (A-1), (A-2) or (A-3), R 2f It is optionally a substituted C3-C8 cycloalkyl or optionally a substituted 3- to 8-membered heterocyclic alkyl, wherein the cycloalkyl or heterocyclic alkyl is monocyclic, bridged, or spirocyclic cycloalkyl or heterocyclic alkyl. In some embodiments of formula (A-1), (A-2), or (A-3), R 2f It is optionally a substituted C3-C8 cycloalkyl group. In some embodiments of formula (A-1), (A-2), or (A-3), R 2f for , , or In some embodiments of formula (A-1), (A-2), or (A-3), R 2h C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Halogenated alkyl groups; each optionally derived from one or more R 6 Replacement. In some embodiments of formula (A-1), (A-2) or (A-3), R 2h For optional access via one or more R 6 Replacement C1-C 20 Alkyl group. In some embodiments of formula (A-1), (A-2), or (A-3), R 2fEach is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclohexyl, -CF3, or -CH2CF3. In some embodiments of formula (A-1), (A-2), or (A-3), R 2f It is methyl, ethyl, propyl, or -CH2CF3. In some embodiments of formula (A-1), (A-2), or (A-3), R 2f It is methyl. In some embodiments of formula (A-1), (A-2), or (A-3), R 2f Each is propyl. In some embodiments of formula (A-1), (A-2), or (A-3), R 2f Each is a cyclohexyl group. In some embodiments of formula (A-1), (A-2), or (A-3), R 2f It is -CH2CF3.

[0615] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), each R 3a Independently hydrogen, -NR 3c R 3d or -NHC(O)R 3e In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), each R 3a Independently hydrogen or -NHC(O)R 3e In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), each R 3a It is hydrogen.

[0616] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 3b Independently hydrogen, -NR 3c R 3d or -NHC(O)R 3eIn some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), each R 3b Independently hydrogen or -NHC(O)R 3e In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), each R 3b It is hydrogen.

[0617] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), the two R 3a Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), the two R... 3a Together with the carbon atom it is attached to, it forms a C3-C6 cycloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), the two R atoms form a C3-C6 cycloalkyl group. 3a Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), the two R groups... 3a Together with the carbon atom to which it is attached, it forms a cyclopropyl or cyclobutyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), the two R groups... 3a Together with the carbon atom it is attached to, it forms a cyclopropyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), the two R groups... 3a Together with the carbon atom it is attached to, it forms a cyclobutyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), the two R... 3aTogether with the carbon atom it is attached to, it forms a 4- to 6-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), the two R... 3a Together with the carbon atom it is attached to, it forms a 4-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), the two R... 3a Together with the carbon atom it is attached to, it forms a 5-membered heterocyclic alkyl group.

[0618] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), the two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocyclic alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), the two R 3b Together with the carbon atom it is attached to, it forms a C3-C6 cycloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), the two R 3b Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), the two R groups...3b Together with the carbon atom to which it is attached, it forms a cyclopropyl or cyclobutyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), the two R groups... 3b Together with the carbon atom to which it is attached, it forms a cyclopropyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), the two R groups... 3b Together with the carbon atom it is attached to, it forms a cyclobutyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), the two R... 3b Together with the carbon atom to which it is attached, it forms a 4- to 6-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), the two R 3bTogether with the carbon atom it is attached to, it forms a 4-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), the two R 3b Together with the carbon atom it is attached to, it forms a 5-membered heterocyclic alkyl group.

[0619] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), an R 3a And an R 3b Together with the atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocyclic alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), an R 3a And an R 3b Together with the atoms to which it is attached, it forms a C3-C6 cycloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), an R 3a And an R 3b Together with the atoms to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), an R 3a And an R 3b Together with the atoms to which it is attached, it forms a cyclopropyl or cyclobutyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), an R 3a And an R 3b Together with the atoms it is attached to, it forms a cyclopropyl group. In some embodiments of formula (A-2), (A-3), (I), (II), or (X), an R 3a And an R 3b Together with the atoms to which it is attached, it forms a 4- to 6-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), an R 3a And an R 3b Together with the atoms it is attached to, it forms a 4-membered heterocyclic alkyl group. In some embodiments of formula (A-2), (A-3), (I), (II), or (X), an R 3a And an R 3bTogether with the atoms it is attached to, it forms a 5-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), or (X), an R 3a And an R 3b Together with the atoms they are attached to, they form a 6-membered heterocyclic alkyl group.

[0620] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), Z is absent, is -C(O)-, or is -C(=NH)-. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), Z is absent or is -C(O)-. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), Z is absent. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), Z is -C(O)-. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X) or (XI), Z is -C(=NH)-.

[0621] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is C1-C 20 Alkylene or C2-C 20 Heteroalkylene. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa) or (X), L is C1-C 20 Alkylene. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa) or (X), L is C1-C 10Alkylene. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is a C1-C8 alkylene. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is a C1-C6 alkylene. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is a C1-C4 alkylene. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is a C1-C3 alkylene. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is a C1-C2 alkylene group. 20 Heteroalkyl. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa) or (VI), L is C2-C. 10 Heteroalkylene. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is a C2-C8 heteroalkylene. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is a C2-C6 heteroalkylene. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is a C2-C4 heteroalkylene. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), the heteroalkylene is polyethylene glycol. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is -(CH2CH2-O). y1- where y1 is an integer in the range of 1-10. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), the heteroalkylene group comprises -(CH2). x3 N(R a (CH2) x4 -, where R a The x3 and x4 are hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 haloalkyl; and each x3 and x4 is independently an integer in the range of 1-6. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), or (X), L is absent.

[0622] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocyclic alkyl or -NR 4a R 4b ;in

[0623] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0624] R 4b Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or

[0625] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0626] Each R 5 Independent of halogen, -CN, -OH, -OR 5a-N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c replace,

[0627] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0628] Each R 5c It is independently a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl.

[0629] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 C1-C8 alkyl or -NR 4a R 4b ;in

[0630] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0631] R 4b Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 Replace; or

[0632] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0633] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5bOptionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c replace,

[0634] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0635] Each R 5c It is independently a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl.

[0636] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 C1-C8 alkyl or -NR 4a R 4b ;in

[0637] R 4a Hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace;

[0638] R 4b C1-C is optionally substituted 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 Replace; or

[0639] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace;

[0640] Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5bOptionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c replace,

[0641] R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and

[0642] Each R 5c It is independently a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl.

[0643] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl or 4- to 12-membered heterocyclic alkyl groups. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 For C3-C 10 Cycloalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 It is a 4- to 12-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is monocyclic, bicyclic, bridged, or spirocyclic heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 For C3-C 10 Cycloalkyl, wherein the cycloalkyl group is monocyclic, bicyclic, bridged, or spirocyclic. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 It is a C1-C8 alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4It is a C1-C6 alkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 It is a C1-C4 alkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 It is methyl, ethyl, propyl, or butyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 It is methyl. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X) or (XI), R 4 It is ethyl. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X) or (XI), R 4 It is phenyl. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X) or (XI), R 4 It is butyl.

[0644] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4 For -NR 4a R 4b .

[0645] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa) or (X), R 4 For -OR 4b .

[0646] In some embodiments

[0647] Or (XI), q8 and q9 are each 0. In some embodiments of equations (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X) or (XI), q8 and q9 are each 1. In some embodiments of equations (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X) or (XI), q8 is 0 and q9 is 1.

[0648] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), B 1 For -CR 8a R 8a -、-O- or -NR 8b - In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), B 1 It is -S-, -S(O)-, or -S(O)2-. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), B 1 For -CR 8a R 8a - In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), B 1 For -O-. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), B 1 For -NR 8b - In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), B 1 For -NH-. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), B 1For -NCH3-. Formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a Hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 Replacement. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a C1-C is optionally substituted 10 Alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a It is optionally a substituted C1-C8 alkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VII), (X), or (XI), R 4a It is optionally a substituted C1-C6 alkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a C1-C is optionally substituted 10 Heteroalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a R is optionally substituted C1-C8 heteroalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4aIt is an optionally substituted C1-C6 heteroalkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a It is hydrogen.

[0649] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b C1-C is optionally substituted 20 Alkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replacement. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b C1-C is optionally substituted 10 Alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b It is optionally a substituted C1-C8 alkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b It is optionally a substituted C1-C6 alkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b C1-C is optionally substituted 10Heteroalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b It is an optionally substituted C1-C8 heteroalkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (X), or (XI), R 4b It is an optionally substituted C1-C6 heteroalkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b C1-C is optionally substituted 10 Alkyl haloide. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b It is an optionally substituted C1-C8 haloalkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b It is an optionally substituted C1-C6 haloalkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b It is hydrogen.

[0650] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b C3-C is optionally substituted 10 Cycloalkyl or optionally substituted 4- to 12-membered heterocyclic alkyl groups.

[0651] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VII), (X), or (XI), R 4b C3-C is optionally substituted 10Cycloalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b It is optionally a substituted C3-C8 cycloalkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b The substituted cyclopropyl group is optionally substituted, the substituted cyclobutyl group is optionally substituted, the substituted cyclopentyl group is optionally substituted, or the substituted cyclohexyl group is optionally substituted. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b Optionally substituted cyclopropyl. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b Optionally substituted cyclobutyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (X), or (XI), (R) 4b Optionally substituted cyclopentyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b It is an optionally substituted cyclohexyl group.

[0652] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b R is optionally substituted 4- to 12-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b R is optionally substituted 4- to 10-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4bIt is optionally a substituted 4- to 6-membered heterocyclic alkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b R is optionally substituted piperidine, optionally substituted piperazine, or optionally substituted morpholine. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (X), or (XI), R 4b R is optionally substituted piperidine. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b The piperazine is optionally substituted. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4b It is a morpholine that is optionally substituted.

[0653] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; and R 4b C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IVa), (IVa), (V), (X), or (XI), R 4a For C1-C 20 Alkyl; and R 4b For C1-C 20 Alkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VII), (X), or (XI), R 4a It is methyl and R 4bIt is methyl. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X) or (XI), R 4a It is hydrogen and R 4b It is hydrogen.

[0654] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 Substitution, wherein the heterocyclic alkyl group is monocyclic, bicyclic, bridged, or spirocyclic. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 6- to 12-membered monocyclic, bridged, or spirocyclic heterocyclic alkyl groups. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 10-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 Replacement. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (IX) or (X), R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 6-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 Replacement. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted piperidine, optionally substituted piperazine, or optionally substituted morpholine. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a and R4b Together with the nitrogen to which it is attached, it forms an optionally substituted piperidine. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted piperazine. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted morpholine.

[0655] In some embodiments of equations (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replacement. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5 Independent of halogen, -OH, -OR 5a -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5 Independently, it is an optionally substituted C2-C6 alkenyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R5 Independently, it is an optionally substituted C2-C6 ynyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5 Independently halogenated. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5 Independently, it is an optionally substituted C3-C8 cycloalkyl, an optionally substituted 4- to 8-membered heterocycloalkyl, or an optionally substituted phenyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5 Independently, it is a C3-C8 cycloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5 Independently, it is an optionally substituted 4- to 8-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5 Independently, it is an optionally substituted phenyl group.

[0656] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 5a and R 5b Each independently is C1-C 20 Alkyl or PEG 1-20 In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 5a and R 5bEach independently is C1-C 10 Alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), (R) 5a and R 5b Each independently for PEG 1-10 In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 5a and R 5b Each is hydrogen independently.

[0657] In some embodiments of equations (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5c Independently, it is a C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl, or phenyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5c Independently, it is a C3-C8 cycloalkyl or a 4- to 8-membered heterocyclic alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5c Independently, it is a C3-C8 cycloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VII), (X), or (XI), each R 5c Independently, it is a 4- to 8-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), each R 5c It is independently phenyl.

[0658] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI),

[0659] -NR 4a R 4b for ,

[0660] in:

[0661] q8 and q9 are each independently 0, 1, or 2;

[0662] p4 is 0-4;

[0663] B 1 For -CR 8a R 8a -、-O-、-NR 8b -、-S-、-S(O)- or -S(O)2-; or B 1 for ,in

[0664] L 2 It does not exist; it is a C1-C4 alkylene group, a C2-C4 alkenylene group, a C2-C4 ynylene group, or a phenylene group.

[0665] Ring B is absent; it is a C3-C6 cycloalkyl, a 4- to 6-membered heterocyclic alkyl, a phenyl, or a 5- to 10-membered heteroaryl.

[0666] R 8a Hydrogen, halogen, -OH, -NH2, -N(CH3)2, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Halogenated or optionally substituted C1-C 10 Heteroalkyl; or

[0667] Two Rs 8a Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C6 cycloalkyl or an optionally substituted 4- to 6-membered heterocycloalkyl;

[0668] R 8b Hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl, -C(O)OR 8c or -C(O)R 8c ;or

[0669] R 8c It is hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 haloalkyl;

[0670] R 9a or R 9b Each of these elements is independently a halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, or a 4- to 6-membered heterocyclic alkyl; and

[0671] p3 is 0, 1, or 2.

[0672] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI),

[0673] -NR 4a R 4b for ,

[0674] in:

[0675] q8 and q9 are each independently 0 or 1;

[0676] p4 is 0-4;

[0677] B 1 For -CR 8a R 8a -、-O-、-NR 8b -; or B 1 for ,in

[0678] L 2 It either does not exist or is a C2-C4 alkyne group;

[0679] Ring B is absent; it is a C3-C6 cycloalkyl, a 4- to 6-membered heterocyclic alkyl, a phenyl, or a 6-membered heteroaryl.

[0680] R 8a Hydrogen, halogen, or optionally substituted C1-C 10 Alkyl or optionally substituted C1-C 10 Halogenated groups;

[0681] Two Rs 8a Together with the carbon atom to which it is attached, it forms optionally substituted 4- to 6-membered heterocyclic alkyl groups;

[0682] R 8b Hydrogen, optionally substituted C1-C 10 Alkyl or optionally substituted C1-C 10 Halogenated groups;

[0683] R 8c It is hydrogen or optionally substituted C1-C6 alkyl;

[0684] R 9a or R 9b Each of them is independently a halogen, -OH, C1-C3 alkyl, or C1-C3 haloalkyl; and

[0685] p3 is either 0 or 1.

[0686] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), and (X),

[0687] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), B 1 for .

[0688] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), ring B is absent, or is a C3-C6 cycloalkyl, a 4- to 6-membered heterocyclic alkyl, a phenyl, or a 5- to 6-membered heteroaryl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), ring B is a C3-C6 cycloalkyl or a 4- to 6-membered heterocyclic alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), ring B is a phenyl or a 6-membered heteroaryl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), ring B is phenyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), ring B is absent.

[0689] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), L 2 It is absent or is a C2-C4 acetylenic group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), L 2 It is a C2-C4 ynylene group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), L 2It is a C2-acetylenic group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), L 2 It is a phenylene oxide. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), L 2 It does not exist.

[0690] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8a Hydrogen, halogen, -OH, or optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 Alkyl haloide. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8a Hydrogen, halogen, -OH, or optionally substituted C1-C 10 Alkyl or optionally substituted C1-C 10 Alkyl haloide. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8a It is a halogen. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8a C1-C is optionally substituted 10 Alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8a C1-C is optionally substituted 10 Heteroalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8a C1-C is optionally substituted 10Alkyl haloide. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8a It is hydrogen.

[0691] In some embodiments of equations (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), the two R 8a Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C6 cycloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), the two R groups... 8a Together with the carbon atom to which it is attached, it forms optionally substituted 4- to 6-membered heterocyclic alkyl groups.

[0692] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8b C1-C is optionally substituted 10 Alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8b C1-C is optionally substituted 10 Heteroalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8b C1-C is optionally substituted 10 Alkyl haloide. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8b -C(O)OR 8c or -C(O)R 8c In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8b It is hydrogen.

[0693] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8c It is optionally a substituted C1-C6 alkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8c It is an optionally substituted C1-C6 haloalkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 8c It is hydrogen.

[0694] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 9a Or R 9b Each of these is independently a halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 9a Or R 9b Each of these is independently a halogen, -OH, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 9a Or R 9b Each of them is independently a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 9a Or R 9b Each of them is independently a C3-C6 cycloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 9a Or R 9bEach of them is independently a 4- to 6-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 9a Or R 9b Each of these is independently a halogen, -OH, -CH3, or -CF3. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), R 9a Or R 9b Each of them is independently either -F or -CF3.

[0695] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p3 is 0. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p3 is 1. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p3 is 2.

[0696] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p4 is 0-4. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p4 is 0-3. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p4 is 1 or 2. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p4 is 0. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p4 is 1. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p4 is 2. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p4 is 3. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), p4 is 4.

[0697] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), for , , , , , , , , , , , , , , , , , , , , , , , or .

[0698] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), for , , , , , , , , , , , , , or .

[0699] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (X), or (XI), for , , , , , , , or .

[0700] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 6 Independently -CN, -OH, -OR 6a -NHC(O)OR 6a -OC(O)NR 6a R 6b -N3, -NR 6a R 6b-CO(O)R 6c -C(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 6 Independent of -CN, OH, OR 6a ,NHC(O)OR 6a OC(O)NR 6a R 6b -N3, -NR 6a R 6b -CO(O)R 6c -C(O)OR 6c -C(O)NR 6a R 6b or -NHC(O)R 6c In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 6 Independently -N3, -NR 6a R 6b -CO(O)R 6c -C(O)OR 6c -C(O)NR 6a R 6b or -NHC(O)R 6cIn some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 6 Independently for -NR 6a R 6b -C(O)NR 6a R 6b or -NHC(O)R 6c In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 6 Independently for -NR 6a R 6b In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 6 Independently -C(O)NR 6a R 6b In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 6 Independently -NHC(O)R 6cIn some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 6 Independently -NHC(O)R 6c , where R 6c PEG 1-20 In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 6 Independently, it is a C3-C6 cycloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), each R 6 Independently -CN, -OH, -OCH3, -N3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), each R 6 It can be -OH, -NH2, -NHCH3 or -N(CH3)2 independently.

[0701] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), R 6a and R 6b Each independently is C1-C 20 Alkyl or PEG 1-20 In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), R 6a and R 6b Each independently is C1-C 10 Alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 6a and R 6b Each independently for PEG 1-10In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), R 6a and R 6b Each is independently hydrogen.

[0702] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl, or phenyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 6c For C1-C 20 Alkyl or PEG 1-20 In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), R 6c For C1-C 10Alkyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 6c PEG 1-10 In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), R 6c It is a C3-C8 cycloalkyl, a 4- to 8-membered heterocyclic alkyl, or a phenyl. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 6c It is a C3-C8 cycloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 6cIt is a 4- to 8-membered heterocyclic alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), R 6c It is a phenyl group.

[0703] In some embodiments of formula (A-1) or (A-2), each R 7 Independently hydrogen, halogen, -OH, or C1-C3 alkyl. In some embodiments of formula (A-1) or (A-2), each R 7 Independently hydrogen, halogen, or -OH. In some embodiments of formula (A-1) or (A-2), each R 7 Independently halogenated. In some embodiments of formula (A-1) or (A-2), each R 7 Independently -OH. In some embodiments of formula (A-1) or (A-2), each R 7 It is hydrogen independently.

[0704] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd), or (XV), W 1 -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl. In some embodiments, each R 1e Independently hydrogen. In some embodiments, each R 1e Independently, it is a C1-C3 alkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), W1 -N = C(N(CH3)2)2. In some embodiments of equations (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), W 1 -N = C(NH2)2. In some embodiments of equations (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), W 1 It is a C1-C3 haloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (III), (IIIa), (IV), (IVa), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), (X), (XI), (XII), (XIII), (XIV), (XIVa), (XIVb), (XIVc), (XIVd) or (XV), W 1 It is hydrogen.

[0705] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (V), (X), or (XI), W 1a For hydrogen, -N=C(N(R) 1e )2)2 or C1-C3 haloalkyl. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (V), (X) or (XI), W 1a It is hydrogen or a C1-C3 haloalkyl group. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (V), (X), or (XI), W 1a It is a C1-C3 haloalkyl group. In some embodiments of formula (A-1), (A-2), (A-3), (I), (II), (V), (X), or (XI), W 1a -N=C(N(R) 1e)2)2. In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (V), (X), or (XI), W 1a It is hydrogen.

[0706] In some embodiments of formulas (A-1), (A-2), (A-3), (I), (II), (V), (X), or (XI), W 1 It is hydrogen and W 1a -CF3. In some embodiments of equations (A-1), (A-2), (A-3), (I), (II), (V), (X), or (XI), W 1 It is hydrogen and W 1a It is hydrogen.

[0707] In some embodiments, non-limiting examples of the transcriptional regulatory compounds described herein are presented in Table 1.

[0708] Table 1.

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760] How to use

[0761] This disclosure also relates to a method for regulating the transcription of dmpk, atxn8, atxn80s, or tcf4, the method comprising the step of contacting dmpk, atxn8, atxn80s, or tcf4 with a transcriptional regulatory molecule as described herein or a pharmaceutically acceptable salt thereof.

[0762] This method can monitor cellular phenotype, cell proliferation, and transcription of dmpk, atxn8, atxn80s, or tcf4; mRNA production transcribed from dmpk, atxn8, atxn80s, or tcf4; translation of dmpk, atxn8, atxn80s, or tcf4; changes in biochemical outputs of proteins encoded by dmpk, atxn8, atxn80s, or tcf4; or non-covalent binding of proteins encoded by dmpk, atxn8, atxn80s, or tcf4 to their natural binding partners. Such methods can be used for disease treatment, bioassays, cell assays, and biochemical assays.

[0763] In some embodiments, the gene is dmpk. In some embodiments, the gene is atxn8. In some embodiments, the gene is atxn80s. In some embodiments, the gene is tcf4.

[0764] This article also provides a method for inhibiting the transcription of the tcf4 gene, which has a nucleotide repeat sequence containing CAG, using a transcriptional regulatory molecule as described herein or a pharmaceutically acceptable salt thereof.

[0765] This article also provides a method for treating diseases mediated by transcription of dmpk, atxn8, atxn80s, or tcf4, comprising administering to a subject in need a therapeutically effective amount of a transcriptional regulatory molecule as disclosed herein or a salt thereof.

[0766] In some embodiments, the treatment methods reduce the formation of hairpin mRNAs. In some embodiments, the methods described herein reduce the formation of nuclear lesions. In some embodiments, the methods described herein reduce the isolation of myoblin-like (MBNL) protein, which in some cases leads to defective RNA splicing or spliceopathies.

[0767] In some cases, defective RNA splicing or spliceopathies can lead to dysfunction and loss of corneal endothelial cells (CECs). In some cases, administration of a composition containing a transcriptional regulatory molecule as described herein or a pharmaceutically acceptable salt thereof can restore CEC function and / or maintain the number of CECs in the cornea.

[0768] In some embodiments, the disease is selected from DM1 and FECD.

[0769] In some embodiments, the disease is DM1.

[0770] In some embodiments, the disease is Fauci's corneal endothelial dystrophy (FECD).

[0771] The binding affinity between transcriptional regulatory molecules and target genes can be modulated based on the molecular composition. In some embodiments, the molecules are capable of binding DNA with an affinity of less than about 1 μM, about 900 nM, about 800 nM, about 700 nM, about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, or about 1 nM. In some embodiments, the molecules are capable of binding DNA with an affinity in the range of about 0.1 nM–1 μM, 1–600 nM, 10–500 nM, 20–500 nM, 50–400 nM, or 100–300 nM.

[0772] In some embodiments, the molecule is capable of binding to DNA with an affinity of less than 500 nM. In some embodiments, the molecule is capable of binding to DNA with an affinity of less than about 300 nM. In some embodiments, the molecule is capable of binding to DNA with an affinity of less than about 200 nM.

[0773] The binding affinity between the molecule and the target DNA can be determined using a quantitative footprint titration assay. This assay involves measuring the dissociation constant K of the molecule to the target sequence at 24°C or 37°C using standard assay solution conditions or approximate intracellular solution conditions.d .

[0774] On the other hand, this article provides a method for treating type 1 myotonic dystrophy (DM1) in a subject in need, the method comprising administering to the subject an effective amount of the molecule disclosed herein or a pharmaceutically acceptable salt thereof.

[0775] On the other hand, this article provides a method for treating Fauci's endothelial dystrophy or Fauci's corneal endothelial dystrophy (FECD) in a subject of need, the method comprising administering to the subject an effective amount of the molecule disclosed herein or a pharmaceutically acceptable salt thereof.

[0776] Pharmaceutical composition and administration

[0777] The compounds described herein are administered to subjects in need, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in accordance with standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0778] On the other hand, this document provides pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts 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, 17th edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0779] 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, humectants, defoamers, antioxidants, preservatives, and any combination thereof.

[0780] 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, as well as other factors that are 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 to treat 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. The optimal dosage of the agent may generally be determined using experimental models and / or clinical trials. The 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 preventative 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, for example, 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.

[0781] Abbreviations and Definitions

[0782] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0783] 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.

[0784] 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.”

[0785] 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, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. 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. For instance, the range “1 to 3 µM (micromoles)” (which is intended to include all values ​​between 1 µM and 3 µM) is equivalent to any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

[0786] Unless otherwise indicated, the following terms have the following meanings as used herein:

[0787] "O" refers to =O.

[0788] The "carboxyl group" refers to -COOH.

[0789] "Cyano" refers to -CN.

[0790] "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 and octyl. Whenever the term "C1-C6 alkyl" or "C1-6 alkyl" appears herein, the numerical range means 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. 10 Alkyl 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 groups such as oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group may optionally be substituted with oxo, 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 halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group may optionally be substituted with halogen.

[0791] "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, etc. Whenever it appears herein, for example, the numerical range of "C2-C6 alkenyl" or "C2-6 alkenyl" means 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 specified in this specification, the alkenyl group may optionally be substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group may optionally be substituted with an oxo, 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.

[0792] "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, etc. Whenever it appears herein, for example, the numerical range of "C2-C6 alkynyl" or "C2-6 alkynyl" means 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 groups such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. 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.

[0793] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specified in this specification, alkylene may optionally be substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. 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.

[0794] "Alkoxy" refers to an alkoxy group with the formula -OR a The group, wherein R a Alkyl groups are defined alkyl groups. Unless otherwise specified in this specification, alkoxy groups may optionally be substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted with halogen, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

[0795] "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 ring 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 through 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 specified in this specification, aryl groups may optionally be substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl groups are optionally substituted with halogen, methyl, ethyl, -N3, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl 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.

[0796] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded by non-aromatic ring atoms), helical, or bridged ring systems. In some embodiments, the cycloalkyl 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 specified in this specification, cycloalkyl groups may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. 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.

[0797] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused or bridging 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.

[0798] "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.

[0799] 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, etc. 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.

[0800] "Fluoroalkyl" refers to an alkyl group as defined above that has been substituted with one or more fluorine groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc.

[0801] "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.

[0802] "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.

[0803] "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 specified in this specification, heteroalkyl groups are optionally substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl. 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.

[0804] "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the 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 specified 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) 10 Fully saturated heterocyclic alkyl or C2-C10Heterocyclic 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, azirropropyl, azirrobutyl, oxacyclobutyl, dioxopentyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidylalkyl, oxazolylalkyl, piperidinyl, piperazine, 4-piperidinoneyl, and pyrrolidine. 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 group has 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is not the same as the total number of atoms constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring), including heteroatoms. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group of 3 to 8 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group of 3 to 7 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group of 3 to 6 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group of 4 to 6 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group of 5 to 6 members. 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 groups such as oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc., 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.

[0805] "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, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three nitrogen atoms. In some embodiments, the heteroaryl comprises one or two nitrogen atoms. In some embodiments, the heteroaryl comprises one nitrogen atom. The heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl is bonded through aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azirrolyl, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxane, benzonaphthuryl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenylyl, dibenzofuranyl, dibenzothienyl, furanyl Furanone, isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, indolinyl, isoindolinyl, isoquinolinyl, indoleazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazapyrrolyl, oxazolyl, epoxyethyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridineyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. (i.e., thienyl). Unless otherwise specified in this specification, heteroaryl groups may optionally be substituted with groups such as halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.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.

[0806] The term "transcription," well-known in the art, refers to the synthesis of RNA (i.e., ribonucleic acid) by DNA-directed RNA polymerase. The term "regulation of transcription" refers to changes in the amount of transcription, which can be measured by methods well-known in the art (e.g., determination of the transcription product mRNA). In some embodiments, regulation is an increase in transcription. In other embodiments, regulation is a decrease in transcription.

[0807] The term "polyamide" refers to a polymer of linkable units chemically bonded by amide (i.e., CONH) bonds; optionally, polyamides include chemical probes 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.

[0808] The term "connector" or "oligomeric backbone" refers to a chain having at least 10 consecutive atoms. In some embodiments, the connector contains no more than 20 non-hydrogen atoms. The terms connector and oligomeric backbone are used interchangeably. In some embodiments, the connector contains no more than 40 non-hydrogen atoms. In some embodiments, the connector contains no more than 60 non-hydrogen atoms. In some embodiments, the connector 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 connector, or to one adjacent atom in the connector and the end of the connector. In some embodiments, the connector forms an amide bond with at least one of the two other groups to which it is attached. In some embodiments, the connector 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 connector 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 connector forms a direct carbon-carbon bond with at least one of the two other groups to which it is attached. In some embodiments, the connector 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 connector comprises a -(CH2OCH2)- unit. In some embodiments, the connector comprises -(CH(CH3)OCH2)- units. In some embodiments, the connector comprises -(CH2NR) units. N CH2) unit, where R N = C 1-4 Alkyl group. In some embodiments, the connector comprises an arylene, cycloalkyl, or heteroalkylene moiety.

[0809] 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.

[0810] 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 with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclo-C1-C6 alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1- C6 haloalkoxy substitution), 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). -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 acid, isocyanate, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," the group may be substituted with the above substituents.

[0811] The term "one or more" when referring to optionally present 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.

[0812] 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.

[0813] In some embodiments, the compounds disclosed herein are in different isotopically concentrated forms (e.g., 2 H, 3 H, 11 C 13 C and / or 14 (C-concentration) is used. In one particular embodiment, the compound is deuterated at at least one site. 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.

[0814] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention, but with hydrogen replaced by deuterium or tritium, or carbon replaced by... 13 C or 14 C-concentrated carbon-substituted compounds are within the scope of this disclosure.

[0815] 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. Covers the tags. 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 I. Isotopic substitution. 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.

[0816] 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.

[0817] Deuterium-substituted compounds were synthesized using various methods described, for example, in the following literature: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0818] Deuterated starting materials are readily available and can be synthesized using the methods described herein to achieve the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0819] In some embodiments of the compounds disclosed herein, the percentage of deuterium contained in one or more substituents is 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.

[0820] In some embodiments of the compounds disclosed herein, the deuterium abundance of each substituent is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total amount of hydrogen and deuterium.

[0821] 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, as well as mixtures thereof.

[0822] 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.

[0823] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from various organic and inorganic relative ions well-known in the field. 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, and phosphoric acid. 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, and salicylic acid. 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, and aluminum. Organic bases that can be derivatized include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0824] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are matched with a reasonable benefit / risk ratio.

[0825] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, 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 terms of compatibility with 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; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, (10) Safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (11) diols, such as propylene glycol; (12) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (13) esters, such as ethyl oleate and ethyl laurate; (14) agar; (15) buffers, such as magnesium hydroxide and aluminum hydroxide; (16) alginic acid; (17) pyrogen-free water; (18) isotonic saline; (19) Ringer's solution; (20) ethanol; (21) phosphate buffer solution; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0826] "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.

[0827] 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.

[0828] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock (e.g., cattle, goats, sheep, pigs, and rabbits), and companion animals (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0829] The term "contact" refers to bringing a compound (such as a transcriptomic molecule of the present 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.

[0830] Example

[0831] 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, are exemplary, and are not intended to limit the scope of the invention. Variations and other uses will be apparent to those skilled in the art, and are covered within the spirit and scope of the invention as defined by the claims.

[0832] Compound Synthesis

[0833] 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.

[0834] The synthetic chemical transformations and methods applicable to the synthesis of the compounds described herein are known in the art and include, for example, those described in the following literature: 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).

[0835] List of abbreviations

[0836] Ac2O = Acetic anhydride; AcCl = Acetyl chloride; ACN = Acetonitrile; AcOH = Acetic acid; AIBN = Azobisisobutyronitrile; aq. = Aqueous; Bu3SnH = Hydrogenated tributyltin; CD3OD = Deuterated methanol; CDCl3 = Deuterated chloroform; CDI = 1,1'-carbonyldiimidazole; DBU = 1,8-diazabicyclo[5.4.0]undecyl-7-ene; DCM = Dichloromethane; DEAD = Diethyl azodicarbonate; DIBAL-H = Hydrogenated diisobutylaluminum; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO-d6 = Deuterated dimethyl sulfoxide; DMS O = dimethyl sulfoxide; DPPA = diphenylphosphoazide; EDC.HCl = EDCI.HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; EA = ethyl acetate; EtOH = ethanol; h = hours; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylureamonium hexafluorophosphate; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-PrOH = isopropanol; LAH = lithium aluminum hydride; LiHMDS = lithium bis(trimethylsilamide); MeCN = acetonitrile; MeOH = methanol; MP-carbonate resin = macroporous triethylammonium methyl Polystyrene carbonate resin; MsCl = methanesulfonyl chloride; MTBE = methyl tert-butyl ether; MW = microwave irradiation; n-BuLi = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)amidide; NaOMe = sodium methoxide; NaOtBu = sodium tert-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMP = N-methyl-2-pyrrolidone; Pd(Ph3)4 = tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = tris(diphenylmethyleneacetone)dipalladium(0); PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; preparative HPLC = preparative high performance liquid chromatography; PyB op = hexafluorophosphate (benzotriazol-1-yloxy)tripyrrolidinephosphonium; Pyr = pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropyloxybiphenyl; sat. = saturated; ss = saturated solution; t-BuOH = tert-butanol; T3P = propylphosphonic anhydride; TBS = TBDMS = tert-butyldimethylsilyl; TBSCl = TBDMSCl = tert-butyldimethylchlorosilane; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; Tol = toluene; TsCl = toluenesulfonyl chloride; XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0837] Synthetic representative compounds disclosed in this paper

[0838] Example 1. Synthesis of compound A-88

[0839] Process 1.

[0840]

[0841] Step 1. TFA (0.50 mL) was added dropwise to a stirred solution of N-[2-(propylcarbamoyl)ethyl]carbamate (50.00 mg, 0.22 mmol, 1.00 equivalent) in DCM (2.00 mL) at room temperature. The mixture was stirred at room temperature for 1.0 h. The mixture was concentrated under vacuum to give 3-amino-N-propylpropionamide (57.00 mg, crude product) as a yellow oil. LC / MS: C6H 14 Calculated mass of N₂O: 130.11, Experimental value: 131.15 [M+H] + .

[0842] Step 2. To a solution of ethyl 4-nitro-1H-imidazolium-2-carboxylate (9.74 g, 52.61 mmol, 1.00 equivalent) in CH3CN (95.00 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (15.87 g, 68.39 mmol, 1.30 equivalent) and K2CO3 (21.81 g, 157.83 mmol, 3.00 equivalent) were added, and the resulting mixture was stirred at 70 °C for 17.0 h. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with PE / EA = 1:1 elution to give ethyl 4-nitro-1-(2,2,2-trifluoroethyl)imidazolium-2-carboxylate (12.10 g, 79.20%) as a white solid. LC / MS: Calculated mass of C8H8F3N3O4: 267.05, Experimental value: 268.10 [M+H] + .

[0843] Step 3. Pd / C (4.82 g, 40% w / w) was added to a solution of ethyl 4-nitro-1-(2,2,2-trifluoroethyl)imidazolium-2-carboxylate (12.10 g, 45.29 mmol, 1.00 equivalent) in EtOH (50.00 mL) and EA (50.00 mL), and the reaction mixture was stirred at room temperature under a H2 atmosphere for 17.0 h. The reaction mixture was filtered and concentrated to give ethyl 4-amino-1-(2,2,2-trifluoroethyl)imidazolium-2-carboxylate (9.50 g, 79.59%) as a white solid. LC / MS: C8H 10 Calculated mass of F3N3O2: 237.07, Experimental mass: 238.15 [M+H]+ .

[0844] Step 4. Diea (19.75 g, 152.80 mmol, 6.00 equivalent), 3-[(tert-butoxycarbonyl)amino]propionic acid (5.30 g, 28.01 mmol, 1.10 equivalent), and PyBOP (13.25 g, 25.47 mmol, 1.00 equivalent) were added fractionally to a stirred solution of 4-amino-1-(2,2,2-trifluoroethyl)imidazolium-2-carboxylate (6.04 g, 25.47 mmol, 1.10 equivalent) in DMF (45.00 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 1.0 h. The reaction mixture was then poured into ice water (150 mL). The precipitated solid was collected by filtration, washed with H₂O (3 × 50 mL), and dried under vacuum to give ethyl 4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-(2,2,2-trifluoroethyl)imidazolium-2-carboxylate (6.60 g, 57.12%) as a white solid. LC / MS: C 16 H 23 Calculated mass of F3N4O5: 408.16, Experimental mass: 409.25 [M+H] + .

[0845] Step 5. LiOH solution (2 M in H₂O, 45.40 mL, 90.80 mmol, 4.00 equivalent) was added dropwise to a stirred solution of 4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-(2,2,2-trifluoroethyl)imidazolium-2-carboxylate (9.27 g, 22.70 mmol, 1.00 equivalent) in MeOH (70.00 mL), and the reaction mixture was stirred for 2.0 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in H₂O (50 mL). The mixture was acidified to pH 3–5 with 2 M HCl. The precipitated solid was collected by filtration, washed with H₂O (3 × 30 mL), and dried under vacuum. The crude product was purified by reverse-phase column chromatography under the following conditions: column: C18 silica gel; mobile phase: water containing ACN (0.05% TFA), 10% to 50% gradient over 30 min; detector: UV 254 nm. The elution fraction was separated and concentrated to give 4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-(2,2,2-trifluoroethyl)imidazolium-2-carboxylic acid (4.10 g, 37.99%) as a yellow solid. LC / MS: C 14 H 19 Calculated mass of F3N4O5: 380.13, Experimental value: 403.05 [M+Na] + .

[0846] Step 6. DIEA (4.49 g, 34.71 mmol, 6.00 equivalent), methyl 4-amino-1-methylpyrrole-2-carboxylic acid (0.89 g, 5.78 mmol, 1.00 equivalent), and PyBOP (3.01 g, 5.78 mmol, 1.00 equivalent) were added fractionally to a stirred solution of 4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-(2,2,2-trifluoroethyl)imidazolium-2-carboxylic acid (2.20 g, 5.78 mmol, 1.00 equivalent) in DMF (20.00 mL) at 0 °C. The mixture was stirred at room temperature for 1.0 h. The reaction mixture was then poured into ice water (60 mL). The precipitated solid was collected by filtration, washed with H₂O (3 × 50 mL), and dried under vacuum to give methyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino)-1-methylpyrrole-2-carboxylate (1.40 g, 42.17%) as a white solid. LC / MS: C 21 H 27 Calculated mass of F3N6O6: 516.19, Experimental mass: 517.15 [M+H] + .

[0847] Step 7. TFA (2.80 mL) was added dropwise to a stirred solution of methyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino)-1-methylpyrrole-2-carboxylate (1.38 g, 2.67 mmol, 1.00 equivalent) in DCM (14.00 mL), and the resulting mixture was stirred for 1.0 h. The reaction mixture was concentrated under vacuum to give ethyl 4-[4-(3-aminopropionylamino)-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino]-1-methylpyrrole-2-carboxylate (1.10 g crude) as a yellow oil. LC / MS: C 16 H 19 Calculated mass of F3N6O4: 416.14, Experimental mass: 417.10 [M+H] + .

[0848] Step 8. DIEA (1.23 g, 9.51 mmol, 6.00 equivalent), 1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-carboxylic acid (393.50 mg, 1.58 mmol, 1.00 equivalent), and PyBOP (824.92 mg, 1.58 mmol, 1.00 equivalent) were added fractionally to a stirred solution of 4-[4-(3-aminopropionylamino)-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino)pyrrole-2-carboxylic acid (393.50 mg, 1.58 mmol, 1.00 equivalent) in DMF (7.00 mL) at 0 °C. The mixture was stirred at room temperature for 1.0 h. Next, the reaction mixture was poured into ice water (21 mL). The precipitated solid was collected by filtration, washed with H₂O (3 × 50 mL), and dried under vacuum. The crude product was purified by silica gel column chromatography by elution with CH₂Cl₂ / MeOH = 10:1 to give methyl 1-methyl-4-[4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino]pyrrolo-2-carboxylate (1.00 g, 87.81%) as a white solid. LC / MS: C 27 H 29 F3N 10 Calculated mass of O6: 646.22, Experimental mass: 647.40 [M+H] + .

[0849] Step 9. At room temperature, add KOH solution (2 M in H₂O, 6.96 mL, 13.92 mmol, 10.00 equivalent) to a stirred solution of methyl 1-methyl-4-[4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino]pyrrolo-2-carboxylate (900.00 mg, 1.39 mmol, 1.00 equivalent) in MeOH (10.00 mL). Stir the resulting mixture at 45 °C for 2.0 h. Then concentrate the mixture under reduced pressure and dissolve the residue in H₂O (50.00 mL). Acidify the mixture to pH 3–5 with 2 M HCl. The precipitated solid was collected by filtration, washed with H₂O (3 × 30 mL), and dried under vacuum to give 1-methyl-4-[4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]carbamate}propionylamino)-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino]pyrrolo-2-carboxylic acid (800.00 mg, 90.86%) as a white solid. LC / MS: C 26 H 27 F3N 10 Calculated mass of O6: 632.21, Experimental mass: 633.35 [M+H] + .

[0850] Step 10. At 0°C, ethyl 4-[4-(3-{[4-(4-aminobutyrylamino)-1-methylimidazol-2-yl]formylamino}propionylamino)-1-methylpyrrole-2-acylamino]-1-methylimidazol-2-carboxylate (400.00 mg, 0.70 mmol, 1.00 equivalent) was added part-wise to a stirred solution of 4-[4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-yl]formylamino}propionylamino)-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino]pyrrole-2-carboxylic acid (620.80 mg, 0.98 mmol, 1.40 equivalent) and PyBOP were added part-wise to a stirred solution of 4-[4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-yl]formylamino}propionylamino)-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino]pyrrole-2-carboxylic acid (620.80 mg, 0.98 mmol, 1.40 equivalent) and PyBOP. (364.80 mg, 0.70 mmol, 1.00 equivalent). The mixture was stirred at room temperature for 1.0 h. The reactants were then poured into ice water (15 mL). The precipitated solid was collected by filtration, washed with H2O (3 × 5 mL) and dried under vacuum to give ethyl 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino]pyrrolo-2-yl}formylamino]butyrylamino]imidazol-2-yl}formylamino]pyrrolo-2-ylamino}imidazol-2-ac ... LC / MS: C 51 H 59 F3N 20 O 11 Calculated mass: 1184.46, Experimental mass: 593.65 [M / 2+H] + .

[0851] Step 11. At room temperature, ethyl 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino]pyrrolo-2-yl}formylamino]butyrylamino]imidazol-2-yl}formylamino]pyrrolo-2-acylamino}imidazol-2-acylamino}imidazol-2-carboxylate (700.00 mg, 0.59 mmol, 1.00 equivalent) in a stirred solution of MeOH (7.00 mL) was added dropwise to a stirred solution of 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]propionylamino]pyrrolo-2-acylamino}imidazol-2-carboxylate (700.00 mg, 0.59 mmol, 1.00 equivalent) in H₂O (2 M, 1.18 mL, 2.36 mmol, 4.00 equivalent), and the reaction mixture was stirred for 2.0 h. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in H₂O (50 mL) and the mixture was acidified to pH 3–5 with 2 M HCl. The precipitated solid was collected by filtration, washed with H₂O (3 × 30 mL), and dried under vacuum to give 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)-1-(2,2,2-trifluoroethyl)imidazol-2-acylamino]pyrrolo-2-yl}formylamino]butyrylamino]imidazol-2-yl}formylamino)propionylamino]pyrrolo-2-ylamino}imidazol-2-acylamino}imidazol-2-carboxylic acid (700.00 mg, 87.06%) as a white solid. LC / MS: C 49 H 55 F3N 20 O 11 Calculated mass: 1156.43, Experimental mass: 579.65 [M / 2+H] + .

[0852] Step 12. At 0°C, add DIEA (111.70 mg, 0.86 mmol, 1.00 equivalent) and 3-amino-N-propylpropionamide (14.63 mg, 0.11 mmol, 0.09 mmol, 1.00 equivalent) part-by-part to a stirred solution of 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)-1-(2,2,2-trifluoroethyl)imidazololo-2-acylamino]pyrrolo-2-yl}formylamino]butyrylamino]imidazololo-2-yl}formylamino]pyrrolo-2-acylamino}imidazol-2-carboxylic acid (100.00 mg, 0.09 mmol, 1.00 equivalent) in DMF (1.00 mL) in portions. 53.97 mg (1.30 mmol, 1.30 equivalent) and PyBOP (53.97 mg, 0.10 mmol, 1.20 equivalent) were added, and the resulting mixture was stirred at room temperature for 1.0 h. The reaction mixture was poured into ice water (3.00 mL). The precipitated solid was collected by filtration, washed with H2O (3 × 3 mL), and dried under vacuum. The residue was purified by TLC (DCM:MeOH = 10:1) to give 4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formamido}propionylamino)-N-[1-methyl-5-({3-[(1-methyl-2-{[2-({1-methyl-5-[(1-methyl-2-{[2-(propylaminocarbamoyl)ethyl]aminocarbamoyl}imidazol-4-yl)aminocarbamoyl]pyrrolo-3-yl}aminocarbamoyl)ethyl]aminocarbamoyl}imidazol-4-yl)aminocarbamoyl]propyl}aminocarbamoyl)pyrrolo-3-yl]-1-(2,2,2-trifluoroethyl)imidazol-2-carboxamide) The filtrate (2.0 mL) was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 µm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 40% B, 40% B over 16 min; wavelength: 254 nm; RT1 (min): 14.36).The eluent was separated and lyophilized to give 4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formamido}propionamido)-N-[1-methyl-5-({3-[(1-methyl-2-{[2-({1-methyl-5-[(1-methyl-2-{[2-(propylaminocarbamoyl)ethyl]aminocarbamoyl}imidazol-4-yl)aminocarbamoyl]pyrrolo-3-yl}aminocarbamoyl)ethyl]aminocarbamoyl}imidazol-4-yl)aminocarbamoyl]propyl}aminocarbamoyl)pyrrolo-3-yl]-1-(2,2,2-trifluoroethyl)imidazol-2-carboxamide (17.60 mg, 15.67%) as a white solid. LC / MS: C. 55 H 67 F3N 22 O 11 Calculated mass: 1268.5312, Experimental value: 1269.5412 [M+H] + .

[0853] Example 2. Synthesis of compound A-117

[0854] Process 2.

[0855]

[0856] Step 1. At room temperature, β-alanine ethyl ester (2.83 g, 24.17 mmol, 1.00 equivalent), PyBOP (15.09 g, 29.00 mmol, 1.20 equivalent), and DIEA (9.37 g, 72.51 mmol, 3.00 equivalent) were added dropwise to a stirred solution of 1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-carboxylic acid (6.00 g, 24.17 mmol, 1.00 equivalent) in DMF (50.00 mL), and the mixture was stirred for 1.0 h. The resulting mixture was then poured into ice water (150 mL). The precipitated solid was collected by filtration, washed with water (100 mL), and dried to give ethyl 3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formamide}propionate (6.90 g, 82.18%) as a yellow solid. LC / MS: C 16 H 21 Calculated mass of N5O4: 347.16, experimental mass: 348.10 [M+H] + .

[0857] Step 2. To a stirred solution of ethyl 3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formamide}propionate (6.30 g, 18.13 mmol, 1.00 equivalent) in MeOH (100.00 mL) and THF (50.00 mL), LiOH (36.27 mL, 72.54 mmol, 4.00 equivalent, 2 M in H₂O) was added dropwise, and the resulting mixture was stirred at 25 °C for 1.0 h. The mixture was concentrated under vacuum. 100 mL of H₂O was added, and the mixture was adjusted to pH 7-8 with 2 M HCl, followed by concentration under reduced pressure. The residue was dissolved in H₂O (50 mL). The mixture was acidified to pH 3-5 with 2 M HCl. The precipitated solid was collected by filtration, washed with water (3 × 100 mL), and dried under vacuum to give 3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formamide}propionic acid (5.30 g, 91.52%) as a white solid. LC / MS: C 16 H 23 Calculated mass of N3O3: 319.13, experimental mass: 320.10 [M+H] + .

[0858] Step 3. To a stirred solution of ethyl 4-nitro-1H-imidazolium-2-carboxylate (1.00 g, 5.40 mmol, 1.00 equivalent) in ACN (15.00 mL), 4-bromobutyl acetate (1.26 g, 6.48 mmol, 1.20 equivalent) and K₂CO₃ (2.24 g, 16.20 mmol, 3.00 equivalent) were added dropwise, and the resulting mixture was stirred at 70 °C for 16.0 h. The reaction mixture was filtered and concentrated under vacuum. Next, the reaction mixture was poured into ice water (50 mL) and extracted with EA (3 × 50 mL). The combined organic phases were washed with H₂O (50 mL) and NaCl (50 mL), dried over anhydrous Na₂SO₄, and concentrated to give ethyl 1-[4-(acetoxy)butyl]-4-nitroimidazolium-2-carboxylate (1.60 g, 98.98%) as a yellow solid. LC / MS: C 12 H 17 Calculated mass of N3O6: 299.11, Experimental mass: 300.01 [M+H] + .

[0859] Step 4. Pd / C (160.00 mg, 10% w / w) was added dropwise to a stirred solution of 1-[4-(acetoxy)butyl]-4-nitroimidazole-2-carboxylate (1.60 g, 5.35 mmol, 1.00 equivalent) in EA (30.00 mL), and the resulting mixture was stirred at 25 °C under a H2 atmosphere for 16.0 h. The mixture was then filtered and concentrated to give 1-[4-(acetoxy)butyl]-4-aminoimidazole-2-carboxylate (1.30 g, 90.30%) as a yellow solid. LC / MS: C 12 H 19 Calculated mass of N3O4: 269.14, experimental mass: 270.10 [M+H] + .

[0860] Step 5. To a stirred solution of ethyl 1-[4-(acetoxy)butyl]-4-aminoimidazolium-2-carboxylate (100.00 mg, 0.37 mmol, 1.00 equivalent) in DMF (3.00 mL), dropwise add 3-{[1-methyl-4-(1-methylimidazolium-2-acylamino)pyrrolo-2-yl]formamide}propionic acid (118.57 mg, 0.37 mmol, 1.00 equivalent), PyBOP (231.89 mg, 0.45 mmol, 1.20 equivalent), and DIEA (143.98 mg, 1.11 mmol, 3.00 equivalent) and stir the resulting mixture at 25 °C for 1.0 h. Then pour the resulting mixture into ice water (10 mL). The precipitated solid was collected by filtration, washed with water (10 mL), and dried under vacuum to give ethyl 1-[4-(acetoxy)butyl]-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formamide}propionamide)imidazol-2-carboxylate (135.00 mg, 63.71%) as a yellow solid. LC / MS: C 26 H 34 Calculated mass of N8O7: 570.26, Experimental mass: 571.30 [M+H] + .

[0861] Step 6. To a stirred solution of 1-[4-(acetoxy)butyl]-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formamide}propionamide)imidazol-2-carboxylic acid ethyl ester (130.00 mg, 0.23 mmol, 1.00 equivalent) in MeOH (3.00 mL), LiOH (0.46 mL, 0.91 mmol, 4.00 equivalent, 2 M in H2O) was added dropwise, and the resulting mixture was stirred at 25 °C for 4.0 h. Next, 10 mL of H2O was added, and the mixture was adjusted to pH 7-8 with 2 M HCl, and the mixture was concentrated under reduced pressure. The residue was dissolved in H2O (30 mL) and acidified to pH 3-5 with 2 M HCl. The precipitated solid was collected by filtration, washed with H₂O (3 × 20 mL), and dried under vacuum to give 1-(4-hydroxybutyl)-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-carboxylic acid (110.00 mg, 96.46%) as a white solid. LC / MS: C 22 H 28 Calculated mass of N8O6: 500.21, Experimental mass: 501.20 [M+H] + .

[0862] Step 7. To a stirred solution of 1-(4-hydroxybutyl)-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formamide}propionamide)imidazol-2-carboxylic acid (100.00 mg, 0.20 mmol, 1.00 equivalent) in DMF (3.00 mL), methyl 4-amino-1-methylpyrrolo-2-carboxylate (30.80 mg, 0.20 mmol, 1.00 equivalent), PyBOP (124.77 mg, 0.24 mmol, 1.20 equivalent), and DIEA (77.47 mg, 0.60 mmol, 3.00 equivalent) were added dropwise, and the resulting mixture was stirred at 25 °C for 1.0 h. The resulting mixture was then poured into ice water (20 mL). The precipitated solid was collected by filtration, washed with water (3 × 20 mL), and dried under vacuum to give methyl 4-[1-(4-hydroxybutyl)-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]-1-methylpyrrolo-2-carboxylate (120.00 mg, 94.34%) as a yellow solid. LC / MS: C 29 H 36 N 10Calculated mass of O7: 636.28, Experimental mass: 637.25 [M+H] + .

[0863] Step 8. At room temperature, KOH (0.35 mL, 0.69 mmol, 4.00 equivalent, 2 M in H2O) was added dropwise to a stirred solution of methyl 4-[1-(4-hydroxybutyl)-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]-1-methylpyrrolo-2-carboxylate (110.00 mg, 0.17 mmol, 1.00 equivalent) in MeOH (3.00 mL) and THF (1.50 mL), and the resulting mixture was stirred at 70 °C for 4.0 h. The mixture was then adjusted to pH 7-8 with 2 M HCl. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O (20 mL) and acidified to pH 3-5 with 2 M HCl. The precipitated solid was collected by filtration, washed with H₂O (3 × 20 mL), and dried under vacuum to give 4-[1-(4-hydroxybutyl)-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]carbamate}propionylamino)imidazol-2-acylamino]-1-methylpyrrolo-2-carboxylic acid (85.00 mg, 79.01%) as a white solid. LC / MS: C 28 H 34 N 10 Calculated mass of O7: 622.26, Experimental mass: 623.25 [M+H] + .

[0864] Step 9. Add 4-(4-{3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formamide}propionylamino)imidazol-2-acylamino]-1-methylpyrrolo-2-carboxylic acid (75.00 mg, 0.12 mmol, 1.00 equivalent) to a stirred solution of 4-[1-(4-hydroxybutyl)-4-(3-{[1-methyl-4-(1-methylimidazol-2-yl)formamide]propionylamino}-1-methylpyrrolo-2-acylamino)-N-[4-(dimethylamino)butyl]-1-methylimidazol-2-carboxamide (80.32 mg, 0.12 mmol, 1.00 equivalent) and DIEA (46.71 mg ...]-N-[4-(dimethylamino)butyl]-1-methylimidazol-2-carboxamide (80.32 mg, 0.12 mmol, 1.00 equivalent) to a stirred solution of 4-[1-(4-hydroxybutyl)-4-(3-{[1-methyl-4-(1-methylimida The reaction mixture was prepared with 75.22 mg (0.36 mmol, 3.00 equivalent) and PyBOP (75.22 mg, 0.14 mmol, 1.20 equivalent) and stirred at room temperature for 1.0 h. The resulting mixture was poured into ice water (10 mL). The precipitated solid was collected by filtration, washed with water (3 × 10 mL), and dried under vacuum. The residue was purified by preparative HPLC: column: YMC-Actus Triart C18 ExRS19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: 20 ​​mm NaOH + 10% ACN; flow rate: 25 mL / min; gradient: 21% B to 46% B over 15 min; wavelength: 254 nm; RT1 (min): 12.33. The eluent was separated and lyophilized to give N-(5-{[(1-{[(2-{[2-({5-[(2-{[4-(dimethylamino)butyl]aminocarbamoyl}-1-methylimidazol-4-yl)aminocarbamoyl]-1-methylpyrrole-3-yl}aminocarbamoyl)ethyl]aminocarbamoyl}-1-methylimidazol-4-yl)aminocarbamoyl]methyl}cyclopropyl)methyl]aminocarbamoyl}-1-methylpyrrole-3-yl)-1-(4-hydroxybutyl)-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-yl]carbamoylamino}propionylamino)imidazol-2-carboxamide (37.20 mg, 23.99%), a white solid. HRMS: C 61 H 81 N 23 O 11 Calculated mass: 1270.6220, Experimental mass: 1271.6332 [M+H] + .

[0865] Example 3. Synthesis of compound A-95

[0866] Step 3.

[0867]

[0868]

[0869] Step 1. Add 4-[3-[(tert-butoxycarbonyl)amino]propionylamino]-1-methylimidazolium-2-carboxylic acid (11.00 g, 35.22 mmol, 1.00 equivalent) and DMF (300.00 mL) to a 1000 mL flask. Cool the mixture to 0 °C, and then add HATU (20.09 g, 52.83 mmol, 1.50 equivalent) and DIEA (18.21 g, 140.88 mmol, 4.00 equivalent) dropwise. Stir the mixture for 10 min, and then add methyl 3-aminopropionate (3.63 g, 35.22 mmol, 1.00 equivalent) fractionally. Stir the reaction mixture at room temperature for 1 h. Then pour the reaction mixture into water / ice (600 mL), filter out the solids, and dry under vacuum. The aqueous phase was extracted with EA (3 × 200 mL), and the combined organic phases were washed with H₂O (1 × 200 mL) and NaCl (1 × 200 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography after elution with pure EA to give methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propionamide]-1-methylimidazol-2-yl)formamide]propionate (13.00 g, 87.95%) as a yellow solid. LC / MS: C 17 H 27 Calculated mass of N5O6: 397.20, Experimental mass: 398.20 [M+H] + .

[0870] Step 2. A solution of methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propionamide]-1-methylimidazol-2-yl)formamide]propionate (11 g, 1.00 equivalent) in HCl / 1,4-dioxane (4 M, 110.00 mL) was stirred at room temperature for 1.0 h. The resulting mixture was concentrated under vacuum to give methyl 3-[[4-(3-aminopropionamide)-1-methylimidazol-2-yl]formamide]propionate hydrochloride (11.00 g crude) as a yellow solid. LC / MS: C 12 H 19 Calculated mass of N5O4: 297.14, experimental mass: 298.20 [M+H] + .

[0871] Step 3. TBTU (38.19 g, 118.94 mmol, 1.50 equivalent), methyl 4-amino-1-methylpyrrole-2-carboxylic acid hydrochloride (16.63 g, 87.24 mmol, 1.10 equivalent), and DIEA (30.74 g, 237.88 mmol, 3.00 equivalent) were added fractionally to a stirred solution of 1-methylimidazolium-2-carboxylic acid (10.00 g, 79.29 mmol, 7.00 equivalent) in DMF (150.00 mL) at 0 °C, and the mixture was stirred at room temperature for 17.0 h. The reaction mixture was then poured into water / ice (450 mL). The precipitated solid was collected by filtration, washed with H₂O (3 × 50 mL), and dried under vacuum to give ethyl 1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-carboxylate (16.5 g, 78.37%) as a white solid. LC / MS: C 12 H 14 Calculated mass of N4O3: 262.11, Experimental mass: 263.15 [M+H] + .

[0872] Step 4. At room temperature, ethyl methyl 1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-carboxylic acid (16.50 g, 1.00 equivalent) was added dropwise to a stirred solution of 1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-carboxylic acid (100.00 mL) in MeOH, and the resulting mixture was stirred at 45 °C for 2.0 h. The mixture was concentrated under reduced pressure. The residue was dissolved in H₂O (50 mL) and the mixture was acidified to pH 3–5 with 2 M HCl. The precipitated solid was collected by filtration, washed with H₂O (3 × 30 mL), and dried under vacuum to give 1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-carboxylic acid (12.00 g, 76.84%) as a white solid. LC / MS: C 11 H 12 Calculated mass of N4O3: 248.09 g / L, experimental mass: 249.10 g / L [M+H] + .

[0873] Step 5. The procedure is the same as step 1 in Example 3. 9.00 g of 1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-carboxylic acid was used, and 14.00 g of the desired product as a yellow solid was obtained (63.54% yield). LC / MS: C 26 H 30 N 10 Calculated mass of O6: 578.23, Experimental mass: 579.10 [M+H] + .

[0874] Step 6. The procedure is the same as step 4 in Example 3. Using 14.00 g of methyl 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formamide]propionamide)imidazol-2-acylamino]pyrrolo-2-yl]formamide carbamate, 12.00 g of the desired product as a yellow solid was obtained (81.49% yield). LC / MS: C 25 H 28 N 10 Calculated mass of O6: 564.22, Experimental mass: 565.15 [M+H] + .

[0875] Step 7. The procedure is the same as step 5 in Example 3. 7.80 g of 4-[(tert-butoxycarbonyl)amino]butyric acid was obtained, along with 11.00 g of the desired product as a slightly pink solid (80.70% yield). LC / MS: C 16 H 26 Calculated mass of N4O5: 354.19 g / L, experimental mass: 355.15 g / L [M+H] + .

[0876] Step 8. The procedure is the same as step 2 in Example 3. Using 9.40 g of ethyl 4-{4-[(tert-butoxycarbonyl)amino]butyrylamino}-1-methylimidazolium-2-carboxylate, 6.20 g of the desired product as a white solid was obtained (90.89% yield). LCMS: C 11 H 18 Calculated mass of N4O3: 254.14, Experimental mass: 255.15 [M+H] + .

[0877] Step 9. Add DIEA (12.50 g, 96.71 mmol, 3.00 equivalent), ethyl 4-(4-aminobutyrylamino)-1-methylimidazolium-2-carboxylic acid (9.02 g, 35.46 mmol, 1.10 equivalent), and PyBOP (20.13 g, 38.68 mmol, 1.20 equivalent) to a stirred solution of 1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazolium-2-acylamino)pyrrole-2-yl]formylamino}propionylamino)imidazolium-2-acylamino]pyrrole-2-carboxylic acid (18.20 g, 32.24 mmol, 1.00 equivalent) in DMF (250.00 mL) at 0 °C, and stir the resulting mixture at room temperature for 1.0 h. Then pour the reaction mixture into ice / water (800 mL). The precipitated solid was collected by filtration, washed with H₂O (3 × 200 mL), and dried under vacuum to give ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-carboxylate (24.70 g, 95.74% yield) as a yellow solid. LC / MS: C 36 H 44 N 14 Calculated mass of O8: 800.35, Experimental mass: 801.30 [M+H] + .

[0878] Step 10. The procedure is the same as step 4 in Example 3. Using 24.00 g of ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-carboxylate, 23.10 g of the desired product as a yellow solid was obtained (99.36% yield). LC / MS: C 34 H 40 N 14 Calculated mass of O8: 772.32, Experimental mass: 773.30 [M+H] + .

[0879] Step 11. EDCI (22.94 g, 119.66 mmol, 2.50 equivalent), ethyl 4-amino-1-methylimidazolium-2-carboxylic acid (8.10 g, 47.87 mmol, 1.00 equivalent), and DMAP (14.62 g, 119.66 mmol, 2.50 equivalent) were added to a stirred solution of 4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-carboxylic acid (11.50 g, 47.87 mmol, 1.00 equivalent) in DMF (200.00 mL) at 0 °C, and the resulting mixture was stirred at 35 °C for 17.0 h. Next, the reaction mixture was poured into 500 mL of ice / water. The precipitated solid was collected by filtration, washed with water (3 × 50 mL), and dried under vacuum to give ethyl 4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-acylamino}-1-methylimidazolium-2-carboxylate (16.00 g, 85.48% yield) as a pale yellow solid. LC / MS: C 18 H 25 Calculated mass of N5O5: 391.19, Experimental mass: 392.30 [M+H] + .

[0880] Step 12. TFA (45.00 mL) was added dropwise to a stirred solution of 4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-acylamino}-1-methylimidazolium-2-carboxylate (16.00 g, 40.88 mmol, 1.00 equivalent) in DCM (135.00 mL), and the resulting mixture was stirred at room temperature for 2.0 h. The mixture was then concentrated under vacuum, and the residue was diluted with Et2O (200 mL). The precipitated solid was collected by filtration, washed with Et2O (2 × 100 mL), and dried under vacuum to give 4-(4-amino-1-methylpyrrole-2-acylamino)-1-methylimidazolium-2-carboxylate (16.00 g, crude product) as a brown solid. LC / MS: C 13 H 17 Calculated mass of N5O3: 291.13, Experimental mass: 292.15 [M+H] + .

[0881] Step 13. A solution of ethyl 4-(4-amino-1-methylpyrrole-2-acylamino)-1-methylimidazolium-2-carboxylate (12.00 g, 41.19 mmol, 1.00 equivalent) and 3-[(tert-butoxycarbonyl)amino]propionic acid (7.50 g, 39.64 mmol, 0.96 equivalent), PyBOP (22.00 g, 42.28 mmol, 1.03 equivalent), and DIEA (45.00 g, 348.18 mmol, 8.45 equivalent) in DMF (120.00 mL) was stirred at room temperature for 1.0 h. The reaction mixture was then poured into ice water (400 mL). The precipitated solid was collected by filtration, washed with water (3 × 150 mL), and dried under vacuum. The aqueous phase was extracted with EA (3 × 150 mL), and the combined organic phases were washed with H2O (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with PE / EA (1:8) to give ethyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylimidazolium-2-carboxylate (17.00 g, 89.28% yield) as a yellow solid. LC / MS: C 21 H 30 Calculated mass of N6O6: 462.22, Experimental mass: 463.35 [M+H] + .

[0882] Step 14. The procedure is the same as step 4 in Example 3. Using 12.00 g of ethyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylimidazolium-2-carboxylate, 10.00 g of the desired product as a white solid was obtained (88.81% yield). LC / MS: C 19 H 26 Calculated mass of N6O6: 434.19 g / L, experimental mass: 435.25 g / L [M+H] + .

[0883] Step 15. A solution of 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylimidazolium-2-carboxylic acid (10.00 g, 23.02 mmol, 1.00 equivalent) and β-alanine ethyl ester hydrochloride (4.90 g, 31.90 mmol, 1.39 equivalent), PyBOP (12.50 g, 24.02 mmol, 1.04 equivalent), and DIEA (9.00 g, 69.64 mmol, 3.03 equivalent) in DMF (120.00 mL) was stirred at room temperature for 1.0 h. The reactants were quenched by adding water (500 mL) at room temperature. The resulting mixture was extracted with EA (3 × 400 mL), and the combined organic layers were washed with brine (3 × 200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography after elution with PE / EA (1:8) to give ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrolo-2-acylamino)-1-methylimidazol-2-yl]formylamino}propionate (12.00 g, 93.80%) as a yellow solid. LC / MS: C 24 H 35 Calculated mass of N7O7: 533.26, Experimental mass: 534.30 [M+H] + .

[0884] Step 16. The procedure is the same as step 12 in Example 3. 12.00 g of ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylimidazol-2-yl]formylamino}propionate was used to obtain 12.00 g of the desired product as a white solid. LC / MS: C 19 H 27 Calculated mass of N7O5: 433.21, Experimental mass: 434.25 [M+H] + .

[0885] Step 17. The procedure is the same as step 9 in Example 3. Using 10.00 g of 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-carboxylic acid, 13.60 g of the desired product as a yellow solid was obtained (88.61% yield). After purification by preparative HPLC, a pure product as a pale yellow solid was obtained. HRMS:C 53 H 65 N 21 O12 Calculated mass: 1187.5122, Experimental value: 1188.5153 [M+H] + .

[0886] Step 18. The procedure is the same as step 4 in Example 3, but the reaction temperature is 35°C. Using 10.60 g of ethyl 3-[(1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazololo-2-yl]pyrrolo-2-yl}formylamino)butyrylamino]imidazololo-2-yl}formylamino)propionylamino]pyrrolo-2-yl]imidazololo-2-yl]formylamino]propionate, 10.00 g of the desired product as a yellow solid was obtained. LC / MS: C 51 H 61 N 21 O 12 Calculated mass: 1159.48, Experimental mass: 581.25 [M / 2+H] + .

[0887] Step 19. Add PyBOP (68.22 mg, 0.13 mmol, 1.50 equivalent) and DIEA to a stirred solution of 3-[(1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazololo-2-yl]pyrrolo-2-yl}formylamino)butyrylamino]imidazololo-2-yl}formylamino)propionylamino]pyrrolo-2-yl]propionic acid (100.00 mg, 0.09 mmol, 1.00 equivalent) and 1-methylpiperazine (8.75 mg, 0.09 mmol, 1.00 equivalent) in DMF (3.00 mL). (28.24 mg, 0.22 mmol, 2.50 equivalents), and the reaction mixture was stirred at room temperature for 2.0 h. The reaction mixture was purified by preparative HPLC under the following conditions: column, Jupiter C18 300A, 21.2 mm × 250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 12% B to 27% B in 14 min, 27% B to 27% B in 16.5 min, 27% B; wavelength: 254 nm; RT1 (min): 15.22. The eluent was separated and lyophilized to give a white solid 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-yl}formylamino)propionylamino]pyrrolo-2-acylamino}-N-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]imidazol-2-carboxamide (56.90 mg, 51.75%). HRMS:C 56 H 71 N 23 O 11 Calculated mass: 1241.5703, Experimental value: 1242.5785 [M+H] + .

[0888] Example 4. Synthesis of compound A-99

[0889] Step 4.

[0890]

[0891] Step 1. The procedure is the same as step 12 in Example 3. 2.00 g of ethyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylimidazolium-2-carboxylate was used, and 2.00 g of the desired product as a white solid was obtained. LC / MS: C 16 H 22 Calculated mass of N6O4: 362.17 g / L, experimental mass: 363.25 g / L [M+H] + .

[0892] Step 2. The procedure is the same as step 9 in Example 3, but the solvent is DMA. Using 3.00 g of 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-carboxylic acid, 4.30 g of the desired product as a yellow solid was obtained (96.84% yield). LC / MS: C 50 H 60 N 20 O 11 Calculated mass: 1116.48, Experimental mass: 1117.60 [M+H] + .

[0893] Step 3. The procedure is the same as step 4 in Example 3, but the reaction temperature is 40℃ and the reaction time is 5.0 h. Using 4.20 g of ethyl 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-yl}formylamino)propionylamino]pyrrolo-2-acylamino}imidazol-2-acylamino}imidazol-2-carboxylate, 4.00 g of the desired product as a yellow solid was obtained (97.97% yield). LC / MS: C 48 H 56 N 20 O 11 Calculated mass: 1088.44, Experimental mass: 1089.55 [M+H] + .

[0894] Step 4. Dissolve 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazololo-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazololo-2-yl}formylamino)propionylamino]pyrrolo-2-acylamino}imidazol-2-carboxylic acid (100.00 mg, 0.09 mmol, 1.00 equivalent), (4-aminobutyl)dimethylamine (16.00 mg, 0.14 mmol, 1.50 equivalent), TCFH (39.00 mg, 0.14 mmol, 1.51 equivalent), and NMI (23.00 mg, 0.28 mmol, 3.05 equivalent) in DMF. The solution in (1.50 mL) was stirred at room temperature for 1.0 h. Next, the reactants were poured into ice water (10 mL) and the mixture was stirred for 15 min. The precipitated solid was collected by filtration, washed with water (3 × 3 mL), and dried under vacuum. The crude product was purified by preparative HPLC: column: XBridge Prep Phenyl OBD column, 19 × 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: MeOH--HPLC; flow rate: 25 mL / min; gradient: 50% B to 70% B, 70% B over 10 min; wavelength: 220 nm; RT1 (min): 9.65. The eluent was separated and lyophilized to give N-[5-({3-[(2-{[2-({5-[(2-{[4-(dimethylamino)butyl]aminocarbamoyl}-1-methylimidazol-4-yl)aminocarbamoyl]-1-methylpyrrole-3-yl}aminocarbamoyl)ethyl]aminocarbamoyl}-1-methylimidazol-4-yl)aminocarbamoyl]propyl}aminocarbamoyl)-1-methylpyrrole-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-yl]carbamoylamino}propionylamino)imidazol-2-carboxamide (31.0 mg, 27.94%), a white solid. HRMS:C 54 H 70 N 22 O 10 Calculated mass: 1186.5645, Experimental mass: 1187.5692 [M+H] + .

[0895] Example 5. Synthesis of compound A-101

[0896] Step 5.

[0897]

[0898] Add 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-yl}formylamino)propionylamino]pyrrolo-2-acylamino}imidazol-2-acylamino}imidazol-2-carboxylic acid (70.00 mg, 0.06 mmol, 1.00 equivalent), DMF (1.5 mL), 3-(4-methylpiperazin-1-yl)propyl-1-amine (15 mg, 0.095 mmol, 1.48 equivalent), and DIEA (56.00 mg, 0.43 mmol, 6.74 equivalent) to a 25 mL flask and stir the mixture at room temperature for 5 min. PyBOP (56.00 mg, 0.11 mmol, 1.67 equivalents) was then added and the reaction mixture was stirred at room temperature for 2.0 h. The reaction mixture was purified by preparative HPLC: column: XBridge Prep Phenyl OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 12% B to 36% B, 36% B over 10 min; wavelength: 220 nm; RT1 (min): 9.68. The eluent was separated and lyophilized to give 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)-N-[1-methyl-5-({3-[(1-methyl-2-{[2-({1-methyl-5-[(1-methyl-2-{[3-(4-methylpiperazin-1-yl)propyl]carbamoyl}imidazol-4-yl)carbamoyl]pyrrolo-3-yl}carbamoyl)ethyl]carbamoyl}imidazol-4-yl)carbamoyl]propyl}carbamoyl)pyrrolo-3-yl]imidazol-2-carboxamide (28.4 mg, 35.22% yield) as a white solid.

[0899] Example 6. Synthesis of compound A-94

[0900] Step 6.

[0901]

[0902] The procedure is the same as step 9 in Example 3. Using 100.00 mg of 3-[(1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-yl}formylamino)propionylamino]pyrrolo-2-yl]propionic acid, 41.50 mg of the desired product as a white solid was obtained (38.42% yield). HRMS: C 56 H 70 N 22 O 11 Calculated mass: 1226.56, Experimental mass: 1227.57 [M+H] + .

[0903] Example 7. Synthesis of compound A-97

[0904] Step 7.

[0905]

[0906] The procedure is the same as step 9 in Example 3. 70.00 mg of 3-[(1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-yl}formylamino)propionylamino]pyrrolo-2-yl]propionic acid was used to obtain 20.00 mg of the desired product as a pale yellow solid (24.30% yield). HRMS: C 59 H 75 N 23 O 11 Calculated mass: 1281.6016, Experimental mass: 1282.6074 [M+H] + .

[0907] Example 8. Synthesis of compound A-98

[0908] Step 8.

[0909]

[0910] Step 1. The procedure is the same as step 9 in Example 3. Using 150.00 mg of 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-yl}formylamino)propionylamino]pyrrolo-2-acylamino}imidazol-2-carboxylic acid, 120.00 mg of the desired product as a pale yellow solid was obtained (74.82% yield). HRMS: C 51 H 60 N 22 O 10 Calculated mass: 1140.49, Experimental value: 1141.4911 [M+H] + .

[0911] Step 2. Saturate a solution of N-(5-{[3-({2-[(2-{[5-({2-[(2-[(2-cyanoethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)-1-methylpyrrole-3-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)propyl]carbamoyl}-1-methylpyrrole-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrole-2-yl]carbamoyl}propionylamino)imidazol-2-carboxamide (110.00 mg, 0.10 mmol, 1.00 equivalent) in ethanol (1.00 mL) with anhydrous HCl (gaseous) (17.57 mg, 0.48 mmol, 5.00 equivalent) at -20 °C. The mixture was stirred at room temperature for 3.0 h and then concentrated under vacuum to give the desired product (120.00 mg, 104.86% yield) as a grayish-white solid. LC / MS: C 53 H 66 N 22 O 11 Calculated mass: 1186.53, Experimental mass: 1187.65 [M+H] + .

[0912] Step 3. Add 1 mL of MeOH containing NH3 (2.87 mg, 0.17 mmol, 2 equivalents) to a solution of ethyl 3-[(1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-yl]pyrrolo-2-yl]formylamino]propion ... The reactants were filtered and purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, water containing ACN, 10% to 60% gradient over 10.0 min; detector, UV 254 nm. The elution fraction was separated and concentrated to give crude product (90.00 mg), which was dissolved in DMA (2 mL) and purified by preparative HPLC under the following conditions (column: Xselect CSH F-Phenyl OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B to 30% B, 30% B over 12 min; wavelength: 220 nm; RT1 (min): 11; number of runs: 5). This produced the desired product as a white solid (14.50 mg, 14.69% yield). HRMS: C 51 H 63 N 23 O 10 Calculated mass: 1157.51, Experimental value: 1158.5205 [M+H] + .

[0913] Example 9. Synthesis of compound A-100

[0914] Step 9.

[0915]

[0916] The procedure is the same as step 9 in Example 3. Using 100.00 mg of 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-yl}formylamino)propionylamino]pyrrolo-2-acylamino}imidazol-2-acylamino}imidazol-2-carboxylic acid, 53.30 mg of the desired product as a white solid was obtained (46.88% yield). HRMS: C 55 H 72 N 22 O 10 Calculated mass: 1200.58, Experimental mass: 1201.59 [M+H] + .

[0917] Example 10. Synthesis of compound A-102

[0918] Step 10.

[0919]

[0920] The procedure is the same as step 9 in Example 3. 80.00 mg of 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-yl}formylamino)propionylamino]pyrrolo-2-acylamino}imidazol-2-acylamino}imidazol-2-carboxylic acid was used, and 27.00 mg of the desired product as a white solid was obtained (29.66% yield). LC / MS: C 55 H 70 N 22 O 11 Calculated mass: 1214.5594, Experimental value: 1215.5654 [M+H] + .

[0921] Example 11. Synthesis of compound A-103

[0922] Step 11.

[0923]

[0924] The procedure is the same as step 9 in Example 3. Using 100.00 mg of 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)pyrrolo-2-yl]formylamino}propionylamino)imidazol-2-acylamino]pyrrolo-2-yl}formylamino)butyrylamino]imidazol-2-yl}formylamino)propionylamino]pyrrolo-2-acylamino}imidazol-2-acylamino}imidazol-2-carboxylic acid, 22.30 mg of the desired product as a white solid was obtained (19.94% yield). HRMS: C 54 H 70 N 22 O 11 Calculated mass: 1202.5994, Experimental mass: 1203.5638 [M+H] + .

[0925] Example 12. Synthesis of compound A-106

[0926] Step 12.

[0927]

[0928] The procedure is the same as step 4 in Example 4. 41.00 mg of 14-(3-aminopropyl)-2,5,8,11,17,20,23,26-octaoxa-14-azahexaoctadecane was used, yielding 37.20 mg (26.18% yield) of the desired product as a white solid. HRMS:C 69 H 100 N 22 O 18 Calculated mass: 1524.7586, Experimental mass: 1525.7657 [M+H] + .

[0929] Example 13. Synthesis of compound A-124

[0930] Step 13.

[0931]

[0932] Step 1. Add PyBOP (3.12 g, 6.00 mmol, 1.00 equivalent) and DIEA (1.79 g, 13.84 mmol, 3.00 equivalent) to a stirred solution of 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-carboxylic acid (2.00 g, 4.61 mmol, 1.00 equivalent) and β-alanine ethyl ester (0.65 g, 5.54 mmol, 1.20 equivalent) in DMF (10.00 mL), and stir the resulting mixture at room temperature for 2.0 h. Pour the resulting mixture into ice water (20 mL). The precipitated solid was collected by filtration, washed with water (3 × 10 mL), and dried under vacuum to give ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propionamide}-1-methylpyrrolo-2-acylamino)-1-methylpyrrolo-2-yl]formamide}propionate (2.10 g, 85.46%), which was a yellow oil. LC / MS: C 25 H 36 Calculated mass of N6O7: 532.26, experimental mass: 555.30 [M+Na] + .

[0933] Step 2. KOH (2 M in H₂O, 23.02 mL, 46.03 mmol, 10.00 equivalent) was added to a stirred solution of methyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-carboxylate (2.06 g, 4.60 mmol, 1.00 equivalent) in THF (25.00 mL), and the resulting mixture was stirred at 40 °C for 1.0 h. Next, the mixture was concentrated under reduced pressure. The residue was dissolved in H₂O (30.00 mL), and the mixture was acidified to pH 4-5 with 2 M HCl. The precipitated solid was collected by filtration, washed with H₂O (3 × 20.00 mL), and dried under vacuum to give 1.70 g (85.19%) of 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-carboxylic acid, which was a yellow oil. LC / MS: C 23 H 32 Calculated mass of N6O7: 504.23, Experimental mass: 505.20 [M+H] + .

[0934] Step 3. PyBOP (2.23 g, 4.28 mmol, 1.00 equivalent) and DIEA (1.28 g, 9.87 mmol, 3.00 equivalent) were added to a stirred solution of 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-yl]formylamino}propionic acid (1.66 g, 3.29 mmol, 1.00 equivalent) and propylamine (0.23 g, 3.95 mmol, 1.20 equivalent) in DMF (30.00 mL), and the resulting mixture was stirred at room temperature for 2.0 h. Next, the reactants were diluted with water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography after elution with CH2Cl2 / MeOH (10:1) to give N-[2-({1-methyl-5-[(1-methyl-5-{[2-(propylcarbamoyl)ethyl]carbamoyl}pyrrolo-3-yl)carbamoyl]pyrrolo-3-yl}carbamoyl)ethyl]carbamate (1.30 g, 72.41%) as a yellow solid. LC / MS: C 26 H 39 Calculated mass of N7O6: 545.30, Experimental mass: 546.25 [M+H] + .

[0935] Step 4. Add N-[2-({1-methyl-5-[(1-methyl-5-{[2-(propylcarbamoyl)ethyl]carbamoyl}pyrrolo-3-yl)carbamoyl]pyrrolo-3-yl}carbamoyl)ethyl]tert-butyl carbamate (150.00 mg, 0.28 mmol, 1.00 equivalent), TFA (1.00 mL), and DCM (5.00 mL) to a 25 mL round-bottom flask, and stir the resulting mixture at room temperature for 1.0 h. Next, concentrate the mixture under vacuum to give 4-(3-aminopropionylamino)-1-methyl-N-(1-methyl-5-{[2-(propylcarbamoyl)ethyl]carbamoyl}pyrrolo-3-yl)pyrrolo-2-carboxamide (120.00 mg, 97.98%) as a yellow solid. LC / MS: C 21 H 31 Calculated mass of N7O4: 445.24 g, experimental mass: 468.30 g [M+Na] + .

[0936] Step 5. HATU (24.32 g, 63.96 mmol, 1.30 equivalent), DIEA (19.04 g, 147.61 mmol, 3.00 equivalent), and methyl 4-amino-1-methylpyrrole-2-carboxylate (9.10 g, 59.04 mmol, 1.20 equivalent) were added to a stirred solution of 4-[(tert-butoxycarbonyl)amino]butyric acid (10.00 g, 49.20 mmol, 1.00 equivalent) in DMF (200.00 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 1.0 h. Next, the reactants were diluted with water (50 mL) and the mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give methyl 4-{4-[(tert-butoxycarbonyl)amino]butyrylamino}-1-methylpyrrole-2-carboxylate (11.00 g, 65.86%) as an orange solid. LC / MS: C 16 H 25 Calculated mass of N3O5: 339.18, experimental mass: 340.15 [M+H] + .

[0937] Step 6. LiOH (2 M in H₂O, 69.97 mL, 139.94 mmol, 10.00 equivalent) was added dropwise to a stirred solution of methyl 4-{4-[(tert-butoxycarbonyl)amino]butyrylamino}-1-methylpyrrole-2-carboxylic acid (4.75 g, 13.99 mmol, 1.00 equivalent) in MeOH (40.00 mL) at room temperature, and the resulting mixture was stirred at 45 °C for 2.0 h. Next, the mixture was concentrated under reduced pressure. The residue was dissolved in H₂O (50.00 mL) and acidified to pH 4-5 with 2 M HCl. The precipitated solid was collected by filtration, washed with H₂O (3 × 40 mL), and dried under vacuum to give 4-{4-[(tert-butoxycarbonyl)amino]butyrylamino}-1-methylpyrrole-2-carboxylic acid (4.00 g, 87.91%) as an orange solid. LC / MS: C 15 H 23 Calculated mass of N3O5: 325.16, experimental mass: 326.05 [M+H] + .

[0938] Step 7. Add PyBOP (139.19 mg, 0.27 mmol, 1.20 equivalent) and DIEA (79.78 mg, 0.62 mmol, 3.00 equivalent) to a stirred solution of 4-(3-aminopropionylamino)-1-methyl-N-(1-methyl-5-{[2-(propylaminocarboxyyl)ethyl]amino}pyrrolo-3-yl)pyrrolo-2-carboxamide (110.00 mg, 0.23 mmol, 1.20 equivalent) and 4-{4-[(tert-butoxycarbonyl)amino]butyrylamino}-1-methylpyrrolo-2-carboxylic acid (66.94 mg, 0.21 mmol, 1.00 equivalent) in DMF (3.00 mL), and stir the resulting mixture at room temperature for 1.0 h. The reaction mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, water containing MeCN (10 mmol / L NH4HCO3), in a 10% to 50% gradient over 40 min; detector, UV 254 nm. The elution fraction was separated and concentrated under vacuum to give N-{3-[(1-methyl-5-{[2-({1-methyl-5-[(1-methyl-5-{[2-(propylcarbamoyl)ethyl]carbamoyl}pyrrolo-3-yl)carbamoyl]pyrrolo-3-yl}carbamoyl)ethyl]carbamoyl}pyrrolo-3-yl)carbamoyl]propyl} tert-butyl carbamate (110.00 mg, 71.01%) as a white solid. LC / MS: C 36 H 52 N 10 Calculated mass of O8: 752.40, Experimental mass: 753.45 [M+H] + .

[0939] Step 8. Add N-{3-[(1-methyl-5-{[2-({1-methyl-5-[(1-methyl-5-{[2-(propylcarbamoyl)ethyl]carbamoyl}pyrrolo-3-yl)carbamoyl]pyrrolo-3-yl}carbamoyl)ethyl]carbamoyl}pyrrolo-3-yl)carbamoyl]propyl}tert-butyl carbamate (105.00 mg, 0.14 mmol, 1.00 equivalent), TFA (1.00 mL), and DCM (5.00 mL) to a 25 mL round-bottom flask, and stir the resulting mixture at room temperature for 1.0 h. The mixture obtained by vacuum concentration yielded a colorless oily 4-(3-{[4-(4-aminobutyrylamino)-1-methylpyrrolo-2-yl]formamido}propionamido)-1-methyl-N-(1-methyl-5-{[2-(propylaminoformamido)ethyl]aminoformamido}pyrrolo-3-yl)pyrrolo-2-carboxamide (90.00 mg, 98.86%). LC / MS: C 31 H 44 N10 Calculated mass of O6: 652.34, Experimental mass: 653.50 [M+H] + .

[0940] Step 9. Add PyBOP (43.18 mg, 0.09 mmol, 1.30 equivalence) and DIEA to a stirred solution of 4-(3-{[4-(4-aminobutyrylamino)-1-methylpyrrolo-2-yl]formylamino}propionylamino)-1-methyl-N-(1-methyl-5-{[2-(propylaminoformyl)ethyl]aminoformyl}pyrrolo-3-yl)pyrrolo-2-carboxamide (50.00 mg, 0.08 mmol, 1.20 equivalence) and 1-hexyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)imidazol-2-acylamino]imidazol-2-carboxylic acid (40.64 mg, 0.06 mmol, 1.00 equivalence) in DMF (2.00 mL). (24.75 mg, 0.19 mmol, 3.00 equivalents), and the resulting mixture was stirred at room temperature for 1.0 h. The reaction mixture was purified by preparative HPLC under the following conditions: column: XSelect CSH Pheny-Hexy, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 22% B to 47% B over 12 min; wavelength: 254 nm; RT1 (min): 11.4. The eluent was separated and lyophilized to give N-[1-hexyl-2-({3-[(1-methyl-5-{[2-({1-methyl-5-[(1-methyl-5-[(1-methyl-5-{[2-(propylaminocarbamoyl)ethyl]aminocarbamoyl}pyrrolo-3-yl)aminocarbamoyl]pyrrolo-3-yl}aminocarbamoyl)ethyl]aminocarbamoyl}pyrrolo-3-yl)aminocarbamoyl]propyl}aminocarbamoyl)imidazol-4-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]carbamoyl}propionylamino)imidazol-2-carbamoylformic acid (15.50 mg, 18.33%) as a white solid. HRMS: C 59 H 78 N 22 O 11 Calculated mass: 1270.6220, Experimental mass: 1271.6253 [M+H] + HPLC: 99.463% purity

[0941] Example 14. Synthesis of compound A-125

[0942] Step 14.

[0943]

[0944] Add Ac2O (16.80 mg, 0.16 mmol, 2.00 equivalents) and TEA (33.30 mg) to a stirred solution of N-(2-{[(3R)-3-amino-3-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-(propylcarbamoyl)pyrrolo-3-yl]carbamoyl}pyrrolo-3-yl)carbamoyl}propyl]carbamoyl}-1-hexylimidazol-4-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]carbamoyl}propionylamino)imidazol-2-carboxamide (100.00 mg, 0.08 mmol, 1.00 equivalent) in DMF (1.00 mL) to a stirred solution. mg (0.33 mmol, 4.00 equivalents), and the resulting mixture was stirred at room temperature for 2.0 h. The reaction mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18; water containing MeCN (0.1% TFA), 10% to 50% gradient over 30 min; detector, UV 254 nm. The eluates were combined and dried under vacuum to give the crude product. The crude product was further purified by preparative HPLC: column: XBridge Prep OBD C18 column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 28% B to 53% B over 12 min; wavelength: 254 nm / 220 nm; RT1 (min): 10.72. The eluent was separated and lyophilized to give N-(2-{[(3R)-3-acetamido-3-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-{[1-methyl-5-(propylaminocarbamoyl)pyrrolo-3-yl]aminocarbamoyl}pyrrolo-3-yl)aminocarbamoyl]ethyl}aminocarbamoyl)pyrrolo-3-yl]aminocarbamoyl}propyl]aminocarbamoyl}-1-hexylimidazol-4-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]carbamoylamino}propionylamino)imidazol-2-carboxamide (15.40 mg, 14.30%) as a white solid. HRMS: C 58 H 76 N 22 O 11 Calculated mass: 1256.6064, Experimental value: 1257.6129 [M+H] + .

[0945] Example 15. Synthesis of compound A-126

[0946] Step 15.

[0947]

[0948] Add methyl chloroformate (16.84 mg, 0.10 mmol) to a stirred solution of N-(2-{[(3R)-3-amino-3-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-(propylaminocarbamoyl)pyrrolo-3-yl]aminocarbamoyl}pyrrolo-3-yl)aminocarbamoyl]ethyl}aminocarbamoyl)pyrrolo-3-yl]aminocarbamoyl}propyl]aminocarbamoyl}-1-hexylimidazol-4-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]carbamoyl}propionylamino)imidazol-2-carboxamide (100.00 mg, 0.08 mmol, 1.00 equivalent) in THF (2.00 mL) and H2O (0.40 mL) to a stirred solution. 34.56 mg (1.20 mmol, 1.20 equivalent) and NaHCO3 (34.56 mg, 0.41 mmol, 5.00 equivalent) were added, and the resulting mixture was stirred at room temperature for 3.0 h. The reaction mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18; water containing MeCN (0.1% TFA), 10% to 50% gradient over 30 min; detector, UV 254 nm. The elution fraction was separated and dried under vacuum to give the crude product, which was further purified by preparative HPLC: column: XBridge Prep OBD C18 column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 35% B to 60% B over 12 min; wavelength: 254 nm / 220 nm; RT1 (min): 11.7. The eluent was separated and lyophilized to give N-[(1R)-3-({1-hexyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)imidazol-2-acylamino]imidazol-2-yl}formylamino)-1-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-(propylaminocarbamoyl)pyrrole-3-yl]aminocarbamoyl}pyrrole-3-yl)aminocarbamoyl]ethyl}aminocarbamoyl)pyrrole-3-yl]aminocarbamoyl}propyl]benzoic acid ester (4.60 mg, 4.04%) as a white solid. HRMS: C 64 H 80 N 22 O 12Calculated mass: 1348.6326, Experimental mass: 1349.6408 [M+H] + .

[0949] Example 16. Synthesis of compound A-127

[0950] Step 16.

[0951]

[0952] Step 1. To a stirred solution of 4-amino-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester (4.50 g, 24.97 mmol, 1.00 equivalent) in DMF (50.00 mL), (2R)-2-[(tert-butoxycarbonyl)amino]-4-{[(9H-fluorene-9-ylmethoxy)carbonyl]amino}butyric acid (11.00 g, 24.97 mmol, 1.00 equivalent), PyBOP (15.62 g, 29.96 mmol, 1.20 equivalent) and DIEA (13.05 mL, 74.91 mmol, 3.00 equivalent) were added, and the resulting mixture was stirred at room temperature for 1.0 h. Next, the resulting mixture was poured into ice water (150 mL). The precipitated solid was collected by filtration, washed with water (2 × 80 mL), and dried under vacuum to give a yellow solid, 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-{[(9H-fluorene-9-ylmethoxy)carbonyl]amino}butyrylamino]-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester (5.30 g, 35.22%). LC / MS: C 33 H 38 Calculated mass of N4O7: 602.27 g / L, Experimental mass: 603.35 g / L [M+H] + .

[0953] Step 2. Add DEA (10.00 mL) to a stirred solution of 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-{[(9H-fluorene-9-ylmethoxy)carbonyl]amino}butyrylamino]-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester (5.75 g, 9.54 mmol, 1.00 equivalent) in DMF (50.00 mL), and stir the resulting mixture at room temperature for 1.0 h. Filter the reaction mixture, and purify the filtrate directly by reverse-phase column chromatography under the following conditions: column, C18 column; mobile phase, water containing MeCN (0.05% TFA), 10% to 50% gradient over 50 min; detector, UV 254 nm. The eluent was separated and dried under vacuum to give 2.80 g (77.14%) of 4-[(2R)-4-amino-2-[(tert-butoxycarbonyl)amino]butyrylamino]-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester, a white solid. LC / MS: C 18 H 28 Calculated mass of N4O5: 380.21, Experimental mass: 381.20 [M+H] + .

[0954] Step 3. Add 1-hexyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)imidazol-2-acylamino]imidazol-2-carboxylic acid (4.62 g, 7.25 mmol, 1.00 equivalent), TCFH (2.44 g, 8.70 mmol, 1.20 equivalent), and NMI (1.79 mL, 21.76 mmol, 3.00 equivalent) to a stirred solution of 4-[(2R)-4-amino-2-[(tert-butoxycarbonyl)amino]butyrylamino]-1-methylpyrrole-2-carboxylic acid (2.76 g, 7.25 mmol, 1.00 equivalent), NMI (1.79 mL, 21.76 mmol, 3.00 equivalent), and stir the resulting mixture at room temperature for 1.0 h. Next, the resulting mixture was poured into ice water (60 mL). The precipitated solid was collected by filtration, washed with water (60 mL), and dried under vacuum. The crude product was purified by silica gel column chromatography by elution with CH2Cl2 / MeOH (12:1) to give a white solid 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-hexyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)imidazol-2-acylamino]imidazol-2-yl}formylamino)butyrylamino]-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester (2.70 g, 37.25%). LC / MS: C46 H 62 N 16 O 10 Calculated mass: 998.48, Experimental mass: 999.50 [M+H] + .

[0955] Step 4. Add phenylsilane (6.50 mL, 0.06 mmol, 1.00 equivalent) and Pd(PPh3)4 (300.72 mg, 0.26 mmol, 0.10 equivalent) to a stirred solution of 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-hexyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)imidazol-2-acyl]imidazol-2-yl}formylamino)butyrylamino]-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester (2.60 g, 2.60 mmol, 1.00 equivalent) in DMF (20.00 mL) and stir the resulting mixture at room temperature for 1.0 h. The reactants were then filtered, and the filtrate was purified by reverse-phase column chromatography under the following conditions: column, C18 column; mobile phase, water containing MeCN (0.05% TFA), in a 10% to 70% gradient over 50 minutes; detector, UV 254 nm. The eluted fraction was separated and dried under vacuum to give 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-hexyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)imidazol-2-yl]formylamino)butyrylamino]-1-methylpyrrole-2-carboxylic acid (1.87 g, 74.93%) as a yellow solid. LC / MS: C 43 H 58 N 16 O 10 Calculated mass: 958.45, Experimental mass: 959.40 [M+H] + .

[0956] Step 5. DIEA (1.49 g, 11.54 mmol, 5.00 equivalent), PyBOP (1.56 g, 3.00 mmol, 1.30 equivalent), and propylamine (163.65 mg, 2.77 mmol, 1.20 equivalent) were added to a stirred solution of 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino) in DMF (10.00 mL), and the reaction mixture was stirred at room temperature for 1.0 h. The reaction mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 column; mobile phase, water containing MeCN (0.1% TFA), 10% to 70% gradient over 30 min; detector, UV 254 nm. The eluent was separated and dried under vacuum to give N-{2-[(1-methyl-5-{[1-methyl-5-(propylcarbamoyl)pyrrolo-3-yl]carbamoyl}pyrrolo-3-yl)carbamoyl]ethyl} tert-butyl carbamate (1.00 g, 91.34%), a yellow oil. LCMS: C 23 H 34 Calculated mass of N6O5: 474.26, experimental mass: 497.35 [M+Na] + .

[0957] Step 6. Add TFA (2.00 mL) to a stirred solution of N-{2-[(1-methyl-5-{[1-methyl-5-(propylcarbamoyl)pyrrolo-3-yl]carbamoyl}pyrrolo-3-yl)carbamoyl]ethyl}carbamate (350.00 mg, 0.738 mmol, 1.00 equivalent) in DCM (5.00 mL), and stir the reaction mixture at room temperature for 1.0 h. Concentrate the reaction mixture under vacuum to give a pale yellow oily 4-(3-aminopropionylamino)-1-methyl-N-[1-methyl-5-(propylcarbamoyl)pyrrolo-3-yl]pyrrolo-2-carboxamide (350.00 mg, crude product). LCMS: C 18 H 26 Calculated mass of N6O3: 374.21, Experimental mass: 375.30 [M+H] + .

[0958] Step 7. Add 4-(3-aminopropionylamino)-1-methyl-N-[1-methyl-5-(propylaminoformyl)pyrrole-3-yl]pyrrole-2-carboxamide (468.53 mg, 1.25 mmol, 2.00 equivalent) and DIEA (326.93 mg) to a stirred solution of 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-hexyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)imidazol-2-acylamino]imidazol-2-yl]-1-methylpyrrole-2-carboxylic acid (600.00 mg, 0.63 mmol, 1.00 equivalent) in DMF (10.00 mL) and stirring solution. μL (1.88 mmol, 3.00 equivalent) and PyBOP (390.69 mg, 0.751 mmol, 1.20 equivalent). The resulting mixture was stirred at room temperature for 1.0 h. The reaction mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 column; mobile phase, water containing MeCN (0.1% TFA), 5% to 50% gradient over 30 min; detector, UV 254 nm. This produces a yellow solid, N-[(1R)-3-({1-hexyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)imidazol-2-acylamino]imidazol-2-yl}formylamino)-1-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-(propylaminocarbamoyl)pyrrolo-3-yl]aminocarbamoyl}pyrrolo-3-yl)aminocarbamoyl]ethyl}aminocarbamoyl)pyrrolo-3-yl]aminocarbamoyl}propyl]tert-butyl carbamate (650.00 mg, 78.98%). LCMS: C 61 H 82 N 22 O 12 Calculated mass: 1314.65, Experimental mass: 658.60 [M / 2+H] + .

[0959] Step 8. Add TFA (0.30 mL) to a stirred solution of N-[(1R)-3-({1-hexyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)imidazol-2-acylamino]imidazol-2-yl}formylamino)-1-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-(propylaminocarbamoyl)pyrrole-3-yl]aminocarbamoyl}pyrrole-3-yl)aminocarbamoyl]ethyl}aminocarbamoyl)pyrrole-3-yl]aminocarbamoyl}propyl]tert-butyl carbamate (80.00 mg, 0.06 mmol, 1.00 equivalent) in DCM (1.00 mL), and stir the reaction mixture at room temperature for 1.0 h. The resulting mixture was concentrated under vacuum and the residue was purified by preparative HPLC: Column: XSelect CSHC18 column, 19×250 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 19% B to 39% B over 9 min; Wavelength: 254 nm; RT1 (min): 8. The eluent was separated and lyophilized to give N-(2-{[(3R)-3-amino-3-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-{[1-methyl-5-(propylaminocarbamoyl)pyrrolo-3-yl]aminocarbamoyl}pyrrolo-3-yl)aminocarbamoyl]ethyl}aminocarbamoyl)pyrrolo-3-yl]aminocarbamoyl}propyl]aminocarbamoyl}-1-hexylimidazol-4-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]carbamoylamino}propionylamino)imidazol-2-carboxamide (16.9 mg, 22.77%), a white solid. HRMS: C 56 H 74 N 22 O 10 Calculated mass: 1214.5958, Experimental value: 1215.6025 [M+H] + .

[0960] Example 17. Synthesis of compound A-128

[0961] Step 17.

[0962]

[0963] Step 1. PyBOP (120.45 mg, 0.23 mmol, 1.30 equivalent) and DIEA (115.06 mg, 0.89 mmol, 5.00 equivalent) were added to a stirred solution of 4-{4-[(tert-butoxycarbonyl)amino]butyrylamino}-1-methylpyrrole-2-carboxylic acid (57.93 mg, 0.18 mmol, 1.00 equivalent) and 4-(3-aminopropionylamino)-1-methyl-N-[1-methyl-5-(propylaminocarboxylo)pyrrole-3-yl]pyrrole-2-carboxamide (80.00 mg, 0.21 mmol, 1.20 equivalent) in DMF (2.00 mL), and the resulting mixture was stirred at room temperature for 1.0 h. The reactants were diluted with water (10 mL) and the resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a yellow oily N-(3-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-(propylcarbamoyl)pyrrolo-3-yl]carbamoyl}pyrrolo-3-yl)carbamoyl]ethyl}carbamoyl)pyrrolo-3-yl]carbamoyl}propyl)tert-butyl carbamate (110.00 mg, 90.62%). LC / MS: C 33 H 47 Calculated mass of N9O7: 681.36, experimental mass: 704.50 [M+Na] + .

[0964] Step 2. At room temperature, add TFA (0.30 mL) part-by-part to a stirred solution of N-(3-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-(propylcarbamoyl)pyrrolo-3-yl]carbamoyl}pyrrolo-3-yl)carbamoyl]ethyl}carbamoyl)pyrrolo-3-yl]carbamoyl}propyl)tert-butyl carbamate (110.00 mg, 0.16 mmol, 1.00 equivalent) in DCM (1.00 mL). The resulting mixture was stirred at room temperature for 1.0 h, followed by vacuum concentration to give 4-(3-{[4-(4-aminobutyrylamino)-1-methylpyrrolo-2-yl]formamido}propionamido)-1-methyl-N-[1-methyl-5-(propylaminoformyl)pyrrolo-3-yl]pyrrolo-2-carboxamide (110.00 mg, crude product), a brown oil. LC / MS: C 28 H 39 Calculated mass of N9O5: 581.31, Experimental mass: 582.25 [M+H] + .

[0965] Step 3. Add TCFH (34.37 mg, 0.12 mmol, 1.30 equivalence) and NMI to a stirred mixture of 4-(3-{[4-(4-aminobutyrylamino)-1-methylpyrrolo-2-yl]formylamino}propionylamino)-1-methyl-N-(1-methyl-5-{[2-(propylaminoformyl)ethyl]aminoformyl}pyrrolo-3-yl)pyrrolo-2-carboxamide (61.52 mg, 0.09 mmol, 1.00 equivalent) and 1-hexyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)imidazol-2-acylamino]imidazol-2-carboxylic acid (60.00 mg, 0.09 mmol, 1.00 equivalent) in DMF (1.00 mL). (23.21 mg, 0.28 mmol, 3.00 equivalents), and the resulting mixture was stirred at room temperature for 1.0 h. The reaction mixture was purified by preparative HPLC under the following conditions: XSelect CSH C18 column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% FA); mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30% B to 55% B over 12 min; RT1 (min): 11.5. The eluent was separated and lyophilized to give N-[1-hexyl-2-({3-[(1-methyl-5-{[2-({1-methyl-5-[(1-methyl-5-{[2-(propylaminocarbamoyl)ethyl]aminocarbamoyl}pyrrolo-3-yl)aminocarbamoyl]pyrrolo-3-yl}aminocarbamoyl)ethyl]aminocarbamoyl}pyrrolo-3-yl)aminocarbamoyl]propyl}aminocarbamoyl)imidazol-4-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]carbamoyl}propionylamino)imidazol-2-carboxamide; formic acid (2.30 mg, 1.77%) as a white solid. HRMS: C 56 H 73 N 21 O 10 Calculated mass: 1199.5849, Experimental value: 1200.5885 [M+H] + .

[0966] Example 18. Other compounds disclosed herein

[0967] The compounds of this application were prepared by a method similar to that of Examples 1-17. An overview of the analytical data is presented in Table 2.

[0968] Table 2. Mass spectrometry data of the compounds disclosed herein.

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975] Biological Examples

[0976] Example B-1. Method for measuring the reduction of DM1 lesions

[0977] Fibroblasts (Coriell GM04602; 1600 CTG repeat sequences) from patients affected by type 1 myotonic dystrophy and wild-type fibroblasts (Coriell GM07492; control cell line) were cultured in Gibco DMEM (1×) supplemented with 10% FBS and 1× penicillin / streptomycin, along with 4.5 g / L D-glucose, L-glutamine, and 110 mg / L sodium pyruvate. Cells were incubated at 37°C and 5% CO2, with the culture medium changed every 48–72 hours.

[0978] At 90-95% confluence, both cell lines were collected using Trypl-E, precipitated at 500×g for 5 minutes, and then resuspended in fresh medium. DM1 fibroblasts were seeded in 200 µL of medium at a density of 5,000 cells / well in Agilent 96-well black plates; 8 wells were reserved for control fibroblasts. The plates were returned to the incubator and incubated at 37°C and 5% CO2 for 24 hours.

[0979] The compound was diluted from a 10 mM stock solution to 1 mM in DMSO, and then further diluted to 6 µM (2× concentration) in culture medium. The culture medium was removed from all plates, and cells were replenished with 100 µL of medium. Cells were treated with an 8-point dose response, a 1:3 dilution, and a maximum dose of 3 µM by adding 100 µL of the 6 µM (2× concentration) compound to 100 µL of cell-containing medium. The plates were returned to the incubator and incubated at 37°C and 5% CO2 for 48 hours.

[0980] After treatment, the compound was removed and the plate was washed with PBS. The cells were then fixed in 75 µL of 4% PFA solution at room temperature for 20 min. The plate was washed twice with PBS and twice with 70% cold ethanol, followed by permeation with 250 µL of 70% cold ethanol at -20°C for 24–72 h.

[0981] After infiltration, the plate was washed once with 30% formamide and 2× SSC buffer, and then rehydrated in the buffer for 15 minutes at room temperature. Cells were cultured overnight at 37°C in 75 µL of a hybrid solution containing 30% formamide, 2× SSC, 25 mg / mL dextran sulfate, 2.5 mg / mL BSA, 0.2 µg / mL herring sperm DNA, 2 mM vanadate ribonucleoside complex, and 5 nM CAG10-Cy3 probe.

[0982] The plate was washed once with 2× SSC buffer containing 30% formamide, followed by two washes with buffer. The plate was then incubated in a shaker at 37°C and 300 RPM for 30 minutes. Cells were stained with 75 µL of PBS containing 2.5 µg / mL DAPI at room temperature for 5 minutes. The plate was then washed twice with PBS and stored in 250 µL of PBS. The plate was sealed with adhesive foil and wiped with 70% ethanol.

[0983] Cells sampled from four regions per well were imaged on a Cytation 5 with a 20× objective lens. Nuclei were captured in the DAPI channel and lesions in the RFP channel. The plate was analyzed for the average number of lesions per nucleus per well. An active compound was defined as one that showed a significant reduction in lesions per nucleus in a dose-responsive manner compared to negative control cells.

[0984] Table 3A presents representative in vitro biochemical data. A < 100 nM; B ≥ 100 nM to 500 nM; C ≥ 500 nM to 1000 nM; D > 1000 nM.

[0985] Table 3A. Representative DM1 biochemical data.

[0986]

[0987]

[0988] Example B-2. Reduction of lesions in FECD

[0989] F35T cells were cultured in Opti-MEM (ThermoFisher) supplemented with 8% FBS, 20 µg / mL ascorbic acid, 200 mg / mL CaCl2, 0.08% chondroitin sulfate, 1× penicillin / streptomycin, 100 µg / mL bovine pituitary extract, 5 ng / mL epidermal growth factor, and 20 ng / mL nerve growth factor. Throughout the culture, cells were kept in an incubator at 37°C and 5% CO2. The medium was changed every 48 hours. Once cells reached sufficient confluence, they were collected and seeded in 200 µL of Opti-MEM supplemented medium at a density of 5000 cells / well in 96-well plates. Cells were returned to the incubator and incubated statically at 37°C and 5% CO2 for 24 hours. Cells were then treated with a compound or negative control at an 8-point dose response and incubated at 37°C and 5% CO2 for 48 hours. After treatment, cells were fixed with 4% PFA for 20 minutes at room temperature, followed by infiltration with 70% ethanol. Cells were incubated at -20°C for a minimum of 1 hour and a maximum of 72 hours, then the ethanol was removed and the cells were washed with PBS. Cells were then rehydrated at room temperature with 30% formamide and 2×SSC buffer for 10 minutes. Cells were then incubated overnight at 37°C in a hybrid solution containing 30% formamide, 2×SSC, 55 mg / mL dextran sulfate, 2.75 mg / mL bovine serum albumin, 0.2 µg / mL herring sperm DNA, 1% vanadate-ribonucleoside complex, and 0.05% 10 µM CAG10-Cy3 probe. Cells were washed twice with 2×SSC containing 30% formamide, incubated with the second wash buffer at 37°C and 200 rpm for 60 minutes. Cells were stained with 5 mg / mL DAPI 1:1000 in PBS and incubated at room temperature for 5 minutes. Cells were then washed with PBS and sealed with adhesive foil, with each well containing a final volume of 150 µL of PBS. Cells were imaged on a Cytation 5, and lesions were analyzed per nucleus. Active compounds were defined as those that, in a dose-response manner, showed a significant reduction in lesions per nucleus compared to negative control cells.

[0990] Representative in vitro biochemical data are presented in Table 3B. A < 50 nM; B ≥ 50 nM to 100 nM; C ≥ 100 nM to 500 nM; D > 500 nM.

[0991] Table 3B. Representative FECD biochemical data.

[0992]

[0993]

[0994] Although preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that the invention can be practiced using various alternatives to the embodiments of the invention described herein. The following claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A transcriptional regulatory molecule having the structure of formula (I) or a pharmaceutically acceptable salt thereof: ， in: W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl; Y 1 Y 2 Y 3 Y 4 Y 6 Y 7 and Y 8 Each can be independently represented as CH or N; L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl; Z does not exist; it is either -C(O)- or -C(=NH)-. R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace; R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace; Each R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace; Each R 3a and R 3b Independently hydrogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,or Two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; 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; wherein R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ; R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl; Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ; Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl; Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

2. The molecule according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 2 Y 4 Y 7 and Y 8 Each is N, and Y 1 Y 3 and Y 6 Each is CH.

3. The molecule according to claim 1 or 2, wherein the molecule has the structure of formula (II), or a pharmaceutically acceptable salt thereof: ， in: W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl; L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl; Z does not exist; it is either -C(O)- or -C(=NH)-. R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace; R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace; Each R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace; Each R 3a and R 3b Independently hydrogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,or Two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; 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; wherein R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ; R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl; Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ; Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl; Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

4. The molecule according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R 3a and R 3b Independently hydrogen, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e .

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein each R 3a and each R 3b It is hydrogen.

6. The molecule according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein two R... 3a Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl.

7. The molecule of claim 6 or a pharmaceutically acceptable salt thereof, wherein each R 3b It is hydrogen.

8. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein two R 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl.

9. The molecule according to claim 8 or a pharmaceutically acceptable salt thereof, wherein each R 3a It is hydrogen.

10. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein one of 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.

11. The molecule according to claim 3, wherein the molecule has the structure of formula (III), or a pharmaceutically acceptable salt thereof: ， in: W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl; L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl; Z does not exist; it is either -C(O)- or -C(=NH)-. R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace; R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 12-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 10-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace; Each R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace; Each R 3b Independently hydrogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,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, wherein R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ; R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl; Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ; Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl; Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

12. The molecule of claim 11 or a pharmaceutically acceptable salt thereof, wherein each R 3b It is hydrogen.

13. The molecule according to claim 11 or a pharmaceutically acceptable salt thereof, wherein one or both R 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl.

14. The molecule of claim 13 or a pharmaceutically acceptable salt thereof, wherein the two Rs 3b Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups.

15. The molecule of claim 14 or a pharmaceutically acceptable salt thereof, wherein the two Rs 3b Together with the atoms it is attached to, it forms a cyclopropyl group.

16. The molecule according to claim 11, wherein the molecule of formula (III) has the structure of formula (IIIa), or a pharmaceutically acceptable salt thereof: 。 17. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C3-C6 cycloalkyl groups, or optionally substituted PEGs 1-20 Each of them may choose to pass through one or more R 6 replace.

18. The molecule of claim 17 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each independently serves as an optional route via one or more R 6 Replacement C1-C 20 alkyl.

19. The molecule of claim 18 or a pharmaceutically acceptable salt thereof, wherein each R 6 Independently -N3, -NR 6a R 6b -CO(O)R 6c -C(O)OR 6c -C(O)NR 6a R 6b or -NHC(O)R 6c .

20. The molecule or a pharmaceutically acceptable salt thereof according to claim 18 or 19, wherein each R 6 Independently -NHC(O)R 6c .

21. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each can be independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclohexyl, -CF3 or -CH2CF3.

22. The molecule of claim 19 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is a methyl group.

23. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R 2a R 2b R 2c R 2d R 2e R 2g or R 2h At least one of them is not an unsubstituted C1-C 20 alkyl.

24. The molecule of claim 23 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.

25. The molecule according to claim 11, wherein the molecule has formula (IV), or a pharmaceutically acceptable salt thereof: ， in: W 1 For hydrogen or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl; L does not exist; it is C1-C. 20 Alkylene or C2-C 20 Heteroalkyl; Z does not exist; it is either -C(O)- or -C(=NH)-. R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace; R 4b 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 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace; Each R 2a R 2c R 2d R 2e and R 2h Independently hydrogen, optionally substituted C1-C 50 Alkyl groups, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkyne group, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heterene groups, optionally substituted C2-C 50 Zeyne group, optionally substituted C1-C 50 Halogenated alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 3- to 8-membered heterocyclic alkyl groups, or optionally substituted PEG. 1-50 Each of them may choose to pass through one or more R 6 replace; Each R 3b Independently hydrogen, halogen, C1-C6 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,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, wherein R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, C1-C3 alkyl (phenyl) or PEG 1-20 ; R 3e For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl; Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ; Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl; Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocyclic alkyl or phenyl.

26. The molecule of claim 25 or a pharmaceutically acceptable salt thereof, wherein each R 3b It is hydrogen.

27. The molecule of claim 26 or a pharmaceutically acceptable salt thereof, wherein the 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.

28. 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 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups.

29. The molecule of claim 28 or a pharmaceutically acceptable salt thereof, wherein the two Rs 3b Together with the atoms it is attached to, it forms a cyclopropyl group.

30. The molecule according to claim 25, wherein the molecule has formula (IV), has a structure of formula (IVa), or a pharmaceutically acceptable salt thereof: 。 31. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, wherein R 2a R 2c R 2d R 2e and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Halogenated or optionally substituted PEG 1-20 Each of them may choose to pass through one or more R 6 replace.

32. The molecule of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2c R 2d R 2e and R 2h Each independently serves as an optional route via one or more R 6 Replacement C1-C 20 alkyl.

33. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, wherein R 2a R 2c R 2d R 2e and R 2h At least one of them is via one or more R 6 Replacement C1-C 20 Alkyl, and R 2a R 2c R 2d R 2e and R 2h Each of the others is independently unsubstituted C1-C 20 alkyl.

34. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, wherein R 2a For one or more R 6 Replacement C1-C 20 Alkyl, and R 2c R 2d R 2e and R 2h Each independently constitutes unsubstituted C1-C 20 alkyl.

35. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, wherein R 2c For one or more R 6 Replacement C1-C 20 Alkyl, and R 2a R 2d R 2e and R 2h Each independently constitutes unsubstituted C1-C 20 alkyl.

36. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, wherein R 2d For one or more R 6 Replacement C1-C 20 Alkyl, and R 2a R 2c R 2e and R 2h Each independently constitutes unsubstituted C1-C 20 alkyl.

37. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, wherein R 2e For one or more R 6 Replacement C1-C 20 Alkyl, and R 2a R 2c R 2d and R 2h Each independently constitutes unsubstituted C1-C 20 alkyl.

38. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, wherein R 2h For one or more R 6 Replacement C1-C 20 Alkyl, and R 2a R 2c R 2d and R 2e Each of the others is independently unsubstituted C1-C 20 alkyl.

39. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 31 to 38, wherein each R 6 Independently -N3, -NR 6a R 6b -CO(O)R 6c -C(O)OR 6c -C(O)NR 6a R 6b or -NHC(O)R 6c .

40. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 31 to 39, wherein each R 6 Independently -NHC(O)R 6c .

41. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, wherein L is C1-C2. 10 Alkylene or C2-C 10 Heteroalkyl groups.

42. The molecule of claim 41 or a pharmaceutically acceptable salt thereof, wherein L is C1-C2. 10 Alkylene.

43. The molecule of claim 41 or a pharmaceutically acceptable salt thereof, wherein L is C2-C 10 Heteroalkyl groups.

44. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, wherein L is absent.

45. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 44, wherein R 4 C1-C8 alkyl or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace; R 4b C1-C is optionally substituted 20 Alkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 20-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace; Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and Each R 5c It is independently a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl.

46. ​​The molecule according to claim 11, wherein the molecule has the structure of formula (V), or a pharmaceutically acceptable salt thereof: ， in: W 1 and W 1a Each is independently hydrogen, C1-C3 haloalkyl, or -N=C(N(R) 1e )2)2, where each R 1e Independently hydrogen or C1-C3 alkyl; Z does not exist; it is either -C(O)- or -C(=NH)-. R 4 C1-C8 alkyl, C3-C 10 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -OR 4b or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 replace; R 4b Hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 Replace; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace; R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is independently hydrogen, optionally substituted C1-C 20 Alkyl, C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Halogenated or optionally substituted PEG 1-20 Each of them may choose to pass through one or more R 6 replace; Each R 3b It is hydrogen; 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; Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ; Each R 5c Independently, it is a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl; Each R 6 Independent of halogen, -CN, -OH, -OR 6a -N3, -NR 6a R 6b -CO(O)R 6c -CO(O)OR 6c -C(O)NR 6a R 6b -NHC(O)R 6c -NHC(O)OR 6c -OC(O)NR 6a R 6b C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein R 6a and R 6b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ; R 6c For C1-C 20 Alkyl, PEG 1-20 C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl or phenyl; and x is between 0 and 10.

47. The molecule of claim 46 or a pharmaceutically acceptable salt thereof, wherein each R 3b It is hydrogen.

48. The molecule or a pharmaceutically acceptable salt thereof according to claim 46 or 47, wherein R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each independently represents the optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Halogenated alkyl groups, each optionally esterified by one or more R... 6 replace.

49. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 46 to 48, wherein each R 6 Independently -N3, -NR 6a R 6b -CO(O)R 6c -C(O)OR 6c -C(O)NR 6a R 6b or -NHC(O)R 6c .

50. The molecule of claim 49 or a pharmaceutically acceptable salt thereof, wherein each R 6 Independently -NHC(O)R 6c .

51. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 46 to 48, wherein R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each can be independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, -CF3 or -CH2CF3.

52. The molecule of claim 51 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 2c R 2d R 2e R 2g and R 2h Each is a methyl group.

53. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 46 or 47, wherein R 2a R 2b R 2c R 2d R 2e R 2g or R 2h At least one of them is not an unsubstituted C1-C 20 alkyl.

54. The molecule of claim 53 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.

55. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 46 to 54, wherein x is 0-6.

56. The molecule of claim 55 or a pharmaceutically acceptable salt thereof, wherein x is 1-4.

57. The molecule or a pharmaceutically acceptable salt thereof according to claim 55 or 56, wherein x is 1.

58. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 46 to 57, wherein R 4 It is a C1-C8 alkyl group.

59. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 46 to 57, wherein R 4 For -NR 4a R 4b .

60. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 57 or 59, wherein R 4a Hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl groups, each optionally via one or more R 5 Replace; and R 4b C1-C is optionally substituted 20 Alkyl, optionally substituted C1-C 20 Halogenated alkyl groups, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 12-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl, each optionally substituted with one or more R... 5 replace; Each R 5 Independent of halogen, -CN, -OH, -OR 5a -N3, -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c Replace, among which R 5a and R 5b Each independently is hydrogen, C1-C 20 Alkyl or PEG 1-20 ;and Each R 5c It is independently a C3-C8 cycloalkyl, a 4- to 8-membered heterocycloalkyl, or a phenyl.

61. The molecule of claim 60 or a pharmaceutically acceptable salt thereof, wherein R 4a Hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; and R 4b C1-C is optionally substituted 20 Alkyl, optionally substituted C1-C 20 Halogenated or optionally substituted C1-C 20 Heteroalkyl groups.

62. The molecule or a pharmaceutically acceptable salt thereof according to claim 60 or 61, wherein R 4a For C1-C 20 Alkyl and R 4b For C1-C 20 alkyl.

63. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 60 to 62, wherein R 4a It is methyl and R 4b It is a methyl group.

64. The molecule of claim 60 or a pharmaceutically acceptable salt thereof, wherein R 4b C3-C is optionally substituted 10 Cycloalkyl or optionally substituted 4- to 12-membered heterocyclic alkyl groups.

65. The molecule of claim 64 or a pharmaceutically acceptable salt thereof, wherein R 4b C3-C is optionally substituted 10 Cycloalkyl.

66. The molecule of claim 65 or a pharmaceutically acceptable salt thereof, wherein R 4b It is an optionally substituted cyclohexyl group.

67. The molecule of claim 64 or a pharmaceutically acceptable salt thereof, wherein R 4b It is an optionally substituted 4- to 12-membered heterocyclic alkyl group.

68. The molecule of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 4b It is optionally substituted piperidine, optionally substituted piperazine, or optionally substituted morpholine.

69. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 57 or 59, wherein R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 12-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 The heterocyclic alkyl group is replaced by a monocyclic, bicyclic, bridged, or spirocyclic alkyl group.

70. The molecule of claim 69 or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 4- to 6-membered heterocyclic alkyl groups, which are optionally substituted with one or more R... 5 replace.

71. The molecule of claim 70 or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted piperidine, optionally substituted piperazine, or optionally substituted morpholine.

72. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 71, wherein each R 5 Independent of halogen, -OH, -OR 5a -NR 5a R 5b Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclic alkyl, or optionally substituted phenyl, each optionally substituted with one or more R 5c replace.

73. The molecule of claim 72 or a pharmaceutically acceptable salt thereof, wherein each R 5 It can be halogen, -OH, -NH2, -N(CH3)2 or -CF3 independently.

74. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 72, wherein Z is absent.

75. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 72, wherein Z is -C(O)-.

76. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 72, wherein Z-C(=NH)-.

77. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 76, wherein W 1 It is hydrogen.

78. The molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 or 46 to 77, wherein W 1a It is hydrogen.

79. A transcriptional regulatory molecule selected from Table 1 or a pharmaceutically acceptable salt thereof.

80. A pharmaceutical composition comprising a molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 79, and a pharmaceutically acceptable excipient.

81. A method of treating a subject in need of Fuchs' endothelial dystrophy or Fuchs' endothelial corneal dystrophy (FECD), the method comprising administering to the subject an effective amount of the molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 79, or the pharmaceutical composition according to claim 80.

82. A method of treating a subject with myotonic dystrophy type 1 (DM1) in need, the method comprising administering to the subject an effective amount of the molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 79, or the pharmaceutical composition according to claim 80.

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