Methods and compounds for modulating genetic diseases

Abstract

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

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Patent Application No. 63 / 352,397, filed Jun. 15, 2022, and U.S. Patent Application No. 63 / 482,751, filed Feb. 1, 2023, both of which are hereby incorporated by reference in their entireties.

[0002] New chimeric cyclic polyamide compounds and compositions, and their use as agents for the treatment of diseases are disclosed herein. Methods for modulating the expression of target genes containing CTG trinucleotide repeat sequences in human or animal subjects are also provided for the treatment of diseases such as myotonic dystrophy type 1 (DM1) or Fuchs endothelial dystrophy or Fuchs corneal endothelial dystrophy (FECD).

Background Art

[0003] This disclosure relates to the treatment of hereditary genetic diseases characterized by overproduction of mRNA.

[0004] Myotonic dystrophy ( "DM") is a class of diseases known as muscular dystrophies, affecting approximately 1 in 8,000 people. DM is the most common form of muscular dystrophy among adult - onset patients, and most DM cases are diagnosed after the age of 20. DM is characterized by the persistence of muscle contraction and is associated with several symptoms including muscle impairment and cataracts, as well as heart and respiratory disorders, both of which are usually seen in the latter half of the disease progression. Treatments for improving related symptoms are available, but currently, no treatment has been used that can stop or reverse the progression of DM. Respiratory failure and cardiac arrhythmia are the most common causes of death among DM patients.

[0005] 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 myotonin-protein kinase. The MDPK protein can be found in muscle, heart, and nerve tissues.

[0006] DM1 is induced by the transcription of the defective dmpk gene in DM1 subjects. Normally, this gene contains a 3' untranslated region with 5 to 37 CTG trinucleotide repeats. In the DM1 genotype, this trinucleotide is expanded to over 50 to 3,000 repeats, most of which have CTG sequence repeats exceeding 1,000. This number tends to increase with each generation, resulting in an earlier onset age in later generations. Furthermore, it has been observed that this number increases over the lifetime of the subject, probably due to abnormal DNA repair.

[0007] The progression of DM1 is due to "RNA toxicity" from dmpk mRNA with an expanded CTG region. This mRNA forms aggregates with certain proteins, and these aggregates interfere with normal cellular function. The binding of the defective mRNA to the muscleblind protein may be the mechanism causing the symptoms of DM1, especially since muscleblind protein activity is required for proper muscle development in flies.

[0008] Fuchs endothelial dystrophy or Fuchs corneal endothelial dystrophy ("FECD") is a non-inflammatory, sporadic or autosomal dominant dystrophy that affects the endothelial layer of the cornea. In Fuchs dystrophy, the cornea begins to swell, causing glare, halos, and decreased vision. The corneal damage in Fuchs endothelial dystrophy can be severe enough to cause corneal blindness. Fuchs dystrophy is classified into early-onset (first 10 years) and late-onset (40 - 50 years), with women being predominant in the latter. Early-onset Fuchs involves the collagen type VIII alpha 2 chain. Late-onset is characterized by the transcription factor 4 (TCF4), transcription factor 8 (TCF8), ATP / GTP-binding protein-like 1 (AGBL1), lipoxygenase homology domain 1 (LOXHD1), solute carrier family 4 member 11 (SLC4A11) genes, and the involvement of transforming growth factor-beta induction and clusterin.

[0009] In some embodiments, the method provides effective treatment of a disease or disorder characterized by the presence of an excessive number of CTG trinucleotide repeat sequences in a target gene. In some embodiments, the pathophysiology of the disease or disorder is due to the presence of mRNA containing an excessive number of CTG trinucleotide repeat sequences. In some embodiments, the pathophysiology of the disease or disorder is due to the presence of a translation product containing an excessive number of glutamine amino acid residues. In some embodiments, the pathophysiology of the disease or disorder is due to a loss of function of the translation product. In some embodiments, the pathophysiology of the disease or disorder is due to a gain of function of the translation product. In some embodiments, the pathophysiology of the disease or disorder can be alleviated by increasing the transcription rate of a defective gene. In some embodiments, the pathophysiology of the disease or disorder can be alleviated by decreasing the transcription rate of a defective gene. SUMMARY OF THE INVENTION

[0010] The present disclosure utilizes regulatory molecules present in the cell nucleus that control gene expression. Eukaryotic cells provide several mechanisms for controlling gene replication, transcription, and / or translation. Regulatory molecules produced by various biochemical mechanisms within the cell can regulate the various processes involved in the conversion of genetic information into cellular components. Some regulatory molecules are known to regulate the production of mRNA, and when directed to a target gene (e.g., dmpk or tcf4), they regulate the production of the target gene mRNA that causes diseases such as DM1 or Fuchs endothelial corneal dystrophy, and thus reverse the progression of these diseases.

[0011] The present disclosure provides compounds and methods for recruiting regulatory molecules in proximity to a target gene containing a CTG trinucleotide repeat sequence. The compounds disclosed herein include a DNA-binding moiety that selectively binds to the target gene. The DNA-binding moiety will selectively bind to the characteristic CTG trinucleotide repeat sequence of dmpk or tcf4. This mechanism provides an effective treatment for DM1 and FECD, respectively, caused by the expression of defective dmpk or tcf4.

[0012] The DNA-binding moiety includes a polyamide segment that selectively binds to the target CTG sequence. For example, polyamides designed by Dervan (U.S. Pat. Nos. 9,630,950 and 8,524,899) can selectively bind to a selected DNA sequence. These polyamides are located in the minor groove of double-stranded DNA and form hydrogen bond interactions with Watson-Crick base pairs. Polyamides that selectively bind to a specific DNA sequence can be designed by linking monoamide components according to established chemical rules. One component is provided for each DNA base pair, and each component binds non-covalently and selectively to one of the DNA base pairs: A / T, T / A, G / C, and C / G. According to this guideline, a trinucleotide binds to a molecule having three amide units, i.e., a triamide. Generally, these polyamides can be oriented in either direction of the DNA sequence.

[0013] In principle, longer DNA sequences can be targeted with higher specificity and / or higher affinity by combining more monoamide components into longer polyamide chains. Ideally, the binding affinity for a polyamide is simply equal to the sum of each individual monoamide / DNA base pair interaction and / or heterocycle / DNA base pair interaction. However, in practice, due to significant geometric mismatches between the polyamide and the DNA structure, longer polyamide sequences do not bind to longer DNA sequences as tightly as expected from simple additive contributions. The geometric mismatch between longer polyamide sequences and longer DNA sequences induces unfavorable geometric strain that reduces the binding affinity otherwise expected.

[0014] Compounds are disclosed herein that include a polyamide moiety that can bind to one or more copies of a CTG trinucleotide repeat sequence and can modulate the expression of a target gene that includes the CTG trinucleotide repeat sequence. Treatment of a subject with these compounds can modulate the expression of the defective target gene, thereby reducing the occurrence, severity, or frequency of symptoms associated with the disease. Certain compounds disclosed herein provide higher binding affinity and selectivity than those previously observed for this class of compounds.

[0015] However, various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from the embodiments for carrying out the invention, and thus, while the embodiments and specific examples are illustrative of specific embodiments of the invention, it is to be understood that they are given by way of illustration only.

[0016] Incorporation by reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Embodiments for Carrying Out the Invention

[0017] The transcription modulator molecules described herein can be programmed to control the expression of a target gene comprising a nucleotide repeat containing CTG. The transcription modulator molecule contains a DNA-binding moiety that selectively binds to one or more copies of the CTG trinucleotide repeat characteristic of the defective target gene (e.g., dmpk, tcf4, atxn8, or atxn8os). The molecules and compounds disclosed herein provide higher binding affinity and selectivity than those previously observed for this class of compounds and may be more effective in the treatment of diseases associated with defective target genes.

[0018] Treatment of a subject with these compounds can modulate the expression of the defective target gene, thereby reducing the occurrence, severity, or frequency of symptoms associated with a genetic disease (e.g., DM1 or FECD, etc.). The compounds described herein recruit regulatory molecules to modulate the expression of the defective target gene and effectively treat and alleviate symptoms associated with the disease.

[0019] Compound - transcription modulator molecule In some embodiments, the transcription modulator molecule is a compound having a DNA-binding moiety that can non-covalently bind to a nucleotide repeat sequence containing CTG. In some embodiments, the DNA-binding moiety is a polyamide.

[0020] In some embodiments, the DNA-binding moiety comprises one or more monomeric subunits.

[0021] In some embodiments, one or more subunits comprise -NH-Q-C(O)-, wherein Q is optionally substituted C6-C 10 arylene, optionally substituted 4- to 10-membered heterocycle, optionally substituted 5- to 10-membered heteroarylene, or optionally substituted alkylene.

[0022] In some embodiments, the DNA-binding moiety is as follows:

[0023]

Chem.

[0024]

Chem.

[0025] In some embodiments, one or more subunits are independently selected from the group consisting of optionally substituted pyrrolecarboxamide monomers, optionally substituted imidazolecarboxamide monomers, optionally substituted δ-aminobutyric acid (gAB), and β-alanine (beta or β). In some embodiments, one or more of the carbonyl groups (C=O) of the polyamide backbone are replaced with oxetane. In some embodiments, at least one of the carbonyl groups of the polyamide backbone is replaced with oxetane.

[0026] In some embodiments, the polyamide comprises at least three aromatic carboxamide moieties selected to correspond to the nucleotide repeat sequence CTG and at least one aliphatic amino acid residue selected from the group consisting of glycine, β-alanine, δ-aminobutyric acid, 2,4-diaminobutyric acid, and 5-aminovaleric acid. In some embodiments, the polyamide comprises one or more subunits selected from the group consisting of optionally substituted N-methylpyrrole carboxamide, optionally substituted N-methylimidazole carboxamide, β-alanine, and δ-aminobutyric acid. In some embodiments, the DNA binding moiety comprises one δ-aminobutyric acid.

[0027] In one aspect, a transcriptional modulator molecule having the structure of formula (A), or a pharmaceutically acceptable salt thereof,

[0028]

Chemical formula

[0029] In some embodiments of formula (A), n0 is 1. In some embodiments, n0 is 0.

[0030] In some embodiments of formula (A), n2 is 2. In some embodiments, n2 is 1. In some embodiments, n2 is 0.

[0031] In some embodiments of formula (A), n3 is 1. In some embodiments, n3 is 0.

[0032] In another aspect, provided is a transcription modulator molecule having the structure of formula (A-1), or a pharmaceutically acceptable salt thereof,

[0033]

Chemical formula

[0034] In some embodiments of formula (A) or (A-1), p1 is 3. In some embodiments, p1 is 4.

[0035] In some embodiments of formula (A) or (A-1), each X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is independently NR 2 . In some embodiments, each X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is independently O.

[0036] In some embodiments of formula (A) or (A-1), W 1 is hydrogen, halogen, optionally substituted C1-C 10 alkyl, -NR 1e C(O)R 1f , -NR 1e C(O)NR 1e R 1f , -C(O)NR 1e R 1f , -OC(O)NR 1e R 1f , -NR 1e C(O)OR 1f , or AA 1~10 . In some embodiments, W 1 is hydrogen or optionally substituted C1-C 10 alkyl. In some embodiments, W 1 is -NR 1e C(O)R 1f , -NR 1e C(O)NR1e R 1f 、 -C(O)NR 1e R 1f 、 -OC(O)NR 1e R 1f 、 or -NR 1e C(O)OR 1f is. In some embodiments, W 1 is AA 1~10 is. In some embodiments, W 1 is AA 1~4 is. In some embodiments, W 1 is AA 1~3 is.

[0037] In some embodiments of formula (A) or (A - 1), W 1 is -Z B -PO(OR 1e )2, -Z B -(CH2) p3 -PO(OR 1e )2, or -Z B -(CH2) p3 -O-PO2(OR 1e )2, wherein Z B is O or N, and p3 is from 1 to 10.

[0038] In some embodiments of formula (A) or (A - 1), W 1 is (azanediylidene)methanediamine or (azanediylidene)-N,N,N’,N’-tetramethylmethanediamine.

[0039] In some embodiments of formula (A) or (A - 1), W 1 is guanidinyl. In some embodiments, W 1 is -N=C(N(R 1e )2)2, wherein each R 1e is independently hydrogen, optionally substituted C1 - C 20 alkyl, optionally substituted C2 - C 20 alkenyl, optionally substituted C2 - C 20 alkynyl, optionally substituted C1 - C 20Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, optionally substituted C2-C 50 Heteroalkynyl, or PEG 1~50 is.

[0040] In some embodiments of formula (A) or (A-1), W 1 is

[0041]

Chemical formula

[0042] In some embodiments of formula (A) or (A-1), W 1 is

[0043]

Chemical formula

[0044]

Chemical formula

[0045] In some embodiments of formula (A) or (A-1), W 1 is hydrogen or -N = C(N(R 1e ))2)2, wherein each R 1e is independently hydrogen or C1-C3 alkyl. In some embodiments, W 1 is hydrogen or -N = C(N(R 1e ))2)2, wherein each R 1e is independently hydrogen or methyl.

[0046] In some embodiments of formula (A) or (A-1), W 1 is hydrogen.

[0047] In some embodiments of formula (A) or (A-1), each R 1e is, independently, optionally substituted C1-C 20 alkyl, optionally substituted C2-C 20 alkenyl, optionally substituted C2-C 20 alkynyl, optionally substituted C1-C 20 heteroalkyl, optionally substituted C2-C 20 heteroalkenyl, optionally substituted C2-C 50 heteroalkynyl, or PEG 1~50 is. In some embodiments, each R 1e is, independently, optionally substituted C1-C 20 alkyl, optionally substituted C2-C 20 alkenyl, or optionally substituted C2-C 20 alkynyl. In some embodiments, each R 1e is, independently, optionally substituted C1-C 20 heteroalkyl, optionally substituted C2-C 20 heteroalkenyl, optionally substituted C2-C 50 heteroalkynyl, or PEG 1~50 is. In some embodiments, each R 1e is, independently, PEG 1~50 is. In some embodiments, each R 1e is, independently, hydrogen.

[0048] In some embodiments of formula (A) or (A-1), each R 1f is, independently, hydrogen, optionally substituted C1-C 20 alkyl, optionally substituted C2-C 20 alkenyl, optionally substituted C2-C 20 alkynyl, optionally substituted C1-C 20 heteroalkyl, optionally substituted C2-C 20 heteroalkenyl, optionally substituted C2-C 20heteroalkynyl, PEG 1~50 , or AA 1~10 is. In some embodiments, each R 1f is, independently, optionally substituted C1-C 20 alkyl, optionally substituted C2-C 20 alkenyl, optionally substituted C2-C 20 alkynyl, optionally substituted C 1~20 heteroalkyl, optionally substituted C2-C 20 heteroalkenyl, optionally substituted C2-C 50 heteroalkynyl, or PEG 1~50 is. In some embodiments, each R 1f is, independently, optionally substituted C1-C 20 alkyl, optionally substituted C2-C 20 alkenyl, or optionally substituted C2-C 20 alkynyl. In some embodiments, each R 1f is, independently, optionally substituted C1-C 20 heteroalkyl, optionally substituted C2-C 20 heteroalkenyl, optionally substituted C2-C 50 heteroalkynyl, or PEG 1~50 is. In some embodiments, each R 1f is, independently, PEG 1~50 is. In some embodiments, each R 1f is, independently, hydrogen.

[0049] In some embodiments of formula (A) or (A-1), R 1e and R 1f together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, R 1e and R 1f together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl. In some embodiments, R 1e and R 1fTogether with the nitrogen atom to which they are attached, they form an optionally substituted 5-membered heterocycloalkyl. In some embodiments, R 1e and R 1f Together with the nitrogen atom to which they are attached, they form an optionally substituted 6-membered heterocycloalkyl. In some embodiments, R 1e and R 1f Together with the nitrogen atom to which they are attached, they form an optionally substituted 7-membered heterocycloalkyl.

[0050] In some embodiments of formula (A) or (A-1), each R 2 is independently an optionally substituted C1-C 50 alkyl, an optionally substituted C2-C 50 alkenyl, an optionally substituted C2-C 50 alkynyl, an optionally substituted C2-C 50 heteroalkyl, an optionally substituted C2-C 50 heteroalkenyl, an optionally substituted C2-C 50 heteroalkynyl, an optionally substituted C1-C 50 aminoalkyl, an optionally substituted C1-C 50 hydroxyalkyl, an optionally substituted C1-C 50 haloalkyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted 3-8 membered heterocycloalkyl, or an optionally substituted PEG 1~50 is. In some embodiments, each R 2 is independently an optionally substituted C1-C 50 alkyl, an optionally substituted C1-C 50 aminoalkyl, an optionally substituted C1-C 50 hydroxyalkyl, or an optionally substituted PEG 1~50 is. In some embodiments, each R 2 is independently an optionally substituted C1-C 30 alkyl, an optionally substituted C1-C 50Aminoalkyl, optionally substituted C1-C 30 Hydroxyalkyl, or optionally substituted PEG 1~30 It is. In some embodiments, each R 2 Is independently optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Aminoalkyl, optionally substituted C1-C 20 Hydroxyalkyl, or optionally substituted PEG 1~20 It is. In some embodiments, each R 2 Is independently optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Hydroxyalkyl, or optionally substituted PEG 1~10 It is. In some embodiments, each R 2 Is optionally substituted with one or more amino, amide, azide, cyano, ester, oxo (=O), urea, optionally substituted aryl, PEG, or optionally substituted 5- to 10-membered heteroaryl.

[0051] In some embodiments of formula (A) or (A-1), each R 2 Is independently hydrogen or optionally substituted C1-C optionally substituted with one or more amino, amide, azide, cyano, ester, oxo (=O), urea, optionally substituted aryl, or optionally substituted 5- to 10-membered heteroaryl 50 Alkyl. In some embodiments, each R 2 Is independently optionally substituted C1-C 30 Alkyl. In some embodiments, each R 2 Is independently optionally substituted C1-C 20 Alkyl. In some embodiments, each R 2 Is independently optionally substituted C1-C 10 Alkyl. In some embodiments, each R2 is independently methyl, ethyl, isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, each R 2 is independently hydrogen or methyl. In some embodiments, each R 2 is ethyl. In some embodiments, each R 2 is isopropyl. In some embodiments, each R 2 is methyl. In some embodiments, each R 2 is hydrogen.

[0052] In some embodiments of formula (A) or (A-1), each R 3 is independently hydrogen, halogen, amino, amide, optionally substituted C1-C 20 alkyl, optionally substituted C1-C 20 haloalkyl, optionally substituted C1-C 20 alkylamino, or optionally substituted C1-C 20 hydroxyalkyl. In some embodiments, each R 3 is independently hydrogen, amino, amide, or optionally substituted C1-C 20 alkylamino. In some embodiments, each R 3 is independently hydrogen, amino, or amide. In some embodiments, each R 3 is independently amino. In some embodiments, each R 3 is independently amide. In some embodiments, each R 3 is hydrogen.

[0053] In some embodiments of formula (A) or (A-1), two Rs 3 together with the atom(s) to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl. In some embodiments, two Rs 3 together with the atom(s) to which they are attached form a C3-C6 cycloalkyl. In some embodiments, two Rs 3together with the atom(s) to which they are attached form a 4- to 6-membered heterocycloalkyl. In some embodiments, two R 3 together with the atom(s) to which they are attached form a 4-membered heterocycloalkyl. In some embodiments, two R 3 together with the atom(s) to which they are attached form a 5-membered heterocycloalkyl. In some embodiments, two R 3 together with the atom(s) to which they are attached form a 6-membered heterocycloalkyl. In some embodiments, two R 3 together with the atom(s) to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, two R 3 together with the atom(s) to which they are attached form a cyclopropyl. In some embodiments, two R 3 together with the atom(s) to which they are attached form a cyclobutyl. In some embodiments, two R 3 together with the atom(s) to which they are attached form a cyclopentyl.

[0054] In some embodiments of formula (A) or (A-1), W 2 is -L 1 -Z-R 4 wherein L 1 is alkylene or heteroalkylene, Z is absent, -C(O)-, or -C(=NH)-, and R 4 is -OR 4b or -NR 4a R 4b In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 20 alkylene or C2-C 20 heteroalkylene, Z is absent, -C(O)-, or -C(=NH)-, and R4 is -OR 4b or -NR 4a R 4bis. In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 10 alkylene or C2-C 10 heteroalkylene, Z is absent, -C(O)-, or -C(=NH)-, and R4 is -OR 4b or -NR 4a R 4b is. In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C8 alkylene or C2-C8 heteroalkylene, Z is absent, -C(O)-, or -C(=NH)-, and R4 is -OR 4b or -NR 4a R 4b is. In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C6 alkylene or C2-C6 heteroalkylene, Z is absent, -C(O)-, or -C(=NH)-, and R4 is -OR 4b or -NR 4a R 4b is.

[0055] In some embodiments of formula (A) or (A-1), W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 20 alkylene, Z is absent, -C(O)-, or -C(=NH)-, and R 4 is -NR 4a R 4b is. In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 10is alkylene, Z is absent, -C(O)-, or -C(=NH)-, and R 4 is -NR 4a R 4b In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C8 alkylene, Z is absent, -C(O)-, or -C(=NH)-, and R 4 is -NR 4a R 4b In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C6 alkylene, Z is absent, -C(O)-, or -C(=NH)-, and R 4 is -NR 4a R 4b In some embodiments of formula (A) or (A-1), W

[0056] is -L 2 -Z-R 1 wherein L 4 is C1-C 1 alkylene or C2-C 20 heteroalkylene, Z is absent or -C(O)-, and R 20 is -OR 4 or -NR 4b or -NR 4a R 4b In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 10 alkylene or C2-C 10 heteroalkylene, Z is absent or -C(O)-, and R 4 is -OR 4b or -NR 4a R 4b In some embodiments, W 2 is -L 1 -Z-R

[0056] 4 and in the formula, L 1 is C1-C8 alkylene or C2-C8 heteroalkylene, Z is absent or -C(O)-, and R 4 is -OR 4b or -NR 4a R 4b In some embodiments, W 2 is -L 1 -Z-R 4 and in the formula, L 1 is C1-C6 alkylene or C2-C6 heteroalkylene, Z is absent or -C(O)-, and R 4 is -OR 4b or -NR 4a R 4b In some embodiments of formula (A) or (A-1), W

[0057] is -L 2 -Z-R 1 and in the formula, L 4 is C1-C 1 alkylene, Z is -C(O)-, and R 20 is -NR 4 R 4a In some embodiments, W 4b is -L 2 -Z-R 1 and in the formula, L 4 is C1-C 1 alkylene, Z is -C(O)-, and R 10 is -NR 4 R 4a In some embodiments, W 4b is -L 2 -Z-R 1 and in the formula, L 4 is C1-C8 alkylene, Z is -C(O)-, and R 1 is -NR 4 R 4a In some embodiments, W 4b is -L 2 -Z-R 1 and in the formula, L 4 is C1-C8 alkylene, Z is -C(O)-, and R 1is C1-C6 alkylene, Z is -C(O)-, R 4 is -NR 4a R 4b is as follows.

[0058] In some embodiments of formula (A) or (A-1), W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 20 alkylene, Z is absent, and R 4 is -NR 4a R 4b is as follows. In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 10 alkylene, Z is absent, and R 4 is -NR 4a R 4b is as follows. In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C8 alkylene, Z is absent, and R 4 is -NR 4a R 4b is as follows. In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C6 alkylene, Z is absent, and R 4 is -NR 4a R 4b is as follows.

[0059] In some embodiments of formula (A) or (A-1), W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 20 alkylene or C1-C 20 heteroalkyl, Z is absent or -C(O)-, and R 4is C1-C6 alkyl. In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 20 alkylene, Z is absent or -C(O)-, and R 4 is C1-C6 alkyl. In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 20 alkylene, Z is -C(O)-, and R 4 is C1-C6 alkyl. In some embodiments, W 2 is -L 1 -Z-R 4 wherein L 1 is C1-C 20 alkylene, Z is absent, and R 4 is C1-C6 alkyl.

[0060] In another aspect, a transcription modulator molecule having the structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0061]

Chemical formula

[0062] In another aspect, there is provided a transcription modulator molecule having the structure of formula (I), or a pharmaceutically acceptable salt thereof,

[0063]

Chemical formula

[0064] In some embodiments, the molecule of formula (I) has the structure of formula (Ia) or is a pharmaceutically acceptable salt thereof,

[0065]

Chemical formula

[0066] In some embodiments, a transcription modulator molecule having the structure of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein

[0067]

Chemical formula

[0068] In some embodiments, the molecule of formula (I) has the structure of formula (Ib), or a pharmaceutically acceptable salt thereof,

[0069]

Chemical formula

[0070] In some embodiments, the molecule of formula (I) has the structure of formula (Ib) or a pharmaceutically acceptable salt thereof,

[0071]

Chemical formula

[0072] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), L 1 is C1-C 10 alkylene or C2-C 10 heteroalkylene. In some embodiments, L 1 is C1-C 10 alkylene, C1-C8 alkylene, C1-C6 alkylene, C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene, or C1-C2 alkylene. In some embodiments, L 1 is C1-C4 alkylene. In some embodiments, L 1 is C1-C3 alkylene. In some embodiments, L 1 is C1-C2 alkylene. In some embodiments, L 1 is C2-C 10 heteroalkylene, C2-C8 heteroalkylene, C2-C6 heterolkylene, C2-C5 heteroalkylene, or C2-C4 heteroalkylene. In some embodiments, L 1 is C2-C 10 heteroalkylene. In some embodiments, L 1is C2-C8 heteroalkylene. In some embodiments, L 1 is C2-C6 heterolkylene. In some embodiments, L 1 is C2-C5 heteroalkylene. In some embodiments, L 1 is C2-C4 heteroalkylene.

[0073] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), the heteroalkylene is polyethylene glycol. In some embodiments, L 1 is PEG 1~10 . In some embodiments, L 1 is PEG 1~8 . In some embodiments, L 1 is -(CH2CH2-O) y1 -, where y1 is an integer in the range of 1-10. In some embodiments, y1 is an integer in the range of 1-8. In some embodiments, y1 is an integer in the range of 1-6. In some embodiments, y1 is an integer in the range of 1-4. In some embodiments, y1 is 1-2.

[0074] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), the heteroalkylene contains -(CH2) x3 N(R a )(CH2) x4 -, where R a is hydrogen or optionally substituted C1-C6 alkyl, and each x3 and x4 is independently an integer in the range of 1-6.

[0075] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), Z is -C(O)- and R 4 is -OR 4b . In some embodiments, Z is -C(O)- and R 4 is -NR 4a R 4bIt is. In some embodiments, Z is -C(=NH)-, and R 4 is -NR 4a R 4b is. In some embodiments, Z is absent, and R 4 is -OR 4b is. In some embodiments, Z is absent, and R 4 is -NR 4a R 4b is. In some embodiments, Z is -C(O)-, and R 4 is C1-C6 alkyl. In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), Z is absent, and R 4 is C1-C6 alkyl.

[0076] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), R 4a is hydrogen, optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 heteroalkyl. In some embodiments, R 4a is optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 heteroalkyl. In some embodiments, R 4a is optionally substituted C1-C 20 alkyl. In some embodiments, R 4a is optionally substituted C1-C 15 alkyl. In some embodiments, R 4a is optionally substituted C1-C 10 alkyl. In some embodiments, R 4a is optionally substituted C1-C 20 heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG). In some embodiments, R 4a is optionally substituted PEG 1~20 is. In some embodiments, R 4ais optionally substituted PEG 1~15 In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), R 4a is optionally substituted PEG 1~10 In some embodiments, R 4a is hydrogen.

[0077] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), R 4b is optionally substituted C1-C 20 alkyl, optionally substituted C2-C 20 alkenyl, optionally substituted C2-C 20 alkynyl, optionally substituted C1-C 20 aminoalkyl, optionally substituted C1-C 20 haloalkyl, optionally substituted C1-C 20 heteroalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 4b is optionally substituted C1-C 20 alkyl, optionally substituted C1-C 20 aminoalkyl, optionally substituted C1-C 20 haloalkyl, optionally substituted C1-C 20 heteroalkyl, optionally substituted C1-C 20 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl.

[0078] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), R 4bis optionally substituted C1-C 20 alkyl, optionally substituted C1-C 20 aminoalkyl, optionally substituted C1-C 20 haloalkyl, optionally substituted C1-C 20 heteroalkyl, or optionally substituted C1-C 20 hydroxyalkyl. In some embodiments, R 4b is optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 heteroalkyl. In some embodiments, R 4b is optionally substituted C1-C 20 alkyl. In some embodiments, R 4b is optionally substituted C1-C 15 alkyl. In some embodiments, R 4b is optionally substituted C1-C 10 alkyl. In some embodiments, R 4b is optionally substituted C1-C 20 heteroalkyl. In some embodiments, R 4b is optionally substituted C1-C 15 heteroalkyl. In some embodiments, R 4b is optionally substituted C1-C 10 heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG). In some embodiments, R 4b is PEG 1~20 . In some embodiments, R 4b is PEG 1~15 . In some embodiments, R 4b is PEG 1~10 .

[0079] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), R 4bis optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 4b is optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, R 4b is optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl. In some embodiments, R 4b is optionally substituted C3-C6 cycloalkyl. In some embodiments, R 4b is cyclopentyl or cyclohexyl. In some embodiments, R 4b is optionally substituted 4- to 6-membered heterocycloalkyl. In some embodiments, R 4b is 5- or 6-membered heterocycloalkyl. In some embodiments, R 4b is piperidine, piperazine, or morpholine. In some embodiments, R 4b is piperidine or piperazine. In some embodiments, R 4b is piperidine. In some embodiments, R 4b is piperazine.

[0080] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), R 4a and R 4b together with the nitrogen to which they are attached form an optionally substituted 4- to 8-membered heterocycloalkyl that is partially or fully unsaturated. In some embodiments, R 4a and R 4b together with the nitrogen to which they are attached form an optionally substituted 4- to 6-membered heterocycloalkyl. In some embodiments, R 4a and R 4bforms, together with the nitrogen to which they are attached, an optionally substituted 4-membered heterocycloalkyl. In some embodiments, R 4a and R 4b form, together with the nitrogen to which they are attached, an optionally substituted 5-membered heterocycloalkyl. In some embodiments, R 4a and R 4b form, together with the nitrogen to which they are attached, an optionally substituted 6-membered heterocycloalkyl.

[0081] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), R 4a is hydrogen, optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 heteroalkyl, and R 4b is optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 heteroalkyl. In some embodiments, R 4a is hydrogen, C1-C 20 alkyl, or C1-C 20 heteroalkyl, and R 4b is C1-C 20 alkyl, or C1-C 20 heteroalkyl.

[0082] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), R 4a is optionally substituted C1-C 20 heteroalkyl, and R 4b is optionally substituted C1-C 20 heteroalkyl. In some embodiments, each heteroalkyl is polyethylene glycol (PEG). In some embodiments, R 4a is hydrogen or PEG 1~20 and R 4b is PEG 1~20 In some embodiments, R 4a is PEG 1~20and R 4b is PEG 1~20 is.

[0083] In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), R 4a is optionally substituted C1-C6 alkyl, and R 4b is optionally substituted C1-C6 alkyl. In some embodiments, R 4a is C1-C6 alkyl, and R 4b is C1-C6 alkyl.

[0084] In another aspect, a transcription modulator molecule having the structure of formula (II), or a pharmaceutically acceptable salt thereof, wherein

[0085]

Chemical formula

[0086] In some embodiments, the molecule of formula (II) has the structure of formula (IIa), or a pharmaceutically acceptable salt thereof,

[0087]

Chemical formula

[0088] In some embodiments of formula (II) or (IIa), L 3 is C1-C 10 alkylene or C2-C 10 heteroalkylene. In some embodiments, L 3 is C1-C 10 alkylene, C1-C8 alkylene, C1-C6 alkylene, C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene, or C1-C2 alkylene. In some embodiments, L 3 is C1-C4 alkylene. In some embodiments, L 3 is C1-C3 alkylene. In some embodiments, L 3 is C1-C2 alkylene. In some embodiments, L 3 is C2-C 10 heteroalkylene, C2-C8 heteroalkylene, C2-C6 heterolkylene, C2-C5 heteroalkylene, or C2-C4 heteroalkylene. In some embodiments, L 3 is C2-C 10 heteroalkylene. In some embodiments, L 3 is C2-C8 heteroalkylene. In some embodiments, L 3 is C2-C6 heterolkylene. In some embodiments, L 3 is C2-C5 heteroalkylene. In some embodiments, L 3 is C2-C4 heteroalkylene.

[0089] In some embodiments of formula (II) or (IIa), the heteroalkylene is polyethylene glycol. In some embodiments, L 3 is PEG 1~10 In some embodiments, L3 is PEG 1~8 In some embodiments, L 31 is -(CH2CH2-O) y1 - and y1 is an integer in the range of 1 to 10. In some embodiments, y1 is an integer in the range of 1 to 8. In some embodiments, y1 is an integer in the range of 1 to 6. In some embodiments, y1 is an integer in the range of 1 to 4. In some embodiments, y1 is 1 to 2.

[0090] In some embodiments of formula (II) or (IIa), the heteroalkylene of L 3 is -(CH2) x3 N(R a )(CH2) x4 - and in the formula, R a is hydrogen or optionally substituted C1-C6 alkyl, and each x3 and x4 is independently an integer in the range of 1 to 6.

[0091] In some embodiments of formula (II) or (IIa), L 3 is AA 1~10 and each AA is independently a naturally occurring amino acid. In some embodiments, L 3 is AA 1~8 In some embodiments, L 3 is AA 1~6 In some embodiments, L 3 is AA 1~5 In some embodiments, L 3 is AA 1~4 In some embodiments, L 3 is AA 1~3 In some embodiments, L 3 is AA 1~2 In some embodiments, each AA is the same or different. In some embodiments, each AA is the same. In some embodiments, each AA is different.

[0092] In some embodiments of formula (II) or (IIa), V is optionally substituted C3-C8 cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, V is optionally substituted C3-C8 cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, V is optionally substituted 5-10 membered heteroaryl. In some embodiments, V is optionally substituted phenyl or optionally substituted 6 membered heteroaryl. In some embodiments, V is optionally substituted phenyl. In some embodiments, V is optionally substituted 6 membered heteroaryl.

[0093] In some embodiments of formula (II) or (IIa), V is absent.

[0094] In some embodiments of formula (II) or (IIa), V is optionally substituted C3-C8 cycloalkyl. In some embodiments, V is optionally substituted C3-C6 cycloalkyl. In some embodiments, V is optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, V is cyclopentyl. In some embodiments, V is cyclohexyl.

[0095] In some embodiments of formula (II) or (IIa), V is an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, V is an optionally substituted 4- to 6-membered heterocycloalkyl. In some embodiments, V is an optionally substituted 6-membered heterocycloalkyl. In some embodiments, V is an optionally substituted piperazine, an optionally substituted piperidine, or an optionally substituted morpholine. In some embodiments, V is an optionally substituted piperazine. In some embodiments, V is an optionally substituted piperidine. In some embodiments, V is an optionally substituted morpholine.

[0096] In some embodiments of formula (II) or (IIa), V has the structure of formula (C) or a pharmaceutically acceptable salt thereof,

[0097]

Chemical formula

[0098]

Chemical formula

[0099] In some embodiments of formula (II) or (IIa), V has the structure of formula (C-1) or a pharmaceutically acceptable salt thereof,

[0100]

Chemical formula

[0101] In some embodiments of formula (II) or (IIa), V has the structure of formula (C-2) or a pharmaceutically acceptable salt thereof,

[0102] [Chemical formula] wherein, B 1 ’ and B 2 are each independently CH or N, B 3 is -CR 7a R 7b -, -O-, -S-, -S(O)-, -S(O)2-, or -NR 7b ]-, R 7a is hydrogen or optionally substituted C1-C 20 alkyl, R 7b is hydrogen, optionally substituted C1-C 20 alkyl, optionally substituted C2-C 20 alkenyl, optionally substituted C2-C 20 alkynyl, optionally substituted C1-C 20 heteroalkyl, -C(O)OR 8 or -C(O)R 8 ]-, R 8 is hydrogen, optionally substituted C1-C 20 alkyl, optionally substituted C1-C 10 haloalkyl, optionally substituted PEG 1~20 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3-6 membered hetero cycloalkyl, or optionally substituted phenyl, L 2 is absent or is C1-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene.

[0103] In some embodiments of formula (C-1) or (C-2), B 1 ’ is CH or N. In some embodiments, B 1 ’ is CH. In some embodiments, B 1 ’ is N.

[0104] In some embodiments of (C-2), B 1 ’ is CH and B 2 is N. In some embodiments, B 1 ’ is N and B 2 is CH.

[0105] In some embodiments of formula (II) or (IIa), V has the structure of formula (C-3) or a pharmaceutically acceptable salt thereof,

[0106]

Chemical Structure

[0107] In some embodiments of formula (C-2) or (C-3), B 2 is CH or N. In some embodiments, B 2 is CH. In some embodiments, B 2 is N.

[0108] In some embodiments of formula (C-2) or (C-3), B 3 is -CR 7a R 7b - or -O-. In some embodiments, B 3 is -CR 7a R 7b -. In some embodiments, B 3 is -O-. In some embodiments, B 3 is -S-, -S(O)-, or -S(O)2-. In some embodiments, B 3 is -NR 7b -.

[0109] In some embodiments of formula (C-2) or (C-3), R 7a is optionally substituted C1-C 20 alkyl. In some embodiments, R 7a is hydrogen.

[0110] In some embodiments of formula (C-2) or (C-3), R 7bis hydrogen, optionally substituted C1-C 20 alkyl, optionally substituted C2-C 20 alkenyl, optionally substituted C2-C 20 alkynyl, or optionally substituted C1-C 20 heteroalkyl. In some embodiments, R 7b is optionally substituted C1-C 20 alkyl. In some embodiments, R 7b is optionally substituted C2-C 20 alkenyl. In some embodiments, R 7b is optionally substituted C2-C 20 alkynyl. In some embodiments, R 7b is -C(O)OR 8 or -C(O)R 8 In some embodiments, R 7b is hydrogen.

[0111] In some embodiments of formula (C-2) or (C-3), R 8 is optionally substituted C1-C 20 alkyl. In some embodiments, R 8 is optionally substituted PEG 1~20 In some embodiments, R 8 is optionally substituted phenyl. In some embodiments, R 8 is hydrogen.

[0112] In some embodiments of formula (C-3), R 9a is optionally substituted C1-C 20 alkylene or optionally substituted PEG 1~20 In some embodiments, R 9a is optionally substituted C1-C 20 alkylene. In some embodiments, R 9a is optionally substituted PEG 1~20 In some embodiments, R 9ais hydrogen.

[0113] In some embodiments of formula (C-3), each R 9 is independently hydrogen or C1-C3 alkyl. In some embodiments, each R 9 is independently C1-C3 alkyl. In some embodiments, each R 9 is independently hydrogen.

[0114] In some embodiments of formula (C-3), s2 is 1 or 2. In some embodiments, s2 is 3. In some embodiments, s2 is 2. In some embodiments, s2 is 1.

[0115] In some embodiments of formula (II) or (IIa), V has the structure of formula (C-4) or a pharmaceutically acceptable salt thereof,

[0116]

Chemical formula

[0117] In some embodiments of formula (C-4), ring D is phenyl. In some embodiments, ring D is absent.

[0118] In some embodiments of (C-4), R 13 is C1-C6 alkyl. In some embodiments, R 13 is C3-C8 cycloalkyl. In some embodiments, R 13 is C3-C6 cycloalkyl. In some embodiments, R 13 is 4- to 8-membered heteroalkyl. In some embodiments, R 13 is 4- to 6-membered heterocycloalkyl.

[0119] In some embodiments of formula (II) or (IIa), V has the structure of formula (C-5) or a pharmaceutically acceptable salt thereof,

[0120]

Chemical formula

[0121] In some embodiments of formula (C-5), A is CH. In some embodiments, A is N.

[0122] In some embodiments of formula (C-5), R 14 is OH. In some embodiments, R 14 is NH2.

[0123] In some embodiments of formula (A) or (A-1), L 1 is C1-C 10 alkylene, R4 is -NR 4a R 4b wherein R 4a and R 4b together with the nitrogen to which they are attached optionally form a 4- to 8-membered heterocycloalkyl which is optionally substituted. In some embodiments, L 1 is C1-C4 alkylene, R4 is -NR 4a R 4b wherein R 4a and R 4b together with the nitrogen to which they are attached optionally form a 4-membered heterocycloalkyl which is optionally substituted. In some embodiments, L 1 is C1-C4 alkylene, R4 is -NR 4a R 4b wherein R 4a and R 4bforms, together with the nitrogen to which they are attached, an optionally substituted 5-membered heterocycloalkyl. In some embodiments, L 1 is C1-C4 alkylene and R4 is -NR 4a R 4b wherein R 4a and R 4b forms, together with the nitrogen to which they are attached, an optionally substituted 6-membered heterocycloalkyl. In some embodiments, L 1 is C1-C4 alkylene and R4 is -NR 4a R 4b wherein R 4a and R 4b forms, together with the nitrogen to which they are attached, an optionally substituted 7-membered heterocycloalkyl.

[0124] In some embodiments, a transcription modulator molecule having the structure of formula (III), or a pharmaceutically acceptable salt thereof,

[0125]

Chemical formula

[0126]

Chemical formula

[0127] In some embodiments of formula (II), (IIa), or (III), x1 is from 0 to 10. In some embodiments, x1 is from 0 to 8. In some embodiments, x1 is from 0 to 6. In some embodiments, x1 is from 1 to 10. In some embodiments, x1 is from 1 to 8. In some embodiments, x1 is from 1 to 6. In some embodiments, x1 is from 1 to 5. In some embodiments, x1 is from 1 to 4. In some embodiments, x1 is from 1 to 3. In some embodiments, x1 is from 1 to 2. In some embodiments, x1 is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, x1 is 1. In some embodiments, x1 is 2. In some embodiments, x1 is 3. In some embodiments, x1 is 4. In some embodiments, x1 is 5. In some embodiments, x1 is 6.

[0128] In another aspect, a transcription modulator molecule having the structure of formula (IV), or a pharmaceutically acceptable salt thereof, wherein

[0129]

Chemical Formula

[0130] In some embodiments of formula (A), (A-1), or (IV), W 2 is optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 heteroalkyl. In some embodiments, W 2 is optionally substituted C1-C 20 alkyl. In some embodiments, W 2 is optionally substituted C1-C 20 heteroalkyl.

[0131] In some embodiments of formula (A), (A-1), or (IV), W 2 is C1-C 20 alkyl. In some embodiments, W 2 is C1-C 15 alkyl. In some embodiments, W 2 is C1-C 10 alkyl. In some embodiments, W 2 is C1-C8 alkyl. In some embodiments, W 2 is C1-C6 alkyl. In some embodiments, W2 is C1-C3 alkyl. In some embodiments, W 2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, W 2 is C1-C3 alkyl. In some embodiments, W 2 is methyl. In some embodiments, W 2 is C1-C3 alkyl. In some embodiments, W 2 is ethyl. In some embodiments, W 2 is methyl, ethyl, n-propyl.

[0132] In some embodiments of formula (A), (A-1), or (IV), W 2 is C1-C 20 heteroalkyl. In some embodiments, W 2 is C1-C 15 heteroalkyl. In some embodiments, W 2 is C1-C 10 heteroalkyl. In some embodiments, W 2 is C1-C8 heteroalkyl. In some embodiments, W 2 is optionally substituted C1-C6 heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG). In some embodiments, W 2 is PEG, and PEG has 1 to 10 units. In some embodiments, W 2 is PEG 1~8 . In some embodiments, W 2 is PEG 1~6 . In some embodiments, W 2 is PEG 1~4 . In some embodiments, W 2 is PEG 1~3 .

[0133] In some embodiments of formula (A), (A-1), or (IV), W 2 is hydrogen.

[0134] In some embodiments of formula (A), (A-1), or (IV), R W is hydrogen. In some embodiments, R W is optionally substituted C1-C 20 alkyl.

[0135] In some embodiments of formula (A), (A-1), or (IV), W 2 and R w together with the nitrogen to which they are attached form an optionally substituted 4- to 8-membered heterocycloalkyl that is partially or fully unsaturated. In some embodiments, W 2 and R w together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocycloalkyl that is partially or fully unsaturated. In some embodiments, W 2 and R w together with the nitrogen to which they are attached form an optionally substituted 4-membered heterocycloalkyl. In some embodiments, W 2 and R w together with the nitrogen to which they are attached form an optionally substituted 5-membered heterocycloalkyl. In some embodiments, W 2 and R w together with the nitrogen to which they are attached form an optionally substituted 6-membered heterocycloalkyl. In some embodiments, W 2 and R w together with the nitrogen to which they are attached form an optionally substituted 7-membered heterocycloalkyl.

[0136] In some embodiments, the transcription modulator molecule has the structure of formula (V) or a pharmaceutically acceptable salt thereof,

[0137] [Chemical formula] wherein, B 1 is -CR5a R 5b is -O-, -NR 5b -, -S-, -S(O)-, or -S(O)2-, or B 1 is

[0138]

Chemical formula

[0139] In some embodiments of formula (C), (C-1), (III) or (V), q1 and q2 are each 2. In some embodiments, q1 and q2 are each 1. In some embodiments, q1 and q2 are each 0. In some embodiments, q1 is 1 or 2 and q2 is 0. In some embodiments, q1 is 0 and q2 is 1 or 2.

[0140] In some embodiments of formula (C), (C-1), (III) or (V), B 1 is -CR 5a R 5b -, -O-, -NR 5b -, or -S-. In some embodiments, B 1 is -O-, -NR 5b -, or -S-. In some embodiments, B 1 is -O-. In some embodiments, B 1 is -S-, -S(O)-, or -S(O)2-. In some embodiments, B 1is -S-. In some embodiments, B 1 is -S(O)-. In some embodiments, B 1 is -S(O)2-. In some embodiments, B 1 is -NR 5b -. In some embodiments, B 1 is -NH-. In some embodiments, B 1 is -CR 5a R 5b -. In some embodiments, B 1 is -CH2-.

[0141] In some embodiments of formula (C), (C-1), (III) or (V), B 1 is

[0142]

Chemical formula

[0143] In some embodiments, ring B is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In some embodiments, ring B is optionally substituted cycloalkyl. In some embodiments, ring B is C3-C8 cycloalkyl. In some embodiments, ring B is C3-C6 cycloalkyl. In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0144] In some embodiments of formula (C), (C-1), (III) or (V), ring B is an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, ring B is an optionally substituted 5- to 7-membered heterocycloalkyl. In some embodiments, ring B is an optionally substituted piperidine or an optionally substituted piperazine. In some embodiments, ring B is an optionally substituted piperidine. In some embodiments, ring B is an optionally substituted piperazine. In some embodiments, ring B is an optionally substituted morpholine.

[0145] In some embodiments of formula (C), (C-1), (C-2), (III) or (V), L 2 is absent or is C1-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene. In some embodiments, L 2 is C1-C4 alkylene. In some embodiments, L 2 is C2-C4 alkenylene. In some embodiments, L 2 is C2-C4 alkynylene.

[0146] In some embodiments of formula (C), (C-1), (C-2), (III) or (V), L 2 is -CH2-, -CH2CH2-,

[0147]

Chemical formula

[0148]

Chemical formula

[0149]

Chemical formula

[0150] In some embodiments of formula (C), (C-1), (C-2), (III) or (V), L 2 does not exist.

[0151] In some embodiments of formula (C), (III), or (V), R 5a is optionally substituted C1-C 20 alkyl. In some embodiments, R 5a is -OH. In some embodiments, R 5a is hydrogen.

[0152] In some embodiments of formula (C), (III), or (V), each R 5b is optionally substituted C1-C 20 alkyl, optionally substituted C2-C 20 alkenyl, or optionally substituted C2-C 20 alkynyl. In some embodiments, R 5b is C1-C 20 alkyl. In some embodiments, R 5b is C2-C 20 alkenyl. In some embodiments, C2-C 20 alkynyl. In some embodiments, R 5b is -C(O)OR 6 or -C(O)R 6 is. In some embodiments, R 5b is -C(O)OR 6 is. In some embodiments, R 5b is -C(O)R 6 is. In some embodiments, R 5b is hydrogen.

[0153] In some embodiments of formula (C), (III), or (V), R 5a and R 5b together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, R 5a and R 5b together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl. In some embodiments, R 5a and R 5b together with the nitrogen atom to which they are attached form an optionally substituted 5-membered heterocycloalkyl. In some embodiments, R 5a and R 5b together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocycloalkyl. In some embodiments, R 5a and R 5b together with the nitrogen atom to which they are attached form an optionally substituted 7-membered heterocycloalkyl.

[0154] In some embodiments of formula (C), (III), or (V), R 6 is optionally substituted C1-C 20 alkyl, optionally substituted C1-C 10 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4- to 6-membered heterocycloalkyl. In some embodiments, R 6 is optionally substituted C1-C 20 alkyl. In some embodiments, R 6 is C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl. In some embodiments, R 6 is optionally substituted phenyl.

[0155] In another aspect, a transcription modulator molecule having the structure of formula (VI), or a pharmaceutically acceptable salt thereof, wherein

[0156]

Chemical formula

[0157] In some embodiments of formula (VI), Y 8 is N, and Y 3 is CH. In some embodiments, Y 8 is CH, and Y 3 is N.

[0158] In some embodiments of formula (VI), Y 8 is N, and Y 3 is CH, and Y 1 is CH. In some embodiments, Y 8 is N, and Y 3 is CH, and Y 1 is N.

[0159] In some embodiments of formula (VI), L 1 is C1-C 10 alkylene or C2-C 10 heteroalkylene. In some embodiments, L 1 is C1-C 10It is alkylene, C1-C8 alkylene, C1-C6 alkylene, C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene, or C1-C2 alkylene. In some embodiments, L 1 is C1-C4 alkylene. In some embodiments, L 1 is C1-C3 alkylene. In some embodiments, L 1 is C1-C2 alkylene. In some embodiments, L 1 is C2-C 10 It is heteroalkylene, C2-C8 heteroalkylene, C2-C6 heterolkylene, C2-C5 heteroalkylene, or C2-C4 heteroalkylene. In some embodiments, L 1 is C2-C 10 heteroalkylene. In some embodiments, L 1 is C2-C8 heteroalkylene. In some embodiments, L 1 is C2-C6 heterolkylene. In some embodiments, L 1 is C2-C5 heteroalkylene. In some embodiments, L 1 is C2-C4 heteroalkylene.

[0160] In some embodiments of formula (VI), the heteroalkylene is polyethylene glycol. In some embodiments, L 1 is PEG 1~10 . In some embodiments, L 1 is PEG 1~8 . In some embodiments, L 1 is -(CH2CH2-O) y1 -, and y1 is an integer in the range of 1 to 10. In some embodiments, y1 is an integer in the range of 1 to 8. In some embodiments, y1 is an integer in the range of 1 to 6. In some embodiments, y1 is an integer in the range of 1 to 4. In some embodiments, y1 is 1 to 2. In some embodiments, the heteroalkylene is -(CH2) x3 N(R a)(CH2) x4 -containing, wherein R a is hydrogen or optionally substituted C1-C6 alkyl, and each of x3 and x4 is, independently, an integer in the range of 1 to 6.

[0161] In some embodiments of formula (VI), Z is -C(O)- and R 4 is -OR 4b . In some embodiments, Z is -C(O)- and R 4 is -NR 4a R 4b . In some embodiments, Z is absent and R 4 is -OR 4b . In some embodiments, Z is absent and R 4 is -NR 4a R 4b . In some embodiments, Z is -C(O)- and R 4 is C1-C6 alkyl. In some embodiments of formula (A), (A-1), (I), (Ia), or (Ib), Z is absent and R 4 is C1-C6 alkyl.

[0162] In some embodiments of formula (VI), n3 is 1 and m1 is 1, 2, or 3. In some embodiments, n3 is 1 and m1 is 1. In some embodiments, n3 is 1 and m1 is 2. In some embodiments, n3 is 1 and m1 is 3.

[0163] In some embodiments of formula (VI), n3 is 0 and m1 is 1, 2, or 3. In some embodiments, n3 is 0 and m1 is 2 or 3. In some embodiments, n3 is 0 and m1 is 1. In some embodiments, n3 is 0 and m1 is 2. In some embodiments, n3 is 0 and m1 is 3.

[0164] In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), W 1 is -N=C(N(R 1e )2)2, where each R 1e is independently hydrogen or C1-C3 alkyl. In some embodiments, each R 1e is independently hydrogen. In some embodiments, each R 1e is independently C1-C3 alkyl.

[0165] In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), W 1 is -N=C(N(CH3)2)2. In some embodiments, W 1 is hydrogen or -N=C(NH2)2.

[0166] In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), W 1 is hydrogen.

[0167] In some embodiments of formula (A), (A-1), (I), or (II), each Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 is independently N. In some embodiments, each Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 is independently CH.

[0168] In some embodiments, each Y 2 , Y 4 , Y 7 , and Y 8is, independently, N, and each Y 1 , Y 3 , and Y 6 is, independently, CH. In some embodiments, each Y 2 , Y 4 , Y 7 , and Y 8 is, independently, N. In some embodiments, each Y 1 , Y 3 , and Y 6 is, independently, CH.

[0169] In some embodiments of formula (A), (A-1), (I), (II), or (VI), each Y 1 is, independently, N. In some embodiments, each Y 1 is, independently, CH.

[0170] In some embodiments of formula (A), (A-1), (I), (II), or (VI), each Y 2 is, independently, N. In some embodiments, each Y 2 is, independently, CH.

[0171] In some embodiments of formula (A), (A-1), (I), (II), or (VI), each Y 3 is, independently, N. In some embodiments, each Y 3 is, independently, CH.

[0172] In some embodiments of formula (A), (A-1), (I), (II), or (VI), each Y 4 is, independently, N. In some embodiments, each Y 4 is, independently, CH.

[0173] In some embodiments of formula (A), (A-1), (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), each Y 5 is, independently, N. In some embodiments, each Y 5 is, independently, CH.

[0174] In some embodiments of formula (A), (A-1), (I), or (II), each Y 6 is, independently, N. In some embodiments, each Y 6 is, independently, CH.

[0175] In some embodiments of formula (A), (A-1), (I), or (II), each Y 7 is, independently, N. In some embodiments, each Y 7 is, independently, CH.

[0176] In some embodiments of formula (A), (A-1), (I), (II), or (VI), each Y 8 is, independently, N. In some embodiments, each Y 8 is, independently, CH.

[0177] In some embodiments of formula (A), (A-1), (I), (Ia), (Ib), (III), or (VI), Z is absent or is -C(O)-. In some embodiments, Z is absent. In some embodiments, Z is -C(O)-. In some embodiments, Z is -C(=NH)-.

[0178] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), or (V), each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , and R 2h is, independently, hydrogen, optionally substituted C1-C 50 alkyl, optionally substituted C2-C 50 alkenyl, optionally substituted C2-C 20 alkynyl, optionally substituted C1-C 50 heteroalkyl, optionally substituted C2-C 50 heteroalkenyl, optionally substituted C2-C50 heteroalkynyl, optionally substituted C1-C 50 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, or optionally substituted PEG 1~50 and each of them is optionally substituted with one or more R 10 . In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , and R 2h is independently hydrogen, optionally substituted C1-C 20 alkyl, optionally substituted C2-C 20 alkenyl, optionally substituted C2-C 20 alkynyl, optionally substituted C1-C 20 heteroalkyl, optionally substituted C2-C 20 heteroalkenyl, optionally substituted C2-C 20 heteroalkynyl, optionally substituted C1-C 20 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, or optionally substituted PEG 1~20 and each of them is optionally substituted with one or more R 10 . In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , and R 2h is independently hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C2-C 10 alkenyl, optionally substituted C2-C 10 alkynyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C2-C 10Heteroalkenyl, optionally substituted C2-C 10 Heteroalkynyl, optionally substituted C1-C 10 Haloalkyl, or optionally substituted PEG 1~10 is.

[0179] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), or (V), each R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h is independently hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, optionally substituted C1-C 10 alkylamino, or optionally substituted PEG 1~10 is. In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h is independently optionally substituted C1-C 10 heteroalkyl. In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h is independently optionally substituted C1-C 10 haloalkyl. In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h is independently -CF3 or -CH2CF3, or -CH2CH2CF3. In some embodiments, each R 2a , R2b , R 2c , R 2d , R 2e , R 2g , and R 2h is, independently, optionally substituted C1-C 10 alkylamino. In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h is, independently, optionally substituted PEG 1~10 . In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h is, independently, optionally substituted C1-C 10 alkyl. In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2g , and R 2h is, independently, methyl, ethyl, isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , and R 2g is, independently, hydrogen, methyl, ethyl, or isopropyl. In some embodiments, each R 2a , R 2b , R 2c , R 2e , R 2f , R 2g , and R 2g is, independently, isopropyl. In some embodiments, each R 2a , R 2b , R 2c , R 2d , R2e , R 2g , and R 2h is independently ethyl. In some embodiments, each R 2a , R 2b , R 2c , R 2e , R 2f , R 2g , and R 2g is methyl. In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , and R 2g is independently hydrogen.

[0180] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), or (V), each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , and R 2h is independently hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted PEG 1~10 , and each of them is optionally substituted with one or more R 10 . In some embodiments, each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , and R 2h is independently C1-C 10 alkyl, and each of them is optionally substituted with one or more R 10 .

[0181] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), or (V), each R 2a , R 2b , R 2d , and R 2g is independently optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted PEG 1~10 , each of which is optionally substituted with one or more R 10 , and each of R 2c , R 2e , and R 2h is independently unsubstituted C1-C 10 alkyl.

[0182] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), or (V), each of R 2c , R 2e , and R 2h is independently unsubstituted C1-C 10 alkyl. In some embodiments, each of R 2c , R 2e , and R 2h is independently methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, each of R 2c , R 2e , and R 2h is independently methyl, ethyl, or isopropyl. In some embodiments, each of R 2c , R 2e , and R 2h is independently methyl or isopropyl. In some embodiments, each of R 2c , R 2e , and R 2h is methyl.

[0183] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), or (V), each R 2a , R 2b , and R2g is, independently, unsubstituted C1-C 10 alkyl. In some embodiments, each R 2a , R 2b , and R 2g is, independently, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, each R 2a , R 2b , and R 2g is, independently, methyl, ethyl, or isopropyl. In some embodiments, each R 2a , R 2b , and R 2g is, independently, methyl or isopropyl. In some embodiments, each R 2a , R 2b , and R 2g is methyl.

[0184] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), or (V), each R 2a , R 2b , R 2c , R 2e , R 2f , R 2g , and R 2h is, independently, unsubstituted alkyl C1-C 10 alkyl optionally substituted with one or more R 10 alkyl, and R 2d is C1-C 10 alkyl. In some embodiments, each R 2a , R 2b , R 2c , R 2e , R 2f , R 2g , and R 2h is methyl, and R 2d is C1-C 10 alkyl optionally substituted with one or more R 10 alkyl.

[0185] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), R 2ais hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted PEG 1~10 and each of them is optionally substituted with one or more R 10 In some embodiments, R 2a is optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 haloalkyl. In some embodiments, R 2a is optionally substituted C1-C 10 alkyl substituted with one or more R 10 In some embodiments, R 2a is unsubstituted C1-C 10 alkyl. In some embodiments, R 2a is methyl, ethyl, or isopropyl. In some embodiments, R 2a is isopropyl. In some embodiments, R 2a is methyl. In some embodiments, R 2a is methyl. In some embodiments, R 2a is hydrogen.

[0186] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), R 2b is hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted PEG 1~10 and each of them is optionally substituted with one or more R 10 In some embodiments, R 2b is optionally substituted C1-C 10alkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 haloalkyl. In some embodiments, R 2b is optionally substituted C1-C 10 alkyl substituted with one or more R 10 In some embodiments, R 2b is unsubstituted C1-C 10 alkyl. In some embodiments, R 2b is methyl, ethyl, or isopropyl. In some embodiments, R 2b is isopropyl. In some embodiments, R 2b is ethyl. In some embodiments, R 2b is methyl. In some embodiments, R 2b is hydrogen.

[0187] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), each R 2c is independently hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted PEG 1~10 and each of them is optionally substituted with one or more R 10 In some embodiments, each R 2c is independently optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 haloalkyl. In some embodiments, each R 2c is independently optionally substituted C1-C 10 alkyl substituted with one or more R 10 In some embodiments, each R 2c is independently unsubstituted C1-C 10It is alkyl. In some embodiments, each R 2c is independently methyl, ethyl, or isopropyl. In some embodiments, each R 2c is independently isopropyl. In some embodiments, each R 2c is independently ethyl. In some embodiments, each R 2c is independently methyl. In some embodiments, each R 2c is independently hydrogen.

[0188] In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), R 2d is hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted PEG 1~10 wherein each is optionally substituted with one or more R 10 In some embodiments, R 2d is optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 haloalkyl. In some embodiments, R 2d is optionally substituted C1-C 10 alkyl substituted with one or more R 10 In some embodiments, R 2d is unsubstituted C1-C 10 alkyl. In some embodiments, R 2d is methyl, ethyl, or isopropyl. In some embodiments, R 2d is isopropyl. In some embodiments, R 2d is ethyl. In some embodiments, R 2d is methyl. In some embodiments, R 2d is hydrogen.

[0189] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), R 2e is hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted PEG 1~10 and each of them is optionally substituted with one or more R 10 In some embodiments, R 2e is optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 haloalkyl. In some embodiments, R 2e is optionally substituted C1-C 10 alkyl substituted with one or more R 10 In some embodiments, R 2e is unsubstituted C1-C 10 alkyl. In some embodiments, R 2e is methyl, ethyl, or isopropyl. In some embodiments, R 2e is isopropyl. In some embodiments, R 2e is ethyl. In some embodiments, R 2e is methyl. In some embodiments, R 2e is hydrogen.

[0190] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), each R 2f is independently hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted PEG 1~10and each of them is one or more R 10 is optionally substituted with. In some embodiments, each R 2f is independently optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 haloalkyl. In some embodiments, each R 2f is independently one or more R 10 substituted, optionally substituted C1-C 10 alkyl. In some embodiments, each R 2f is independently unsubstituted C1-C 10 alkyl. In some embodiments, each R 2d is independently methyl, ethyl, or isopropyl. In some embodiments, each R 2f is independently isopropyl. In some embodiments, each R 2f is independently ethyl. In some embodiments, each R 2f is independently methyl. In some embodiments, each R 2f is independently hydrogen.

[0191] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), or (V), R 2g is hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted PEG 1~10 and each of them is one or more R 10 is optionally substituted with. In some embodiments, R 2g is optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 haloalkyl. In some embodiments, R2g is optionally substituted C1-C alkyl substituted with one or more R 10 is. In some embodiments, R 10 is alkyl. In some embodiments, R 2g is unsubstituted C1-C 10 is alkyl. In some embodiments, R 2g is methyl, ethyl, or isopropyl. In some embodiments, R 2g is isopropyl. In some embodiments, R 2g is ethyl. In some embodiments, R 2g is methyl. In some embodiments, R 2g is hydrogen.

[0192] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), or (V), R 2h is hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, optionally substituted C1-C 10 haloalkyl, or optionally substituted PEG 1~10 and each of them is optionally substituted with one or more R 10 . In some embodiments, R 2h is optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 heteroalkyl, or optionally substituted C1-C 10 haloalkyl. In some embodiments, R 2h is optionally substituted C1-C substituted with one or more R 10 alkyl. In some embodiments, R 10 is alkyl. In some embodiments, R 2h is unsubstituted C1-C 10 is alkyl. In some embodiments, R 2h is methyl, ethyl, or isopropyl. In some embodiments, R 2h is isopropyl. In some embodiments, R 2his ethyl. In some embodiments, R 2h is methyl. In some embodiments, R 2h is hydrogen.

[0193] In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), each R 3a is independently hydrogen, deuterium, halogen, amino, optionally substituted C1-C 20 alkyl, optionally substituted C1-C 20 haloalkyl, optionally substituted C1-C 20 alkylamino, or optionally substituted C1-C 20 hydroxyalkyl. In some embodiments, each R 3a is independently hydrogen, amino, or optionally substituted C1-C 20 alkylamino. In some embodiments, each R 3a is hydrogen.

[0194] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), each R 3b is independently hydrogen, deuterium, halogen, amino, optionally substituted C1-C 20 alkyl, optionally substituted C1-C 20 haloalkyl, optionally substituted C1-C 20 alkylamino, or optionally substituted C1-C 20 hydroxyalkyl. In some embodiments, each R 3b is independently hydrogen, amino, or optionally substituted C1-C 20 alkylamino. In some embodiments, each R 3b is hydrogen.

[0195] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), each R 3b is hydrogen and each R 3ais, independently, hydrogen, halogen, amino, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 haloalkyl, optionally substituted C1-C 10 alkylamino, or optionally substituted C1-C 10 hydroxyalkyl. In some embodiments, each R 3b is hydrogen, and each R 3a is, independently, hydrogen, halogen, amino, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 haloalkyl, optionally substituted C1-C 10 alkylamino, or optionally substituted C1-C 10 hydroxyalkyl. In some embodiments, each R 3b is hydrogen, and each R 3a is, independently, hydrogen or amino.

[0196] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), each R 3a and each R 3b is hydrogen.

[0197] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), two R 3a together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, two R 3a together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, two R 3a together with the carbon atom to which they are attached form cyclopropyl. In some embodiments, two R 3a together with the carbon atom to which they are attached form cyclobutyl. In some embodiments, two R 3a together with the carbon atom to which they are attached form cyclopentyl. In some embodiments, two R3a together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl. In some embodiments, two R's 3a together with the carbon atom to which they are attached form a 4-membered heterocycloalkyl. In some embodiments, two R's 3a together with the carbon atom to which they are attached form a 5-membered heterocycloalkyl. In some embodiments, two R's 3a together with the carbon atom to which they are attached form a 6-membered heterocycloalkyl.

[0198] In some embodiments of formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), two R's 3b together with the carbon atom to which they are attached form a C3-C6 cycloalkyl ring. In some embodiments, two R's 3b together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, two R's 3b together with the carbon atom to which they are attached form cyclopropyl. In some embodiments, two R's 3b together with the carbon atom to which they are attached form cyclobutyl. In some embodiments, two R's 3b together with the carbon atom to which they are attached form cyclopentyl. In some embodiments, two R's 3b together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl. In some embodiments, two R's 3b together with the carbon atom to which they are attached form a 4-membered heterocycloalkyl. In some embodiments, two R's 3b together with the carbon atom to which they are attached form a 5-membered heterocycloalkyl. In some embodiments, two R's 3b together with the carbon atom to which they are attached form a 6-membered heterocycloalkyl.

[0199] In some embodiments of formula (A), (A-1), (I), (Ia), (Ib), or (VI), R 4a is hydrogen, optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 heteroalkyl. In some embodiments, R 4a is optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 heteroalkyl. In some embodiments, R 4a is optionally substituted C1-C 20 alkyl. In some embodiments, R 4a is optionally substituted C1-C 15 alkyl. In some embodiments, R 4a is optionally substituted C1-C 10 alkyl. In some embodiments, R 4a is optionally substituted C1-C 20 heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG). In some embodiments, R 4a is optionally substituted PEG 1~20 . In some embodiments, R 4a is optionally substituted PEG 1~15 . In some embodiments, R 4a is optionally substituted PEG 1~10 . In some embodiments, R 4a is hydrogen.

[0200] In some embodiments of formula (A), (A-1), (I), (Ia), (Ib), or (VI), R 4b is optionally substituted C1-C 20 alkyl, optionally substituted C1-C 20 aminoalkyl, optionally substituted C1-C 20 haloalkyl, optionally substituted C1-C 20Heteroalkyl, or optionally substituted C1-C 20 is hydroxyalkyl. In some embodiments, R 4b is optionally substituted C1-C 20 alkyl, or optionally substituted C1-C 20 heteroalkyl. In some embodiments, R 4b is optionally substituted C1-C 20 alkyl. In some embodiments, R 4b is optionally substituted C1-C 15 alkyl. In some embodiments, R 4b is optionally substituted C1-C 10 alkyl. In some embodiments, R 4b is optionally substituted C1-C 20 heteroalkyl. In some embodiments, R 4b is optionally substituted C1-C 15 heteroalkyl. In some embodiments, R 4b is optionally substituted C1-C 10 heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG). In some embodiments, R 4b is PEG 1~20 . In some embodiments, R 4b is PEG 1~15 . In some embodiments, R 4b is PEG 1~10 .

[0201] In some embodiments of formula (A), (A-1), (I), (Ia), (Ib), or (VI), R 4b is optionally substituted C3-C8 cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R 4bis optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, R 4b is optionally substituted C3-C6 cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl. In some embodiments, R 4b is optionally substituted C3-C6 cycloalkyl. In some embodiments, R 4b is cyclopentyl or cyclohexyl. In some embodiments, R 4b is optionally substituted 4- to 6-membered heterocycloalkyl. In some embodiments, R 4b is 5- or 6-membered heterocycloalkyl. In some embodiments, R 4b is piperidine, piperazine, or morpholine. In some embodiments, R 4b is piperidine or piperazine. In some embodiments, R 4b is piperidine. In some embodiments, R 4b is piperazine.

[0202] In some embodiments of formula (A), (A-1), (I), (Ia), (Ib), or (VI), R 4a and R 4b together with the nitrogen to which they are attached form an optionally substituted 4- to 8-membered heterocycloalkyl that is partially or fully unsaturated. In some embodiments, R 4a and R 4b together with the nitrogen to which they are attached form an optionally substituted 4- to 6-membered heterocycloalkyl. In some embodiments, R 4a and R 4b together with the nitrogen to which they are attached form an optionally substituted 4-membered heterocycloalkyl. In some embodiments, R 4a and R 4b together with the nitrogen to which they are attached form an optionally substituted 5-membered heterocycloalkyl. In some embodiments, R 4a and R4b together with the nitrogen to which they are attached, form an optionally substituted 6-membered heterocycloalkyl.

[0203] In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), each R 10 is independently -CN, -OH, -OR 10a , -N3, -NR 10a R 10b , -CO(O)R 10c , -C(O)OR 10c , -C(O)NR 10a R 10b , -NHC(O)R 10c , -NHC(O)OR 10c , -OC(O)NR 10a R 10b , or an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, each R 10 is independently -CN, -OH, -OR 10a , -N3, -NR 10a R 10b , -C(O)OR 10c , -C(O)NR 10a R 10b , -NHC(O)R 10c , or an optionally substituted 5-membered heteroaryl. In some embodiments, each R 10 is independently -CN, -OH, -OR 10a , -N3, or -NR 10a R 10b . In some embodiments, each R 10 is independently -CO(O)R 10c , -C(O)OR 10c , -C(O)NR 10a R 10b , -NHC(O)R 10c , -NHC(O)OR 10c , or -OC(O)NR 10a R 10b . In some embodiments, each R 10 is independently -C(O)NR 10a R 10b , -NHC(O)R10c 、 or -OC(O)NR 10a R 10b wherein. In some embodiments, each R 10 is, independently, an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, each R 10 is, independently, an optionally substituted 5-membered heteroaryl. In some embodiments, each R 10 is, independently, an optionally substituted triazine.

[0204] In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), each R 10a and R 10b is, independently, hydrogen, alkyl, or PEG. In some embodiments, each R 10a and R 10b is, independently, hydrogen, C1-C 20 alkyl, or PEG 1~20 wherein. In some embodiments, each R 10a and R 10b is, independently, C1-C 20 alkyl. In some embodiments, each R 10a and R 10b is, independently, PEG 1~20 wherein. In some embodiments, each R 10a and R 10b is, independently, hydrogen.

[0205] In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, R 10c is C1-C 20 alkyl, PEG 1~20 , C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or phenyl. In some embodiments, R 10c is C1-C 20 alkyl or PEG1~20 is. In some embodiments, R 10c is C1-C 20 alkyl. In some embodiments, R 10c is independently PEG 1~20 is. In some embodiments, R 10c is C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, or phenyl. In some embodiments, R 10c is C3-C6 cycloalkyl. In some embodiments, R 10c is 4-6 membered heterocycloalkyl. In some embodiments, R 10c is phenyl.

[0206] In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), R 11a and R 11b are each independently hydrogen, alkyl, or PEG. In some embodiments, R 11a and R 11b are each independently hydrogen, C1-C 20 alkyl, or PEG 1~20 is. In some embodiments, R 11a and R 11b are each independently C1-C 20 alkyl. In some embodiments, R 11a and R 11b are each independently PEG 1~20 is. In some embodiments, R 11a and R 11b are each independently hydrogen.

[0207] In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments, R 12 is C1-C 20 alkyl, PEG 1~20, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, or phenyl. In some embodiments, R 12 is C1-C 20 alkyl or PEG 1~20 . In some embodiments, R 12 is C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, or phenyl. In some embodiments, R 12 is C1-C 20 alkyl. In some embodiments, R 12 is PEG 1~20 . In some embodiments, R 12 is C3-C6 cycloalkyl. In some embodiments, R 12 is 4-6 membered heterocycloalkyl. In some embodiments, R 12 is phenyl.

[0208] In some embodiments of formula (A), (A-1), (II), or (IIa), each AA is, independently, a naturally occurring amino acid. In some embodiments, each AA is independently selected from lysine, arginine, serine, threonine, or cysteine. In some embodiments, each AA is independently selected from lysine or arginine. In some embodiments, each AA is independently selected from lysine. In some embodiments, each AA is independently selected from arginine.

[0209] In some embodiments of formula (A), (A-1), (I), (Ia), (Ib), (II), (III), (IV), (V), n1 is 1. In some embodiments, n1 is 0.

[0210] In some embodiments of formula (A), (A-1), (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), m1 is 1, 2, or 3. In some embodiments, m1 is 1 or 2. In some embodiments, m1 is 0 or 1. In some embodiments, m1 is 3. In some embodiments, m1 is 2. In some embodiments, m1 is 1. In some embodiments, m1 is 0.

[0211] Polyamide-DNA binding moiety The binding affinity between the compound and the target gene can be adjusted based on the composition of the polyamide sequence portion of the compound. In some embodiments, the compound can bind to DNA with an affinity of less than about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, or about 50 nM. In some embodiments, the compound can bind to DNA with an affinity in the range of about 1 - 600 nM, 10 - 500 nM, 20 - 500 nM, 50 - 400 nM, or 100 - 300 nM.

[0212] In some embodiments, the compound can bind to DNA with an affinity of less than 500 nM. In some embodiments, the compound can bind to DNA with an affinity of less than about 300 nM. In some embodiments, the compound can bind to DNA with an affinity of less than about 200 nM.

[0213] The binding affinity between the compound and the target DNA can be determined using a quantitative footprint titration experiment. The experiment measures the dissociation constant K of the polyamide for the target sequence using either standard polyamide assay solution conditions or approximate intracellular solution conditions, at either 24°C or 37°C. d This involves measuring.

[0214] The compound has a high binding affinity for sequences having a plurality of nucleotide repeats containing CTG and preferentially binds to the target nucleotide repeat over other nucleotide repeats or other nucleotide sequences. In some embodiments, the compound has a higher binding affinity for a sequence having a plurality of nucleotide repeats containing CTG than for a sequence having a CGG repeat. In some embodiments, the compound has a higher binding affinity for a sequence having a plurality of nucleotide repeats containing CTG than for a sequence having a CCG repeat. In some embodiments, the compound has a higher binding affinity for a sequence having a plurality of nucleotide repeats containing CTG than for a sequence having a CCTG repeat. In some embodiments, the compound has a higher binding affinity for a sequence having a plurality of nucleotide repeats containing CTG than for a sequence having a TGGAA repeat. In some embodiments, the compound has a higher binding affinity for a sequence having a plurality of nucleotide repeats containing CTG than for a sequence having a GGGGCC repeat. In some embodiments, the compound has a higher binding affinity for a sequence having a plurality of nucleotide repeats containing CTG than for a sequence having a GAA repeat.

[0215] Due to the preferential binding between the polyamide sequence and the target nucleotide repeats, the transcription modulator molecules described herein will localize around regions having sequences with multiple nucleotide repeats containing CTG. In some embodiments, the local concentration of the molecule is higher near sequences having multiple nucleotide repeats containing CTG than near sequences having CGG repeats. In some embodiments, the local concentration of the molecule is higher near sequences having multiple nucleotide repeats containing CTG than near sequences having CCG repeats. In some embodiments, the local concentration of the molecule is higher near sequences having multiple nucleotide repeats containing CTG than near sequences having CCTG repeats. In some embodiments, the local concentration of the molecule is higher near sequences having multiple nucleotide repeats containing CTG than near sequences having TGGAA repeats. In some embodiments, the local concentration of the molecule is higher near sequences having multiple nucleotide repeats containing CTG than near sequences having GGGGCC repeats. In some embodiments, the local concentration of the molecule is higher near sequences having multiple nucleotide repeats containing CTG than near sequences having GAA repeats.

[0216] In certain aspects provided herein, the molecules of the present disclosure preferentially bind to the repeated CTGs of dmpk, atxn8, atxn8os, or tcf4 over CTGs at other locations within the subject's DNA due to the high number of CTG repeats associated with dmpk, atxn8, atxn8os, or tcf4. In some embodiments, the molecules of the present disclosure are more likely to bind to the repeated CTGs of dmpk than to CTGs at other locations within the subject's DNA due to the high number of CTG repeats associated with dmpk. In some embodiments, the molecules of the present disclosure are more likely to bind to the repeated CTGs of atxn8 or atxn8os than to CTGs at other locations within the subject's DNA due to the high number of CTG repeats associated with atxn8 or atxn8os. In some embodiments, the molecules of the present disclosure are more likely to bind to the repeated CTGs of the tcf4 gene than to CTGs at other locations within the subject's DNA due to the high number of CTG repeats associated with tcf4.

[0217] The polyamide localizes to a sequence having a plurality of nucleotide repeats containing CTG and preferentially binds to the target nucleotide repeat over other nucleotide repeats. In some embodiments, the sequence has at least 2, 3, 4, 5, 8, 10, 12, 15, 20, 25, 30, 40, 50, 100, 200, 300, 400, or 500 repeats of CTG. In some embodiments, the sequence comprises at least 1000 nucleotide repeats of CTG. In some embodiments, the sequence comprises at least 500 nucleotide repeats of CTG. In some embodiments, the sequence comprises at least 200 nucleotide repeats of CTG. In some embodiments, the sequence comprises at least 100 nucleotide repeats of CTG. In some embodiments, the sequence comprises at least 50 nucleotide repeats of CTG. In some embodiments, the sequence comprises at least 20 nucleotide repeats of CTG.

[0218] Polyamides consisting of a preselected combination of subunits can bind selectively to DNA in the minor groove. In their hairpin structures, antiparallel parallel pairs of two aromatic amino acids bind to the DNA sequence, along with polyamide rings specifically filled for each DNA base. N-methylpyrrole (Py) prefers T, A, and C bases except G, N-methylimidazole (Im) is a G-reading factor, and 3-hydroxyl-N-methylpyrrole (Hp) is specific for thymine bases. Nucleotide base pairs can be recognized using various pairings of amino acid subunits according to the pairing principles shown in Tables 1A and 1B below. For example, the Im / Py pairing reads G·C by symmetry, the Py / Im pairing reads C·G, the Hp / Py pairing can distinguish T·A from A·T, G·C, and C·G, and the Py / Py pairing non-specifically distinguishes both A·T and T·A from G·C and C·G.

[0219] In some embodiments, the polyamide compound comprises Im corresponding to nucleotide G, Im or Nt corresponding to nucleotide pair G, Py corresponding to nucleotide C, where Im is N-alkylimidazole, Py is N-alkylpyrrole, Hp is 3-hydroxy N-methylpyrrole, and β-alanine. In some embodiments, the polyamide comprises Im / Py corresponding to nucleotide pair G / C, Py / Im corresponding to nucleotide pair C / G, where Im is N-alkylimidazole (e.g., N-methylimidazole), Py is N-alkylpyrrole (e.g., N-methylpyrrole), and Hp is 3-hydroxy N-methylpyrrole.

[0220]

Table 1-1

[0221]

Table 1-2

[0222]

Table 1-3

[0223]

Table 2-1

[0224]

Table 2-2

[0225] The monomer subunits of the polyamide compound can be linked together based on the pairing principles shown in Table 1A and Table 1B. The monomer subunits of the polyamide compound can be linked together based on the pairing principles shown in Table 1C.

[0226] Table 1C shows examples of monomer subunits that can bind to specific nucleotides. A polyamide can have several monomer subunits linked together with monomer subunits selected from each column. For example, a polyamide can include Py-β-Im that binds to CTG, where Py is selected from column C, β is selected from column T, and Im is selected from column G.

[0227] In addition, the polyamide portion of the compound can also include partial or multiple sets of 5 subunits, such as 1.5, 2, 2.5, 3, 3.5, or 4 sets of 3 subunits. The polyamide portion of the compound can include 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, and 16 monomer subunits.

[0228] The polyamide portion of the compound can include monomer subunits that bind to 2, 3, 4, or 5 nucleotides of CTG. For example, the polyamide portion of the compound can bind to CT, CTG, TGC, CTGC, CTGCT, CTGCTG, or CTGCTGC. The polyamide portion of the compound can include monomer subunits that bind to 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides of the CTG repeat.

[0229] When the monomer subunit is located as a terminal unit, it does not have an amine group, a carbonyl group, or a carboxylic acid group at the terminal. The terminal amine or carboxylic acid group is replaced by hydrogen. For example, when Py is used as a terminal unit,

[0230]

Chemical Structure

[0231]

Chemical Structure

[0232]

Table 3

[0233] The polyamide compound can also include a hairpin polyamide having subunits that are linked together based on the pairing principle shown in Table 1B. Table 1D shows some examples of pairs of monomer subunits that selectively bind to nucleotide pairs.

[0234] Because the target gene can contain multiple nucleotide repeats containing CTG, the subunits can be linked together to bind to at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in one or more CTG repeats (e.g., CTGCTGCTG). For example, a polyamide compound can bind to a CTG repeat by binding to a partial copy, complete copy, or multiple repeats containing CTG such as CT, CTG, TGC, CTGC, CTGCT, or CTGCTG. For example, a polyamide compound can contain Im-Im-Im-Im-β-β-W-Im-Im-β-Py-β-Py that binds to GGGGCC and its complementary nucleotides on double-stranded DNA, where the Im / Py pair binds to G·C, the Im / β pair binds to G·C, the Im / Py pair binds to G·C, the Im / β binds to G·C, the β / Im binds to C·G, and the β / Im binds to C·G. In one example, Py-β-Im-β-W-Im-Py-Py-Im that binds to CTGC and its complementary nucleotides on double-stranded DNA, where the Py / Im pair binds to C·G, the β / Py pair binds to T·A, the Im / Im pair binds to C·G, and the β / Py pair binds to C·G. W can be an aliphatic amino acid residue such as gAB or other suitable spacer as shown in Table 4. In another example, a polyamide compound can contain Im-Py-Py-Im-Py-gAB-Im-Py-Py-Im-β that binds to GCTGC and its complementary nucleotides on double-stranded DNA, where the Im / β pair binds to G·C, the Py / Im pair binds to C·G, the Py / Py binds to T·A, the Im / Py pair binds to G·C, and the Py / Im binds to C·G. In another example, Im-Py-Py-Im-Py-gAB-Im-Py-Py binds to a part (ACG) of the complementary nucleotides and GCTGC on double-stranded DNA, where Im binds to G, Py binds to C, Py / Py binds to T·A, Im / Py binds to G·C, and Py / Im binds to C·G.

[0235]

Table 4

[0236] Recognition of nucleotide repeats or DNA sequences by two antiparallel polyamide strands usually depends on the code of parallel aromatic amino acid pairs in the minor groove, which are oriented from N to C with respect to the 5' to 3' direction of the DNA helix. Enhanced affinity and specificity of polyamide-nucleotide binding are achieved by covalently linking the antiparallel strands. The "hairpin motif" connects the N- and C-termini of the two strands to W (e.g., a gamma-aminobutyric acid unit (gamma turn)) to form a folded straight chain.

[0237] Although various embodiments of the present invention are shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Without departing from the present invention, numerous variations, modifications, and substitutions may occur to those skilled in the art. It should be understood that various alternatives to the embodiments described herein may be used.

[0238] In some embodiments, non-limiting examples of the transcription modulator compounds described herein are shown in Table 2.

[0239] [Table 5-1]

[0240] [Table 5-2]

[0241] [Table 5-3]

[0242] [Table 5-4]

[0243] [Table 5-5]

[0244]

Table 5-6

[0245]

Table 5-7

[0246]

Table 5-8

[0247]

Table 5-9

[0248]

Table 5-10

[0249]

Table 5-11

[0250]

Table 5-12

[0251]

Table 5-13

[0252]

Table 5-14

[0253]

Table 5-15

[0254]

Table 5-16

[0255]

Table 5-17

[0256]

Table 5-18

[0257]

Table 5-19

[0258]

Table 5-20

[0259]

Table 5-21

[0260]

Table 5-22

[0261]

Table 5-23

[0262]

Table 5-24

[0263]

Table 5-25

[0264]

Table 5-26

[0265]

Table 5-27

[0266]

Table 5-28

[0267]

Table 5-29

[0268]

Table 5-30

[0269]

Table 5-31

[0270]

Table 5-32

[0271]

Table 5-33

[0272]

Table 5-34

[0273]

Table 5-35

[0274]

Table 5-36

[0275]

Table 5-37

[0276]

Table 5-38

[0277]

Table 5-39

[0278]

Table 5-40

[0279]

Table 5-41

[0280]

Table 5-42

[0281]

Table 5-43

[0282]

Table 5-44

[0283]

Table 5-45

[0284]

Table 5-46

[0285]

Table 5-47

[0286]

Table 5-48

[0287]

Table 5-49

[0288]

Table 5-50

[0289]

Table 5-51

[0290]

Table 5-52

[0291]

Table 5-53

[0292]

Table 5-54

[0293]

Table 5-55

[0294]

Table 5-56

[0295]

Table 5-57

[0296]

Table 5-58

[0297]

Table 5-59

[0298]

Table 5-60

[0299]

Table 5-61

[0300]

Table 5-62

[0301]

Table 5-63

[0302]

Table 5-64

[0303]

Table 5-65

[0304]

Table 5-66

[0305]

Table 5-67

[0306]

Table 5-68

[0307]

Table 5-69

[0308]

Table 5-70

[0309]

Table 5-71

[0310]

Table 5-72

[0311]

Table 5-73

[0312]

Table 5-74

[0313]

Table 5-75

[0314]

Table 5-76

[0315]

Table 5-77

[0316]

Table 5-78

[0317]

Table 5-79

[0318]

Table 5-80

[0319]

Table 5-81

[0320]

Table 5-82

[0321]

Table 5-83

[0322]

Table 5-84

[0323]

Table 5-85

[0324]

Table 5-86

[0325]

Table 5-87

[0326]

Table 5-88

[0327]

Table 5-89

[0328]

Table 5-90

[0329]

Table 5-91

[0330]

Table 5-92

[0331]

Table 5-93

[0332]

Table 5-94

[0333]

Table 5-95

[0334]

Table 5-96

[0335]

Table 5-97

[0336]

Table 5-98

[0337]

Table 5-99

[0338]

Table 5-100

[0339]

Table 5-101

[0340]

Table 5-102

[0341]

Table 5-103

[0342]

Table 5-104

[0343]

Table 5-105

[0344]

Table 5-106

[0345]

Table 5-107

[0346]

Table 5-108

[0347]

Table 5-109

[0348]

Table 5-110

[0349]

Table 5-111

[0350]

Table 5-112

[0351]

Table 5-113

[0352]

Table 5-114

[0353]

Table 5-115

[0354]

Table 5-116

[0355]

Table 5-117

[0356]

Table 5-118

[0357]

Table 5-119

[0358]

Table 5-120

[0359]

Table 5-121

[0360]

Table 5-122

[0361]

Table 5-123

[0362]

Table 5-124

[0363]

Table 5-125

[0364]

Table 5-126

[0365]

Table 5-127

[0366]

Table 5-128

[0367]

Table 5-129

[0368]

Table 5-130

[0369]

Table 5-131

[0370]

Table 5-132

[0371]

Table 5-133

[0372]

Table 5-134

[0373]

Table 5-135

[0374]

Table 5-136

[0375]

Table 5-137

[0376]

Table 5-138

[0377]

Table 5-139

[0378]

Table 5-140

[0379]

Table 5-141

[0380]

Table 5-142

[0381]

Table 5-143

[0382]

Table 5-144

[0383]

Table 5-145

[0384]

Table 5-146

[0385]

Table 5-147

[0386]

Table 5-148

[0387]

Table 5-149

[0388]

Table 5-150

[0389]

Table 5-151

[0390]

Table 5-152

[0391]

Table 5-153

[0392]

Table 5-154

[0393]

Table 5-155

[0394]

Table 5-156

[0395]

Table 5-157

[0396]

Table 5-158

[0397]

Table 5-159

[0398]

Table 5-160

[0399]

Table 5-161

[0400]

Table 5-162

[0401]

Table 5-163

[0402]

Table 5-164

[0403]

Table 5-165

[0404]

Table 5-166

[0405]

Table 5-167

[0406]

Table 5-168

[0407] Usage method The present disclosure also relates to a method of regulating the transcription of dmpk, atxn8, atxn80s, or tcf4, the method comprising contacting dmpk, atxn8, atxn80s, or tcf4 with a transcription modulator molecule described herein, or a pharmaceutically acceptable salt thereof.

[0408] Cell phenotypes, cell proliferation, transcription of dmpk, atxn8, atxn80s, or tcf4; production of mRNA from the transcription of dmpk, atxn8, atxn80s, or tcf4; translation of dmpk, atxn8, atxn80s, or tcf4; changes in biochemical output produced by the proteins encoded by dmpk, atxn8, atxn80s, or tcf4; or non-covalent binding of the proteins encoded by dmpk, atxn8, atxn80s, or tcf4 to natural binding partners may be monitored. Such methods can be in the form of disease treatment, biological assays, cell assays, biochemical assays, etc.

[0409] 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.

[0410] Also provided herein is a method of treating a disease mediated by the transcription of dmpk, atxn8, atxn80s, or tcf4, the method comprising administering to a patient in need thereof a therapeutically effective amount of a transcription modulator molecule or a salt thereof disclosed herein.

[0411] In some embodiments, the disease is selected from DM1 and FECD.

[0412] In some embodiments, the disease is DM1.

[0413] In some embodiments, the disease is Fuchs endothelial corneal dystrophy (FECD).

[0414] In another aspect, provided herein is a method of treating myotonic dystrophy type 1 (DM1) in a subject in need thereof, the method comprising administering to the subject an effective amount of a molecule disclosed herein, or a pharmaceutically acceptable salt thereof.

[0415] In another aspect, provided herein is a method of treating Fuchs endothelial dystrophy or Fuchs endothelial corneal dystrophy (FECD) in a subject in need thereof, the method comprising administering to the subject an effective amount of a molecule disclosed herein, or a pharmaceutically acceptable salt thereof.

[0416] Pharmaceutical Compositions and Administration The compounds described herein are administered as pharmaceutical compositions to a subject in need thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, according to standard pharmaceutical practices. In some embodiments, the compounds described herein are administered to an animal.

[0417] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a preparation that can be pharmaceutically used. The appropriate formulation depends on the route of administration selected. An overview of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, (N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), and such disclosures are incorporated herein by reference.

[0418] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizing agents, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, and any combination thereof.

[0419] The dosage of the agent described herein for treating a disease or disorder may depend on the condition of the subject, i.e., the stage of the disease, the severity of the symptoms caused by the disease, general health, as well as age, gender, and weight, and other factors that will be apparent to those skilled in the medical arts. The pharmaceutical composition may be administered in a manner appropriate for the disease being treated as determined by those skilled in the medical arts. In addition to the factors described herein and above related to the use of a pharmaceutical for treating a disease or disorder, the preferred period and frequency of administration of the pharmaceutical may also be determined or adjusted by 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 can generally be determined using experimental models and / or clinical trials. The optimal dosage may depend on the body mass, weight, or blood volume of the subject. Usually, it is preferred to use the minimum dosage sufficient to provide an effective therapy. The design and conduct of the preclinical and clinical studies of the pharmaceuticals described herein are well within the scope of the skill of those skilled in the art, including when administered for prophylactic benefit. When two or more pharmaceuticals are administered to treat a disease or disorder, the optimal dosage of each pharmaceutical may be different, such as less than when either agent is administered alone as monotherapy. In certain embodiments, two pharmaceuticals can be combined to act synergistically or additively and can be used in an amount less than when either agent is administered alone. The amount of the pharmaceutical that can be administered per day can be, for example, about 0.01 mg / kg to 100 mg / kg, such as about 0.1 to 1 mg / kg, about 1 to 10 mg / kg, about 10 to 50 mg / kg, about 50 to 100 mg / kg body weight. In other embodiments, the amount of the pharmaceutical that can be administered per day can be about 0.01 mg / kg to 1000 mg / kg body weight, about 100 to 500 mg / kg body weight, or about 500 to 1000 mg / kg body weight. The optimal dosage per day or per course of treatment may vary for the disease or disorder being treated and may also vary depending on the route of administration and the treatment regimen.

[0420] Abbreviations and Definitions Unless otherwise defined, all technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0421] Unless the context requires otherwise, throughout this specification and the following claims, the word "comprise", and variations such as "comprises" and "comprising", are to be construed in an open, inclusive sense, i.e., "including, but not limited to". Further, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0422] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Also, note that the term "or" is generally used in the sense of "and / or" unless the context clearly dictates otherwise regarding its content.

[0423] When a range of values is disclosed and the notation "n1…~n2" or "between n1…~n2" is used, n1 and n2 are numbers and, unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range can be integral or continuous and can include the final value. For example, since carbon is in integer units, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons. In comparison, as an example, the range "1 to 3 μM (micromoles)" is intended to include 1 μM, 3 μM, and all values in between to any significant digit (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0424] The following terms used herein shall have the following meanings unless otherwise indicated.

[0425] "Oxo" refers to =O.

[0426] "Carboxyl" refers to -COOH.

[0427] "Cyano" refers to -CN.

[0428] "Alkyl" refers to a monovalent group of a straight-chain or branched-chain saturated hydrocarbon having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups such as heptyl, octyl, etc. Whenever it appears in this specification, numerical ranges such as "C1-C6 alkyl" or "C1-6 alkyl" mean that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses the presence of the term "alkyl" for which no numerical range is specified. In some embodiments, alkyl is C1- 10It is alkyl. In some embodiments, the alkyl is C1-6 alkyl. In some embodiments, the alkyl is C1-5 alkyl. In some embodiments, the alkyl is C1-4 alkyl. In some embodiments, the alkyl is C1-3 alkyl. Unless otherwise specifically described herein, the alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0429] "Alkenyl" refers to a monovalent group of a straight-chain or branched hydrocarbon having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. This group may be in either the cis or trans conformation with respect to the double bond(s) and is to be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears in this specification, numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl" mean that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses the presence of the term "alkenyl" where no numerical range is specified. Unless otherwise specified herein, the alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0430] "Alkynyl" refers to a monovalent group of a straight-chain or branched hydrocarbon having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, numerical ranges such as "C2-C6 alkynyl" or "C2-6 alkynyl" mean that the alkynyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also encompasses the presence of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically described herein, the alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0431] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically described herein, the alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkylene is optionally substituted with oxo, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0432] "Alkoxy" refers to a group of the formula -OR a wherein R a is an alkyl group as defined. Unless otherwise specified herein, the alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted with halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0433] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system can contain only hydrogen and carbon, as well as 5 to 18 carbon atoms, and at least one of the rings in the ring system is aromatic, that is, according to Hückel's theory, it contains a cyclic delocalized (4n + 2)π electron system. Examples of the ring system from which the aryl group is derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. The aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that can include a fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring system. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Examples of aryl groups include, but are not limited to, aryl groups derived from hydrocarbon ring systems such as anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, perylene, pyrene, and triphenylene. Unless otherwise specified herein, the aryl can be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -N3, -CN, -C(O)OH, -C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0434] "Cycloalkyl" refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring which may include fused (when fused to an aryl or heteroaryl ring, cycloalkyl is attached via a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (e.g., a fully saturated cycloalkyl of C3-C 15 or a C3-C 15 cycloalkenyl), cycloalkyls having 3 to 10 carbon atoms (e.g., a fully saturated cycloalkyl of C3-C 10 or a C3-C 10cycloalkenyl), cycloalkyl having 3 to 8 carbon atoms (e.g., a fully saturated C3-C8 cycloalkyl or a C3-C8 cycloalkenyl), cycloalkyl having 3 to 6 carbon atoms (e.g., a fully saturated C3-C6 cycloalkyl or a C3-C6 cycloalkenyl), cycloalkyl having 3 to 5 carbon atoms (e.g., a fully saturated C3-C5 cycloalkyl or a C3-C5 cycloalkenyl), or cycloalkyl having 3 to 4 carbon atoms (e.g., a fully saturated C3-C4 cycloalkyl or a C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically described herein, the cycloalkyl may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -N3, -CN, -C(O)OH, -C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0435] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, including a fused ring system or a bridged ring system, preferably having 3 to 12 carbon atoms and containing at least one double bond. In certain embodiments, the cycloalkenyl contains 3 to 10 carbon atoms. In other embodiments, the cycloalkenyl contains 5 to 7 carbon atoms. The cycloalkenyl can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0436] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0437] As used herein, the terms "haloalkyl" or "haloalkane" refer to an alkyl group defined as being substituted with one or more halogen groups, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When the alkyl group is substituted with more than one halogen group, each halogen can be independently selected, for example, in 1-chloro, 2-fluoroethane.

[0438] "Fluoroalkyl" refers to an alkyl group defined as being substituted with one or more fluoro groups, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0439] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with 1, 2, or 3 hydroxyls. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0440] "Aminoalkyl" refers to an alkyl group as defined above, substituted by one or more amines. In some embodiments, the alkyl is substituted by one amine. In some embodiments, the alkyl is substituted by 1, 2, or 3 amines. Examples of aminoalkyl include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0441] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule by a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is C1-C6 heteroalkyl, where the heteroalkyl is composed of 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, and the heteroalkyl is attached to the remainder of the molecule by a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified herein, the heteroalkyl may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0442] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, the heterocycloalkyl contains 1 nitrogen. In some embodiments, the heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specifically stated herein, the heterocycloalkyl group may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom), spiro, or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having 2 to 15 carbon atoms (e.g., C2-C 15 of fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), heterocycloalkyls having 2 to 10 carbon atoms (e.g., C2-C 10 of fully saturated heterocycloalkyl or C2-C 10(heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (e.g., fully saturated heterocycloalkyl of C2-C8 or C2-C8 heterocycloalkenyl), heterocycloalkyl having 2 to 7 carbon atoms (e.g., fully saturated heterocycloalkyl of C2-C7 or C2-C7 heterocycloalkenyl), heterocycloalkyl having 2 to 6 carbon atoms (e.g., fully saturated heterocycloalkyl of C2-C6 or C2-C6 heterocycloalkenyl), heterocycloalkyl having 2 to 5 carbon atoms (e.g., fully saturated heterocycloalkyl of C2-C5 or C2-C5 heterocycloalkenyl), or heterocycloalkyl having 2 to 4 carbon atoms (e.g., fully saturated heterocycloalkyl of C2-C4 or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyl has 2 to 10 carbons in the ring.When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a fully saturated 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a fully saturated 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a fully saturated 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a fully saturated 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a fully saturated 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specifically stated herein, the heterocycloalkyl may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -C(O)OH, -C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0443] "Heteroaryl" refers to a 5- to 14-membered ring system group containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, heteroaryl contains 1 to 3 nitrogens. In some embodiments, heteroaryl contains 1 or 2 nitrogens. In some embodiments, heteroaryl contains 1 nitrogen. The heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fusion (when fused with a cycloalkyl ring or a heterocycloalkyl ring, heteroaryl is bonded via a non-aromatic ring atom), or a bridged ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized, and the nitrogen atom may optionally be quaternized. In some embodiments, heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, heteroaryl is a 6-membered heteroaryl. In some embodiments, heteroaryl is a 5-membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4 - benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2 - a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2 - oxoazepinyl, oxazolyl, oxiranyl, 1 - oxidopyridinyl, 1 - oxidopyrimidinyl, 1 - oxidopyrazinyl, 1 - oxidopyridazinyl, 1 - phenyl - 1H - pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, - CN, - C(O)OH, - C(O)OMe, - CF3, - OH, - OMe, - NH2, or - NO2.In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0444] The term "oligonucleotide sequence" refers to a defined sequence and multiple nucleic acids having a length (e.g., 2, 3, 4, 5, 6, or more nucleotides). The term "oligonucleotide repeat sequence" refers to a contiguous extension of an oligonucleotide sequence.

[0445] The term "transcription" is well known in the art and refers to the synthesis of RNA (i.e., ribonucleic acid) by a DNA-directed RNA polymerase. The term "regulating transcription" refers to a change in the transcription level that can be measured by methods well known in the art, e.g., an assay of the mRNA that is the transcription product. In certain embodiments, the regulation is an increase in transcription. In other embodiments, the regulation is a decrease in transcription.

[0446] The term "polyamide" refers to a polymer of bondable units chemically bonded by amide (i.e., CONH) bonds, and optionally, the polyamide includes a chemical probe attached thereto. Polyamides can be synthesized by the stepwise condensation of carboxylic acid (COOH) and amine (RR’NH) using methods known in the art. Alternatively, polyamides can also be formed by using an enzymatic reaction in vitro or by fermentation by microorganisms.

[0447] The term "bondable unit" refers to methylimidazole, methylpyrrole, and linear and branched aliphatic functional groups (e.g., methylene, ethylene, propylene, butylene, etc.) optionally containing a nitrogen substituent, and their chemical derivatives. The aliphatic functional groups of the bondable units can be provided, for example, by the condensation of B-alanine or dimethylaminopropylamine during the synthesis of polyamides by methods well known in the art.

[0448] The term "linker" or "oligomeric backbone" refers to a chain of at least 10 contiguous atoms. In certain embodiments, the linker comprises 20 or fewer non-hydrogen atoms. The terms "linker" and "oligomeric backbone" may be used synonymously. In some embodiments, the linker comprises 40 or fewer non-hydrogen atoms. In some embodiments, the linker comprises 60 or fewer non-hydrogen atoms. In certain embodiments, the linker comprises atoms selected from C, H, N, O, and S. In some embodiments, all non-hydrogen atoms are chemically bonded to either two adjacent atoms within the linker, or one adjacent atom within the linker and either end of the linker. In some embodiments, the linker forms an amide bond with at least one of the two other groups to which it is attached. In certain embodiments, the linker forms an ester or ether bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms a thioester or thioether bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms a direct carbon-carbon bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms an amine or amide bond with at least one of the two other groups to which it is attached. In some embodiments, the linker comprises -(CH2OCH2)- units. In some embodiments, the linker comprises -(CH(CH3)OCH2)- units. In some embodiments, the linker is R N =C 1~4 In the case of alkyl, it comprises -(CH2NR N CH2) units. In some embodiments, the linker comprises an arylene, cycloalkylene, or heterocycloalkylene moiety.

[0449] The term "bond" refers to a covalent bond between two atoms, or to two moieties when the atoms joined by the bond are considered to be part of a larger substructure. Unless otherwise specified, a bond can be a single, double, or triple bond. A dashed line between two atoms in a molecular drawing indicates that an additional bond may or may not be present at that position.

[0450] As used herein, "optionally substituted" means that the substituent is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced by another atom or group. Unless otherwise indicated, when a group is considered to be "substituted" or "optionally substituted", the group is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclic (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl,It means being substituted with one or more substituents independently selected from nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo(=O). When a group is described as "optionally substituted", the group can always be substituted with the above substituents.

[0451] The term "one or more", when referring to an optional substituent, means that the group in question is optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, the group in question is optionally substituted with 1, 2, or 3 substituents. In some embodiments, the group in question is optionally substituted with 1 or 2 substituents. In some embodiments, the group in question is optionally substituted with 1 substituent. In some embodiments, the group in question is optionally substituted with 2 substituents.

[0452] A chemical substance having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in the Z-form or E-form (or cis-form or trans-form). Further, some chemical substances can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z, E, and tautomeric forms.

[0453] In some embodiments, the compounds disclosed herein are in different enriched isotopic forms, for example, 2 H, 3 H, 11 C, 13 C and / or 14The content of C is used in a concentrated form. In one particular embodiment, the compound is deuterated at at least one position. Such 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 extending the duration of action of the drug.

[0454] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in that one or more isotope-enriched atoms are present. For example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for replacement of carbon with C-enriched carbon are within the scope of the present disclosure.

[0455] The compounds of the present disclosure optionally also contain non-natural proportions of atomic isotopes in one or more atoms that make up such compounds. For example, the compound may be labeled with an isotopic element such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br,81 Br, and 125 Isotopic substitution with I is contemplated for all. All isotopic variants of the compounds of the present invention are included within the scope of the present invention, whether radioactive or not. In some embodiments in which isotopic variants are illustrated, the remaining atoms of the compound may optionally contain moieties of non-natural atomic isotopes.

[0456] In certain embodiments, the compounds disclosed herein 1 Some or all of the H atoms are 2 Replaced by H atoms. Methods for synthesizing deuterium-containing compounds are known in the art, and non-limiting examples of such synthesis methods include the following.

[0457] Deuterium-substituted compounds are synthesized using a variety of methods as described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0458] Deuterated starting materials are readily available and provide for the synthesis of deuterium-containing compounds according to the synthesis methods described herein. A number of deuterium-containing reagents and components are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0459] In some embodiments of the compounds disclosed herein, one or more of the substituents contain deuterium at a higher percentage than the natural abundance of deuterium. In some embodiments of the compounds disclosed herein, one or more hydrogens are replaced with one or more deuteriums.

[0460] In some embodiments of the compounds disclosed herein, the abundance of deuterium in each of the substituents is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total number of hydrogens and deuteriums.

[0461] The compounds of the present disclosure also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrides), conformational polymorphs, and amorphous forms, and mixtures thereof, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity.

[0462] The compounds described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomers. When the absolute stereochemistry is not specified, the compounds presented herein include all forms of diastereomers, enantiomers, and epimers, and suitable mixtures thereof. Separation of stereoisomers can be accomplished by chromatography, or by forming diastereomers and separating them by recrystallization or chromatography, or by any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, which is hereby incorporated by reference herein for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0463] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Examples of inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Examples of inorganic bases from which the salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Examples of organic bases from which the salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine can be mentioned. In some embodiments, the pharmaceutically acceptable base addition salts can be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0464] The phrase "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without excessive toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0465] As used herein, the terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" mean pharmaceutically acceptable materials, compositions or vehicles such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and must not be harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers are: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as carboxymethylcellulose sodium, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl polyoleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0466] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses that is effective to produce the desired therapeutic effect.

[0467] As used herein, the terms "treat", "treating", or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, alleviating a disease or condition, reversing a disease or condition, alleviating a condition caused by a disease or condition, or arresting the symptoms of a disease or condition.

[0468] As used herein, the term "patient" is generally synonymous with the term "subject" and includes all mammals including humans. Examples of patients include domestic animals such as humans, cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and guinea pigs. Preferably, the patient is a human.

[0469] As used herein, the term "contact" refers to bringing a compound (e.g., a transcriptional molecular molecule of the present disclosure) into proximity with a desired target gene. Contacting can result in binding to the target moiety or can result in a conformational change in the target moiety.

[0470] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein may exist in unsolvated forms or in solvated forms with pharmaceutically acceptable solvents such as water, ethanol. Solvated forms of the compounds presented herein are also considered to be those disclosed herein. EXAMPLES

[0471] The following examples are provided for the purpose of illustrating various embodiments of the present invention and are not intended to limit the present invention in any way. These examples, together with the methods described herein, presently represent the preferred embodiments, are exemplary, and do not limit the scope of the present invention. Modifications and other uses that fall within the scope of the spirit of the present invention as defined by the scope of the claims will be apparent to those skilled in the art.

[0472] Synthesis of Compounds The compounds of the present disclosure can be prepared using the methods illustrated by the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes and experimental procedures are for illustrative purposes and are not intended to be limiting. The starting materials used to prepare the compounds of the present disclosure are commercially available or can be prepared using conventional methods known in the art.

[0473] Synthetic chemical transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0474] List of Abbreviations Ac2O = acetic anhydride, AcCl = acetyl chloride, ACN = acetonitrile, AcOH = acetic acid, AIBN = azobisisobutyronitrile, aq. = aqueous; Bu3SnH = tributyltin hydride; CD3OD = deuterated methanol; CDCl3 = deuterated chloroform; CDI = 1,1’-carbonyldiimidazole; DBU = 1,8-diazabicyclo[5.4.0] Undeca-7-ene; DCM = Dichloromethane; DEAD = Diethyl azodicarboxylate; DIBAL-H = Di-iso-butylaluminum hydride; DIEA = DIPEA = N,N-Diisopropylethylamine; DMAP = 4-Dimethylaminopyridine; DMF = N,N-Dimethylformamide; DMSO-d6 = Deuterated dimethyl sulfoxide; DMSO = Dimethyl sulfoxide; DPPA = Diphenylphosphoryl azide; EDC·HCl = EDCI·HCl = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = Diethyl ether; EA = Ethyl acetate; EtOH = Ethanol; h = hour; HATU = 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methylaminium; HMDS = Hexamethyldisilazane; HOBT = 1-Hydroxybenzotriazole; i-PrOH = Isopropanol; LAH = Lithium aluminum hydride; LiHMDS = Lithium bis(trimethylsilyl)amide; MeCN = Acetonitrile; MeOH = Methanol; MP-Carbonate resin = Macroporous triethylammonium methylpolystyrene carbonate resin; MsCl = Mesyl chloride; MTBE = Methyl tertiary butyl ether; MW = Microwave irradiation; n-BuLi = n-Butyllithium; NaHMDS = Sodium bis(trimethylsilyl)amide; NaOMe = Sodium methoxide; NaOtBu = Sodium t-butoxide; NBS = N-Bromosuccinimide; NCS = N-Chloro-succinimide; NMP = N-Methyl-2-pyrrolidone; Pd(Ph3)4 = Tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2 = Bis(triphenylphosphine)palladium(II) dichloride; PG = Protecting group; prep-HPLC = Preparative high performance liquid chromatography; PyBop = (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; Pyr = Pyridine; RT = Room temperature; RuPhos = 2-Dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl; sat.=Saturation; 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 = Tosyl chloride; XPhos = 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl.

[0475] Synthesis of Representative Polyamides Example 1. Synthesis of 1-Methyl-4-(3-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-4-(3-(1-methyl-1H-pyrrole-2-carboxamido)propanamido)-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)propanamido)-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)propanamido)-1H-imidazole-2-carboxylic acid (PA-03) Scheme 1.

[0476] [Chemical Structure] Step 1: To a solution of ethyl 1-methyl-4-nitroimidazole-2-carboxylate (30.00 g, 150.63 mmol, 1.00 equiv) in EtOH (120.00 mL) and EA (120.00 mL) was added Pd / C (8.01 g, 27% w / w). The reaction mixture was then stirred at room temperature for 17.0 h under a H2 atmosphere. The solid was filtered off and the filtrate was concentrated to give ethyl 4-amino-1-methylimidazole-2-carboxylate (22.30 g, 75.20%) as a yellow solid. LC / MS: C7H 11 Calculated mass for C7H3N3O2: 169.09, Found: 170.10 [M+H] + .

[0477] Step 2: To a 500 mL flask was added 3-[(tert-butoxycarbonyl)amino]propanoic acid (22.45 g, 118.65 mmol, 0.90 eq) in DMF (180.00 mL). The mixture was cooled to 0 °C, then HATU (75.18 g, 197.71 mmol, 1.50 eq) and DIEA (51.11 g, 395.43 mmol, 3.00 eq) were added, and the mixture was stirred for 10 minutes. Then ethyl 4-amino-1-methylimidazole-2-carboxylate (22.30 g, 131.81 mmol, 1.00 eq) was added in portions, and the reaction was stirred at room temperature for 1.0 h. The reaction was quenched with ice water (600 mL), and the solution was stirred for 15 minutes. The precipitated solid was collected by filtration, washed with water (3 × 50 mL), and dried under high vacuum. This gave ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylate (34.50 g, 76.90%) as a pale yellow solid. LC / MS: C 15 H 24 Calculated mass for C14H22N4O5: 340.17, Found: 341.20 [M+H] + .

[0478] Step 3: To a stirred solution of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylate (34.50 g, 101.36 mmol, 1.00 eq) in MeOH (200.00 mL) was added dropwise a LiOH solution (2 M, 202 mL, 4.00 eq) at room temperature. 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 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 high vacuum to give 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (30.00 g, 94.77%) as a white solid. LC / MS: C 13 H 20 Calculated mass for C12H18N4O5: 312.14, Found: 313.15 [M+H] + .

[0479] Step 4: To a stirred solution of 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid (16.00 g, 51.23 mmol, 1.00 equiv) in CH3CN (150.00 mL) was added TCFH (21.56 g, 76.84 mmol, 1.50 equiv), NMI (12.62 g, 153.69 mmol, 3.00 equiv), and methyl 4-amino-1-methylpyrrole-2-carboxylate hydrochloride (10.74 g, 56.34 mmol, 1.10 equiv) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 2.0 h. The precipitated solid was collected by filtration, washed with CH3CN (3 × 20 mL), and dried under high vacuum. Methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-amide)-1-methylpyrrole-2-carboxylate (19.00 g, 82.70%) was obtained as a white solid. LC / MS: C 20 H 28 Calculated mass for C19H28N6O6: 448.21, found: 449.25 [M+H] + .

[0480] Step 5: A solution of methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-amide)-1-methylpyrrole-2-carboxylate (19.00 g, 42.37 mmol, 1.00 equiv) in HCl / 1,4-dioxane (4 M, 200.00 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under high vacuum to give methyl 4-[4-(3-aminopropanamide)-1-methylimidazole-2-amide]-1-methylpyrrole-2-carboxylate hydrochloride (19.00 g of crude material) as a yellow solid. LC / MS: C 15 H 21 Calculated mass for C14H22ClN6O4: 348.15, found: 349.05 [M+H] + .

[0481] Step 6: The procedure was the same as for methyl 4-[4-(3-aminopropanamido)-1-methylimidazol-2-amide]-1-methylpyrrole-2-carboxylate hydrochloride. However, using 2.00 g of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylate, 2.00 g of the desired crude product was obtained as an off-white solid. LC / MS: C 10 H 16 Calculated mass for C 10 H 16 N4O3: 240.12, found: 241.10 [M+H] + .

[0482] Step 7: To a solution of 1-methylpyrrole-2-carboxylic acid (600.00 mg, 4.80 mmol, 1.00 equiv) in CH3CN (20.00 mL) was added NMI (1.22 g, 14.87 mmol, 3.10 equiv), TCFH (1.48 g, 5.28 mmol, 1.10 equiv), and methyl 4-[4-(3-aminopropanamido)-1-methylimidazol-2-amide]-1-methylpyrrole-2-carboxylate (2004.53 mg, 5.75 mmol, 1.20 equiv). The mixture was stirred at room temperature for 2.0 h. The solvent was then removed and the residue was purified by reverse phase column under the following conditions. Column, C18 column, MeCN / H2O (0.05% TFA), 5% - 50% gradient over 100 min; detector, 254 nm. The fractions were combined and concentrated to give 1.30 g of the desired product as a white solid (56% yield). LC / MS: C 21 H 25 Calculated mass for C 21 H 25 N7O5: 455.19, found: 456.30 [M+H] + .

[0483] Step 8: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid. However, using 2.00 g of methyl 1-methyl-4-(1-methyl-4-[3-[(1-methylpyrrol-2-yl)formamido]propanamide]imidazole-2-amide)pyrrole-2-carboxylate, 1.90 g of the desired product was obtained as a white solid (yield 92.00%). LC / MS: C 20 H 23 Calculated mass for C + .

[0484] Step 9: The procedure was the same as for methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-amide)-1-methylpyrrole-2-carboxylate, but the filtrate was concentrated and purified by a reverse-phase column. The reaction was carried out with 1.90 g of 1-methyl-4-(1-methyl-4-[3-[(1-methylpyrrol-2-yl)formamido]propanamide]imidazole-2-amide)pyrrole-2-carboxylic acid to give 2.70 g of the desired product as a white solid (yield 71.00%). LC / MS: C 35 H 41 N 13 Calculated mass for C + .

[0485] Step 10: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid, but using 2.70 g of methyl 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methyl-4-[3-[(1-methylpyrrol-2-yl)formamido]propanamide]imidazole-2-amide)pyrrole-2-yl]formamido]propanamide)imidazole-2-amide]pyrrole-2-carboxylate, 2.80 g of the desired product was obtained as a white solid (yield 78.00%). LC / MS: C 34 H39 N 13 Calculated mass for O8: 757.30, measured value: 758.50 [M+H] + .

[0486] Step 11: To a solution of 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methyl-4-[3-[(1-methylpyrrol-2-yl)formamide]propanamide]imidazol-2-yl)pyrrol-2-yl]formamide]propanamide)imidazol-2-yl]pyrrole-2-carboxylic acid (2.90 g, 3.83 mmol, 1.00 equivalent) in DMF (25.00 mL) were added NMI (3.20 g, 39.04 mmol, 10.20 equivalents), TCFH (1.18 g, 4.21 mmol, 1.10 equivalents), and ethyl 4-(3-aminopropanamide)-1-methylimidazole-2-carboxylate (1.16 g, 4.21 mmol, 1.10 equivalents). The reaction mixture was then stirred at room temperature for 3.0 h. The mixture was then poured into ice water and the solid was filtered off. The crude product was then purified by silica gel column chromatography (DCM / MeOH = 10:1) to afford 2.5 g of the desired product as a white solid (yield 66.00%). LC / MS: C 44 H 53 N 17 O 10 Calculated mass for: 979.42, measured value: 980.80 [M+H] + .

[0487] Step 12: The procedure was the same as that for 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid, but the reaction temperature was 40 °C and the reaction time was 4.0 h. Using 2.50 g of ethyl 1-methyl-4-[3-([1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methyl-4-[3-[(1-methylpyrrol-2-yl)formamide]propanamide]imidazole-2-amide)pyrrol-2-yl]formamide]propanamide)imidazole-2-amide]pyrrol-2-yl]formamide)propanamide]imidazole-2-carboxylate, 1.90 g of the desired product was obtained as a white solid (yield 78.00%). LC / MS: C 42 H 49 N 17 O 10 Calculated mass for: 951.38, found: 952.65 [M+H] + .

[0488] Example 2. Synthesis of 3-[(1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amide)pyrrol-2-yl]formamide}propanamide)imidazole-2-amide]pyrrol-2-yl}formamide)butanamide]imidazole-2-yl}formamide)propanamide]pyrrol-2-amide}imidazole-2-yl)formamide]propanoic acid (PA-004) Scheme 2.

[0489]

Chemical formula

[0490]

Chemical formula

[0491]

Chemical formula

[0492] Step 2: The procedure was the same as that for methyl 4-[4-(3-aminopropanamide)-1-methylimidazole-2-amide]-1-methylpyrrole-2-carboxylate hydrochloride (Step 6 of Example 1), but the reaction time was 1.0 hour. Using methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-yl)formamide]propanoate (11.00 g), 11.00 g of the desired product as a crude substance was obtained as a yellow oil. LC / MS: C 12 H 19 Calculated mass for C13H21N5O4: 297.14, found: 298.20 [M+H]+ .

[0493] Step 3: To a stirred solution of 1-methylimidazole-2-carboxylic acid (10.00 g, 79.29 mmol, 7.00 eq) in DMF (150.00 mL) was added TBTU (38.19 g, 118.94 mmol, 1.50 eq), methyl 4-amino-1-methylpyrrole-2-carboxylate hydrochloride (16.63 g, 87.24 mmol, 1.10 eq), and DIEA (30.74 g, 237.88 mmol, 3.00 eq) in portions at 0 °C. The resulting mixture was stirred at room temperature for 17.0 h. The reaction was poured into water / ice (450 mL), and the precipitated solid was collected by filtration, washed with H2O (3 × 50 mL), and dried under high vacuum. Methyl 1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2-carboxylate (16.5 g, 78.37%) was obtained as a white solid. LC / MS: C 12 H 14 Calculated mass for C11H13N4O3: 262.11, found: 263.15 [M+H] + .

[0494] Step 4: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1). Using methyl 1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2-carboxylate (16.50 g), 12.00 g of 1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2-carboxylic acid (yield 76.84%) was obtained as a white solid. LC / MS: C 11 H 12 Calculated mass for C10H11N4O3: 248.09, found: 249.10 [M+H] + .

[0495] Step 5: The procedure was the same as that of ethyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazol-2-yl)formamido]propanoate (Step 2 of Example 1). Using 1-methyl-4-(1-methylimidazol-2-amide)pyrrole-2-carboxylic acid (9.00 mg), 14.00 g of the desired product (yield 63.54%) was obtained as a yellow solid. LC / MS: C 26 H 30 N 10 Calculated mass for C, H, N, O6: 578.23, found: 579.10 [M+H] + .

[0496] Step 6: The procedure was the same as that of 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1). Using methyl 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-yl)pyrrole-2-yl]formamido]propanamido)imidazol-2-amido]pyrrole-2-yl]formamide carboxylate (14.00 g), 12.00 g of the desired product (yield 81.49%) was obtained as a yellow solid. LC / MS: C 25 H 28 N 10 Calculated mass for C, H, N, O6: 564.22, found: 565.15 [M+H] + 。

[0497] Step 7: The procedure was the same as that of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylate (Step 2 of Example 1). Using 4-[(tert-butoxycarbonyl)amino]butanoic acid (7.80 g), 11.00 g of the desired product was obtained as a peach-colored solid (yield 80.70%). LC / MS: C 16 H 26 Calculated mass for C, H, N4O5: 354.19, found: 355.15 [M+H] + 。

[0498] Step 8: The procedure was the same as that for methyl 4-[4-(3-aminopropanamido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate hydrochloride (Step 6 of Example 1). Using ethyl 4-{4-[(tert-butoxycarbonyl)amino]butanamido}-1-methylimidazole-2-carboxylate (9.40 g), 6.20 g of the desired product was obtained as a white solid (yield 90.89%). LCMS: C 11 H 18 Calculated mass for C + H

[0499] Step 9: To a stirred solution of 1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]pyrrole-2-carboxylic acid (18.20 g, 32.24 mmol, 1.00 equiv) in DMF (250.00 mL) was added DIEA (12.50 g, 96.71 mmol, 3.00 equiv), ethyl 4-(4-aminobutanamido)-1-methylimidazole-2-carboxylate (9.02 g, 35.46 mmol, 1.10 equiv), and PyBOP (20.13 g, 38.68 mmol, 1.20 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1.0 h and then poured into ice / water (800 mL). The precipitated solid was collected by filtration, washed with H2O (3 × 200 mL), and dried under high vacuum to give 24.70 g of ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate as a yellow solid (yield 95.74%). LC / MS: C 36 H 44 N 14 Calculated mass for C + H

[0500] Step 10: The procedure was the same as that for 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1). Using ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amide)pyrrol-2-yl]formamide}propanamide)imidazole-2-amide]pyrrol-2-yl}formamide)butanamide]imidazole-2-carboxylate (24.00 g), 23.10 g of the desired product was obtained as a yellow solid (yield 99.36%). LC / MS: C 34 H 40 N 14 Calculated mass for C H N O8: 772.32, found: 773.30 [M+H] + .

[0501] Step 11: 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) was added EDCI (22.94 g, 119.66 mmol, 2.50 equivalents), ethyl 4-amino-1-methylimidazole-2-carboxylate (8.10 g, 47.87 mmol, 1.00 equivalent), and DMAP (14.62 g, 119.66 mmol, 2.50 equivalents) at 0 °C. The resulting mixture was stirred at 35 °C for 17.0 h. The reaction was then poured into 500 mL of ice / water and the precipitated solid was collected by filtration, washed with water (3 × 50 mL), and dried under high vacuum. This gave ethyl 4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amide}-1-methylimidazole-2-carboxylate (16.00 g, 85.48% yield) as a pale yellow solid. LC / MS: C 18 H 25 Calculated mass for C H N5O5: 391.19, found: 392.30 [M+H] + .

[0502] Step 12: To a stirred solution of ethyl 4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-carboxamido}-1-methylimidazole-2-carboxylate (16.00 g, 40.88 mmol, 1.00 equiv) in DCM (135.00 mL) was added dropwise TFA (45.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 2.0 h and then concentrated under high vacuum. The resulting brown oil was diluted with Et2O (200 mL). The precipitated solid was collected by filtration, washed with Et2O (2 × 100 mL), and dried under high vacuum. This gave ethyl 4-(4-amino-1-methylpyrrole-2-carboxamido)-1-methylimidazole-2-carboxylate (16.00 g, crude) as a brown solid. LC / MS: C 13 H 17 Calculated mass for C15H20N5O3: 291.13, found: 292.15 [M+H] + .

[0503] Step 13: A solution of ethyl 4-(4-amino-1-methylpyrrole-2-carboxamide)-1-methylimidazole-2-carboxylate (12.00 g, 41.19 mmol, 1.00 equiv), 3-[(tert-butoxycarbonyl)amino]propanoic acid (7.50 g, 39.64 mmol, 0.96 equiv), PyBOP (22.00 g, 42.28 mmol, 1.03 equiv), and DIEA (45.00 g, 348.18 mmol, 8.45 equiv) in DMF (120.00 mL) was stirred at room temperature for 1.0 h. The reaction mixture was poured into ice water (400 mL), and the mixture was stirred for 15 min. The precipitated solid was collected by filtration, washed with water (3 × 150 mL), and dried under high vacuum. The aqueous phase was extracted with EA (3 × 150 mL), the combined organic phases were combined, washed with H2O (200 mL), and dried over anhydrous Na2SO4. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:8). This gave 17.00 g of ethyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propanamide}-1-methylpyrrole-2-carboxamide)-1-methylimidazole-2-carboxylate as a yellow solid (yield 89.28%). LC / MS: C 21 H 30 Calculated mass for C22H30N6O6: 462.22, found: 463.35 [M+H] + 。

[0504] Step 14: The procedure was the same as that for 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1). Using ethyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propanamide}-1-methylpyrrole-2-carboxamide)-1-methylimidazole-2-carboxylate (12.00 g), 10.00 g of the desired product was obtained as a white solid (yield 88.81%). LC / MS: C 19 H 26 Calculated mass for C20H26N6O6: 434.19, found: 435.25 [M+H] + 。

[0505] Step 15: A solution of 4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-1-methylpyrrole-2-carboxamido)-1-methylimidazole-2-carboxylic acid (10.00 g, 23.02 mmol, 1.00 equiv), β-alanine ethyl ester hydrochloride (4.90 g, 31.90 mmol, 1.39 equiv), PyBOP (12.50 g, 24.02 mmol, 1.04 equiv), and DIEA (9.00 g, 69.64 mmol, 3.03 equiv) in DMF (120.00 mL) was stirred at room temperature for 1.0 h. The reaction was quenched with water (500 mL) at room temperature and extracted with EA (3 × 400 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure and the residue was purified using silica gel column chromatography, eluting with PE / EA (1:8) to give ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-1-methylpyrrole-2-carboxamido)-1-methylimidazol-2-yl]formamido}propanoate (12.00 g, 93.80%) as a yellow solid. LC / MS: C 24 H 35 Calculated mass for C23H33N7O7: 533.26, Found: 534.30 [M+H] + .

[0506] Step 16: The procedure was the same as for ethyl 4-(4-amino-1-methylpyrrole-2-carboxamido)-1-methylimidazole-2-carboxylate (Step 12 of Example 2). Using ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propanamido}-1-methylpyrrole-2-carboxamido)-1-methylimidazol-2-yl]formamido}propanoate (12.00 g), 12.00 g of the desired product as a crude material was obtained as a white solid. LC / MS: C 19 H 27 Calculated mass for C19H25N7O5: 433.21, Found: 434.25 [M+H] + .

[0507] Step 17: The procedure was the same as that for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Step 12 of Example 2). Using 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylic acid (10.00 g), 13.60 g of the desired product was obtained as a yellow solid (yield 88.61%). After purification by Prep-HPLC, the desired product was obtained as a pale yellow solid. HRMS: C 53 H 65 N 21 O 12 Calculated mass for: 1187.5122, Found: 1188.5153 [M+H] + 。

[0508] Step 18: The procedure was the same as that for 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1), but the reaction temperature was 35 °C. Using ethyl 3-[(1-methyl-4-{1-methyl-4-[3-{[1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-yl}formamido)propanamido]pyrrol-2-amido}imidazole-2-yl)formamido]propanoate (10.60 g), 10.00 g of the desired product was obtained as a yellow solid. LC / MS: C 51 H 61 N 21 O 12Calculated mass value for: 1159.48, Measured value: 581.25 [M / 2 + H] + .

[0509] Example 3. Synthesis of 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamide)imidazole-2-carboxamido]pyrrole-2-yl}formamido)butanamide]imidazole-2-yl}formamido)propanamide]pyrrole-2-carboxamide}imidazole-2-carboxylic acid (PA-040-OH) Scheme 3.

[0510]

Chemical Structure

[0511] Step 2: The procedure was the same as that of ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Step 9 of Example 2), except that the solvent was DMA. Using 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylic acid (3.00 g), 4.30 g of the desired product was obtained as a yellow solid (yield 96.84%). LC / MS: C 50 H 60 N 20 O 11 Calculated mass for: 1116.48, found: 1117.60 [M+H] + 。

[0512] Step 3: The procedure was the same as that of 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1), except that the reaction temperature was 40 °C and the reaction time was 5.0 h. Using ethyl 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-yl}formamido)propanamido]pyrrol-2-carboxamido}imidazole-2-carboxylate (4.20 g), 4.00 g of the desired product was obtained as a yellow solid (yield 97.97%). LC / MS: C 48 H 56 N 20 O 11 Calculated mass for: 1088.44, found: 1089.55 [M+H] + 。

[0513] Example 4. Synthesis of 3-[(4-{4-[3-({4-[(2R)-2-[(tert-Butoxycarbonyl)amino]-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrole-2-yl}formamido)butanamido]-1-methylimidazole-2-yl}formamido)propanamido]-1-methylpyrrole-2-carboxamido}-1-methylimidazole-2-yl)formamido]propanoic acid (PA-004-NHBoc-OH) Scheme 4.

[0514]

Chem.

[0515] Step 2: To a 50 mL flask, ethyl 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}butanamide]-1-methylimidazole-2-carboxylate (500.00 mg, 0.85 mmol, 1.00 equiv), DMF (5.00 mL), and piperidine (1.00 mL) were added. The reaction mixture was stirred at room temperature for 30 minutes. Piperidine was removed and the reaction mixture was purified by reverse flash chromatography under the following conditions. Column, C18 column; mobile phase, CH3CN in water (0.5% NH4HCO3), gradient of 10% - 50% over 30 minutes; detector, UV 254 nm. The fractions were combined and concentrated to give ethyl 4-[(2R)-4-amino-2-[(tert-butoxycarbonyl)amino]butanamide]-1-methylimidazole-2-carboxylate (250.00 mg, 96.10%) as a yellow oil. LC / MS: C 16 H 27 Calculated mass for C19H29N5O5: 369.20, found: 370.35 [M+H] + 。

[0516] Step 3: The procedure was the same as that for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-ylamide)pyrrol-2-yl]formamide}propanamide)imidazol-2-ylamide]pyrrol-2-yl}formamide)butanamide]imidazole-2-carboxylate (step 9 of Example 2). Using ethyl 4-[(2R)-4-amino-2-[(tert-butoxycarbonyl)amino]butanamide]-1-methylimidazole-2-carboxylate (200.00 mg), 200.00 mg of the desired product was obtained as a yellow solid (yield 68.39%). LC / MS: C 41 H 53 N 15 O 10 Calculated mass for C43H55N9O7: 915.41, found: 916.75 [M+H] + 。

[0517] Step 4: The procedure was the same as that for 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1), except that the reaction solvent was a mixture of MeOH / THF (5:3), the reaction temperature was room temperature, and the reaction time was 1.0 h. Using ethyl 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amide)pyrrol-2-yl]formamide}propanamide)imidazole-2-amide]pyrrol-2-yl}formamide)butanamide]-1-methylimidazole-2-carboxylate (570 mg), 370.00 mg of the desired product was obtained as a yellow solid (yield 66.90%). LC / MS: C 39 H 49 N 15 O 10 Calculated mass for: 887.38, Found: 888.85 [M+H] + 。

[0518] Step 5: The procedure was the same as that for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amide)pyrrol-2-yl]formamide}propanamide)imidazole-2-amide]pyrrol-2-yl}formamide)butanamide]imidazole-2-carboxylate (Step 9 of Example 2). Using 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amide)pyrrol-2-yl]formamide}propanamide)imidazole-2-amide]pyrrol-2-yl}formamide)butanamide]-1-methylimidazole-2-carboxylic acid (380.00 mg), 521.00 mg of the desired product was obtained as a white solid (yield 91.75%). After purification by Prep-HPLC, the desired compound was obtained as a white solid. HRMS: C 58 H 74 N 22 O 14Mass calculated value for: 1302.5755, measured value: 1303.5867 [M+H] + .

[0519] Step 6: The procedure was the same as that for 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1), except that the reaction temperature was room temperature. Using ethyl 3-[(4-{4-[3-({4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amide)pyrrole-2-yl]formamide}propanamide)imidazole-2-amide]pyrrole-2-yl}formamide)butanamide]-1-methylimidazole-2-yl}formamide)propanamide]-1-methylpyrrole-2-amide}-1-methylimidazole-2-yl)formamide]propanoate (150.00 mg), 146.00 mg of the desired product was obtained as a white solid. LC / MS: C 56 H 70 N 22 O 14 Mass calculated value for: 1274.54, measured value: 638.85 [M / 2+H] + .

[0520] Example 5. Synthesis of 3-[(4-{4-[3-({4-[(2R)-2-acetamido-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amide)pyrrole-2-yl]formamide}propanamide)imidazole-2-amide]pyrrole-2-yl}formamide)butanamide]-1-methylimidazole-2-yl}formamide)propanamide]-1-methylpyrrole-2-amide}-1-methylimidazole-2-yl)formamide]propanoic acid (PA-004-NHAc-OH) Scheme 5.

[0521]

Chemical Structure

[0522] Step 2: To a stirred solution of ethyl 3-[(4-{4-[3-({4-[(2R)-2-amino-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamide)imidazole-2-carboxamido]pyrrole-2-yl}formamido)butanamide]-1-methylimidazole-2-yl}formamido)propanamide]-1-methylpyrrole-2-carboxamido}-1-methylimidazole-2-yl)formamido]propanoate (294.50 mg, 0.25 mmol, 1.00 equiv) in DCM (6.00 mL) was added Ac2O (0.23 mL, 2.45 mmol, 10.00 equiv) and Et3N (0.34 mL, 2.45 mmol, 10.00 equiv) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 1.0 h and then concentrated under reduced pressure. The crude product was purified by reverse-phase column under the following conditions. Column, C18; mobile phase, ACN in water (0.5% TFA), gradient of 10% - 50% in 30 min; detector, UV254 nm. The fractions were combined and lyophilized to give ethyl 3-[(4-{4-[3-({4-[(2R)-2-acetamido-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamide)imidazole-2-carboxamido]pyrrole-2-yl}formamido)butanamide]-1-methylimidazole-2-yl}formamido)propanamide]-1-methylpyrrole-2-carboxamido}-1-methylimidazole-2-yl)formamido]propanoate (200.00 mg, 64.31%) as a white solid. LC / MS: C 55 H 68 N 22 O 13 Calculated mass for: 1244.5336, found: 1245.5392 [M+H] + 。

[0523] Step 3: The procedure was the same as that for 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1), except that the reaction temperature was room temperature. Using ethyl (R)-3-(4-(4-(3-(4-(2-acetamido-4-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)propanamide)-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)butanamide)-1-methyl-1H-imidazole-2-carboxamido)propanamide)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-imidazole-2-carboxamido)propanoate (190.00 mg), 91.50 mg of the desired product was obtained as a white solid (yield 50.12%). LC / MS: C 53 H 64 N 22 O 13 Calculated mass for: 1216.50, found: 609.80 [M / 2+H] + 。

[0524] Example 6. Synthesis of 1-methyl-4-(1-methyl-4-{3-[(1-methyl-4-{1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amide)pyrrole-2-yl]formamide}propanamide)imidazole-2-amide]pyrrole-2-yl}formamide)butanamide]imidazole-2-amide}pyrrole-2-yl)formamide]propanamide}imidazole-2-amide)pyrrole-2-carboxylic acid (PA-049-OH) Scheme 6.

[0525]

Chemical Structure

[0526] Step 2: The procedure was the same as that for ethyl 4-(4-amino-1-methylpyrrole-2-carboxamide)-1-methylimidazole-2-carboxylate (Step 12 of Example 2), but after concentration, the crude material was used directly in the next step without further purification. Using methyl 4-{4-[3-({4-[(tert-butoxycarbonyl)amino]-1-methylpyrrol-2-yl}formamido)propanamide]-1-methylimidazole-2-carboxamide}-1-methylpyrrole-2-carboxylate (355.00 g), 350.00 mg of methyl 4-(4-{3-[(4-amino-1-methylpyrrol-2-yl)formamido]propanamide}-1-methylimidazole-2-carboxamide)-1-methylpyrrole-2-carboxylate was obtained as a brown oil. LC / MS: C 21 H 26 Calculated mass for C N8O5: 470.20, Found: 471.45 [M+H] + 。

[0527] Step 3: The procedure was the same as that of ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Step 9 of Example 2). Using 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylic acid (450.00 g), 790.00 mg of the desired product was obtained as a white solid (yield 95.77%). LC / MS: C 55 H 64 N 22 O 12 Calculated mass for: 1224.51, Found: 1225.85 [M+H] + .

[0528] Step 4: The procedure was the same as that of 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1), except that the reaction solvent was MeOH / THF = 1:1. Using methyl 1-methyl-4-(1-methyl-4-{3-[(1-methyl-4-{1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxamido}pyrrol-2-yl)formamido]propanamido}imidazole-2-carboxylate (300.00 mg), 290.00 mg of the desired product was obtained as a white solid (yield 68.45%). LC / MS: C 54 H 62 N 22 O 12 Calculated mass for: 1210.49, Found: 1211.80 [M+H]+ .

[0529] Example 7. Synthesis of 4-{3-[(4-{4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-[(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylpyrrole-2-carboxamido)pyrrole-2-carboxamido]imidazole-2-carboxamido}pyrrole-2-yl)formamido]butanamide]-1-methylimidazole-2-carboxamido}-1-methylpyrrole-2-yl)formamido]propanamide}-1-methylimidazole-2-carboxylic acid (PA-044-NHBoc) Scheme 7.

[0530]

Chemical formula

[0531] Step 2: The procedure was the same as that for 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1), except that the reaction temperature was 50 °C and the reaction time was 1.0 hour. Using ethyl 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-[(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylpyrrole-2-carboxamido)pyrrole-2-carboxamido]imidazole-2-carboxamido}pyrrole-2-yl)formamide]butanamide]-1-methylimidazole-2-carboxylate (460.00 mg), 370.00 mg of the desired product was obtained as a white solid (yield 83.20%). LC / MS: C 37 H 45 N 13 Calculated mass for C, H, N, O9: 815.35, found: 816.60 [M+H] + .

[0532] Step 3: The procedure was the same as that for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamide}propanamide)imidazole-2-carboxamido]pyrrole-2-yl}formamide)butanamide]imidazole-2-carboxylate (Step 9 of Example 2). Using 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-[(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylpyrrole-2-carboxamido)pyrrole-2-carboxamido]imidazole-2-carboxamido}pyrrole-2-yl)formamide]butanamide]-1-methylimidazole-2-carboxylic acid (370.00 mg), 500.00 mg of the desired product was obtained as a red solid (yield 95.02%). LC / MS: C 53 H 65 N 19 O 12 Calculated mass for C, H, N, O: 1159.51, found: 1161.05 [M+H] + 。

[0533] Step 4: The procedure was the same as that of 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1), but the reaction time was 1.0 hour. Using ethyl 4-{3-[(4-{4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-[(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylpyrrole-2-carboxamido)pyrrole-2-carboxamido]imidazole-2-carboxamido}pyrrole-2-yl)formamido]butanamide]-1-methylimidazole-2-carboxamido}-1-methylpyrrole-2-yl)formamido]propanamide}-1-methylimidazole-2-carboxylate (300.00 mg), 240.00 mg of the desired product was obtained as a yellow solid (yield 81.98%). LC / MS: C 51 H 61 N 19 O 12 Calculated mass for: 1131.47, found: 1133.05 [M+H] + .

[0534] Example 8. Synthesis of 4-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-4-{[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamide)imidazole-2-yl]formamido}butanamide]-1-methylpyrrole-2-carboxamido}-1-methylimidazole-2-carboxylic acid (PA-023) Scheme 8.

[0535]

Chem.

[0536] Step 2: The procedure was the same as that for 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Step 3 of Example 1), except that the reaction temperature was room temperature and the reaction time was 2.0 hours. Using ethyl 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxylate (2.00 g), 1.80 g of 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxylic acid was obtained as an off-white solid (yield 95.71%). LC / MS: C 19 H 22 Calculated mass for C N8O5: 442.17, found: 443.10 [M+H] + .

[0537] Step 3: The procedure was the same as that for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Step 9 of Example 2), except that the reaction time was 2.0 h. Using ethyl 4-{4-[(2S)-4-amino-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}butanamido]-1-methylpyrrole-2-carboxamido}-1-methylimidazole-2-carboxylate (1.60 g), 1.90 g of the desired product was obtained as a yellow solid (yield 70.20%). LC / MS: C 51 H 55 N 15 O 10 Calculated mass for: 1037.43, found: 1038.45 [M+H] + .

[0538] Step 4: A mixture of ethyl 4-{4-[(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-{[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-yl]formamido}butanamido]-1-methylpyrrole-2-carboxamido}-1-methylimidazole-2-carboxylate (1.90 g, 1.83 mmol, 1.00 equiv) and LiOH (0.22 g, 9.15 mmol, 5.00 equiv) in MeOH (5.00 mL), THF (15.00 mL), and H2O (18.30 mL) was stirred at room temperature for 2.0 h. The resulting mixture was used in the next step without further purification. LC / MS: C 34 H 41 N 15 Calculated mass for C H N O8: 787.33, found: 788.40 [M+H] + .

[0539] Step 5: To a mixture of 4-{4-[(2S)-2-amino-4-{[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-yl]formamido}butanamido]-1-methylpyrrole-2-carboxamido}-1-methylimidazole-2-carboxylic acid (1.40 g, 1.78 mmol, 1.00 eq) in MeOH / THF / H2O (5.00 mL / 15.00 mL / 18.30 mL) was added di-tert-butyl dicarbonate (0.78 g, 3.55 mmol, 2.00 eq) and DMAP (0.02 g, 0.18 mmol, 0.10 eq). The reaction mixture was stirred at room temperature for 3.0 h and then H2O (30 mL) was added. The resulting mixture was filtered through a Celite pad and the solid was washed with EA (3×30 mL) to give 4-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-4-{[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-yl]formamido}butanamido]-1-methylpyrrole-2-carboxamido}-1-methylimidazole-2-carboxylic acid (1.20 g, yield 76.05%) as a yellow solid. LC / MS: C 39 H 49 N 15 O 10 Calculated mass for: 887.38, Found: 888.45 [M+H] + .

[0540] Step 6: The procedure was the same as that of 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Step 9 of Example 2), except that the reaction time was 2.0 h. Using 4-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-4-{[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-yl]formamido}butanamido]-1-methylpyrrole-2-carboxamido}-1-methylimidazole-2-carboxylic acid (1.20 g), 1.10 g of the desired product was obtained as a yellow solid (yield 71.01%). LC / MS: C 52 H 63 N 19 O 12 Calculated mass for: 1145.49, found: 1146.50 [M+H] + .

[0541] Step 7: The procedure was the same as that for 4-[4-(4-{4-[(2S)-2-[(tert-Butoxycarbonyl)amino]-4-[(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylimidazole-2-carboxamide)pyrrole-2-carboxamide]pyrrole-2-carboxamide}imidazol-2-yl)formamide]butanamide]-1-methylpyrrole-2-carboxamide}-1-methylimidazole-2-carboxamide)-1-methylpyrrole-2-carboxamide]-1-methylpyrrole-2-carboxylic acid. Methyl 4-[4-(4-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-4-{[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamide)pyrrole-2-yl]formamide}propanamide)imidazol-2-yl]formamide}butanamide]-1-methylpyrrole-2-carboxamide}-1-methylimidazole-2-carboxamide)-1-methylpyrrole-2-carboxamide]-1-methylpyrrole-2-carboxylate (1.00 g) was used to obtain 400.00 mg of the desired product as a white solid (yield 39.16%). LC / MS: C 51 H 61 N 19 O 12 Calculated mass for: 1131.47, Found: 1132.65 [M+H] +

[0542] Synthesis of Representative Compounds of the Present Disclosure Example 9. Synthesis of Compound B-1 Scheme 9.

[0543]

Chemical Structure

[0544] Example 10. Synthesis of Compound B-3 Scheme 10.

[0545]

Chemical Structure

[0546] Step 2: The procedure was the same as in Step 16 of Example 2, but the crude product was purified by preparative HPLC. Using tert-butyl N-[(1R)-1-[(1-methyl-2-{[2-({1-methyl-5-[(1-methyl-2-{[2-(propylcarbamoyl)ethyl]carbamoyl}imidazole-4-yl)carbamoyl]pyrrole-3-yl}carbamoyl)ethyl]carbamoyl}imidazole-4-yl)carbamoyl]-3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)propyl]carbamate (20.00 g), 6.10 mg of the desired product was obtained as a white solid (yield 32.53%). HRMS: C 54 H 69 N 23 O 11 Calculated mass for: 1215.5547, found: 1216.5581 [M+H] +

[0547] Example 11. Synthesis of Compound B-79 Scheme 11.

[0548]

Chem.

[0549] Example 12. Synthesis of Compounds B-29 and B-156 Scheme 12.

[0550]

Chem.

[0551] Step 2: The procedure was the same as in Example 2, but the reaction time was 4.0 h. Using tert-butyl 4-[1-(4-nitrophenyl)piperidin-4-yl]piperazine-1-carboxylate (1.00 g), 0.70 g of the desired product was obtained as a yellow oil (yield 94.14%). LC / MS: C 15 H 22 Calculated mass for N4O2: 290.17, measured value: 291.15 [M+H] + .

[0552] Step 3: Synthesis of Compound B-29. The procedure was the same as in Example 9, but the reaction time was 2.0 h and the reaction mixture was purified by preparative HPLC. Using 1-[1-(4-nitrophenyl)piperidin-4-yl]piperazine (30.03 mg), 20.10 mg of the desired product was obtained as a yellow solid (yield 19.67%). HRMS: C 66 H 81 N 25 O 13 Calculated mass for: 1431.6446, measured value: 1432.6538 [M+H] + .

[0553] Step 4: Synthesis of Compound 156. The procedure was the same as that for ethyl 4-amino-1-methylimidazole-2-carboxylate (Example 1). Using 1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-ylamide)pyrrol-2-yl]formamide}propanamide)imidazol-2-ylamide]pyrrol-2-yl}formamide)butanamide]imidazol-2-yl}formamide)propanamide]pyrrol-2-ylamide}-N-(3-{4-[1-(4-nitrophenyl)piperidin-4-yl]piperazin-1-yl}-3-oxopropyl)imidazole-2-carboxamide (17.00 mg), 7.90 mg of the desired product was obtained as an off-white solid (yield 47.34%). HRMS: C 66 H 83 N 25 O 11 Calculated mass for: 1401.6704, Found: 1402.6823 [M+H] + .

[0554] Example 13. Synthesis of Compound B-367 Scheme 13.

[0555]

Chem.

[0556] Example 14. Synthesis of Compound B-127 Scheme 14.

[0557]

Chemical Structure

[0558] Step 2: The procedure was the same as in Example 1, but the reaction time was 16.0 hours. Using tert-butyl 4-({1-[(benzyloxy)carbonyl]piperidin-4-yl}methyl)piperazine-1-carboxylate (3.00 g), 1.40 g of the desired product was obtained as a yellow solid (yield 68.75%). LC / MS: C 15 H 29 Calculated mass for C15H23N3O2: 283.23, Measured value: 284.15 [M+H] + .

[0559] Step 3: The procedure was the same as in Example 9 (Compound B-1), but the reaction time was 2.0 h. Using tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (120.00 mg), 270.00 mg of the desired product was obtained as a yellow solid (yield 44.73%). LC / MS: LC / MS: C 66 H 88 N 24 O 13 Calculated mass for: 1424.70, found: 1425.50 [M+H] + .

[0560] Step 4: The procedure was the same as Step 12 of Example 2, but the reaction time was 2.0 h and the reaction mixture was purified by preparative HPLC. Using tert-butyl 4-[(1-{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-ylamide)pyrrol-2-yl]formamide}propanamide)imidazol-2-ylamide]pyrrol-2-yl}formamide)butanamide]imidazol-2-yl}formamide)propanamide]pyrrol-2-ylamide}imidazol-2-yl)formamide]propanoyl}piperidin-4-yl)methyl]piperazine-1-carboxylate (250.00 mg), 5.70 mg of the desired product was obtained as a pale yellow solid (yield 2.45%). LC / MS: HRMS: C 61 H 80 N 24 O 11 Calculated mass for: 1324.64, found: 1325.65 [M+H] + .

[0561] Example 15. Synthesis of Compounds B-126, B-378, and B-379 Scheme 15.

[0562]

Chemical Structure

[0563] Step 2: Synthesis of compound B-378. The procedure was the same as in Example 9 (compound B-1). After the reaction, the mixture was poured into ice water and the resulting solid was used directly in the next step without further purification. Using 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-ylamide)pyrrol-2-yl]formamide}propanamide)imidazol-2-ylamide]pyrrol-2-yl}formamide)butanamide]imidazol-2-yl}formamide)propanamide]pyrrol-2-ylamide}imidazol-2-yl)formamide]propanoic acid (100.00 mg), 90.00 mg of the desired product was obtained as a white solid (yield 50.58%). HRMS: C 68 H86 N 24 O 12 : Calculated value: 1457.6854, measured value: 1458.6929 [M+H] + .

[0564] Step 3: Synthesis of compound B-126. The procedure was the same as step 16 of Example 2, but the crude product was purified by preparative HPLC. Using tert-butyl 4-[4-(1-{3-[(1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamide)pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxamide]pyrrol-2-yl}formamide)butanamide]imidazole-2-yl}formamide)propanamide]pyrrol-2-carboxamide}imidazole-2-yl)formamide]propanoyl}piperidin-4-yl)buta-1,3-dien-1-yl]piperidine-1-carboxylate (80.00 mg), 25.20 mg of the desired product was obtained as a yellow solid. HRMS: C 65 H 79 N 23 O 11 Calculated value for: 1357.6329, measured value: 1358.6396 [M+H] + .

[0565] Step 4: Synthesis of Compound B-379. The procedure was the same as Step 2 of Example 5, except that the obtained solid was purified by preparative HPLC. Using 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamide)-N-(1-methyl-5-{[3-({1-methyl-2-[(2-{[1-methyl-5-({1-methyl-2-[(3-oxo-3-{4-[4-(piperidin-4-yl)buta-1,3-dien-1-yl]piperidin-1-yl}propyl)carbamoyl]imidazol-4-yl}carbamoyl)pyrrol-3-yl]carbamoyl}ethyl)carbamoyl]imidazol-4-yl}carbamoyl)propyl]carbamoyl}pyrrol-3-yl)imidazole-2-carboxamide (112.00 mg), 18.80 mg of the desired product was obtained as a white solid (yield 16.19%). HRMS: C 67 H 81 N 23 O 12 Calculated mass for: 1399.6435, Found: 1400.6460 [M+H] + .

[0566] Example 16. Synthesis of Compound B-137 Scheme 16.

[0567]

Chem.

[0568] Step 2: The procedure was the same as that for tert-butyl 4-[4-(piperidin-4-yl)buta-1,3-dien-1-yl]piperidine-1-carboxylate (Step 1 of Example 15), but the crude product was used directly in the next step. Using 4-(2-iodoethynyl)piperidine (500.00 mg), 400.00 mg of the desired product was obtained as a yellow solid. LCMS: C 15 H 22 Calculated mass for N2O2: 262.17, measured value: 263.30 [M+H] + 。

[0569] Step 3: A solution of tert-butyl N-[5-(piperidin-4-yl)penta-2,4-dien-1-yl]carbamate (130.00 mg, 0.50 mmol, 1.00 equiv), 2,5-dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (180.00 mg, 0.53 mmol, 1.08 equiv) and DIEA (127.00 mg, 0.98 mmol, 1.98 equiv) in THF (3.00 mL) was stirred at room temperature for 2.0 h. The reaction was quenched with water (30 mL) at room temperature and extracted with EA (3×30 mL). The combined organic layers were washed with water (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 3:1) to give 9H-fluoren-9-ylmethyl 4-{5-[(tert-butoxycarbonyl)amino]penta-1,3-dien-1-yl}piperidine-1-carboxylate (110.00 mg, yield 45.81%) as a white oil. LCMS: C 30 H 32 Calculated mass for N2O4: 484.24, measured value: 485.25 [M+H] + 。

[0570] Step 4: The procedure was the same as step 16 of Example 2. Using 9H-fluoren-9-ylmethyl 4-{5-[(tert-butoxycarbonyl)amino]penta-1,3-dien-1-yl}piperidine-1-carboxylate (110.00 mg), 110.00 mg of the desired product was obtained as a yellow oil. LCMS: C 25 H 24 Calculated mass for N2O2: 384.18, found: 385.25 [M+H] + 。

[0571] Step 5: A solution of 3-[(1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)butanamido]imidazole-2-yl}formamido)propanamido]pyrrol-2-carboxamido}imidazole-2-yl)formamido]propanoic acid (270.00 mg, 0.23 mmol, 0.81 eq), 9H-fluoren-9-ylmethyl 4-(5-aminopenta-1,3-dien-1-yl)piperidine-1-carboxylate (110.00 mg, 0.29 mmol, 1.00 eq), PyBOP (150.00 mg, 0.29 mmol, 1.01 eq), and DIEA (160.00 mg, 1.24 mmol, 4.33 eq) in DMF (3.00 mL) was stirred at room temperature for 1.0 h. Then, piperidine (1.0 mL) was added and the reaction mixture was stirred at room temperature for an additional 1.0 h. The reaction was purified by reverse-phase flash chromatography under the following conditions. Column, C18 silica gel; mobile phase, ACN in water (0.05% TFA), 5% - 48% gradient over 25 min; detector, UV 254 nm. The fractions were combined and concentrated to give the desired product (120.00 mg, 70.22% yield) as a yellow solid.

[0572] The crude product (70 mg) 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), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 30% B - 44% B gradient over 10 minutes, 44% B; Wavelength: 254 nm; RT1 (min): 9.72. The fractions were combined and lyophilized to obtain 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamide)pyrrol-2-yl]formamide}propanamide)-N-(1-methyl-5-{[3-({1-methyl-2-[(2-{[1-methyl-5-({1-methyl-2-[(2-{[5-(piperidin-4-yl)penta-2,4-dien-1-yl]carbamoyl}ethyl)carbamoyl]imidazole-4-yl}carbamoyl)pyrrol-3-yl]carbamoyl}ethyl)carbamoyl]imidazole-4-yl}carbamoyl)propyl]carbamoyl}pyrrol-3-yl)imidazole-2-carboxamide (12.60 mg, yield 18.00) as a white solid. HRMS (ESI): C 61 H 73 N 23 O 11 Calculated mass for: 1303.5860, Found: 1304.5942 [M+H] + .

[0573] Example 17. Synthesis of Compound B-150 Scheme 17.

[0574]

Chem.

[0575] Step 2: To a stirred solution of (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]pentanoic acid (6.30 g, 27.12 mmol, 1.00 equiv) in MeOH (100.00 mL), ethyl 2,2,2-trifluoroacetate (5.78 g, 40.68 mmol, 1.50 equiv) and Et3N (5.49 g, 54.24 mmol, 2.00 equiv) were added at room temperature. The resulting mixture was stirred at room temperature for 4.0 h. Then, Pd / C was filtered off, the resulting mixture was quenched with water (100 mL), extracted with EA (100 mL), the aqueous phase was adjusted to pH = 3 - 5 with 2M HCl, and then extracted with EA (3 x 100 mL), the combined organic phases were washed with NaCl solution (100 mL), dried over Na2SO4 (filtered off), and the organic phase was concentrated. Thereby, (2S)-2-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroacetamido)pentanoic acid (12.00 g crude) was obtained as an orange oil.

[0576] Step 3: To a stirred solution of (2S)-2-{[(2,2-dimethylpropanoyl)oxy]amino}-5-(2,2,2-trifluoroacetamido)pentanoic acid (1.00 g, 3.05 mmol, 1.00 equiv) in THF (10.00 mL) was added NMM (308.11 mg, 3.05 mmol, 1.00 equiv) dropwise at room temperature. The resulting mixture was cooled to -15 °C, and Cbz-Cl (545.62 mg, 3.20 mmol, 1.05 equiv) in THF (5.00 mL) was added to the resulting mixture at -15 °C. The resulting mixture was stirred at -15 °C for 2 minutes, warmed to 0 °C, and stirred for 15 minutes. DMAP (93.04 mg, 0.761 mmol, 0.25 equiv) was added to the resulting mixture, and the resulting mixture was warmed to room temperature and stirred for 2.0 hours. The reaction was quenched with H2O (15 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 15 mL). The combined organic layers were washed with brine (1 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give benzyl (2S)-2-{[(2,2-dimethylpropanoyl)oxy]amino}-5-(2,2,2-trifluoroacetamido)pentanoate (780.00 mg, 52.22%) as a yellow oil. LC / MS: C 19 H 25 Calculated mass for C17H22F3N2O5: 418.17, Found: 441.30 [M+Na] + .

[0577] Step 4: The procedure was the same as in Example 2, except that the solvent used was CH2Cl2. Using benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroacetamido)pentanoate (700.00 mg), 440.00 mg of the desired product was obtained as a brown oil. LC / MS: C 14 H 17 Calculated mass for C13H18F3N2O3: 318.12, Found: 319.30 [M+H] + .

[0578] Step 5: The procedure was the same as in Example 9. After the reaction, the reaction mixture was poured into ice water and the solid was used in the next step without further purification. Using (2S)-2-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroacetamido)pentanoic acid (477.00 mg), 550.00 mg of the desired product was obtained as a white solid (yield 34.37%).

[0579] Step 6: To a solution of benzyl (2S)-2-[(2S)-2-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroacetamido)pentanamido]-5-(2,2,2-trifluoroacetamido)pentanoate (500.00 mg, 1.00 equiv) in MeOH (10.00 mL) was added Pd / C (200 mg, 40% w / w). The reaction was stirred at room temperature for 17.0 h under a H2 atmosphere. The mixture was then filtered and the filtrate was concentrated to give (2S)-2-[(2S)-2-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroacetamido)pentanamido]-5-(2,2,2-trifluoroacetamido)pentanoic acid (390.00 mg crude) as a colorless oil. LC / MS: C 19 H 28 Calculated mass for C16H20F6N4O7: 538.19, found: 561.35 [M+Na] + .

[0580] Step 7: The procedure was the same as in Example 9. After the reaction, the reaction mixture was poured into ice water and the resulting solid was used without further purification. Using (2S)-2-[(2S)-2-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroacetamido)pentanamido]-5-(2,2,2-trifluoroacetamido)pentanoic acid (390.00 mg), 300.00 mg of the desired product was obtained as a white solid (yield 65.27%). LC / MS: C 23 H 36 Calculated mass for C20H28F6N8O6: 634.27, found: 657.30 [M+Na] + .

[0581] Step 8: To a solution of tert-butyl N-[(1S)-1-{[(1S)-1-[(4-azidobutyl)carbamoyl]-4-(2,2,2-trifluoroacetamido)butyl]carbamoyl}-4-(2,2,2-trifluoroacetamido)butyl]carbamate (280.00 mg, 0.44 mmol, 1.00 equiv) in MeOH (5.00 mL) was added 2.5 mL of aqueous Na2CO3 solution (467.66 mg, 4.41 mmol, 10.00 equiv). The reaction was then stirred at 55 °C for 17.0 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by reverse-phase flash chromatography under the following conditions. Column, C18 silica gel; mobile phase, ACN in water (0.05% NH4HCO3), gradient 10% - 80% over 40 min; detector, UV 254 nm. The fractions were combined and concentrated to give tert-butyl N-[(1S)-1-{[(1S)-1-[(4-azidobutyl)carbamoyl]-4-carbamimidamidebutyl]carbamoyl}-4-carbamimidamidebutyl]carbamate (230.00 mg, yield 98.98%) as a colorless oil. LC / MS: C 21 H 42 N 12 Calculated mass for C, H, N, O4: 526.34, found: 527.35 [M+H] + .

[0582] Step 9: The procedure was the same as step 16 of Example 2. Using tert-butyl N-[(1S)-1-{[(1S)-1-[(4-azidobutyl)carbamoyl]-4-carbamimidamidebutyl]carbamoyl}-4-carbamimidamidebutyl]carbamate (60.00 mg), 60.00 mg of the desired product as a crude material was obtained as a brownish-yellow oil. LC / MS: C 16 H 34 N 12 Calculated mass for C, H, N, O2: 426.29, found: 427.50 [M+H] + .

[0583] Example 18. Synthesis of Compound B-76 Scheme 18.

[0584] [Chemistry] The procedure was the same as step 2 of Example 5, but the crude product obtained was purified by preparative HPLC. Using N-{5-[(3-{[2-({2-[(5-{[2-({2-[(17-amino-3,6,9,12,15-pentaoxaheptadecane-1-yl)carbamoyl]ethyl}carbamoyl)-1-methylimidazol-4-yl]carbamoyl}-1-methylpyrrol-3-yl)carbamoyl]ethyl}carbamoyl)-1-methylimidazol-4-yl]carbamoyl}propyl)carbamoyl]-1-methylpyrrol-3-yl}-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxamide (500.00 mg), 158.90 mg of the desired product was obtained as a white solid (yield 30.30%). HRMS: C 65 H 89 N 23 O 17 Calculated mass for: 1463.6807, Found: 1464.6862 [M+H] + .

[0585] Example 19. Synthesis of Compound B-296 Scheme 19.

[0586] [Chemistry] Step 1: The procedure was the same as that of ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrole-2-yl}formamido)butanamido]imidazole-2-carboxylate (Step 9 of Example 2). Using 3-({4-[4-(3-{[4-(4-{[1-(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl)-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrole-2-yl]formamido}butanamido)-1-methylimidazole-2-yl]formamido}propanamido)-1-methylpyrrole-2-carboxamido]-1-methylimidazole-2-yl}formamido)propanoic acid (180.00 mg), 180.00 mg of the desired product was obtained as a yellow solid (60.94%). LC / MS: C 73 H 94 N 24 O 14 : 1530.74, found: 766.75 [M / 2 + H] + 。

[0587] Step 2: The procedure was the same as in Compound B-1 of Example 9. Using tert-butyl N-{2-[2-(2-{[3-({1-methyl-2-[(2-{[1-methyl-5-({1-methyl-2-[(3-oxo-3-{4-[4-(piperidin-4-yl)buta-1,3-diyn-1-yl]piperidin-1-yl}propyl)carbamoyl]imidazol-4-yl}carbamoyl)pyrrol-3-yl]carbamoyl}ethyl)carbamoyl]imidazol-4-yl}carbamoyl)propyl]carbamoyl}-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amide)pyrrol-2-yl]formamide}propanamide)imidazol-2-amide]pyrrol-1-yl)ethoxy]ethyl}carbamate (140.00 mg), 70.00 mg of the desired product was obtained as a brown solid (yield 46.23%). LC / MS: C 75 H 96 N 24 O 15 : 1572.75, found: 787.65 [M / 2 + H] + 。

[0588] Step 3: The procedure was the same as in Step 16 of Example 2, but the reaction mixture was purified by preparative HPLC. Using tert-butyl N-{2-[2-(2-{[3-({2-[(2-{[5-({2-[(3-{4-[4-(1-acetylpiperidin-4-yl)buta-1,3-diyn-1-yl]piperidin-1-yl}-3-oxopropyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)-1-methylpyrrol-3-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)propyl]carbamoyl}-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amide)pyrrol-2-yl]formamide}propanamide)imidazol-2-amide]pyrrol-1-yl)ethoxy]ethyl}carbamate (56.00 mg), 13.2 mg of the desired product was obtained as a white solid (yield 25.10%). HRMS: C 70 H 88 N 24 O13 : Calculated value for C7H + : 126.07, measured value: 127.10 [M+H]

[0589] Example 20. Synthesis of Compound B-435 Scheme 20.

[0590]

Chemical Structure

[0591] Step 2: To a stirred mixture of crude ethyl 2-cyclopropylideneacetate were added CH3NO2 (4.01 mL, 74.83 mmol, 2.36 equivalents) and DBU (1.99 mL, 13.32 mmol, 0.42 equivalent) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 6.0 h. The resulting mixture was concentrated under reduced pressure. The residue was purified using silica gel column chromatography and eluted with ethyl acetate / petroleum ether (1:8) to give ethyl 2-[1-(nitromethyl)cyclopropyl]acetate (3.00 g, 50.54%) as a pale yellow oil. LC / MS:C8H 13 Calculated value for C8H + NO4: 187.08, measured value: 188.20 [M+H]

[0592] Step 3: To a stirred mixture of ethyl 2-[1-(nitromethyl)cyclopropyl]acetate (3.00 g, 16.03 mmol, 1.00 equiv) in EtOH (30.00 mL) was added Pd / C (0.30 g, 10% w / w) and TFA (0.10 mL) at room temperature. The mixture was stirred at room temperature for 6.0 h under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOH (10 mL×5). The filtrate was concentrated under reduced pressure to give ethyl 2-[1-(aminomethyl)cyclopropyl]acetate (1.50 g, 59.54%) as a pale yellow oil. LC / MS: C8H 15 Calculated mass for NO2: 157.11, found: 158.15 [M+H] + .

[0593] Step 4: To a stirred mixture of ethyl 2-[1-(aminomethyl)cyclopropyl]acetate (0.50 g, 3.19 mmol, 1.20 equiv), 1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamido)imidazole-2-carboxamide]pyrrole-2-carboxylic acid (1.50 g, 2.66 mmol, 1.00 equiv) and PyBOP (1.66 g, 3.19 mmol, 1.20 equiv) in DMF (20.00 mL) was added DIEA (1.03 g, 7.97 mmol, 3.00 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2.0 h. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EA (30 mL×3). The combined organic layers were washed with water (30 mL×3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamido)imidazole-2-carboxamide]pyrrole-2-yl}formamido)methyl]cyclopropyl}acetate (1.70 g, 90.92%) as a pale yellow solid. LC / MS: C 33 H 41 N 11 Calculated mass for O7: 703.32, found: 704.25 [M+H] +.

[0594] Step 5: To a stirred mixture of ethyl 2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetate (1.70 g, 2.42 mmol, 1.00 equiv) in MeOH (3 mL) and THF (15.00 mL) was added 2M LiOH in water (2M, 7.26 mL, 14.52 mmol, 6.00 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2.0 h. The solvent was removed under reduced pressure and the residue was dissolved in H2O (20 mL). The mixture was acidified to pH 3 - 5 at 0 °C with 2M HCl. The precipitated solid was collected by filtration, washed with H2O (3 × 30 mL) and dried under high vacuum. The desired product, {1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetic acid (1.50 g, 86.79%) was obtained as a pale yellow solid. LC / MS: C 31 H 37 N 11 Calculated mass for C + 。

[0595] Step 6: To a stirred mixture of [(1-methyl-4-[(1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido)pyrrol-2-yl]formamido)methyl]cyclopropyl}acetic acid (0.97 g, 1.43 mmol, 1.00 equiv), ethyl 4-amino-1-methylimidazole-2-carboxylate (0.29 g, 1.72 mmol, 1.20 equiv) and PyBOP (0.89 g, 1.72 mmol, 1.20 equiv) in DMF (10.00 mL) was added DIEA (0.56 g, 4.30 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2.0 h. The reaction was poured into water (50 mL). The precipitated solid was collected by filtration, and the filter cake was washed with H2O (50 mL × 3) and dried under high vacuum. The precipitated solid was collected by filtration, washed with water (30 mL × 3) and dried under high vacuum to give ethyl 1-methyl-4-(2-{1-[(1-methyl-4-[(1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido)pyrrol-2-yl]formamido)methyl]cyclopropyl}acetamido)imidazole-2-carboxylate (600.00 mg, 50.65%) as a pale yellow solid. LC / MS: C 38 H 46 N 14 Calculated mass for C41H53N11O8: 826.36, Found: 827.40 [M+H] + .

[0596] Step 7: To a stirred mixture of ethyl 1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazole-2-carboxylate (600.00 mg, 0.73 mmol, 1.00 equiv) in MeOH (2.00 mL) and THF (10.00 mL) was added 2M LiOH in water (2.19 mL, 4.38 mmol, 6.00 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2.0 h. The solvent was removed under reduced pressure. The residue was dissolved in H2O (10 mL). The mixture was acidified to pH 3 - 5 with 2M HCl at 0 °C. The precipitated solid was collected by filtration, washed with water (5 mL × 5), and dried under high vacuum to give 1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazole-2-carboxylic acid (500.00 mg, 86.26%) as a pale yellow solid. LC / MS: C 36 H 42 N 14 Calculated mass for C41H53N11O8: 798.33, Found: 799.35 [M+H] + .

[0597] Step 8: To a stirred mixture of 1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazole-2-carboxylic acid (170.00 mg, 0.21 mmol, 1.00 equiv), ethyl 4-[4-(3-aminopropanamido)-1-methylpyrrole-2-carboxamido]-1-methylimidazole-2-carboxylate (84.83 mg, 0.23 mmol, 1.10 equiv) and PyBOP (132.90 mg, 0.26 mmol, 1.20 equiv) in DMF (2.00 mL) was added DIEA (82.52 mg, 0.64 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2.0 h. The reaction was poured into water (10 mL). The precipitated solid was collected by filtration, and the filter cake was washed with H2O (5 mL×3) and dried under high vacuum. Ethyl 1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazole-2-yl]formamido}propanamido)pyrrole-2-carboxamido]imidazole-2-carboxylate (200.00 mg, 82.21%) was obtained as a pale yellow solid. LC / MS: C 52 H 62 N 20 O 11 Calculated mass for: 1142.49, Found: 1143.50 [M+H] + .

[0598] Step 9: To a stirred mixture of ethyl 1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazole-2-yl]formamido}propanamido)pyrrol-2-carboxylate (180.00 mg, 0.16 mmol, 1.00 eq) in MeOH (2.00 mL) and THF (10.00 mL) was added 2M LiOH in water (2.38 mL, 4.77 mmol, 6.00 eq) at room temperature. The reaction mixture was stirred at room temperature for 2.0 h. The solvents were removed under reduced pressure. The residue was dissolved in H2O (10 mL). The mixture was acidified to pH 3 - 5 with 2M HCl at 0 °C. The precipitated solid was collected by filtration, washed with water (5 mL × 5), and dried under high vacuum to give 1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazole-2-yl]formamido}propanamido)pyrrol-2-carboxylic acid (150.00 mg, 85.43%) as an off-white solid. LC / MS: C 50 H 58 N 20 O 11 Calculated mass for: 1114.46, Found: 1115.50 [M+H] + .

[0599] Step 10: To a stirred mixture of 1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamide)pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxamide]pyrrol-2-yl]formamide}methyl)cyclopropyl}acetamide)imidazole-2-yl]formamide}propanamide)pyrrol-2-carboxamide]imidazole-2-carboxylic acid (70.00 mg, 0.06 mmol, 1.00 equiv), propylamine (4.45 mg, 0.08 mmol, 1.20 equiv) and PyBOP (39.20 mg, 0.08 mmol, 1.20 equiv) in DMF (2.00 mL) was added DIEA (24.34 mg, 0.19 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2.0 h. The reaction mixture was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD column, 19*250 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: 18% B to 43% B in 15 min, 43% B; wavelength: 254 nm; RT1 (min): 12; number of runs: 4) to give 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamide)pyrrol-2-yl]formamide}propanamide)-N-[1-methyl-5-({[1-({[1-methyl-2-({2-[(1-methyl-5-{[1-methyl-2-(propylcarbamoyl)imidazole-4-yl]carbamoyl}pyrrol-3-yl)carbamoyl]ethyl}carbamoyl)imidazole-4-yl]carbamoyl}methyl)cyclopropyl]methyl}carbamoyl)pyrrol-3-yl]imidazole-2-carboxamide (5.20 mg, 7.11%) as a white solid. HRMS: C 53 H 65 N 21 O 10 Calculated mass for: 1155.5223, found: 1156.5264 [M+H] + . HPLC: Purity 99.190%.

[0600] Example 21. Synthesis of Compound B-439 Scheme 21

[0601] [Chemical Structure Diagram] Step 1: To a stirred solution of tert-butyl 3-oxoazetidine-1-carboxylate (5.00 g, 29.21 mmol, 1.00 equiv) in DCM (15.00 mL) was added ethyl 2-(triphenyl-λ5-phosphanylidene)acetate (10.17 g, 29.21 mmol, 1.00 equiv) portionwise at room temperature. The reaction mixture was stirred at room temperature for 16.0 h. The reaction was then quenched by adding 40 mL of water. The resulting solution was extracted with CH2Cl2 (50 mL × 3). The combined organic layers were washed with aqueous sodium carbonate (50 mL × 2) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under high vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (5:1) to give tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (7.00 g, 99.34%) as a colorless oil. LC / MS: C 12 H 19 Calculated mass for C11H16NO4: 241.13, Found: 242.20 [M+H] + . 1 H NMR (300 MHz, chloroform-d) δ 5.78 - 5.80 (m, 1H), 4.82 - 4.85 (m, 2H), 4.59 - 4.62 (m, 2H), 4.16 - 4.23 (m, 2H), 1.47 (s, 9H), 1.30 (t, J = 7.2 Hz, 3H).

[0602] Step 2: To a stirred solution of tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (3.70 g, 15.33 mmol, 1.00 equiv) in CH3NO2 (5.00 mL) was added DBU (0.50 mL, 3.37 mmol, 0.22 equiv) portionwise at room temperature. The reaction mixture was stirred at room temperature for 16.0 h. The resulting mixture was concentrated under high vacuum. EA (30 mL) was added to the mixture. The resulting mixture was washed with 0.5 N HCl (10 mL×4) and dried over Na2SO4. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (1:10), to give tert-butyl 3-(2-ethoxy-2-oxoethyl)-3-(nitromethyl)azetidine-1-carboxylate (4.00 g, 82.72%) as a colorless oil. LC / MS: C 13 H 22 Calculated mass for C12H20N2O6: 302.15, Found: 247.10 [M-56+H] + .

[0603] Step 3: To a stirred solution of tert-butyl 3-(2-methoxy-2-oxoethyl)-3-(nitromethyl)azetidine-1-carboxylate (3.90 g, 13.53 mmol, 1.00 equiv) in EtOH (50.00 mL) were added Pd / C (1.00 g, 26% w / w) and TFA (0.10 mL) at room temperature. The flask was evacuated and flushed with nitrogen three times, followed by hydrogen. The mixture was stirred under a hydrogen atmosphere at room temperature for 16.0 h. The resulting mixture was filtered and the filter cake was washed with MeOH (5×10 mL). The solid was filtered off and the filtrate was concentrated. This gave tert-butyl 3-(aminomethyl)-3-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate (3.70 g, crude) as a colorless oil. LC / MS: C 13 H 24 Calculated mass for C11H21N2O4: 272.17, Found: 273.05 [M+H] + .

[0604] Step 4: To a stirred mixture of tert-butyl 3-(aminomethyl)-3-(2-ethoxy-2-oxoethyl)azetidine-1-carboxylate (1.89 g, 6.95 mmol, 2.50 eq) and 1-methyl-4-[1-methyl-4-(3-{[1-methyl-5-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide]pyrrole-2-carboxylic acid (1.57 g, 2.78 mmol, 1.00 eq) in DMF (20.00 mL) was added PyBOP (1.88 g, 3.62 mmol, 1.30 eq) and DIEA (0.90 g, 6.95 mmol, 2.50 eq) at room temperature. The reaction mixture was stirred at room temperature for 2.0 h. The reaction was poured into water (70 mL). The precipitated solid was collected by filtration, and the filter cake was washed with H2O (50 mL × 3) and dried under high vacuum. This gave tert-butyl 3-{[(4-{4-[3-({5-[2-(dimethylamino)acetamido]-1-methylpyrrol-2-yl}formamido)propanamido]-1-methylimidazole-2-carboxamide}-1-methylpyrrol-2-yl)formamido]methyl}-3-(2-ethoxy-2-oxoethyl)azetidine-1-carboxylate (2.00 g, 72.29%) as a yellow solid. LC / MS: C 38 H 50 N 12 Calculated mass for C41H58N10O9: 818.38, found: 819.50 [M+H] + . -

[0605] Step 5: To a stirred solution of ethyl 3-{[4-(4-{3-[(4-{4-[(4-{4-[(2S)-2-hydroxy-3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido]-1-methylimidazole-2-carboxamido}-1-methylpyrrol-2-yl)formamido]butanamido}-1-methylimidazole-2-yl)formamido]propanamido}-1-methylpyrrol-2-carboxamido)-1-methylimidazole-2-yl]formamido}propanoate (1.90 g, 2.32 mmol, 1.00 equiv) in MeOH (5.00 mL) and THF (25.00 mL) was added 2 M LiOH in water (6.96 mL, 13.93 mmol, 6.00 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2.0 h. The solvents were removed under reduced pressure. The residue was dissolved in H2O (20 mL). The mixture was acidified to pH 3 - 5 at 0 °C with 2 M HCl. The precipitated solid was collected by filtration, washed with H2O (3 × 30 mL), and dried under high vacuum. This gave 3-{[4-(4-{3-[(4-{4-[(4-{4-[(2S)-2-hydroxy-3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido]-1-methylimidazole-2-carboxamido}-1-methylpyrrol-2-yl)formamido]butanamido}-1-methylimidazole-2-yl)formamido]propanamido}-1-methylpyrrol-2-carboxamido)-1-methylimidazole-2-yl]formamido}propanoic acid (1.50 g, 81.68%) as a yellow solid. LC / MS: C 36 H 46 N 12 Calculated mass for C, H, N, O9: 790.35, found: 791.45 [M + H] + .

[0606] Step 6: To a stirred mixture of [1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetic acid (1.50 g, 1.90 mmol, 1.00 equiv) and ethyl 4-amino-1-methylimidazole-2-carboxylate (0.80 g, 4.74 mmol, 2.50 equiv) in DMF (20.00 mL) was added HATU (0.94 g, 2.47 mmol, 1.30 equiv) and DIEA (0.74 g, 5.69 mmol, 3.00 equiv). The reaction mixture was stirred at room temperature for 2.0 h. The reaction mixture was filtered and the filtrate in DMF (22 mL) was purified by reverse phase column under the following conditions. Column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% - 50% gradient in 10 min; detector, UV254 nm. Thereby, ethyl 4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl}acetamido}-1-methylimidazole-2-carboxylate (1.50 g, 82.01%) was obtained as a yellow oil. LC / MS: C 43 H 55 N 15 O 10 Calculated mass for: 941.43, found: 942.60 [M+H] + .

[0607] Step 7: To a stirred solution of ethyl 4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazole-2-carboxylate (1.45 g, 1.54 mmol, 1.00 eq) in MeOH (2.00 mL) and THF (10.00 mL) was added 2 M LiOH in water (4.62 mL, 9.23 mmol, 6.00 eq) at room temperature. The reaction mixture was stirred at room temperature for 2.0 h. The solvent was removed under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions. Column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), 10% - 50% gradient over 10 min, detector, UV 254 nm. This gave 4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazole-2-carboxylic acid (1.30 g, 86.09%) as a yellow oil. LC / MS: C 41 H 51 N 15 O 10 Calculated mass for: 913.39, found: 914.50 [M+H] + .

[0608] Step 8: To a stirred mixture of 4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamide)pyrrole-2-yl]formamide}propanamide)imidazole-2-carboxamide]pyrrole-2-yl}formamide)methyl]azetidin-3-yl]acetamide}-1-methylimidazole-2-carboxylic acid (1.30 g, 1.42 mmol, 1.00 equiv) and ethyl 4-[4-(3-aminopropanamide)-1-methylpyrrole-2-carboxamide]-1-methylimidazole-2-carboxylate (0.62 g, 1.71 mmol, 1.20 equiv) in DMF (15.00 mL) was added PyBOP (0.96 g, 1.85 mmol, 1.30 equiv) and DIEA (0.46 g, 3.56 mmol, 2.50 equiv). The reaction mixture was stirred at room temperature for 2.0 h. The reaction mixture was filtered and the filtrate in DMF (20.0 mL) was purified by reverse phase column under the following conditions. Column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% - 50% gradient over 10 min; detector, UV 254 nm. The fractions were combined and concentrated under high vacuum. Thereby, ethyl 4-(4-{3-[(4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamide)pyrrole-2-yl]formamide}propanamide)imidazole-2-carboxamide]pyrrole-2-yl}formamide)methyl]azetidin-3-yl]acetamide}-1-methylimidazole-2-yl)formamide]propanamide}-1-methylpyrrole-2-carboxamide)-1-methylimidazole-2-carboxylate (2.00 g, 73.90%) was obtained as a yellow oil. LC / MS: C 57 H 71 N 21 O 13 Calculated mass for: 1257.55, found: 630.10 [M / 2 + H] + 。

[0609] Step 9: To a stirred solution of ethyl 4-(4-{3-[(4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrole-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazole-2-yl)formamido]propanamido}-1-methylpyrrole-2-carboxylate (1.00 g, 0.80 mmol, 1.00 eq) in MeOH (5.00 mL) and THF (25.00 mL) was added 2 M LiOH in water (2.38 mL, 4.77 mmol, 6.00 eq) at room temperature. The reaction mixture was stirred at room temperature for 2.0 h. The solvent was removed under reduced pressure. The residue was purified by reverse phase column under the following conditions. Column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), gradient 10% - 50% in 10 min, detector, UV254 nm. Thereby, 4-(4-{3-[(4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrole-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazole-2-yl)formamido]propanamido}-1-methylpyrrole-2-carboxylic acid (900.00 mg, 69.96%) was obtained as a yellow oil. LC / MS: C 55 H 67 N 21 O 13 Calculated mass for: 1229.52, Found: 1230.55 [M+H] + 。

[0610] Step 10: To a stirred mixture of 4-(4-{3-[(4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrole-2-yl]formamido}methyl)azetidin-3-yl]acetamido}-1-methylimidazole-2-yl)formamido]propanamido}-1-methylpyrrole-2-carboxylic acid (80.00 mg, 0.07 mmol, 1.00 equiv) and propylamine (4.61 mg, 0.08 mmol, 1.20 equiv) in DMF (2.00 mL) was added PyBOP (43.99 mg, 0.09 mmol, 1.40 equiv) and DIEA (21.01 mg, 0.16 mmol, 2.50 equiv) at room temperature. The reaction mixture was stirred at room temperature for 1.0 h. The reaction mixture was purified by reverse-phase flash chromatography under the following conditions. Column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 10% - 50% gradient over 10 min; detector, UV 254 nm. The fractions were combined and concentrated under high vacuum. This gave tert-butyl 3-({[1-methyl-2-({2-[(1-methyl-5-{[1-methyl-2-(propylcarbamoyl)imidazole-4-yl]carbamoyl}pyrrole-3-yl)carbamoyl]ethyl}carbamoyl)imidazole-4-yl]carbamoyl}methyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-carboxamido)pyrrole-2-yl]formamido}propanamido)imidazole-2-carboxamido]pyrrole-2-yl]formamido)methyl]azetidine-1-carboxylate (40.00 mg, 46.53%) as a yellow oil. LC / MS: C 58 H 74 N 22 O 12 Calculated mass for: 1270.59, Found: 1271.65 [M + H] + .

[0611] Step 11: To a mixture of tert-butyl 3-(2-((1-methyl-2-((3-((1-methyl-5-((1-methyl-2-(propylcarbamoyl)-1H-imidazol-4-yl)carbamoyl)-1H-pyrrol-3-yl)amino)-3-oxopropyl)carbamoyl)-1H-imidazol-4-yl)amino)-2-oxoethyl)-3-((1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-1H-imidazol-2-carboxamido)-1H-pyrrol-2-carboxamido)propanamido)-1H-imidazol-2-carboxamido)-1H-pyrrol-2-carboxamido)methyl)azetidine-1-carboxylate (35.00 mg, 0.03 mmol, 1.00 eq) in CH2Cl2 (2.00 mL) was added TFA (0.40 mL). The reaction mixture was stirred at room temperature for 1.0 h. The reaction mixture was concentrated under reduced pressure. The crude product in DMF (1.50 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), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 11% B to 31% B in 18 min, 31% B for 22 min, 31% B; wavelength: 254 nm; RT1 (min): 21; number of runs: 4) to give 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-ylamide)pyrrol-2-yl]formamide}propanamide)-N-[1-methyl-5-({[3-({[1-methyl-2-({2-[(1-methyl-5-{[1-methyl-2-(propylcarbamoyl)imidazol-4-yl]carbamoyl}pyrrol-3-yl)carbamoyl]ethyl}carbamoyl)imidazol-4-yl]carbamoyl}methyl)azetidine-3-yl]methyl}carbamoyl)pyrrol-3-yl]imidazol-2-carboxamide (2.20 mg, 6.39%) as a white solid. HRMS: C 53 H 66 N 22 O 10 Calculated mass for: 1170.5332, found: 1171.5489 [M+H] + . HPLC: Purity 93.582%.

[0612] Example 22. Synthesis of Additional Compounds of the Present Disclosure The compounds of this application were prepared by the same method as in Examples 1 to 22. An overview of the analytical data is shown in Table 3.

[0613] [Table 6-1]

[0614] [Table 6-2]

[0615] [Table 6-3]

[0616] [Table 6-4]

[0617] [Table 6-5]

[0618] Biological Examples Example B-1. EC 50 Assay DM1 Lesion Reduction Assay Method Myotonic dystrophy type 1 affected patient fibroblasts (Coriell GM04602; 1600 CTG repeats) and wild-type fibroblasts (Coriell GM07492; control strain) were cultured separately in Gibco DMEM (1×) supplemented with 10% FBS and 1× penicillin / streptomycin + 4.5 g / L D-glucose + L-glutamine + 110 mg / L sodium pyruvate. The cells were maintained in an incubator at 37 °C and 5% CO2 with fresh medium every 48 - 72 hours.

[0619] Both cell lines were harvested using Trypl-E at a culture density of 90 - 95%, then pelleted at 500 x g for 5 minutes and resuspended in fresh medium. DM1 fibroblasts were seeded into an Agilent 96-well black plate at a density of 5,000 cells / well in 200 μL of medium, and eight wells were reserved for control fibroblasts. The plate was returned and incubated at 37 °C, 5% CO2 for 24 hours.

[0620] The compound was diluted from a 10 mM stock to 1 mM in DMSO and then diluted again to 6 μM (2x concentration) in the medium. The medium was removed from all plates and the cells were replenished with 100 μL of medium. The cells were treated with an 8-point dose response, 1:3 fold dilution, with a maximum dose of 3 μM by adding 100 μL of 6 μM (2x concentration) compound to 100 μL of medium containing the cells. The plate was returned and incubated at 37 °C, 5% CO2 for 48 hours.

[0621] After treatment, the compound was removed, the plate was washed with PBS, and then the cells were fixed in 75 μL of 4% PFA solution at room temperature for 20 minutes. The plate was washed twice with PBS and twice with cold 70% ethanol, and then permeabilized with 250 μL of cold 70% ethanol at -20 °C for 24 - 72 hours.

[0622] After permeabilization, the plate was washed once with 30% formamide and 2x SSC buffer and rehydrated in that buffer at room temperature for 15 minutes. The cells were incubated overnight at 37 °C in 75 μL of hybridization solution containing 30% formamide, 2x SSC, 25 mg / mL dextran sulfate, 2.5 mg / mL BSA, 0.2 μg / mL herring sperm DNA, 2 mM vanadyl-ribonucleoside complex, and 5 nM CAG10-Cy3 probe.

[0623] The plate was washed once with 30% formamide in 2×SSC buffer and then washed twice with buffer for 30 minutes at 37°C and 300 RPM in an incubating plate shaker. The cells were stained with 75 μL of 2.5 μg / mL DAPI in PBS for 5 minutes at room temperature. 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.

[0624] Cells were imaged on a Cytation5 using 20× objective sampling from four regions of each well. Nuclei were captured under the DAPI channel and lesions were captured under the RFP channel. The plate was analyzed based on the average lesion per well and per nucleus. Active compounds were defined as those that showed a significant decrease in lesions per nucleus from negative control cells in a dose-responsive manner.

[0625] Lesion reduction in FECD F35T cells were cultured in a medium supplemented with 8% FBS, 20 μg / mL ascorbic acid, 200 mg / mL CaCl2, 0.08% chondroitin sulfate, 1X penicillin / streptomycin, 100 μg / mL bovine pituitary extract, 5 ng / mL epidermal growth factor, and 20 ng / mL nerve growth factor in Opti-MEM (ThermoFisher). During the culture, the cells were maintained in an incubator at 37 °C and 5% CO2. The medium was replaced with fresh medium every 48 hours. Once the cells reached an appropriate culture density, they were harvested and seeded at a density of 5000 cells per well in a 96-well plate in 200 μL of supplemented Opti-MEM medium. The cells were returned to the incubator and left at 37 °C and 5% CO2 for 24 hours. The cells were then treated with the compound or negative control in an 8-point dose response and incubated at 37 °C and 5% CO2 for 48 hours. After the treatment, the cells were fixed with 4% PFA at room temperature for 20 minutes, followed by permeabilization with 70% ethanol. The cells were incubated at -20 °C for at least 1 hour and up to 72 hours, after which the ethanol was removed and the cells were washed with PBS. The cells were rehydrated in 30% formamide and 2XSSC buffer at room temperature for 10 minutes. The cells were then incubated overnight at 37 °C in a hybridization solution containing 30% formamide, 2XSSC, 55 mg / mL dextran sulfate, 2.75 mg / mL bovine serum albumin, 0.2 μg / mL salmon sperm DNA, 1% vanadyl-ribonucleoside complex, and 0.05% 10 μM CAG10-Cy3 probe. The cells were washed twice with 30% formamide in 2XSSC, and during the second wash, the cells were incubated with shaking at 37 °C and 200 rpm for 60 minutes. The cells were stained with 5 mg / mL DAPI 1:1000 in PBS and incubated at room temperature for 5 minutes. The cells were then washed with PBS, 150 μL of PBS was added to each well, and the wells were sealed with adhesive foil. The cells were imaged with Cytation5 and analyzed based on the lesions per nucleus. An active compound was defined as a compound that showed a significant decrease in lesions per nucleus from negative control cells in a dose-responsive manner.

[0626] Representative in vitro biochemical data are presented in Table 4. A < 100 nM; B ≥ 100 nM to 500 nM; C ≥ 500 nM to 1000 nM; D > 1000 nM.

[0627]

Table 7-1

[0628]

Table 7-2

[0629]

Table 7-3

[0630]

Table 7-4

[0631]

Table 7-5

[0632]

Table 7-6

[0633]

Table 7-7

[0634]

Table 7-8

[0635]

Table 7-9

[0636]

Table 7-10

[0637] Preferred embodiments of the present invention are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Without departing from the present invention, numerous variations, modifications, and substitutions will occur to those skilled in the art here. It should be understood that various alternative forms to the embodiments of the present invention described herein may be used in practicing the present invention. The following claims define the scope of the present invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. A transcription modulator molecule having the structure of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, W １ However, hydrogen or -N=C(N(R １ｅ ) ２ ) ２ And each R １ｅ However, independently, hydrogen or C １ ~C ３ It is alkyl, Each Y １ 、Y ２ 、Y ３ 、Y ４ 、Y ５ 、Y ６ 、Y ７ 、and Y ８ is independently N or CH, L １ However, C １ ~C ２０ Alkylene or C ２ ~C ２０ It is a heteroalkylene, Z does not exist, or is -C(O)-, or -C(=NH)-, R ４ However, C １ ~C ６ Alkyl, -OR ４ｂ , or -NR ４ａ R ４ｂ And, R ４ａ However, hydrogen, optionally substituted C １ ~C ２０ Alkyl or optionally substituted C １ ~C ２０ It is heteroalkyl, R ４ｂ However, C is optionally substituted. １ ~C ２０ Alkyl, optionally substituted C ２ ~C ２０ Alkenyl, optionally substituted C ２ ~C ２０ Alkinyl, optionally substituted C １ ~C ２０ aminoalkyl, optionally substituted C １ ~C ２０ Haloalkyl, optionally substituted C １ ~C ２０ Heteroalkyl, optionally substituted C １ ~C ２０ Hydroxyalkyl, optionally substituted C ３ ~C ８ A cycloalkyl, an optionally substituted 4- to 8-membered heterocycloalkyl, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl, or R ４ａ and R ４ｂ However, together with the nitrogen to which they are bound, they form a selectively substituted 4- to 8-membered heterocycloalkyl group that is partially or completely unsaturated. Each R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ２ｅ , R ２ｆ , R ２ｇ , and R ２ｈ However, independently, hydrogen, and optionally substituted C １ ~C ５０ Alkyl, optionally substituted C ２ ~C ５０ Alkenyl, optionally substituted C ２ ~C ５０ Alkinyl, optionally substituted C １ ~C ５０ Heteroalkyl, optionally substituted C ２ ~C ５０ Heteroalkenyl, optionally substituted C ２ ~C ５０ Heteroalkynyl, optionally substituted C １ ~C ５０ Haloalkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 3- to 8-membered heterocycloalkyl groups, or optionally substituted PEG groups. １～５０ And each of them has one or more R １０ It is optionally replaced by Each R ３ａ and R ３ｂ However, independently, hydrogen, halogen, -NR １１ａ R １１ｂ , or -NHC(O)R １２ And, R １１ａ and R １１ｂ However, each is independently hydrogen, alkyl, or PEG. R １２ However, whether it is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl, Or two R ３ａ or two R ３ｂ However, along with the carbon atoms to which they are bonded, C ３ ~C ６ Forming a cycloalkyl or a 4-6 member heterocycloalkyl, Each R １０ is independently, -CN, -OH, -OR １０ａ , -N ３ , -NR １０ａ R １０ｂ , -CO(O)R １０ｃ , -C(O)OR １０ｃ , -C(O)NR １０ａ R １０ｂ , -NHC(O)R １０ｃ , -NHC(O)OR １０ｃ , -OC(O)NR １０ａ R １０ｂ , or optionally substituted 5- to 10-membered heteroaryl, R １０ａ and R １０ｂ However, each is independently hydrogen, alkyl, or PEG. R １０ｃ However, it is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. n １ and m １ A transcription modulator molecule, or a pharmaceutically acceptable salt thereof, wherein each is independently 0 or 1.

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

3. Each Y １ , Y ３ , and Y ６ The transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the molecule is CH.

4. The transcription modulator molecule has the structure of formula (Ia), or is a pharmaceutically acceptable salt thereof. 【Chemistry 2】 During the ceremony, W １ However, hydrogen or -N=C(N(R １ｅ ) ２ ) ２ And each R １ｅ However, independently, hydrogen or C １ ~C ３ It is alkyl, Each Y ５ However, independently, it is N or CH, L １ However, C １ ~C ２０ Alkylene or C ２ ~C ２０ It is a heteroalkylene, Z does not exist, or is -C(O)-, or -C(=NH)-, R ４ However, C １ ~C ６ Alkyl, -OR ４ｂ , or -NR ４ａ R ４ｂ And, R ４ａ However, hydrogen, optionally substituted C １ ~C ２０ Alkyl or optionally substituted C １ ~C ２０ It is heteroalkyl, R ４ｂ However, C is optionally substituted. １ ~C ２０ Alkyl, optionally substituted C ２ ~C ２０ Alkenyl, optionally substituted C ２ ~C ２０ Alkinyl, optionally substituted C １ ~C ２０ aminoalkyl, optionally substituted C １ ~C ２０ Haloalkyl, optionally substituted C １ ~C ２０ Heteroalkyl, optionally substituted C １ ~C ２０ Hydroxyalkyl, optionally substituted C ３ ~C ８ A cycloalkyl, an optionally substituted 4- to 8-membered heterocycloalkyl, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl, or R ４ａ and R ４ｂ However, together with the nitrogen to which they are bound, they form a selectively substituted 4- to 8-membered heterocycloalkyl group that is partially or completely unsaturated. Each R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ２ｅ , R ２ｆ , R ２ｇ , and R ２ｈ However, independently, hydrogen, and optionally substituted C １ ~C ５０ Alkyl, optionally substituted C ２ ~C ５０ Alkenyl, optionally substituted C ２ ~C ５０ Alkinyl, optionally substituted C １ ~C ５０ Heteroalkyl, optionally substituted C ２ ~C ５０ Heteroalkenyl, optionally substituted C ２ ~C ５０ Heteroalkynyl, optionally substituted C １ ~C ５０ Haloalkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 3- to 8-membered heterocycloalkyl groups, or optionally substituted PEG groups. １～５０ And each of them has one or more R １０ It is optionally replaced by Each R ３ａ and R ３ｂ However, independently, hydrogen, halogen, -NR １１ａ R １１ｂ , or -NHC(O)R １２ And, R １１ａ and R １１ｂ However, each is independently hydrogen, alkyl, or PEG. R １２ However, whether it is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl, Or two R ３ａ or two R ３ｂ However, along with the carbon atoms to which they are bonded, C ３ ~C ６ Forming a cycloalkyl or a 4-6 member heterocycloalkyl, Each R １０ However, independently, -CN, -OH, -OR １０ａ , -N ３ , -NR １０ａ R １０ｂ , -CO(O)R １０ｃ , -C(O)OR １０ｃ , -C(O)NR １０ａ R １０ｂ ,-NHC(O)R １０ｃ , -NHC(O)OR １０ｃ , -OC(O)NR １０ａ R １０ｂ , or a 5-10 member heteroaryl that is optionally substituted, R １０ａ and R １０ｂ However, each is independently hydrogen, alkyl, or PEG. R １０ｃ However, it is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. n １ and m １ A transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each is independently 0 or 1.

5. L １ However, C １ ~C ２０ Alkylene or C ２ ~C ２０ It is a heteroalkylene, Z does not exist, or is -C(O)-. R ４ However, -NR ４ａ R ４ｂ The transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof.

6. A transcription modulator molecule according to claim 5, or a pharmaceutically acceptable salt thereof, wherein Z is absent.

7. A transcription modulator molecule according to claim 5, or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)-.

8. L １ However, C １ ~C １０ A transcription modulator molecule according to claim 5, which is alkylene, or a pharmaceutically acceptable salt thereof.

9. R ４ａ However, hydrogen, optionally substituted C １ ~C ２０ Alkyl or optionally substituted C １ ~C ２０ It is heteroalkyl, R ４ｂ However, C is optionally substituted. １ ~C ２０ Alkyl or optionally substituted C １ ~C ２０ A transcription modulator molecule according to claim 1, which is a heteroalkyl group, or a pharmaceutically acceptable salt thereof.

10. A transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 3a is hydrogen and each R 3b is independently selected from hydrogen, -NR 11a R 11b, and -NHC(O)R 12.

11. The transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R3a and each R3b is hydrogen.

12. The transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof, wherein two R3b atoms, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl or a 4-6 member heterocycloalkyl, and each R3a atom is hydrogen.

13. A transcription modulator molecule according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 2a, R 2b, R 2c, R 2d, R 2e, R 2f, R 2g, and R 2h is independently hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C1-C10 haloalkyl, or optionally substituted PEG 1-10, each of which is optionally substituted with one or more R 10.

14. The transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 2a, R 2b, R 2c, R 2d, R 2e, R 2f, R 2g, and R 2h is independently a C1-C10 alkyl, and each of them is optionally substituted with one or more R10 atoms.

15. The transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n 1 is 1.

16. The transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m1 is 0.

17. The transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently -N 3, -NR 10a R 10b, -CO(O)R 10c, -C(O)OR 10c, -C(O)NR 10a R 10b, -NHC(O)R 10c, -NHC(O)OR 10c, -OC(O)NR 10a R 10b, or an optionally substituted 5- to 10-membered heteroaryl.

18. The transcription modulator molecule according to claim 1, or a pharmaceutically acceptable salt thereof, wherein W1 is hydrogen.

19. A transcription modulator molecule selected from Table 2, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a transcription modulator molecule according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Images