Methods and compounds for modulating hereditary genetic diseases

Abstract

The present disclosure relates to transcription regulator molecule compounds, compositions, and methods for the treatment of DM1 and FECD.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Application No. 63 / 352,397, filed June 15, 2022, and U.S. Application No. 63 / 482,751, filed February 1, 2023, both of which are incorporated herein by reference in their entirety. Technical Field

[0003] Disclosed herein are novel chimeric heterocyclic polyamide compounds and compositions, and their use as pharmaceuticals for treating diseases. Also provided are methods for modulating expression of a target gene comprising a CTG trinucleotide repeat sequence in a human or animal subject for treating diseases such as myotonic dystrophy type 1 ("DM1"), Fuchs' endothelial dystrophy, or Fuchs' corneal endothelial dystrophy ("FECD"). Background Art

[0004] The present disclosure relates to the treatment of inherited genetic diseases characterized by overproduction of mRNA.

[0005] Myotonic dystrophy ("DM") is a type of muscular dystrophy that affects approximately 1 in 8,000 people. DM is the most common form of muscular dystrophy in adult-onset patients, with most cases of DM diagnosed after the age of 20. DM is characterized by persistent muscle contractions and is associated with several symptoms, including muscle problems and cataracts, as well as heart and respiratory problems, both of which typically appear later in the disease's progression. Although treatments are available to improve symptoms, there are currently no treatments that can halt or reverse the progression of DM. Respiratory failure and cardiac arrhythmias are the most common causes of death in patients with DM.

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

[0007] DM1 is induced by transcription of the defective dmpk gene in DM1 individuals. Typically, this gene contains a 3' untranslated region with a CTG trinucleotide repeat count of 5 to 37. In the DM1 genotype, this trinucleotide repeat count increases from 50 to over 3,000, with the majority having over 1,000 repeats of the CTG sequence. This count tends to increase in offspring, leading to an earlier age of onset. Furthermore, it has been observed that this count increases throughout an individual's lifetime, possibly due to abnormalities in DNA repair.

[0008] The progression of DM1 has been attributed to "RNA toxicity" from dmpk mRNA, which has an expanded CTG region. This mRNA forms aggregates with certain proteins, and these aggregates interfere with normal cellular function. The defective mRNA binding to myoblin may be the mechanism that leads to DM1 symptoms, particularly because myoblin activity is required for normal muscle development in flies.

[0009] Fuchs' endothelial dystrophy, or Fuchs' corneal endothelial dystrophy (FECD), is a non-inflammatory, sporadic, autosomal dominant dystrophy involving the corneal endothelium. With Fuchs' dystrophy, the cornea begins to swell, causing glare, halos, and decreased vision. Damage to the cornea can be severe, even leading to blindness. Fuchs' dystrophy is divided into early-onset (first decade) and late-onset (fourth to fifth decade), with the latter being more common in women. Early-onset Fuchs' disease involves the α2 chain of type 8 collagen. The late-onset form is characterized by the involvement of transcription factor 4 (TCF4), transcription factor 8 (TCF8), ATP / GTP-binding protein-like protein 1 (AGBL1), lipoxygenase homology domain 1 (LOXHD1), solute carrier family 4 member 11 (SLC4A11), transforming growth factor-β-induced protein, and clusterin.

[0010] In some embodiments, the method provides effective treatment for a disease or condition characterized by the presence of an excessive number of CTG trinucleotide repeats in a target gene. In some embodiments, the pathology of the disease or condition is due to the presence of an mRNA containing an excessive number of CTG trinucleotide repeats. In some embodiments, the pathology of the disease or condition is due to the presence of a translation product containing an excessive number of glutamine amino acid residues. In some embodiments, the pathology of the disease or condition is due to the loss of function of the translation product. In some embodiments, the pathology of the disease or condition is due to the gain of function of the translation product. In some embodiments, the pathology of the disease or condition can be alleviated by increasing the transcription rate of the defective gene. In some embodiments, the pathology of the disease or condition can be alleviated by reducing the transcription rate of the defective gene. Summary of the Invention

[0011] 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 various processes involved in converting genetic information into cellular components. Several regulatory molecules are known to regulate the production of mRNA, and if directed against a target gene (e.g., dmpk or tcf4), they will regulate the production of target gene mRNA that causes diseases such as DM1 or Fuchs' corneal endothelial dystrophy; and thus reverse the progression of these diseases.

[0012] The present disclosure provides compounds and methods for recruiting regulatory molecules to target genes that contain CTG trinucleotide repeats in close proximity. The compounds disclosed herein contain a DNA-binding moiety that selectively binds to the target gene. The DNA-binding moiety selectively binds to the characteristic CTG trinucleotide repeats of DMPK or TCF4. This mechanism provides effective treatment for DM1 or FECD caused by defective expression of DMPK or TCF4, respectively.

[0013] The DNA-binding moiety comprises a polyamide segment that selectively binds to a target CTG sequence. For example, polyamides designed by Dervan (U.S. Patents 9,630,950 and 8,524,899) and others can selectively bind to selected DNA sequences. These polyamides reside in the minor groove of double-helical DNA and form hydrogen bonding interactions with Watson-Crick base pairs. Polyamides that selectively bind to specific DNA sequences can be designed by linking single amide building blocks according to established chemical rules. A building block is provided for each DNA base pair, where each building block non-covalently and selectively binds to one of the following DNA base pairs: A / T, T / A, G / C, and C / G. Following this principle, trinucleotides bind to molecules with three amide units (i.e., triamides). Generally, these polyamides can be oriented in either direction of the DNA sequence.

[0014] In principle, longer DNA sequences can be targeted with higher specificity and / or higher affinity by combining a larger number of monoamide building blocks into longer polyamide chains. Ideally, the binding affinity of polyamides would simply be equal to the sum of the interactions of each individual monoamide / DNA base pair and / or heterocycle / DNA base pair. However, in reality, due to the geometric mismatch between the extremely rigid polyamide and DNA structure, longer polyamide sequences will not be as tightly bound to longer DNA sequences as expected based on simple addition of fractions. The geometric mismatch between longer polyamide sequences and longer DNA sequences induces an unfavorable geometric strain that reduces the originally expected binding affinity.

[0015] Disclosed herein are compounds comprising polyamide moieties that can bind to one or more copies of a CTG trinucleotide repeat sequence and modulate the expression of a target gene comprising a CTG trinucleotide repeat sequence. Treatment of an individual with these compounds will modulate the expression of the defective target gene, and this can reduce the incidence, severity, or frequency of symptoms associated with the disease. Certain compounds disclosed herein will provide binding affinity and selectivity that is higher than previously observed for such compounds.

[0016] It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art upon reading this detailed description. DETAILED DESCRIPTION

[0017] References incorporated

[0018] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0019] The transcriptional regulator molecules described herein can be programmed to regulate the expression of target genes containing nucleotide repeats comprising CTG. The transcriptional regulator molecules contain a DNA binding portion that selectively binds to one or more copies of the CTG trinucleotide repeat sequence that is characteristic of a defective target gene (e.g., dmpk, tcf4, atxn8, or atxn80s). The molecules and compounds disclosed herein provide higher binding affinity and selectivity than previously observed for such compounds and can more effectively treat diseases associated with defective target genes.

[0020] Treating individuals with these compounds will modulate the expression of defective target genes, and this can reduce the incidence, severity, or frequency of symptoms associated with genetic diseases (e.g., DM1 or FECD). The compounds described herein recruit regulatory molecules to modulate the expression of defective target genes and effectively treat and alleviate the symptoms associated with the disease.

[0021] Compounds - Transcriptional Regulator Molecules

[0022] In some embodiments, the transcriptional regulator molecule is a compound having a DNA binding moiety capable of non-covalently binding to a nucleotide repeat sequence comprising CTG. In some embodiments, the DNA binding moiety is a polyamide.

[0023] In some embodiments, the DNA binding moiety comprises one or more monomeric subunits.

[0024] In some embodiments, one or more subunits comprise -NH-QC(O)-, wherein Q is an optionally substituted C6-C 10 arylene, optionally substituted 4- to 10-membered heterocyclylene, optionally substituted 5- to 10-membered heteroarylene, or optionally substituted alkylene.

[0025] In some embodiments, the DNA binding moiety comprises a polyamide having one or more subunits selected from:

[0026] -NH-benzopyrazinylene-C(O)-, -NH-phenylene-C(O)-, -NH-pyridinylene-C(O)-, -NH-piperidinylene-C(O)-, -NH-pyrimidinylene-C(O)-, -NH-anthracenylene-C(O)-, -NH-quinolinylene-C(O)-, and wherein each R' is independently hydrogen, an optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 Heteroalkyl, optionally substituted C1-C 20 Haloalkyl or optionally substituted C1-C 20 and Z is H, NH2, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkyl-NH2.

[0027] In some embodiments, one or more subunits are independently selected from the group consisting of an optionally substituted pyrrolecarboxamide monomer, an optionally substituted imidazolecarboxamide monomer, an optionally substituted delta-aminobutyric acid (gAB), and beta-alanine (beta or beta). In some embodiments, one or more polyamide backbone carbonyl groups (C═O) are replaced with an oxetane. In some embodiments, at least one polyamide backbone carbonyl group is replaced with an oxetane.

[0028] 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-aminopentanoic acid. In some embodiments, the polyamide comprises one or more subunits selected from the group consisting of optionally substituted N-methylpyrrolecarboxamide, optionally substituted N-methylimidazolecarboxamide, β-alanine, and δ-aminobutyric acid. In some embodiments, the DNA binding moiety comprises a δ-aminobutyric acid.

[0029] In one aspect, provided herein is a transcriptional regulator molecule having the structure of Formula (A) or a pharmaceutically acceptable salt thereof:

[0030]

[0031] in:

[0032] Each X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 and X 8 are independently O or NR 2 ;

[0033] Each Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 and Y 8 are independently CH or N;

[0034] 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 、-N=C(N(PO(OR 1e )2, -Z B -(CH2) p3 -PO(OR 1e )2 or -Z B -(CH2) p3 -O-PO(OR 1e )2, where

[0035] Each R 1e are 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 ;

[0036] Each R 1f are 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, PEG 1-50 or AA 1-10 ;

[0037] or R 1e and R 1f Together with the nitrogen to which it is attached, it forms an optionally substituted 5- to 7-membered heterocycloalkyl group, wherein

[0038] Each AA is independently a naturally occurring amino acid;

[0039] Z B is N or O; and

[0040] p3 is 1 to 10;

[0041] W 2 is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl; or

[0042] -L 1 -ZR 4 ,in

[0043] L 1 is an alkylene group or a heteroalkylene group;

[0044] Z is absent, -C(O)-, or -C(=NH)-; and

[0045] R 4 C1-C6 alkyl, -OR 4b or -NR 4a R 4b ;in

[0046] R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl;

[0047] 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; or

[0048] R 4a and R 4b together with the nitrogen to which it is attached, form a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl;

[0049] R w is hydrogen or optionally substituted C1-C 20 alkyl;

[0050] or W 2 and R w together with the nitrogen to which it is attached, form a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl;

[0051] Each R 2 are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 Heteroalkynyl, optionally substituted C1-C 50 Hydroxyalkyl, optionally substituted C1-C 50 aminoalkyl, optionally substituted C1-C 50 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, or optionally substituted PEG 1-50 ;

[0052] Each R 3 are independently hydrogen, deuterium, halogen, acetyl, amino, amide, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20Haloalkyl, optionally substituted C1-C 20 Alkylamino or optionally substituted C1-C 20 hydroxyalkyl; or

[0053] Two R's 3 Together with the atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0054] p1 is 3 or 4;

[0055] n1 and n2 are each independently 0 or 1;

[0056] n3 is 1 or 2;

[0057] m1 is 0, 1, 2, or 3; and

[0058] n0 is 0 or 1, wherein n0 and m1 are both non-zero.

[0059] In some embodiments of Formula (A), n0 is 1. In some embodiments, n0 is 0.

[0060] In some embodiments of Formula (A), n2 is 2. In some embodiments, n2 is 1. In some embodiments, n2 is 0.

[0061] In some embodiments of Formula (A), n3 is 1. In some embodiments, n3 is 0.

[0062] In another aspect, provided herein is a transcriptional regulator molecule having the structure of Formula (A-1) or a pharmaceutically acceptable salt thereof:

[0063]

[0064] in:

[0065] Each X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 and X 8 are independently O or NR 2 ;

[0066] Each Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 and Y 8 are independently CH or N;

[0067] W1 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 、-N=C(N(R 1e )2)2、AA 1-10 、-Z B -PO(OR 1e )2, -Z B -(CH2) p3 -PO(OR 1e )2 or -Z B -(CH2) p3 -O-PO(OR 1e )2, where

[0068] Each R 1e are 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 50 Heteroalkynyl or PEG 1-50 ;

[0069] Each R 1f are 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, PEG 1-50 or (AA) 1-10 ;

[0070] or R 1e and R 1f Together with the nitrogen to which it is attached, it forms an optionally substituted 5- to 8-membered heterocycloalkyl group, wherein

[0071] Each AA is independently a naturally occurring amino acid;

[0072] Z B is N or O; and

[0073] p3 is 1 to 10;

[0074] W 2 is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl,

[0075] or -L 1 -ZR 4 ;in

[0076] L 1 is an alkylene group or a heteroalkylene group;

[0077] Z is absent, -C(O)-, or -C(=NH)-; and

[0078] R 4 C1-C6 alkyl, -OR 4b or -NR 4a R 4b ;in

[0079] R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl;

[0080] 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-C7 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl; or

[0081] R 4a and R 4b together with the nitrogen to which it is attached, form a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl;

[0082] R wis hydrogen or optionally substituted C1-C 20 alkyl;

[0083] or W 2 and R w together with the nitrogen to which it is attached, form a partially or fully unsaturated optionally substituted 4- to 10-membered heterocycloalkyl;

[0084] Each R 2 are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 Heteroalkynyl, optionally substituted C1-C 50 aminoalkyl, optionally substituted C1-C 50 Haloalkyl, optionally substituted C1-C 50 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3 to 8 membered heterocycloalkyl ring, or optionally substituted PEG 1-50 ;

[0085] Each R 3 are independently hydrogen, deuterium, halogen, acetyl, 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; or

[0086] Two R's 3 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group;

[0087] p1 is 3 or 4; and

[0088] m1 and n1 are each independently 0 or 1.

[0089] In some embodiments of formula (A) or (A-1), p1 is 3. In some embodiments, p1 is 4.

[0090] In some embodiments of Formula (A) or (A-1), each X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X7 and X 8 Independently NR 2 In some embodiments, each X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 and X 8 are independently O.

[0091] 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 In some embodiments, W 1 -NR 1e C(O)R 1f 、-NR 1e C(O)NR 1e R 1f 、-C(O)NR 1e R 1f 、-OC(O)NR 1e R 1f or -NR 1e C(O)OR 1f In some embodiments, W 1 AA 1-10 In some embodiments, W 1 AA 1-4 In some embodiments, W 1 AA 1-3 .

[0092] In some embodiments of Formula (A) or (A-1), W 1 -Z B -PO(OR 1e )2, -Z B -(CH2) p3 -PO(OR1e )2 or -Z B -(CH2) p3 -O-PO2(OR 1e )2, where Z B is O or N, and p3 is 1 to 10.

[0093] In some embodiments of Formula (A) or (A-1), W 1 It is (azoalkylene)methanediamine or (azoalkylene)-N,N,N',N'-tetramethylmethanediamine.

[0094] In some embodiments of Formula (A) or (A-1), W 1 In some embodiments, W 1 -N=C(N(R 1e )2)2, where each R 1e are 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 50 Heteroalkynyl or PEG 1-50 .

[0095] In some embodiments of Formula (A) or (A-1), W 1 for Among them, each R 1e are independently hydrogen or optionally substituted C1-C 20 alkyl.

[0096] In some embodiments of Formula (A) or (A-1), W 1 for In some embodiments, W 1 for

[0097] In some embodiments of Formula (A) or (A-1), W 1 is hydrogen or -N=C(N(R 1e )2)2, where 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, where each R 1e are independently hydrogen or methyl.

[0098] In some embodiments of Formula (A) or (A-1), W 1For hydrogen.

[0099] In some embodiments of Formula (A) or (A-1), each R 1e are 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 In some embodiments, each R 1e are independently optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl or optionally substituted C2-C 20 In some embodiments, each R 1e are independently optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, optionally substituted C2-C 50 Heteroalkynyl or PEG 1-50 In some embodiments, each R 1e Independently PEG 1-50 In some embodiments, each R 1e are independently hydrogen.

[0100] In some embodiments of Formula (A) or (A-1), each R 1f are 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, PEG 1-50 or AA 1-10 In some embodiments, each R 1f are 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-C50 Heteroalkynyl or PEG 1-50 In some embodiments, each R 1f are independently optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl or optionally substituted C2-C 20 In some embodiments, each R 1f are independently optionally substituted C1-C 20 Heteroalkyl, optionally substituted C2-C 20 Heteroalkenyl, optionally substituted C2-C 50 Heteroalkynyl or PEG 1-50 In some embodiments, each R 1f Independently PEG 1-50 In some embodiments, each R 1f are independently hydrogen.

[0101] In some embodiments of Formula (A) or (A-1), R 1e and R 1f Together with the nitrogen atom to which it is attached, R forms an optionally substituted 4- to 8-membered heterocycloalkyl. 1e and R 1f Together with the nitrogen atom to which it is attached, R forms an optionally substituted 5- to 7-membered heterocycloalkyl. 1e and R 1f Together with the nitrogen atom to which it is attached, it forms an optionally substituted 5-membered heterocycloalkyl. 1e and R 1f Together with the nitrogen atom to which it is attached, R forms an optionally substituted 6-membered heterocycloalkyl. 1e and R 1f Together with the nitrogen atom to which it is attached, it forms an optionally substituted 7-membered heterocycloalkyl.

[0102] In some embodiments of Formula (A) or (A-1), each R 2 are independently optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C2-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 Heteroalkynyl, optionally substituted C1-C 50 aminoalkyl, optionally substituted C1-C 50 Hydroxyalkyl, optionally substituted C1-C50 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, or optionally substituted PEG 1-50 In some embodiments, each R 2 are independently optionally substituted C1-C 50 Alkyl, optionally substituted C1-C 50 aminoalkyl, optionally substituted C1-C 50 Hydroxyalkyl or optionally substituted PEG 1-50 In some embodiments, each R 2 are independently optionally substituted C1-C 30 Alkyl, optionally substituted C1-C 50 aminoalkyl, optionally substituted C1-C 30 Hydroxyalkyl or optionally substituted PEG 1-30 In some embodiments, each R 2 are 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 In some embodiments, each R 2 are 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 In some embodiments, each R 2 Optionally substituted with one or more amino, amide, azide, cyano, ester, oxo (=0), urea, optionally substituted aryl, PEG, or optionally substituted 5- to 10-membered heteroaryl.

[0103] In some embodiments of Formula (A) or (A-1), each R 2 are independently hydrogen or optionally substituted C1-C 50 alkyl, which is optionally substituted with one or more amino, amide, azido, cyano, ester, oxo (=O), urea, optionally substituted aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, each R 2 are independently optionally substituted C1-C 30 In some embodiments, each R 2 are independently optionally substituted C1-C 20 In some embodiments, each R 2are independently optionally substituted C1-C 10 In some embodiments, each R 2 is independently methyl, ethyl, isopropyl, isobutyl, sec-butyl or tert-butyl. 2 In some embodiments, each R 2 In some embodiments, each R 2 In some embodiments, each R 2 In some embodiments, each R 2 For hydrogen.

[0104] In some embodiments of Formula (A) or (A-1), each R 3 are 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 In some embodiments, each R 3 are independently hydrogen, amino, amide or optionally substituted C1-C 20 In some embodiments, each R 3 is independently hydrogen, amino or amide. 3 In some embodiments, each R 3 In some embodiments, each R 3 For hydrogen.

[0105] In some embodiments of Formula (A) or (A-1), two R 3 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 3 to 6 membered heterocycloalkyl group. 3 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group. 3 Together with the atoms to which they are attached, they form a 4- to 6-membered heterocycloalkyl group. 3 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl. 3 Together with the atoms to which they are attached, they form a 5-membered heterocycloalkyl. 3 Together with the atoms to which they are attached, they form a 6-membered heterocycloalkyl group. 3 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, or cyclopentyl group. 3Together with the atoms to which they are attached, they form a cyclopropyl group. 3 Together with the atoms to which they are attached, they form a cyclobutyl group. 3 Together with the atoms to which it is attached, it forms a cyclopentyl group.

[0106] In some embodiments of Formula (A) or (A-1), W 2 -L 1 -ZR 4 ; where L 1 is alkylene or heteroalkylene; Z is absent, -C(O)- or -C(=NH)-; and R 4 For-OR 4b or -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 C1-C 20 Alkylene or C2-C 20 heteroalkylene; Z is absent, -C(O)- or -C(=NH)-; and R 4 For-OR 4b or -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 C1-C 10 Alkylene or C2-C 10 heteroalkylene; Z is absent, -C(O)- or -C(=NH)-; and R 4 For-OR 4b or -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 is C1-C8 alkylene or C2-C8 heteroalkylene; Z is absent, -C(O)- or -C(=NH)-; and R 4 For-OR 4b or -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 is C1-C6 alkylene or C2-C6 heteroalkylene; Z is absent, -C(O)- or -C(=NH)-; and R4 For-OR 4b or -NR 4a R 4b .

[0107] In some embodiments of Formula (A) or (A-1), W 2 -L 1 -ZR 4 ; where L 1 C1-C 20 Alkylene; Z is absent, -C(O)- or -C(=NH)-; and R 4 -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 C1-C 10 Alkylene; Z is absent, -C(O)- or -C(=NH)-; and R 4 -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 is C1-C8 alkylene; Z is absent, -C(O)- or -C(=NH)-; and R 4 -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 is C1-C6 alkylene; Z is absent, -C(O)- or -C(=NH)-; and R 4 -NR 4a R 4b .

[0108] In some embodiments of Formula (A) or (A-1), W 2 -L 1 -ZR 4 ; where L 1 C1-C 20 Alkylene or C2-C 20 heteroalkylene; Z is absent or -C(O)-; and R 4 For-OR 4b or -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR4 ; where L 1 C1-C 10 Alkylene or C2-C 10 heteroalkylene; Z is absent or -C(O)-; and R 4 For-OR 4b or -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 is C1-C8 alkylene or C2-C8 heteroalkylene; Z is absent or is -C(O)-; and R 4 For-OR 4b or -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 is C1-C6 alkylene or C2-C6 heteroalkylene; Z is absent or is -C(O)-; and R 4 For-OR 4b or -NR 4a R 4b .

[0109] In some embodiments of Formula (A) or (A-1), W 2 -L 1 -ZR 4 ; where L 1 C1-C 20 Alkylene; Z is -C(O)-; and R 4 -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 C1-C 10 Alkylene; Z is -C(O)-; and R 4 -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 is C1-C8 alkylene; Z is -C(O)-; and R 4 -NR 4a R 4b In some embodiments, W 2 -L 1-ZR 4 ; where L 1 is C1-C6 alkylene; Z is -C(O)-; and R 4 -NR 4a R 4b .

[0110] In some embodiments of Formula (A) or (A-1), W 2 -L 1 -ZR 4 ; where L 1 C1-C 20 alkylene; Z is absent; and R 4 -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 C1-C 10 alkylene; Z is absent; and R 4 -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 is C1-C8 alkylene; Z is absent; and R 4 -NR 4a R 4b In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 is C1-C6 alkylene; Z is absent; and R 4 -NR 4a R 4b .

[0111] In some embodiments of Formula (A) or (A-1), W 2 -L 1 -ZR 4 ; where L 1 C1-C 20 Alkylene or C1-C 20 heteroalkyl; Z is absent or -C(O)-; and R 4 In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 C1-C 20 Alkylene; Z is absent or -C(O)-; and R4 In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 C1-C 20 Alkylene; Z is -C(O)-; and R 4 In some embodiments, W 2 -L 1 -ZR 4 ; where L 1 C1-C 20 alkylene; Z is absent; and R 4 It is a C1-C6 alkyl group.

[0112] In another aspect, provided herein is a transcriptional regulator molecule having the structure of Formula (I) or a pharmaceutically acceptable salt thereof:

[0113]

[0114] in:

[0115] W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl;

[0116] Each Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 and Y 8 are independently N or CH;

[0117] L 1 C1-C 20 Alkylene or C2-C 20 heteroalkylene;

[0118] Z is absent, -C(O)- or -C(=NH)-;

[0119] R 4 C1-C6 alkyl, -OR 4b or -NR 4a R 4b ;in

[0120] R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl;

[0121] 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; or

[0122] R 4a and R 4b together with the nitrogen to which it is attached, form a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl;

[0123] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace;

[0124] Each R 3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0125] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0126] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0127] or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group;

[0128] Each R 10 are 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; wherein

[0129] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0130] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

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

[0132] In another aspect, provided herein is a transcriptional regulator molecule having the structure of Formula (I) or a pharmaceutically acceptable salt thereof:

[0133]

[0134] in:

[0135] W 1 is hydrogen;

[0136] Each Y 5 are independently CH or N;

[0137] L 1 C1-C 20 alkylene;

[0138] Z is absent or -C(O)-;

[0139] R 4 -NR 4a R 4b;in

[0140] R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl;

[0141] 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; or

[0142] R 4a and R 4b together with the nitrogen to which it is attached, form an optionally substituted 4- to 8-membered heterocycloalkyl;

[0143] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2h are 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 ; each of which is optionally replaced by one or more R 10 replace;

[0144] Each R 3a and R 3b are independently hydrogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0145] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0146] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

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

[0148] Each R 10 are 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; wherein

[0149] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0150] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0151] n1 and m1 are each independently 0 or 1.

[0152] In some embodiments, the molecule of Formula (I) or a pharmaceutically acceptable salt thereof has the structure of Formula (Ia):

[0153]

[0154] in:

[0155] W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl;

[0156] Each Y 5 is CH or N;

[0157] L 1 C1-C 20 Alkylene or C2-C 20 heteroalkylene;

[0158] Z is absent, -C(O)- or -C(=NH)-;

[0159] R 4 C1-C6 alkyl, -OR 4b or -NR 4a R4b ;in

[0160] R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl;

[0161] 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-C7 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl; or

[0162] R 4a and R 4b together with the nitrogen to which it is attached, form a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl;

[0163] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace;

[0164] Each R 3a and R 3b are independently hydrogen, halogen, -NR11a R 11b or -NHC(O)R 12 ,in

[0165] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0166] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0167] or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group;

[0168] Each R 10 are 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; wherein

[0169] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0170] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0171] n1 and m1 are each independently 0 or 1.

[0172] In some embodiments, provided herein is a transcriptional regulator molecule having the structure of Formula (Ia) or a pharmaceutically acceptable salt thereof:

[0173]

[0174] in:

[0175] W 1 is hydrogen;

[0176] Each Y 5 are independently CH or N;

[0177] L 1 C1-C20 alkylene;

[0178] Z is absent or -C(O)-;

[0179] R 4 -NR 4a R 4b ;in

[0180] R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl;

[0181] 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; or

[0182] R 4a and R 4b together with the nitrogen to which it is attached, form an optionally substituted 4- to 8-membered heterocycloalkyl;

[0183] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2h are 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 ; each of which is optionally replaced by one or more R 10 replace;

[0184] Each R 3a and R 3b are independently hydrogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0185] R 11a and R11b Each is independently hydrogen, alkyl or PEG;

[0186] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0187] or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group;

[0188] Each R 10 are 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; wherein

[0189] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0190] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0191] n1 and m1 are each independently 0 or 1.

[0192] In some embodiments, the molecule of Formula (I) or a pharmaceutically acceptable salt thereof has the structure of Formula (Ib):

[0193]

[0194] in:

[0195] W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl;

[0196] Each Y 5 is CH or N;

[0197] L 1 C1-C 20 Alkylene or C2-C 20 heteroalkylene;

[0198] Z is absent, -C(O)- or -C(=NH)-;

[0199] R 4 C1-C6 alkyl, -OR 4b or -NR 4a R 4b ;in

[0200] R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl;

[0201] 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-C7 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl; or

[0202] R 4a and R 4b together with the nitrogen to which it is attached, form a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl;

[0203] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 Heteroalkynyl, optionally substituted C1-C 50haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, or optionally substituted PEG 1-50 ; each of which is optionally replaced by one or more R 10 replace;

[0204] Each R 3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0205] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0206] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0207] or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group;

[0208] Each R 10 are 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; wherein

[0209] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0210] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0211] n1 and m1 are each independently 0 or 1.

[0212] In some embodiments, the molecule of Formula (I) or a pharmaceutically acceptable salt thereof has the structure of Formula (Ib):

[0213]

[0214] in:

[0215] W 1 is hydrogen;

[0216] Each Y 5 are independently CH or N;

[0217] L 1 C1-C 20 alkylene;

[0218] Z is absent or -C(O)-;

[0219] R 4 -NR 4a R 4b ;in

[0220] R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl;

[0221] 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; or

[0222] R 4a and R 4b together with the nitrogen to which it is attached, form an optionally substituted 4- to 8-membered heterocycloalkyl;

[0223] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2h are 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 ; each of which is optionally replaced by one or more R 10 replace;

[0224] Each R 3a and R 3b are independently hydrogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0225] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0226] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0227] or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group;

[0228] Each R 10 are 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; wherein

[0229] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0230] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0231] n1 and m1 are each independently 0 or 1.

[0232] In some embodiments of Formula (A), (A-1), (I), (Ia), or (Ib), L 1 C1-C 10 Alkylene or C2-C 10 In some embodiments, L 1 C1-C 10In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 C2-C 10 In some embodiments, L 1 C2-C 10 In some embodiments, L 1 In some embodiments, L 1 is C2-C6 heteroalkylene. In some embodiments, L 1 In some embodiments, L 1 It is a C2-C4 heteroalkylene group.

[0233] In some embodiments of Formula (A), (A-1), (I), (Ia), or (Ib), the heteroalkylene group is polyethylene glycol. In some embodiments, L 1 PEG 1-10 In some embodiments, L 1 PEG 1-8 In some embodiments, L 1 -(CH2CH2-O) y1 -, wherein 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.

[0234] In some embodiments of Formula (A), (A-1), (I), (Ia), or (Ib), the heteroalkylene group comprises -(CH2) x3 N(R a )(CH2) x4 -, where R a is hydrogen or an optionally substituted C1-C6 alkyl group; and each of x3 and x4 is independently an integer in the range of 1 to 6.

[0235] In some embodiments of Formula (A), (A-1), (I), (Ia), or (Ib), Z is -C(O)-; and R 4 For-OR 4bIn some embodiments, Z is -C(O)-; and R 4 -NR 4a R 4b In some embodiments, Z is -C(=NH)-; and R 4 -NR 4a R 4b In some embodiments, Z is absent; and R 4 For-OR 4b In some embodiments, Z is absent; and R 4 -NR 4a R 4b In some embodiments, Z is -C(O)-; and R 4 is a C1-C6 alkyl group. In some embodiments of Formula (A), (A-1), (I), (Ia), or (Ib), Z is absent; and R 4 It is a C1-C6 alkyl group.

[0236] 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 In some embodiments, R 4a is optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 In some embodiments, R 4a is optionally substituted C1-C 20 In some embodiments, R 4a is optionally substituted C1-C 15 In some embodiments, R 4a is optionally substituted C1-C 10 In some embodiments, R 4a is optionally substituted C1-C 20 In some embodiments, the heteroalkyl group 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 of Formula (A), (A-1), (I), (Ia), or (Ib), R 4a is optionally substituted PEG 1-10 In some embodiments, R 4a For hydrogen.

[0237] 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 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.

[0238] In some embodiments of Formula (A), (A-1), (I), (Ia), or (Ib), 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 or optionally substituted C1-C 20 In some embodiments, R 4b is optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 In some embodiments, R 4b is optionally substituted C1-C 20 In some embodiments, R 4b is optionally substituted C1-C 15 In some embodiments, R 4b is optionally substituted C1-C 10 In some embodiments, R 4b is optionally substituted C1-C20 In some embodiments, R 4b is optionally substituted C1-C 15 In some embodiments, R 4b is optionally substituted C1-C 10 In some embodiments, the heteroalkyl group is polyethylene glycol (PEG). In some embodiments, R 4b PEG 1-20 In some embodiments, R 4b PEG 1-15 In some embodiments, R 4b PEG 1-10 .

[0239] In some embodiments of Formula (A), (A-1), (I), (Ia), or (Ib), R 4b is an optionally substituted C3-C8 cycloalkyl, an optionally substituted 4 to 8 membered heterocycloalkyl, an optionally substituted phenyl, or an optionally substituted 5 to 10 membered heteroaryl. 4b is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4 to 8 membered heterocycloalkyl. 4b is an optionally substituted C3-C6 cycloalkyl or an optionally substituted 4 to 6 membered heterocycloalkyl. 4b is an optionally substituted C3-C6 cycloalkyl. 4b In some embodiments, R 4b is an optionally substituted 4 to 6 membered heterocycloalkyl. 4b is a 5- or 6-membered heterocycloalkyl group. 4b is piperidine, piperazine or morpholine. In some embodiments, R 4b In some embodiments, R 4b In some embodiments, R 4b For piperazine.

[0240] In some embodiments of Formula (A), (A-1), (I), (Ia), or (Ib), R 4a and R 4b Together with the nitrogen to which it is attached, it forms a partially or fully unsaturated optionally substituted 4 to 8 membered heterocycloalkyl. 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 4- to 6-membered heterocycloalkyl. 4a and R 4bTogether with the nitrogen to which it is attached, it forms an optionally substituted 4-membered heterocycloalkyl. 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 5-membered heterocycloalkyl. 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 6-membered heterocycloalkyl.

[0241] 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 In some embodiments, R 4a is hydrogen, C1-C 20 Alkyl or C1-C 20 heteroalkyl; and R 4b C1-C 20 Alkyl or C1-C 20 Heteroalkyl.

[0242] 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 In some embodiments, each heteroalkyl group is polyethylene glycol (PEG). In some embodiments, R 4a is hydrogen or PEG 1-20 ; and R 4b PEG 1-20 In some embodiments, R 4a PEG 1-20 ; and R 4b PEG 1-20 .

[0243] In some embodiments of Formula (A), (A-1), (I), (Ia), or (Ib), R 4a is an optionally substituted C1-C6 alkyl group; and R 4b is an optionally substituted C1-C6 alkyl. 4a is a C1-C6 alkyl group; and R 4b It is a C1-C6 alkyl group.

[0244] In another aspect, provided herein is a transcriptional regulator molecule having the structure of Formula (II) or a pharmaceutically acceptable salt thereof:

[0245]

[0246] in:

[0247] W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl;

[0248] Each Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 and Y 8 are independently N or CH;

[0249] L 3 C1-C 20 Alkylene, C2-C 20 Heteroalkylene or AA 1-10 ;in

[0250] Each AA is independently a naturally occurring amino acid;

[0251] V is absent, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl;

[0252] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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; each of which is optionally replaced by one or more R 10 replace;

[0253] Each R 3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0254] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0255] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0256] or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group;

[0257] Each R 10 are 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; wherein

[0258] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0259] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0260] n1 and m1 are each independently 0 or 1; and

[0261] x1 is 0 to 10.

[0262] In some embodiments, the molecule of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIa):

[0263]

[0264] in:

[0265] W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl;

[0266] Each Y 5 are independently N or CH;

[0267] L 3 C1-C 20 Alkylene, C2-C 20 Heteroalkylene or AA 1-10 ;in

[0268] Each AA is independently a naturally occurring amino acid;

[0269] V is absent, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl;

[0270] R 2d is hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace;

[0271] R 3a is hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0272] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0273] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0274] Each R 10 are independently -CN, -OH, -OR10a 、-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; wherein

[0275] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0276] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0277] m1 is 0 or 1; and

[0278] x1 is 0 to 10.

[0279] In some embodiments of Formula (II) or (IIa), L 3 C1-C 10 Alkylene or C2-C 10 In some embodiments, L 3 C1-C 10 In some embodiments, L 3 In some embodiments, L 3 In some embodiments, L 3 In some embodiments, L 3 C2-C 10 In some embodiments, L 3 C2-C 10 In some embodiments, L 3 In some embodiments, L 3 is C2-C6 heteroalkylene. In some embodiments, L 3 In some embodiments, L 3 It is a C2-C4 heteroalkylene group.

[0280] In some embodiments of Formula (II) or (IIa), the heteroalkylene group is polyethylene glycol. 3 PEG 1-10 In some embodiments, L 3 PEG 1-8 In some embodiments, L 3 -(CH2CH2-O) y1 -, wherein 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.

[0281] In some embodiments of Formula (II) or (IIa), L 3 The heteroalkylene group contains -(CH2) x3 N(R a )(CH2) x4 -, where R a is hydrogen or an optionally substituted C1-C6 alkyl group; and each of x3 and x4 is independently an integer in the range of 1 to 6.

[0282] In some embodiments of Formula (II) or (IIa), L 3 AA 1-10 , wherein each AA is independently a naturally occurring amino acid. In some embodiments, L 3 AA 1-8 In some embodiments, L 3 AA 1-6 In some embodiments, L 3 AA 1-5 In some embodiments, L 3 AA 1-4 In some embodiments, L 3 AA 1-3 In some embodiments, L 3 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.

[0283] In some embodiments of formula (II) or (IIa), V is 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, V is optionally substituted C3-C8 cycloalkyl or optionally substituted 4 to 8 membered heterocycloalkyl. In some embodiments, V is optionally substituted phenyl or optionally substituted 5 to 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.

[0284] In some embodiments of Formula (II) or (IIa), V is absent.

[0285] In some embodiments of formula (II) or (IIa), V is an optionally substituted C3-C8 cycloalkyl. In some embodiments, V is an optionally substituted C3-C6 cycloalkyl. In some embodiments, V is an optionally substituted cyclopentyl or an optionally substituted cyclohexyl. In some embodiments, V is a cyclopentyl. In some embodiments, V is a cyclohexyl.

[0286] In some embodiments of formula (II) or (IIa), V is an optionally substituted 4 to 8 membered heterocycloalkyl. In certain embodiments, V is an optionally substituted 4 to 6 membered heterocycloalkyl. In certain embodiments, V is an optionally substituted 6 membered heterocycloalkyl. In certain embodiments, V is an optionally substituted piperazine, an optionally substituted piperidine, or an optionally substituted morpholine. In certain embodiments, V is an optionally substituted piperazine. In certain embodiments, V is an optionally substituted piperidine. In certain embodiments, V is an optionally substituted morpholine.

[0287] In some embodiments of Formula (II) or (IIa), V or a pharmaceutically acceptable salt thereof has the structure of Formula (C):

[0288]

[0289] in:

[0290] B 1 -CR 5a R 5b -、-O-、-NR 5b -, -S(O)-, -S(O)2- or -S-; or B 1 for in

[0291] R 5a is hydrogen, -OH or an optionally substituted C1-C 20alkyl;

[0292] R 5b 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 6 or -C(O)R 6 ;or

[0293] R 5a and R 5b together with the nitrogen atom to which it is attached, form an optionally substituted 4- to 8-membered heterocycloalkyl;

[0294] R 6 is hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 10 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, or optionally substituted phenyl;

[0295] Ring B is absent, optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl;

[0296] L 2 is absent, is C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene; and

[0297] q1 and q2 are each independently 0, 1 or 2.

[0298] In some embodiments of Formula (II) or (IIa), V or a pharmaceutically acceptable salt thereof has the structure of Formula (C-1):

[0299]

[0300] in:

[0301] Ring B is optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl;

[0302] L 2 Absent, C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene;

[0303] B 1 ' is CH or N; and

[0304] q1 and q2 are each independently 0, 1 or 2.

[0305] In some embodiments of Formula (II) or (IIa), V or a pharmaceutically acceptable salt thereof has the structure of Formula (C-2):

[0306]

[0307] in:

[0308] B 1 ' and B 2 are each independently CH or N; and

[0309] B 3 -CR 7a R 7b -, -O-, -S-, -S(O)-, -S(O)2- or -NR 7b -;in

[0310] R 7a is hydrogen or optionally substituted C1-C 20 alkyl;

[0311] 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 ;

[0312] 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- to 6-membered heterocycloalkyl, or optionally substituted phenyl; and

[0313] L 2 is absent, is C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene.

[0314] 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.

[0315] In some embodiments of Formula (C-2), B1 ' is CH and B 2 is N. In some embodiments, B 1 ' is N and B 2 For CH.

[0316] In some embodiments of Formula (II) or (IIa), V or a pharmaceutically acceptable salt thereof has the structure of Formula (C-3):

[0317]

[0319] in:

[0320] B 2 is CH or N;

[0321] B 3 -CR 7a R 7b -, -O-, -S-, -S(O)-, -S(O)2- or -NR 7b -;in

[0322] R 7a is hydrogen or optionally substituted C1-C 20 alkyl;

[0323] 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 ;and

[0324] 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- to 6-membered heterocycloalkyl, or optionally substituted phenyl;

[0325] R 9a is hydrogen, optionally substituted C1-C 20 Alkylene or optionally substituted PEG 1-20 ;

[0326] Each R 9 are independently hydrogen or C1-C3 alkyl; and

[0327] s2 is 1, 2, or 3.

[0328] In some embodiments of formula (C-2) or (C-3), B 2 is CH or N. In some embodiments, B 2 In some embodiments, B 2 is N.

[0329] In some embodiments of formula (C-2) or (C-3), B 3 -CR 7a R 7b -or-O-. In some embodiments, B 3 -CR 7a R 7b -. In some embodiments, B 3 In some embodiments, B 3 In some embodiments, B 3 -NR 7b -.

[0330] In some embodiments of formula (C-2) or (C-3), R 7a is optionally substituted C1-C 20 In some embodiments, R 7a For hydrogen.

[0331] In some embodiments of formula (C-2) or (C-3), R 7b is 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 In some embodiments, R 7b is optionally substituted C1-C 20 In some embodiments, R 7b is optionally substituted C2-C 20 In some embodiments, R 7b is optionally substituted C2-C 20 In some embodiments, R 7b -C(O)OR 8 or -C(O)R 8 In some embodiments, R 7b For hydrogen.

[0332] In some embodiments of formula (C-2) or (C-3), R 8 is optionally substituted C1-C 20In some embodiments, R 8 is optionally substituted PEG 1-20 In some embodiments, R 8 is an optionally substituted phenyl group. In some embodiments, R 8 For hydrogen.

[0333] 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 In some embodiments, R 9a is optionally substituted PEG 1-20 In some embodiments, R 9a For hydrogen.

[0334] In some embodiments of formula (C-3), each R 9 is independently hydrogen or C1-C3 alkyl. In some embodiments, each R 9 In some embodiments, each R 9 are independently hydrogen.

[0335] 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.

[0336] In some embodiments of Formula (II) or (IIa), V or a pharmaceutically acceptable salt thereof has the structure of Formula (C-4):

[0337]

[0338] in;

[0339] Ring D is absent or is phenyl; and

[0340] R 13 It is a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a 4- to 8-membered heterocycloalkyl group or a phenyl group.

[0341] In some embodiments of Formula (C-4), Ring D is phenyl. In some embodiments, Ring D is absent.

[0342] In some embodiments of Formula (C-4), R 13 In some embodiments, R 13 In some embodiments, R 13is a C3-C6 cycloalkyl group. In some embodiments, R 13 is a 4- to 8-membered heteroalkyl group. 13 is a 4- to 6-membered heterocycloalkyl group.

[0343] In some embodiments of Formula (II) or (IIa), V or a pharmaceutically acceptable salt thereof has the structure of Formula (C-5):

[0344]

[0345] in,

[0346] A is CH or N; and

[0347] R 14 It is OH or NH2.

[0348] In some embodiments of Formula (C-5), A is CH. In some embodiments, A is N.

[0349] In some embodiments of Formula (C-5), R 14 In some embodiments, R 14 is NH2.

[0350] In some embodiments of Formula (A) or (A-1), L 1 C1-C 10 Alkylene and R 4 -NR 4a R 4b , where R 4a and R 4b Together with the nitrogen to which it is attached, L forms an optionally substituted 4 to 8 membered heterocycloalkyl. 1 is C1-C4 alkylene and R 4 -NR 4a R 4b , where R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 4-membered heterocycloalkyl. 1 is C1-C4 alkylene and R 4 -NR 4a R 4b , where R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 5-membered heterocycloalkyl. 1 is C1-C4 alkylene and R 4 -NR 4a R 4b , where R 4a and R 4bTogether with the nitrogen to which it is attached, it forms an optionally substituted 6-membered heterocycloalkyl. 1 is C1-C4 alkylene and R 4 -NR 4a R 4b , where R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 7-membered heterocycloalkyl.

[0351] In some embodiments, provided herein is a transcriptional regulator molecule having the structure of Formula (III) or a pharmaceutically acceptable salt thereof:

[0352]

[0353] in:

[0354] B 1 -CR 5a R 5b -、-O-、-NR 5b -, -S-, -S(O)- or -S(O)2-; or B 1 for in

[0355] R 5a is hydrogen, -OH or an optionally substituted C1-C 20 alkyl;

[0356] R 5b 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)R 6 or C(O)R 6 ;or

[0357] R 5a and R 5b together with the nitrogen atom to which it is attached, form an optionally substituted 4- to 8-membered heterocycloalkyl;

[0358] R 6 is hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 10 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, or optionally substituted phenyl;

[0359] Ring B is absent, optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl;

[0360] L 2 Absent, C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene;

[0361] W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl;

[0362] Z is absent or C(O);

[0363] Each Y 5 are independently N or CH;

[0364] R 2d is hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace;

[0365] R 3a is hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0366] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0367] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0368] Each R 10 are 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; wherein

[0369] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0370] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0371] m1 is 0 or 1;

[0372] q1 and q2 are each independently 0 to 2; and

[0373] x1 is 0 to 10.

[0374] In some embodiments of Formula (II), (IIa), or (III), x1 is 0 to 10. In some embodiments, x1 is 0 to 8. In some embodiments, x1 is 0 to 6. In some embodiments, x1 is 1 to 10. In some embodiments, x1 is 1 to 8. In some embodiments, x1 is 1 to 6. In some embodiments, x1 is 1 to 5. In some embodiments, x1 is 1 to 4. In some embodiments, x1 is 1 to 3. In some embodiments, x1 is 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.

[0375] In another aspect, provided herein is a transcriptional regulator molecule having the structure of Formula (IV) or a pharmaceutically acceptable salt thereof:

[0376]

[0377] in:

[0378] W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl;

[0379] W 2 is hydrogen, optionally substituted C1-C 20Alkyl or optionally substituted C1-C 20 heteroalkyl;

[0380] R w is hydrogen or optionally substituted C1-C 20 alkyl;

[0381] or W 2 and R w together with the nitrogen to which it is attached, form a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl;

[0382] Each Y 5 are independently N or CH;

[0383] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace;

[0384] Each R 3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0385] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0386] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0387] or two R 3a or two R 3bTogether with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group;

[0388] Each R 10 are 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; wherein

[0389] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0390] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; and

[0391] n1 and m1 are each independently 0 or 1.

[0392] 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 In some embodiments, W 2 is optionally substituted C1-C 20 In some embodiments, W 2 is optionally substituted C1-C 20 Heteroalkyl.

[0393] In some embodiments of Formula (A), (A-1) or (IV), W 2 C1-C 20 In some embodiments, W 2 C1-C 15 In some embodiments, W 2 C1-C 10 In some embodiments, W 2 is a C1-C8 alkyl group. 2 In some embodiments, W 2 In some embodiments, W 2Is methyl, ethyl, n-propyl or isopropyl. In some embodiments, W 2 In some embodiments, W 2 In some embodiments, W 2 In some embodiments, W 2 In some embodiments, W 2 It is methyl, ethyl, and n-propyl.

[0394] In some embodiments of Formula (A), (A-1) or (IV), W 2 C1-C 20 In some embodiments, W 2 C1-C 15 In some embodiments, W 2 C1-C 10 In some embodiments, W 2 is C1-C8 heteroalkyl. In some embodiments, W 2 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG). In some embodiments, W 2 is PEG, wherein PEG has 1 to 10 units. In some embodiments, W 2 PEG 1-8 In some embodiments, W 2 PEG 1-6 In some embodiments, W 2 PEG 1-4 In some embodiments, W 2 PEG 1-3 .

[0395] In some embodiments of Formula (A), (A-1) or (IV), W 2 For hydrogen.

[0396] In some embodiments of Formula (A), (A-1), or (IV), R W In some embodiments, R W is optionally substituted C1-C 20 alkyl.

[0397] In some embodiments of Formula (A), (A-1) or (IV), W 2 and R w Together with the nitrogen to which it is attached, W forms a partially or fully unsaturated optionally substituted 4 to 8 membered heterocycloalkyl. 2 and R wTogether with the nitrogen to which it is attached, W forms a partially or fully unsaturated optionally substituted 4 to 7 membered heterocycloalkyl. 2 and R w Together with the nitrogen to which it is attached, it forms an optionally substituted 4-membered heterocycloalkyl. In some embodiments, W 2 and R w Together with the nitrogen to which it is attached, it forms an optionally substituted 5-membered heterocycloalkyl. 2 and R w Together with the nitrogen to which it is attached, it forms an optionally substituted 6-membered heterocycloalkyl. In some embodiments, W 2 and R w Together with the nitrogen to which it is attached, it forms an optionally substituted 7-membered heterocycloalkyl.

[0398] In some embodiments, the transcriptional regulator molecule or a pharmaceutically acceptable salt thereof has the structure of Formula (V):

[0399]

[0400] in:

[0401] B 1 -CR 5a R 5b -、-O-、-NR 5b -, -S-, -S(O)- or -S(O)2-; or B 1 for in

[0402] R 5a is hydrogen, -OH or an optionally substituted C1-C 20 alkyl;

[0403] R 5b 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 6 or -C(O)R 6 ;or

[0404] R 5a and R 5b together with the nitrogen atom to which it is attached, form an optionally substituted 4- to 8-membered heterocycloalkyl;

[0405] R 6 is hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, or optionally substituted phenyl;

[0406] Ring B is absent, optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl;

[0407] L 2 Absent, C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene;

[0408] W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl;

[0409] Each Y 5 are independently N or CH;

[0410] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace;

[0411] Each R 3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0412] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0413] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0414] or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group;

[0415] Each R 10 are 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; wherein

[0416] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0417] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0418] n1 and m1 are each independently 0 or 1; and

[0419] q1 and q2 are each independently 0 to 2.

[0420] 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.

[0421] In some embodiments of Formula (C), (C-1), (III) or (V), B 1 -CR 5a R 5b -、-O-、-NR 5b -or-S-. In some embodiments, B 1 -O-, -NR 5b -or-S-. In some embodiments, B 1 In some embodiments, B1 In some embodiments, B 1 In some embodiments, B 1 In some embodiments, B 1 In some embodiments, B 1 -NR 5b -. In some embodiments, B 1 In some embodiments, B 1 -CR 5a R 5b -. In some embodiments, B 1 It is -CH2-.

[0422] In some embodiments of Formula (C), (C-1), (III) or (V), B 1 for

[0423] In some embodiments, Ring B is an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl. In some embodiments, Ring B is an optionally substituted cycloalkyl. In some embodiments, Ring B is a C3-C8 cycloalkyl. In some embodiments, Ring B is a C3-C6 cycloalkyl. In some embodiments, Ring B is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0424] 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.

[0425] In some embodiments of Formula (C), (C-1), (C-2), (III) or (V), L 2 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 It is a C2-C4 alkynylene group.

[0426] In some embodiments of Formula (C), (C-1), (C-2), (III) or (V), L 2is -CH2-, -CH2CH2-, -C≡C- or -C≡CC≡C-. In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 It is -C≡CC≡C-.

[0427] In some embodiments of Formula (C), (C-1), (C-2), (III) or (V), L 2 Does not exist.

[0428] In some embodiments of Formula (C), (III) or (V), R 5a is optionally substituted C1-C 20 In some embodiments, R 5a In some embodiments, R 5a For hydrogen.

[0429] In some embodiments of Formula (C), (III) or (V), R 5b is optionally substituted C1-C 20 Alkyl, optionally substituted C2-C 20 Alkenyl or optionally substituted C2-C 20 In some embodiments, R 5b C1-C 20 In some embodiments, R 5b C2-C 20 In some embodiments, C2-C 20 In some embodiments, R 5b -C(O)OR 6 or -C(O)R 6 In some embodiments, R 5b -C(O)OR 6 In some embodiments, R 5b -C(O)R 6 In some embodiments, R 5b For hydrogen.

[0430] In some embodiments of Formula (C), (III) or (V), R 5a and R 5b Together with the nitrogen atom to which it is attached, R forms an optionally substituted 4- to 8-membered heterocycloalkyl. 5a and R 5bTogether with the nitrogen atom to which it is attached, R forms an optionally substituted 5- to 7-membered heterocycloalkyl. 5a and R 5b Together with the nitrogen atom to which it is attached, it forms an optionally substituted 5-membered heterocycloalkyl. 5a and R 5b Together with the nitrogen atom to which it is attached, R forms an optionally substituted 6-membered heterocycloalkyl. 5a and R 5b Together with the nitrogen atom to which it is attached, it forms an optionally substituted 7-membered heterocycloalkyl.

[0431] In some embodiments of Formula (C), (III) or (V), R 6 is optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 10 In some embodiments, R 6 is optionally substituted C1-C 20 In some embodiments, R 6 is a C3-C6 cycloalkyl group or a 4 to 6-membered heterocycloalkyl group. 6 is optionally substituted phenyl.

[0432] In another aspect, provided herein is a transcriptional regulator molecule having the structure of Formula (VI) or a pharmaceutically acceptable salt thereof:

[0433]

[0434] in:

[0435] W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl;

[0436] Each Y 1 、Y 2 、Y 3 、Y 4 、Y 5 and Y 8 are independently N or CH;

[0437] L 1 C1-C 20 Alkylene or C2-C 20 heteroalkylene;

[0438] Z is absent, -C(O)- or -C(=NH)-;

[0439] R 4 C1-C6 alkyl, -OR 4b or -NR 4a R 4b ;in

[0440] R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl;

[0441] 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; or

[0442] R 4a and R 4b together with the nitrogen to which it is attached, form a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl;

[0443] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace;

[0444] Each R3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in

[0445] R 11a and R 11b Each is independently hydrogen, alkyl or PEG;

[0446] R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0447] or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group;

[0448] Each R 10 are 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; wherein

[0449] R 10a and R 10b Each is independently hydrogen, alkyl or PEG;

[0450] R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl;

[0451] n3 is 0 or 1; and

[0452] m1 is 1, 2, or 3.

[0453] In some embodiments of Formula (VI), Y 8 N and Y 3 In some embodiments, Y 8 CH and Y 3 is N.

[0454] In some embodiments of Formula (VI), Y 8 N; Y 3 is CH; and Y 1In some embodiments, Y 8 N; Y 3 is CH; and Y 1 is N.

[0455] In some embodiments of Formula (VI), L 1 C1-C 10 Alkylene or C2-C 10 In some embodiments, L 1 C1-C 10 In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 C2-C 10 In some embodiments, L 1 C2-C 10 In some embodiments, L 1 In some embodiments, L 1 is C2-C6 heteroalkylene. In some embodiments, L 1 In some embodiments, L 1 It is a C2-C4 heteroalkylene group.

[0456] In some embodiments of Formula (VI), the heteroalkylene group is polyethylene glycol. In some embodiments, L 1 PEG 1-10 In some embodiments, L 1 PEG 1-8 In some embodiments, L 1 -(CH2CH2-O) y1 -, wherein 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 group comprises -(CH2) x3 N(R a )(CH2) x4 -, where R ais hydrogen or an optionally substituted C1-C6 alkyl group; and each of x3 and x4 is independently an integer in the range of 1 to 6.

[0457] In some embodiments of Formula (VI), Z is -C(O)-; and R 4 For-OR 4b In some embodiments, Z is -C(O)-; and R 4 -NR 4a R 4b In some embodiments, Z is absent; and R 4 For-OR 4b In some embodiments, Z is absent; and R 4 -NR 4a R 4b In some embodiments, Z is -C(O)-; and R 4 is a C1-C6 alkyl group. In some embodiments of Formula (A), (A-1), (I), (Ia), or (Ib), Z is absent; and R 4 It is a C1-C6 alkyl group.

[0458] 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.

[0459] 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.

[0460] In some embodiments of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V) or (VI), W 1 -N=C(N(R 1e )2)2, where each R 1e is independently hydrogen or C1-C3 alkyl. In some embodiments, each R 1e are independently hydrogen. In some embodiments, each R 1e are independently C1-C3 alkyl.

[0461] In some embodiments of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V) or (VI), W 1 In some embodiments, W 1 It is hydrogen or -N=C(NH2)2.

[0462] In some embodiments of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V) or (VI), W 1 For hydrogen.

[0463] 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 are independently CH.

[0464] In some embodiments, each Y 2 、Y 4 、Y 7 and Y 8 are independently N; and each Y 1 、Y 3 and Y 6 are 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 are independently CH.

[0465] In some embodiments of Formula (A), (A-1), (I), (II), or (VI), each Y 1 is independently N. In some embodiments, each Y 1 are independently CH.

[0466] In some embodiments of Formula (A), (A-1), (I), (II), or (VI), each Y 2 is independently N. In some embodiments, each Y 2 are independently CH.

[0467] In some embodiments of Formula (A), (A-1), (I), (II), or (VI), each Y 3is independently N. In some embodiments, each Y 3 are independently CH.

[0468] In some embodiments of Formula (A), (A-1), (I), (II), or (VI), each Y 4 is independently N. In some embodiments, each Y 4 are independently CH.

[0469] 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 are independently CH.

[0470] In some embodiments of Formula (A), (A-1), (I) or (II), each Y 6 is independently N. In some embodiments, each Y 6 are independently CH.

[0471] In some embodiments of Formula (A), (A-1), (I) or (II), each Y 7 is independently N. In some embodiments, each Y 7 are independently CH.

[0472] In some embodiments of Formula (A), (A-1), (I), (II), or (VI), each Y 8 is independently N. In some embodiments, each Y 8 are independently CH.

[0473] 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)-.

[0474] 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 are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C20 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by 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 are 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 ; each of which is optionally replaced by 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 are 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 10 Heteroalkenyl, optionally substituted C2-C 10 Heteroalkynyl, optionally substituted C1-C 10 Haloalkyl or optionally substituted PEG 1-10 .

[0475] 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 are 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 In some embodiments, each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2g and R 2h are independently optionally substituted C1-C 10 In some embodiments, each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2g and R 2h are independently optionally substituted C1-C 10 In some embodiments, each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2g and R 2h In some embodiments, each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2g and R 2h are independently optionally substituted C1-C 10 In some embodiments, each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2g and R 2h is independently optionally substituted PEG1-10 In some embodiments, each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2g and R 2h are independently optionally substituted C1-C 10 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. 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 In some embodiments, each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2g and R 2h In some embodiments, each R 2a 、R 2b 、R 2c 、R 2e 、R 2f 、R 2g and R 2g In some embodiments, each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2g are independently hydrogen.

[0476] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), or (V), each R2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g and R 2h are 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 ; each of which is optionally replaced by 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 Independently C1-C 10 Alkyl, each of which is optionally replaced by one or more R 10 replace.

[0477] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), or (V), each R 2a 、R 2b 、R 2d and R 2g are 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 replaced by one or more R 10 Replace; and R 2c 、R 2e and R 2h Each of which is independently unsubstituted C1-C 10 alkyl.

[0478] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), or (V), R 2c 、R 2e and R 2h Each of which is independently unsubstituted C1-C 10 In some embodiments, R 2c 、R 2e and R 2hEach of R is independently methyl, ethyl, isopropyl or tert-butyl. In some embodiments, R 2c 、R 2e and R 2h Each of R is independently methyl, ethyl or isopropyl. In some embodiments, R 2c 、R 2e and R 2h Each of R is independently methyl or isopropyl. In some embodiments, R 2c 、R 2e and R 2h Each of them is a methyl group.

[0479] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), or (V), each R 2a 、R 2b and R 2g are independently unsubstituted C1-C 10 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 In some embodiments, each R 2a 、R 2b and R 2g It is a methyl group.

[0480] 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 are independently unsubstituted alkyl C1-C 10 alkyl; and R 2d is optionally replaced by one or more R 10 Substituted C1-C 10 In some embodiments, each R 2a 、R 2b 、R 2c 、R 2e 、R 2f 、R 2g and R 2h is methyl; and R2d is optionally replaced by one or more R 10 Substituted C1-C 10 alkyl.

[0481] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), R 2a 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 , each of which is optionally replaced by 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 In some embodiments, R 2a is optionally substituted C1-C 10 Alkyl, which is replaced by one or more R 10 In some embodiments, R 2a For unsubstituted C1-C 10 In some embodiments, R 2a is methyl, ethyl or isopropyl. In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a For hydrogen.

[0482] 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 , each of which is optionally replaced by one or more R 10 In some embodiments, R 2b is optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 In some embodiments, R 2bis optionally substituted C1-C 10 Alkyl, which is replaced by one or more R 10 In some embodiments, R 2b For unsubstituted C1-C 10 In some embodiments, R 2b is methyl, ethyl or isopropyl. In some embodiments, R 2b In some embodiments, R 2b In some embodiments, R 2b In some embodiments, R 2b For hydrogen.

[0483] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), each R 2c are 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 , each of which is optionally replaced by one or more R 10 In some embodiments, each R 2c are independently optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 In some embodiments, each R 2c are independently optionally substituted C1-C 10 Alkyl, which is replaced by one or more R 10 In some embodiments, each R 2c are independently unsubstituted C1-C 10 In some embodiments, each R 2c is independently methyl, ethyl or isopropyl. In some embodiments, each R 2c In some embodiments, each R 2c In some embodiments, each R 2c In some embodiments, each R 2c are independently hydrogen.

[0484] 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-C10 Heteroalkyl, optionally substituted C1-C 10 Haloalkyl or optionally substituted PEG 1-10 , each of which is optionally replaced by 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 In some embodiments, R 2d is optionally substituted C1-C 10 Alkyl, which is replaced by one or more R 10 In some embodiments, R 2d For unsubstituted C1-C 10 In some embodiments, R 2d is methyl, ethyl or isopropyl. In some embodiments, R 2d In some embodiments, R 2d In some embodiments, R 2d In some embodiments, R 2d For hydrogen.

[0485] 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 , each of which is optionally replaced by 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 In some embodiments, R 2e is optionally substituted C1-C 10 Alkyl, which is replaced by one or more R 10 In some embodiments, R 2e For unsubstituted C1-C 10 In some embodiments, R 2e is methyl, ethyl or isopropyl. In some embodiments, R 2e In some embodiments, R 2eIn some embodiments, R 2e In some embodiments, R 2e For hydrogen.

[0486] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), each R 2f are 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 , each of which is optionally replaced by one or more R 10 In some embodiments, each R 2f are independently optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 In some embodiments, each R 2f are independently optionally substituted C1-C 10 Alkyl, which is replaced by one or more R 10 In some embodiments, each R 2f are independently unsubstituted C1-C 10 In some embodiments, each R 2d is independently methyl, ethyl or isopropyl. In some embodiments, each R 2f In some embodiments, each R 2f In some embodiments, each R 2f In some embodiments, each R 2f are independently hydrogen.

[0487] 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 , each of which is optionally replaced by one or more R 10 In some embodiments, R 2g is optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10In some embodiments, R 2g is optionally substituted C1-C 10 Alkyl, which is replaced by one or more R 10 In some embodiments, R 2g For unsubstituted C1-C 10 In some embodiments, R 2g is methyl, ethyl or isopropyl. In some embodiments, R 2g In some embodiments, R 2g In some embodiments, R 2g In some embodiments, R 2g For hydrogen.

[0488] 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 , each of which is optionally replaced by 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 In some embodiments, R 2h is optionally substituted C1-C 10 Alkyl, which is replaced by one or more R 10 In some embodiments, R 2h For unsubstituted C1-C 10 In some embodiments, R 2h is methyl, ethyl or isopropyl. In some embodiments, R 2h In some embodiments, R 2h In some embodiments, R 2h In some embodiments, R 2h For hydrogen.

[0489] In some embodiments of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), each R 3a are independently hydrogen, deuterium, halogen, amino, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C20 Haloalkyl, optionally substituted C1-C 20 Alkylamino or optionally substituted C1-C 20 In some embodiments, each R 3a are independently hydrogen, amino or optionally substituted C1-C 20 In some embodiments, each R 3a For hydrogen.

[0490] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), each R 3b are 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 In some embodiments, each R 3b are independently hydrogen, amino or optionally substituted C1-C 20 In some embodiments, each R 3b For hydrogen.

[0491] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), each R 3b is hydrogen; and each R 3a are 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 In some embodiments, each R 3b is hydrogen; and each R 3a are 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 In some embodiments, each R 3b is hydrogen; and each R 3a are independently hydrogen or amino.

[0492] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), each R 3a and each R 3b For hydrogen.

[0493] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), both R 3a Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group. 3a Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl or cyclopentyl group. In some embodiments, the two R 3a Together with the carbon atom to which it is attached, it forms a cyclopropyl group. In some embodiments, two R 3a Together with the carbon atom to which it is attached, it forms a cyclobutyl group. 3a Together with the carbon atom to which it is attached, it forms a cyclopentyl group. 3a Together with the carbon atom to which it is attached, it forms a 4- to 6-membered heterocycloalkyl group. 3a Together with the carbon atom to which it is attached, it forms a 4-membered heterocycloalkyl. 3a Together with the carbon atom to which it is attached, it forms a 5-membered heterocycloalkyl. 3a Together with the carbon atom to which it is attached, it forms a 6-membered heterocycloalkyl.

[0494] In some embodiments of Formula (I), (Ia), (Ib), (II), (IV), (V), or (VI), both R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl ring. 3b Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl or cyclopentyl group. In some embodiments, the two R 3b Together with the carbon atom to which it is attached, it forms a cyclopropyl group. 3b Together with the carbon atom to which it is attached, it forms a cyclobutyl group. 3b Together with the carbon atom to which it is attached, it forms a cyclopentyl group. 3b Together with the carbon atom to which it is attached, it forms a 4- to 6-membered heterocycloalkyl. 3b Together with the carbon atom to which it is attached, it forms a 4-membered heterocycloalkyl. 3b Together with the carbon atom to which it is attached, it forms a 5-membered heterocycloalkyl. 3b Together with the carbon atom to which it is attached, it forms a 6-membered heterocycloalkyl.

[0495] In some embodiments of Formula (A), (A-1), (I), (Ia), (Ib), or (VI), R 4ais hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 In some embodiments, R 4a is optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 In some embodiments, R 4a is optionally substituted C1-C 20 In some embodiments, R 4a is optionally substituted C1-C 15 In some embodiments, R 4a is optionally substituted C1-C 10 In some embodiments, R 4a is optionally substituted C1-C 20 In some embodiments, the heteroalkyl group 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 For hydrogen.

[0496] 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 20 Heteroalkyl or optionally substituted C1-C 20 In some embodiments, R 4b is optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 In some embodiments, R 4b is optionally substituted C1-C 20 In some embodiments, R 4b is optionally substituted C1-C 15 In some embodiments, R 4b is optionally substituted C1-C 10 In some embodiments, R 4bis optionally substituted C1-C 20 In some embodiments, R 4b is optionally substituted C1-C 15 In some embodiments, R 4b is optionally substituted C1-C 10 In some embodiments, the heteroalkyl group is polyethylene glycol (PEG). In some embodiments, R 4b PEG 1-20 In some embodiments, R 4b PEG 1-15 In some embodiments, R 4b PEG 1-10 .

[0497] In some embodiments of Formula (A), (A-1), (I), (Ia), (Ib), or (VI), R 4b is an optionally substituted C3-C8 cycloalkyl, an optionally substituted 4 to 8 membered heterocycloalkyl, an optionally substituted phenyl, or an optionally substituted 5 to 10 membered heteroaryl. 4b is an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4 to 8 membered heterocycloalkyl. 4b is an optionally substituted C3-C6 cycloalkyl or an optionally substituted 4 to 6 membered heterocycloalkyl. 4b is an optionally substituted C3-C6 cycloalkyl. 4b In some embodiments, R 4b is an optionally substituted 4 to 6 membered heterocycloalkyl. 4b is a 5-membered or 6-membered heterocycloalkyl group. 4b is piperidine, piperazine or morpholine. In some embodiments, R 4b In some embodiments, R 4b In some embodiments, R 4b For piperazine.

[0498] In some embodiments of Formula (A), (A-1), (I), (Ia), (Ib), or (VI), R 4a and R 4b Together with the nitrogen to which it is attached, it forms a partially or fully unsaturated optionally substituted 4 to 8 membered heterocycloalkyl. 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 4- to 6-membered heterocycloalkyl. 4a and R4b Together with the nitrogen to which it is attached, it forms an optionally substituted 4-membered heterocycloalkyl. 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 5-membered heterocycloalkyl. 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 6-membered heterocycloalkyl.

[0499] In some embodiments of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), each R 10 are 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 are 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 are independently -CN, -OH, -OR 10a , -N3 or -NR 10a R 10b In some embodiments, each R 10 are 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 are independently -C(O)NR 10a R10b 、-NHC(O)R 10c or -OC(O)NR 10a R 10b In some embodiments, each R 10 is independently an optionally substituted 5- to 10-membered heteroaryl. 10 is independently an optionally substituted 5-membered heteroaryl. 10 and R is independently an optionally substituted triazine.

[0500] 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 are independently hydrogen, C1-C 20 Alkyl or PEG 1-20 In some embodiments, each R 10a and R 10b Independently C1-C 20 In some embodiments, each R 10a and R 10b Independently PEG 1-20 In some embodiments, each R 10a and R 10b are independently hydrogen.

[0501] 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 C1-C 20 Alkyl, PEG 1-20 , C3-C6 cycloalkyl, 4 to 6 membered heterocycloalkyl or phenyl. In some embodiments, R 10c C1-C 20 Alkyl or PEG 1-20 In some embodiments, R 10c C1-C 20 In some embodiments, R 10c PEG 1-20 In some embodiments, R 10c is C3-C6 cycloalkyl, 4 to 6 membered heterocycloalkyl or phenyl. 10c is a C3-C6 cycloalkyl group. In some embodiments, R 10cis a 4- to 6-membered heterocycloalkyl group. 10c It is phenyl.

[0502] In some embodiments of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IV), (V), or (VI), R 11a and R 11b Each is independently hydrogen, alkyl or PEG. In some embodiments, R 11a and R 11b are independently hydrogen, C1-C 20 Alkyl or PEG 1-20 In some embodiments, R 11a and R 11b Each independently is C1-C 20 In some embodiments, R 11a and R 11b Each independently is PEG 1-20 In some embodiments, R 11a and R 11b are each independently hydrogen.

[0503] 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 C1-C 20 Alkyl, PEG 1-20 , C3-C6 cycloalkyl, 4 to 6 membered heterocycloalkyl or phenyl. In some embodiments, R 12 C1-C 20 Alkyl or PEG 1-20 In some embodiments, R 12 is C3-C6 cycloalkyl, 4 to 6 membered heterocycloalkyl or phenyl. 12 C1-C 20 In some embodiments, R 12 PEG 1-20 In some embodiments, R 12 is a C3-C6 cycloalkyl group. In some embodiments, R 12 is a 4- to 6-membered heterocycloalkyl group. 12 It is phenyl.

[0504] 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.

[0505] In some embodiments of Formula (A), (A-1), (I), (Ia), (Ib), (II), (III), (IV), and (V), n1 is 1. In some embodiments, n1 is 0.

[0506] 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.

[0507] Polyamide-DNA binding moiety

[0508] 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 is capable of binding to DNA with an affinity of less than about 600nM, about 500nM, about 400nM, about 300nM, about 250nM, about 200nM, about 150nM, about 100nM, or about 50nM. In some embodiments, the compound is capable of binding to DNA with an affinity in the range of about 1-600nM, 10-500nM, 20-500nM, 50-400nM, or 100-300nM.

[0509] In some embodiments, the compound is capable of binding to DNA with an affinity of less than 500 nM. In some embodiments, the compound is capable of binding to DNA with an affinity of less than about 300 nM. In some embodiments, the compound is capable of binding to DNA with an affinity of less than about 200 nM.

[0510] The binding affinity between the compound and the target DNA can be determined using a quantitative footprint titration experiment. This involves measuring the dissociation constant, K, of the polyamide towards the target sequence at 24°C or 37°C. d , and using standard polyamide assay solution conditions or approximate intracellular solution conditions.

[0511] The compound has a high binding affinity for sequences having multiple nucleotide repeats containing CTG and preferentially binds to the target nucleotide repeat sequence over other nucleotide repeats or other nucleotide sequences. In some embodiments, the compound has a higher binding affinity for sequences having multiple nucleotide repeats containing CTG than for sequences having CGG repeats. In some embodiments, the compound has a higher binding affinity for sequences having multiple nucleotide repeats containing CTG than for sequences having CCG repeats. In some embodiments, the compound has a higher binding affinity for sequences having multiple nucleotide repeats containing CTG than for sequences having CCTG repeats. In some embodiments, the compound has a higher binding affinity for sequences having multiple nucleotide repeats containing CTG than for sequences having TGGAA repeats. In some embodiments, the compound has a higher binding affinity for sequences having multiple nucleotide repeats containing CTG than for sequences having GGGGCC repeats. In some embodiments, the compound has a higher binding affinity for sequences having multiple nucleotide repeats containing CTG than for sequences having GAA repeats.

[0512] Due to the preferential binding between the polyamide sequence and the target nucleotide repeat sequence, the transcriptional regulatory molecules described herein are localized around regions having multiple nucleotide repeat sequences containing CTG. In some embodiments, the local concentration of the molecule is higher near a sequence having multiple nucleotide repeat sequences containing CTG than near a sequence having CGG repeat sequences. In some embodiments, the local concentration of the molecule is higher near a sequence having multiple nucleotide repeat sequences containing CTG than near a sequence having CCG repeat sequences. In some embodiments, the local concentration of the molecule is higher near a sequence having multiple nucleotide repeat sequences containing CTG than near a sequence having CCTG repeat sequences. In some embodiments, the local concentration of the molecule is higher near a sequence having multiple nucleotide repeat sequences containing CTG than near a sequence having TGGAA repeat sequences. In some embodiments, the local concentration of the molecule is higher near a sequence having multiple nucleotide repeat sequences containing CTG than near a sequence having GGGGCC repeat sequences. In some embodiments, the local concentration of the molecule is higher near a sequence having multiple nucleotide repeat sequences containing CTG than near a sequence having GAA repeat sequences.

[0513] In one aspect provided herein, due to the high number of CTG repeats associated with dmpk, atxn8, atxn80s, or tcf4, the molecules of the present disclosure preferentially bind to the repetitive CTGs of dmpk, atxn8, atxn80s, or tcf4 compared to CTGs elsewhere in an individual's DNA. In some embodiments, due to the high number of CTG repeats associated with dmpk, the molecules of the present disclosure are more likely to bind to the repetitive CTGs of dmpk compared to CTGs elsewhere in an individual's DNA. In some embodiments, due to the high number of CTG repeats associated with atxn8 or atxn80s, the molecules of the present disclosure are more likely to bind to the repetitive CTGs of atxn8 or atxn80s compared to CTGs elsewhere in an individual's DNA. In some embodiments, due to the high number of CTG repeats associated with tcf4, the molecules of the present disclosure are more likely to bind to the repetitive CTGs of the tcf4 gene compared to CTGs elsewhere in an individual's DNA.

[0514] Polyamides are targeted to sequences having multiple nucleotide repeats containing CTG and preferentially bind to target nucleotide repeats 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 CTG repeats. In some embodiments, the sequence comprises at least 1000 CTG nucleotide repeats. In some embodiments, the sequence comprises at least 500 CTG nucleotide repeats. In some embodiments, the sequence comprises at least 200 CTG nucleotide repeats. In some embodiments, the sequence comprises at least 100 CTG nucleotide repeats. In some embodiments, the sequence comprises at least 50 CTG nucleotide repeats. In some embodiments, the sequence comprises at least 20 CTG nucleotide repeats.

[0515] Polyamides composed of preselected subunit combinations can selectively bind to DNA in the minor groove. In their hairpin structure, two antiparallel, juxtaposed pairs of aromatic amino acids bind to the DNA sequence, with the polyamide rings stacking specifically for each DNA base. N-methylpyrrole (Py) prefers T, A, and C bases to the exclusion of G; N-methylimidazole (Im) reads G; and 3-hydroxy-N-methylpyrrole (Hp) is specific for thymine bases. Nucleotide base pairs can be identified using the pairing principles shown in Tables 1A and 1B below, using different pairings of amino acid subunits. For example, Im / Py pairing is read as G·C based on symmetry, Py / Im pairing is read as C·G, Hp / Py pairing can distinguish T·A from A·T, G·C, and C·G, and Py / Py pairing nonspecifically distinguishes both A·T and T·A from G·C and C·G.

[0516] 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; and β-alanine, wherein Im is N-alkylimidazole, Py is N-alkylpyrrole, and Hp is 3-hydroxyN-methylpyrrole. In some embodiments, the polyamide comprises Im / Py corresponding to nucleotide pair G / C, Py / Im corresponding to nucleotide pair C / G, wherein Im is N-alkylimidazole (e.g., N-methylimidazole), Py is N-alkylpyrrole (e.g., N-methylpyrrole), and Hp is 3-hydroxyN-methylpyrrole.

[0517] Table 1A. Base pairing of single amino acid subunits (favorable (+), unfavorable (-)).

[0518]

[0519]

[0520]

[0521]

[0522] *Subunits HpBi, ImBi, and PyBi act as binders of two monomeric subunits and bind to two nucleotides. The binding properties of HpBi, ImBi, and PyBi correspond to those of Hp-Py, Im-Py, and Py-Py, respectively.

[0523] Table 1B. Representative base pairings for hairpin polyamides.

[0524]

[0525]

[0526]

[0527] The monomer subunits of the polyamide compound can be linked together in series based on the pairing principles shown in Table 1A and Table 1 B. The monomer subunits of the polyamide compound can be linked together in series based on the pairing principles shown in Table 1C.

[0528] Table 1C shows examples of monomer subunits that can bind to specific nucleotides. A polyamide can have several monomer subunits linked together, where the monomer subunits are selected from each row. For example, a polyamide can include Py-β-Im bound to CTG, where Py is selected from the C column, β is selected from the T column, and Im is selected from the G column.

[0529] Additionally, the polyamide portion of the compound may also include fractions or multiples of five subunits, such as 1.5, 2, 2.5, 3, 3.5, or 4 sets of three subunits. The polyamide portion of the compound may include 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, and 16 monomer subunits.

[0530] The polyamide portion of the compound may include monomeric subunits that are bound to 2, 3, 4, or 5 nucleotides of CTG. For example, the polyamide portion of the compound may be bound to CT, CTG, TGC, CTGC, CTGCT, CTGCTG, or CTGCTGC. The polyamide portion of the compound may include monomeric subunits that are bound to 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides of the CTG repeat sequence.

[0531] When positioned as a terminal unit, the terminus of the monomer subunit does not have an amine, carbonyl or carboxylic acid group. The amine or carboxylic acid group at the terminal is replaced by hydrogen. For example, Py, when used as a terminal unit, is understood to have the structure (For example ); and Im when positioned as a terminal unit should be understood to have a structure (For example ).

[0532] Table 1C. Examples of monomer subunits bound to CTG in linear polyamides.

[0533]

[0534]

[0535] Polyamide compounds can also include hairpin polyamides having subunits linked together based on the pairing principles shown in Table 1 B. Table 1 D shows some examples of monomer subunit pairs that selectively bind to nucleotide pairs.

[0536] Since the target gene may include multiple CTG-containing nucleotide repeats, the subunits can be linked together to bind to at least two, three, four, five, six, seven, eight, nine, or ten nucleotides in one or more CTG repeats (e.g., CTGCTGCTG). For example, the polyamide compound can bind to CTG repeats by binding to a partial copy, a full copy, or multiple repeats of a CTG-containing sequence (e.g., CT, CTG, TGC, CTGC, CTGCT, or CTGCTG). For example, the polyamide compound may include Im-Im-Im-Im-β-β-W-Im-Im-β-Py-β-Py, which binds to GGGGCC and its complementary nucleotides on double-stranded DNA, wherein 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 pair binds to G·C, and the β / Im pair binds to C·G; and the β / Im pair binds to C·G. In one example, the polyamide compound may comprise Py-β-Im-β-W-Im-Py-Py-Im, which binds to CTGC and its complementary nucleotide on double-stranded DNA, wherein 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 spacers as shown in Table 4. In another example, the polyamide compound may comprise Im-Py-Py-Im-Py-gAB-Im-Py-Py-Im-β, which binds to GCTGC and its complementary nucleotide on double-stranded DNA, wherein the Im / β pair binds to G·C, the Py / Im pair binds to C·G, the Py / Py pair 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 GCTGC having a portion of complementary nucleotides (ACG) on double-stranded DNA, wherein 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.

[0537] Table ID. Examples of monomer pairs bound to CTG in hairpin polyamides.

[0538]

[0539]

[0540] Recognition of nucleotide repeats or DNA sequences by two antiparallel polyamide chains relies on the coding of juxtaposed aromatic amino acid pairs in a minor groove, which is generally oriented N to C relative to the 5' to 3' direction of the DNA helix. Enhanced affinity and specificity of polyamide nucleotide binding is achieved by covalently linking the antiparallel chains. A "hairpin motif" connects the N and C termini of the two chains through a W (e.g., a γ-aminobutyric acid unit (γ-turn)) to form a folded linear chain.

[0541] Although various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided for illustrative purposes only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the present invention. It will be appreciated that numerous alternatives to the embodiments of the present invention described herein may be used.

[0542] In some embodiments, non-limiting examples of transcriptional regulator compounds described herein are presented in Table 2.

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

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[0600]

[0601]

[0602]

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[0652]

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[0671]

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[0680]

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[0718]

[0719]

[0720] How to use

[0721] The present invention also relates to a method of regulating the transcription of dmpk, atxn8, atxn80s or tcf4, comprising the steps of contacting dmpk, atxn8, atxn80s or tcf4 with a transcriptional regulator molecule as described herein or a pharmaceutically acceptable salt thereof.

[0722] Cell phenotype, cell proliferation, transcription of DMPK, ATXN8, ATXN80S, or TCF4; mRNA production from transcripts of DMPK, ATXN8, ATXN80S, or TCF4; translation of DMPK, ATXN8, ATXN80S, or TCF4; changes in biochemical output produced by proteins encoded by DMPK, ATXN8, ATXN80S, or TCF4; or non-covalent binding of proteins encoded by DMPK, ATXN8, ATXN80S, or TCF4 to their natural binding partners can be monitored. Such methods can be therapeutic models for disease, biological assays, cell-based assays, biochemical assays, or the like.

[0723] 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.

[0724] Also provided herein is a method of treating a disease mediated by the transcription of dmpk, atxn8, atxn80s or tcf4, comprising administering to an individual in need thereof a therapeutically effective amount of a transcriptional regulator molecule as disclosed herein or a salt thereof.

[0725] In some embodiments, the disease is selected from DM1 and FECD.

[0726] In some embodiments, the disease is DM1.

[0727] In some embodiments, the disease is Fuchs endothelial corneal dystrophy (FECD).

[0728] In another aspect, provided herein is a method of treating myotonic dystrophy type 1 (DM1) in an individual in need thereof, comprising administering to the individual an effective amount of a molecule disclosed herein, or a pharmaceutically acceptable salt thereof.

[0729] In another aspect, provided herein is a method of treating Fuchs endothelial dystrophy or Fuchs corneal endothelial dystrophy (FECD) in a subject in need thereof, comprising administering to the subject an effective amount of a molecule disclosed herein, or a pharmaceutically acceptable salt thereof.

[0730] Pharmaceutical compositions and administration

[0731] The compounds described herein are administered to an individual in need thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, as a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0732] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation will depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, (NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entireties.

[0733] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combination thereof.

[0734] The dosage of the agents described herein for treating a disease or condition may depend on the individual's condition, i.e., the stage of the disease, the severity of the symptoms caused by the disease, general health, as well as age, sex, and weight, and other factors known to those skilled in the medical field. The pharmaceutical composition may be administered in a manner determined by those skilled in the medical field to be suitable for the disease to be treated. In addition to the factors described herein and above regarding the use of agents for treating a disease or condition, the suitable duration and frequency of administration of the agent may also be determined or adjusted by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Experimental models and / or clinical trials are generally used to determine the optimal dosage of the agent. The optimal dosage may depend on the individual's body mass, weight, or blood volume. It is generally preferred to use the minimum dose sufficient to provide effective therapy. The design and execution of preclinical and clinical studies of the agents described herein (including when administered for preventive benefit) are fully within the skill of those skilled in the relevant art. When two or more agents are administered to treat a disease or condition, the optimal dosage of each agent may be different, for example, less than the dosage of any one agent when administered alone as a single agent therapy. In some specific embodiments, two kinds of pharmaceutical combinations can work in coordination or addition, and any medicament can be used less than the amount when applying alone.The amount of the medicament that can be used every day can be for example between about 0.01mg / kg and 100mg / kg, for example, between about 0.1 to 1mg / kg, between about 1 to 10mg / kg, between about 10 to 50mg / kg, between about 50 to 100mg / kg body weight.In other embodiments, the amount of the medicament that can be used every day is between about 0.01mg / kg and 1000mg / kg, between about 100 to 500mg / kg or between about 500 to 1000mg / kg body weight.The most preferred dosage for every day or each treatment course for the treatment of disease or illness can be different, and also can change with route of administration and treatment regimen.

[0735] Abbreviations and definitions

[0736] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0737] Unless the context requires otherwise, in this specification and the claims that follow, the word "comprise" and variations thereof (e.g., "comprises" and "comprising") should be construed in an open-ended, inclusive sense, that is, as "including, but not limited to." Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0738] 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. It should also be noted that the term "or" is generally employed in its sense including "and / or" unless the context clearly dictates otherwise.

[0739] When a range of values ​​is disclosed and the notation "n1 ... to n2" or "between n1 ... and n2" is used, where n1 and n2 are numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range therebetween. Such ranges can be integers or continuous between and inclusive of the endpoints. For example, the range "2 to 6 carbons" is intended to include two, three, four, five, and six carbons, since carbon appears in integer units. For example, the reference range "1 to 3 μM (micromolar)" is intended to include 1 μM, 3 μM, and all numbers therebetween, including any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0740] As used herein, unless otherwise indicated, the following terms have the following meanings:

[0741] "Oxo" refers to =0.

[0742] "Carboxyl" refers to -COOH.

[0743] "Cyano" refers to -CN.

[0744] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monovalent radical having from one to about ten carbon atoms, more preferably from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, and longer alkyl groups such as heptyl, octyl, and the like. Whenever it appears in this document, for example, "C1-C6 alkyl" or "C 1-6 The numerical range of "alkyl" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the existence of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is C 1-10 In some embodiments, the alkyl group is C 1-6 In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3 Alkyl. Unless otherwise specifically stated in this specification, alkyl can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl and similar groups. In certain embodiments, alkyl is optionally substituted by oxo, halogen, -N3, -CN, -C (O) OH, -C (O) OMe, -OH, -OMe, -NH2 or -NO2. In certain embodiments, alkyl is optionally substituted by halogen, -CN, -OH or -OMe. In certain embodiments, alkyl is optionally substituted by halogen.

[0745] "Alkenyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group can be in a cis or trans configuration about the double bond and is understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, for example, "C2-C6 alkenyl" or "C 2-6The numerical range of "alkenyl" means that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the existence of the term "alkenyl" without specifying a numerical range. Unless otherwise specifically stated in the specification, the alkenyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl and the like. In some embodiments, the alkenyl group is optionally substituted with oxo, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl group is optionally substituted with halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl group is optionally substituted with halogen.

[0746] "Alkynyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" or "C2-C6 alkynyl" appears herein, it means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses the presence of the term "alkynyl" without specifying a numerical range. Unless otherwise specifically stated herein, an alkynyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -N , -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH , or -NO . In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0747] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in this specification, alkylene can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl and similar groups. In certain embodiments, alkylene is optionally substituted by oxo, halogen, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2 or -NO2. In certain embodiments, alkylene is optionally substituted by halogen, -CN, -OH or -OMe. In certain embodiments, alkylene is optionally substituted by halogen.

[0748] "Alkoxy" refers to a group of the formula -OR a A group in which Ra For alkyl as defined. Unless otherwise specifically stated in this specification, alkoxy can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl and similar groups. In certain embodiments, alkoxy is optionally substituted by halogen ,-N ,-CN ,-C (O) OH, C (O) OMe ,-OH ,-OMe ,-NH or-NO . In certain embodiments, alkoxy is optionally substituted by halogen ,-CN ,-OH or-OMe. In certain embodiments, alkoxy is optionally substituted by halogen .

[0749] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system may contain only hydrogen and carbon and contain from five to eighteen carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, radicals such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Aryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, aryl groups are 6- to 10-membered aryl groups. In some embodiments, aryl groups are 6-membered aryl groups (phenyl). Aryl groups include, but are not limited to, those derived from the following hydrocarbon ring systems: anthracene, naphthylene, phenanthrenyl, anthracene, azulene, benzene, Fluoranthene, fluorene, α-dicyclopentadienyl acene, α-dicyclopentadienyl acene, indane, indene, naphthalene, phenanthrene, phenanthrene, pleiadene (pleiadene), pyrene and triphenylene.Unless otherwise specifically stated in this specification, aryl can be optionally substituted by, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl and similar groups thereof.In certain embodiments, aryl is optionally substituted by halogen, methyl, ethyl ,-N 3 ,-CN ,-C (O) OH, C (O) OMe ,-CF 3 ,-OH ,-OMe ,-NH 2 or-NO 2.In certain embodiments, aryl is optionally substituted by halogen, methyl, ethyl ,-CN ,-CF 3 ,-OH or-OMe.In certain embodiments, aryl is optionally substituted by halogen.

[0750] "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, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyl groups include, but are not limited to, groups having three to fifteen carbon atoms (e.g., C3-C15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), three to ten carbon atoms (e.g. C3-C 10 Fully saturated cycloalkyl or C3-C 10 In some embodiments, the cycloalkyl group is a 3-10 fully saturated cycloalkyl or a 3-10 membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3-6 fully saturated cycloalkyl or a 3-6 membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5-6 fully saturated cycloalkyl or a 5-6 membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthalene, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, 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]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically stated in this specification, cycloalkyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl and the like. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -N , -CN, -C(O)OH, C(O)OMe, -CF , -OH, -OMe, -NH or -NO . In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0751] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, preferably having three to twelve carbon atoms and comprising at least one double bond, including fused or bridged ring systems. In certain embodiments, the cycloalkenyl radical comprises three to ten carbon atoms. In other embodiments, the cycloalkenyl radical comprises five to seven carbon atoms. The cycloalkenyl radical can be connected to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0752] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0753] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above that is substituted with one or more halogen groups, such as 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 alkanes substituted with halogens ("haloalkanes") include methyl halides (e.g., methyl chloride, methyl bromide, methyl fluoride, methyl iodide), 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 an alkyl group is substituted with more than one halogen group, each halogen can be independently selected, for example, 1-chloro, 2-fluoroethane.

[0754] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0755] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0756] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0757] " assorted alkyl " refers to an alkyl group wherein one or more skeleton atoms of an alkyl group are selected from the group consisting of oxygen, nitrogen (e.g., -NH-, -N (alkyl)-), sulphur, phosphorus or a combination thereof, in addition to carbon. Assorted alkyl is connected to the remainder of the molecule at the carbon atom of the assorted alkyl group. In one embodiment, assorted alkyl is a C1-C6 assorted alkyl group, wherein the assorted alkyl group comprises 1 to 6 carbon atoms and one or more atoms in addition to carbon, such as oxygen, nitrogen (e.g., -NH-, -N (alkyl)-), sulphur, phosphorus or a combination thereof, wherein the assorted alkyl group is connected to the remainder of the molecule at the carbon atom of the assorted alkyl group. The example of such assorted alkyl is for example -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3 or -CH2CH2N(CH3)2. Unless otherwise specifically stated in this specification, heteroalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl and similar groups. In certain embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF , -OH, -OMe, -NH or -NO . In certain embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In certain embodiments, heteroalkyl is optionally substituted by halogen.

[0758] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl group is fully saturated. In some embodiments, the heterocycloalkyl group contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl group contains one to three nitrogen atoms. In some embodiments, the heterocycloalkyl group contains one or two nitrogen atoms. In some embodiments, the heterocycloalkyl group contains one nitrogen atom. In some embodiments, the heterocycloalkyl group contains one nitrogen atom and one oxygen atom. Unless otherwise specified herein, a heterocycloalkyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group may be optionally oxidized; and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, groups having two to fifteen carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl), two to ten carbon atoms (e.g. C2-C 10Fully saturated heterocycloalkyl or C2-C 10C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, Pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, 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 ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycloalkyl group has 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in the heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is not the same as the total number of atoms (i.e., the backbone atoms of the heterocycloalkyl ring) (including heteroatoms) that constitute the heterocycloalkyl group. In some embodiments, heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered fully saturated heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered fully saturated heterocycloalkyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered fully saturated heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specifically stated in this specification, heterocycloalkyl may be optionally substituted, for example, as described below, with oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF , -OH, -OMe, -NH or -NO . In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0759] "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl group comprises one to three nitrogen atoms. In some embodiments, the heteroaryl group comprises one or two nitrogen atoms. In some embodiments, the heteroaryl group comprises one nitrogen atom. The heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may be optionally quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azobenzene, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxolyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazole 1-H-pyrrolyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 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 specifically stated in this specification, heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF , -OH, -OMe, -NH , or -NO .In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, heteroaryl is optionally substituted by halogen.

[0760] The term "oligonucleotide sequence" refers to a plurality of nucleic acids of defined sequence and length (eg, 2, 3, 4, 5, 6 or even more nucleotides). The term "oligonucleotide repeat sequence" refers to contiguous stretches of an oligonucleotide sequence.

[0761] The term "transcription," as is well known in the art, refers to the synthesis of RNA (i.e., ribonucleic acid) by an RNA polymerase guided by DNA. The term "regulating transcription" refers to a change in the amount of transcription, which can be measured by methods well known in the art (e.g., analysis of the transcript mRNA). In certain embodiments, regulation is to increase transcription. In other embodiments, regulation is to decrease transcription.

[0762] The term "polyamide" refers to a polymer of linkable units chemically bonded via amide (i.e., CONH) linkages; optionally, the polyamide includes chemical probes bound thereto. Polyamides can be synthesized by the stepwise condensation of carboxylic acids (COOH) and amines (RR'NH) using methods known in the art. Alternatively, polyamides can be formed in vitro using enzymatic reactions or by fermentation using microorganisms.

[0763] The term "linkable unit" refers to methylimidazole, methylpyrrole, and linear and branched aliphatic functional groups (e.g., methylene, ethylene, propylene, butylene, and the like), optionally containing nitrogen substituents, and chemical derivatives thereof. The aliphatic functional group of the linkable unit can be provided, for example, by condensing B-alanine or dimethylaminopropylamine during the synthesis of the polyamide by methods well known in the art.

[0764] The term "linking group" or "oligomeric backbone" refers to a chain of at least 10 consecutive atoms. In certain embodiments, the linking group contains no more than 20 non-hydrogen atoms. The terms linking group and oligomeric backbone are used interchangeably. In some embodiments, the linking group contains no more than 40 non-hydrogen atoms. In some embodiments, the linking group contains no more than 60 non-hydrogen atoms. In certain embodiments, the linking group contains atoms selected from C, H, N, O, and S. In some embodiments, each non-hydrogen atom is chemically bonded to two adjacent atoms in the linking group, or to one adjacent atom in the linking group and the end of the linking group. In some embodiments, the linking group forms an amide bond with at least one of the two other groups to which it is connected. In certain embodiments, the linking group forms an ester bond or an ether bond with at least one of the two other groups to which it is connected. In some embodiments, the linking group forms a thioester bond or a thioether bond with at least one of the two other groups to which it is connected. In some embodiments, the linking group forms a direct carbon-carbon bond with at least one of the two other groups to which it is connected. In some embodiments, the linking group forms an amine bond or an amide bond with at least one of the two other groups to which it is connected. In some embodiments, the linking group comprises -(CH2OCH2)- units. In some embodiments, the linking group comprises -(CH(CH3)OCH2)- units. In some embodiments, the linking group comprises -(CH2NR N CH2) unit, R N =C 1-4 In some embodiments, the linking group comprises an arylene, cycloalkylene, or heterocycloalkylene moiety.

[0765] The term "bond" refers to a covalent bond between two atoms, or between two moieties when the atoms connected by the bond are considered to be part of a larger substructure. Unless otherwise specified, a bond can be a single bond, a double bond, or a triple bond. A dashed line between two atoms in a molecular diagram indicates that an additional bond may or may not be present at that position.

[0766] As used herein, "optionally substituted" is a substituted group derived from an unsubstituted parent group in which one or more hydrogen atoms are replaced by another atom or group. Unless otherwise indicated, when a group is considered to be "substituted" or "optionally substituted", it means that the group is substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (which is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclyl-C1-C6 alkyl (which is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclyl-C1-C6 alkyl (which is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclyl-C1-C6 alkyl (which is optionally substituted by halo, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl (which is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl-C1-C6 alkyl (which is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (which is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (which is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6) alkyl (which is optionally substituted by halo , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (which is optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (which is 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(Ci-C6)alkyl (e.g., -CF3), halo(Ci-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(Ci-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," the group may be substituted with the substituents described above.

[0767] When mentioning the substituent group that optionally exists, term " one or more " means that described theme group is optionally replaced by one, two, three or four substituent groups.In certain embodiments, described theme group is optionally replaced by one, two or three substituent groups.In certain embodiments, described theme group is optionally replaced by one or two substituent groups.In certain embodiments, described theme group is optionally replaced by a substituent group.In certain embodiments, described theme group is optionally replaced by two substituent groups.

[0768] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z or E form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise stated, the compounds described herein are also intended to include all Z forms, E forms, and tautomeric forms.

[0769] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, e.g. 2 H. 3 H. 11 C. 13 C and / or 14 In a specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of drug action.

[0770] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium or the replacement of carbon by 13 C or 14 Compounds having the present structures except for C-enriched carbon substitutions are within the scope of this disclosure.

[0771] The disclosed compounds optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compound may be isotopically labeled, for example, with 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 substitutions are encompassed. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. In some embodiments, when an isotopic variation is specified, the remaining atoms of the compound may optionally contain an unnatural portion of atomic isotopes.

[0772] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom replacement. Methods for synthesizing deuterium-containing compounds are known in the art and include the following synthetic methods by way of non-limiting example only.

[0773] Deuterium-substituted compounds are synthesized using various methods such as those described in Dean, Dennis C., ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0774] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A large number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers, such as Aldrich Chemical Company.

[0775] In some embodiments of the compounds disclosed herein, one or more substituents comprise a percentage of deuterium above the natural abundance of deuterium. In some embodiments of the compounds disclosed herein, one or more hydrogens are replaced with one or more deuteriums.

[0776] In some embodiments of the compounds disclosed herein, the deuterium abundance of each substituent is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total amount of hydrogen and deuterium.

[0777] The compounds of the present disclosure also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), configurational polymorphs and amorphous forms of the compounds, and mixtures thereof.

[0778] In some cases, the compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms. When absolute stereochemistry is not specified, the compounds presented herein include all diastereoisomers, enantiomers, and epimeric forms, as well as appropriate mixtures thereof. Stereoisomers may be separated by chromatography or by forming diastereomers and by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, incorporated herein by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0779] 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 and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0780] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0781] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, 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 glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0782] "Effective amount" or "therapeutically effective amount" refers to that amount of a compound administered to a mammalian subject, either in a single dose or as part of a series of doses, which is effective to produce the desired therapeutic effect.

[0783] As used herein, the terms "treat," "treating," or "treatment" include alleviating, alleviating, or ameliorating at least one symptom of a disease or condition; preventing additional symptoms; inhibiting the disease or condition, such as arresting the development of the disease or condition; relieving the disease or condition; causing regression of the disease or condition; alleviating symptoms caused by the disease or condition; or halting the symptoms of the disease or condition.

[0784] The term "patient" is generally synonymous with the term "individual" and includes all mammals, including humans. Examples of patients include humans, livestock (e.g., cows, goats, sheep, pigs, and rabbits), and companion animals (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0785] The term "contacting" refers to bringing a compound (eg, a transcriptional molecule of the present disclosure) into proximity with a desired target gene. Contacting can result in binding to the target moiety or in a conformational change in the target moiety.

[0786] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. In some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of the present invention. In addition, the compounds described herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0787] Examples

[0788] The following examples are provided for the purpose of illustrating various embodiments of the present invention and are not intended to limit the invention in any way. The present examples and the methods described herein are representative of presently preferred embodiments and are illustrative and not intended to limit the scope of the invention. Those skilled in the art will appreciate variations and other uses thereof that are within the spirit of the invention as defined by the scope of the claims.

[0789] Compound synthesis

[0790] The disclosed compounds can be prepared using the methods described in the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes and experimental procedures are provided for illustrative purposes and are not intended to be limiting. The starting materials used to prepare the disclosed compounds can be purchased or prepared using conventional methods known in the art.

[0791] Synthetic chemistry transformations and methods suitable for 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 PGM Wuts, Protective Groups in Organic Synthesis, 2nd 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).

[0792] List of abbreviations

[0793] Ac2O = acetic anhydride; AcCl = acetyl chloride; ACN = acetonitrile; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous solution; Bu3SnH = tributyltin hydride; CD3OD = deuterated methanol; CDCl3 = deuterated chloroform; CDI = 1,1'-carbonyldiimidazole; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = diisobutylaluminum 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 methylammonium hexafluorophosphate; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-PrOH = isopropanol; LAH = lithium aluminum hydride; LiHMDS = lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeOH = methanol; MP-carbonate resin = triethylammonium methyl polystyrene carbon = a macroporous resin; MsCl = methanesulfonyl chloride; MTBE = methyl tert-butyl ether; MW = microwave irradiation; n-BuLi = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)amide; NaOMe = sodium methoxide; NaOtBu = sodium tert-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMP = N-methyl-2-pyrrolidone; Pd(Ph3)4 = tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2 = dichlorobis(triphenylphosphine)palladium(II); PG = protecting group; preparative HPLC = preparative high performance liquid chromatography; PyBop = hexadecene (Benzotriazol-1-yloxy)tris(N-pyrrolidinyl)phosphonium fluorophosphate; Pyr = pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropyloxybiphenyl; sat. = saturated; ss = saturated solution; t-BuOH = tert-butyl alcohol; T3P = propylphosphonic anhydride; TBS = TBDMS = tert-butyldimethylsilyl; TBSCl = TBDMSCl = tert-butyldimethylchlorosilane; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; Tol = toluene; TsCl = toluenesulfonyl chloride; XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0794] Synthesis of representative polyamides

[0795] Example 1. 1-methyl-4-(3-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-4-(3-(1- Methyl-1H-pyrrole-2-carboxamido)propionamido)-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)propionyl (amino)-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)propionamido)-1H-imidazole-2-carboxylic acid (PA-03) Synthesis

[0796] Process 1.

[0797]

[0798] 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 was then stirred at room temperature under H2 atmosphere for 17.0 hours. 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: CH 11 Calculated mass of N3O2: 169.09, found: 170.10 [M+H] + .

[0799] Step 2: To a 500 mL flask was added 3-[(tert-butoxycarbonyl)amino]propanoic acid (22.45 g, 118.65 mmol, 0.90 equiv) in DMF (180.00 mL). The mixture was cooled to 0°C, followed by the addition of HATU (75.18 g, 197.71 mmol, 1.50 equiv) and DIEA (51.11 g, 395.43 mmol, 3.00 equiv), and the mixture was stirred for 10 minutes. Ethyl 4-amino-1-methylimidazole-2-carboxylate (22.30 g, 131.81 mmol, 1.00 equiv) was then added portionwise, and the reaction was stirred at room temperature for 1.0 hour. 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 x 50 mL), and dried under vacuum. Ethyl 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylate (34.50 g, 76.90%) was obtained as a light yellow solid. LC / MS: C 15 H 24 Calculated mass of N4O5: 340.17, found: 341.20 [M+H] + .

[0800] Step 3: To a stirred solution of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylate (34.50 g, 101.36 mmol, 1.00 equiv) in MeOH (200.00 mL) was added LiOH solution (2 M, 202 mL, 4.00 equiv) dropwise at room temperature. The resulting mixture was stirred at 45 ° C for 2.0 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in H2O (50 mL) and acidified to pH 3 to 5 with 2M HCl. The precipitated solid was collected by filtration and washed with H2O (3×30 mL) and dried in vacuo to give 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (30.00 g, 94.77%) as a white solid. LC / MS: C 13 H 20 Calculated mass of N4O5: 312.14, found: 313.15 [M+H] + .

[0801] Step 4: To a stirred solution of 4-[3-[(tert-butoxycarbonyl)amino]propionamido-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 vacuum. Methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazol-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 of N6O6: 448.21, found: 449.25 [M+H] + .

[0802] Step 5: A solution of methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazol-2-amido)-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 hours. The resulting mixture was concentrated in vacuo to afford methyl 4-[4-(3-aminopropionamido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate hydrochloride (19.00 g crude material) as a yellow solid. LC / MS: C 15 H 21 Calculated mass of ClN6O4: 348.15, found: 349.05 [M+H] + .

[0803] Step 6: The procedure was the same as for methyl 4-[4-(3-aminopropionamido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate hydrochloride. 2.00 g of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazol-2-carboxylate was used, and 2.00 g of the desired product was obtained as a crude off-white solid. LC / MS: C 10 H 16 Calculated mass of N4O3: 240.12, found: 241.10 [M+H] + .

[0804] 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 4-[4-(3-aminopropionamido)-1-methylimidazole-2-amido]-1-methylpyrrole-2-carboxylic acid methyl ester (2004.53 mg, 5.75 mmol, 1.20 equiv). The mixture was stirred at room temperature for 2.0 hours. Next, the solvent was removed and the residue was purified by reverse phase column under the following conditions: column, C18 column, MeCN / water (0.05% TFA), 5% to 50% gradient in 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 of N7O5: 455.19, found: 456.30 [M+H] + .

[0805] Step 8: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid. However, 2.00 g of methyl 1-methyl-4-(1-methyl-4-[3-[(1-methylpyrrol-2-yl)formamido]propionamido]imidazol-2-amido)pyrrole-2-carboxylate was used to obtain 1.90 g of the desired product as a white solid (92.00% yield). LC / MS: C 20 H 23 Calculated mass of N7O5: 441.18, found: 442.25 [M+H] + .

[0806] Step 9: The procedure was the same as for methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazol-2-amido)-1-methylpyrrole-2-carboxylate, but the filtrate was concentrated and purified by reverse phase column. 1.90 g of 1-methyl-4-(1-methyl-4-[3-[(1-methylpyrrol-2-yl)formamido]propionamido]imidazol-2-amido)pyrrole-2-carboxylic acid was reacted to give 2.70 g of the desired product as a white solid (71.00% yield). LC / MS: C 35 H 41 N 13 Calculated mass of O8: 771.32, found: 772.35 [M+H] + .

[0807] Step 10: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-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]propionamido]imidazol-2-amido)pyrrol-2-yl]formamido]propionamido)imidazol-2-amido]pyrrole-2-carboxylate to afford 2.80 g of the desired product (78.00% yield) as a white solid. LC / MS: C 34 H 39 N 13 Calculated mass of O8: 757.30, found: 758.50 [M+H] + .

[0808] Step 11: To a solution of 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methyl-4-[3-[(1-methylpyrrol-2-yl)formamido]propionamido]imidazol-2-amido)pyrrol-2-yl]formamido]propionamido)imidazol-2-amido]pyrrole-2-carboxylic acid (2.90 g, 3.83 mmol, 1.00 equiv) in DMF (25.00 mL) was added NMI (3.20 g, 39.04 mmol, 10.20 equiv), TCFH (1.18 g, 4.21 mmol, 1.10 equiv) and ethyl 4-(3-aminopropionamido)-1-methylimidazole-2-carboxylate (1.16 g, 4.21 mmol, 1.10 equiv). The reactants were then stirred at room temperature for 3.0 hours. Next, the mixture was 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 give 2.5 g of the desired product (66.00% yield) as a white solid. LC / MS: C 44 H 53 N 17 O 10 Calculated mass: 979.42, found: 980.80 [M+H] + .

[0809] Step 12: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid, except that the reaction temperature was 40°C and the reaction time was 4.0 hours. 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)formamido]propionamido]imidazol-2-amido)pyrrol-2-yl]formamido]propionamido)imidazol-2-amido]pyrrol-2-yl]formamido)propionamido]imidazole-2-carboxylate, 1.90 g of the desired product was observed as a white solid (78.00% yield). LC / MS: C 42 H 49 N 17 O 10 Calculated mass: 951.38, found: 952.65 [M+H] + .

[0810] Example 2. 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-amido)pyrrol-2-yl]formamido}propionamido)imidazole-2-amido] pyrrol-2-yl}formamido)butyramido]imidazol-2-yl}formamido)propionamido]pyrrole-2-amido}imidazol-2-yl Synthesis of [4-[(1-amino-3-methyl-1-formamido)propionic acid (PA-004)]

[0811] Process 2.

[0812]

[0813]

[0814] Step 1: 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (11.00 g, 35.22 mmol, 1.00 equivalent) and DMF (300.00 mL) were added to a 1000 ml flask. The mixture was cooled to 0° C., and HATU (20.09 g, 52.83 mmol, 1.50 equivalent) and DIEA (18.21 g, 140.88 mmol, 4.00 equivalent) were then added dropwise. The resulting mixture was stirred for 10 minutes, and methyl 3-aminopropionate (3.63 g, 35.22 mmol, 1.00 equivalent) was added portionwise. The reaction mixture was stirred at room temperature for 1.0 hour. Next, the reaction mixture was poured into water / ice (600 mL) and the solid was filtered off and dried in vacuo. The aqueous phase was extracted with EA (3×200 mL), and the combined organic phases were washed with H 2 O (1×200 mL) and NaCl (1×200 mL), and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column and eluted with pure EA. The fractions were combined and concentrated to give methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazol-2-yl)formamido]propanoate (13.00 g, 87.95%) as a yellow solid. LC / MS: C 17 H 27 Calculated mass of N5O6: 397.20, found: 398.20 [M+H] + .

[0815] Step 2: The procedure was the same as for 4-[4-(3-aminopropionamido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylic acid methyl ester hydrochloride (Example 1, Step 6), except that the reaction time was 1.0 hour. Using 3-[(4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazol-2-yl)formamido]propanoic acid methyl ester (11.00 g), 11.00 g of the desired product crude material was obtained as a yellow oil. LC / MS: C 12 H 19 Calculated mass of N5O4: 297.14, found: 298.20 [M+H] + .

[0816] Step 3: To a stirred solution of 1-methylimidazole-2-carboxylic acid (10.00 g, 79.29 mmol, 7.00 equiv) in DMF (150.00 mL) was added TBTU (38.19 g, 118.94 mmol, 1.50 equiv), methyl 4-amino-1-methylpyrrole-2-carboxylate hydrochloride (16.63 g, 87.24 mmol, 1.10 equiv) and DIEA (30.74 g, 237.88 mmol, 3.00 equiv) portionwise at 0°C. The resulting mixture was stirred at room temperature for 17.0 hours. 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 vacuum. Methyl 1-methyl-4-(1-methylimidazol-2-amido)pyrrole-2-carboxylate (16.5 g, 78.37%) was obtained as a white solid. LC / MS: C 12 H 14 Calculated mass of N4O3: 262.11, found: 263.15 [M+H] + .

[0817] Step 4: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3). 1-Methyl-4-(1-methylimidazole-2-amido)pyrrole-2-carboxylic acid methyl ester (16.50 g) was used to obtain 12.00 g of 1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2-carboxylic acid as a white solid (76.84% yield). LC / MS: C 11 H 12 Calculated mass of N4O3: 248.09, found: 249.10 [M+H] + .

[0818] Step 5: The procedure was the same as for ethyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazol-2-yl)formamido]propanoate (Example 1, Step 2). 1-Methyl-4-(1-methylimidazol-2-amido)pyrrole-2-carboxylic acid (9.00 mg) was used to obtain 14.00 g of the desired product as a yellow solid (63.54% yield). LC / MS: C 26 H 30 N 10 Calculated mass of O6: 578.23, found: 579.10 [M+H] + .

[0819] Step 6: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3). 1-Methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido]propionamido)imidazol-2-amido]pyrrol-2-yl]formamidomethylcarboxylate (14.00 g) was used to obtain 12.00 g of the desired product as a yellow solid (81.49% yield). LC / MS: C 25 H 28 N 10 Calculated mass of O6: 564.22, found: 565.15 [M+H] + .

[0820] Step 7: The procedure was the same as for ethyl 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylate (Example 1, Step 2). 4-[(tert-butoxycarbonyl)amino]butanoic acid (7.80 g) was used to obtain 11.00 g of the desired product as a pink solid (80.70% yield). LC / MS: C 16 H 26 Calculated mass of N4O5: 354.19, found: 355.15 [M+H] + .

[0821] Step 8: The procedure was the same as for methyl 4-[4-(3-aminopropionamido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate hydrochloride (Example 1, Step 6). Using ethyl 4-{4-[(tert-butoxycarbonyl)amino]butanamido}-1-methylimidazol-2-carboxylate (9.40 g), 6.20 g of the desired product was obtained as a white solid (90.89% yield). LCMS: C 11 H 18 Calculated mass of N4O3: 254.14, found: 255.15 [M+H] + .

[0822] 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}propionamido)imidazol-2-amido]pyrrole-2-carboxylic acid (18.20 g, 32.24 mmol, 1.00 equiv) in DMF (250.00 mL) at 0° C. 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). 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 in vacuo 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}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate as a yellow solid (95.74% yield). LC / MS: C 36 H 44 N 14 Calculated mass of O8: 800.35, found: 801.30 [M+H] + .

[0823] Step 10: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3). 1-Methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylic acid ethyl ester (24.00 g) was used to obtain 23.10 g of the desired product as a yellow solid (99.36% yield). LC / MS: C 34 H 40 N 14 Calculated mass of O8: 772.32, found: 773.30 [M+H] + .

[0824] Step 11: To a stirred solution of 4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-carboxylic acid (11.50 g, 47.87 mmol, 1.00 equiv) in DMF (200.00 mL) was added EDCI (22.94 g, 119.66 mmol, 2.50 equiv), ethyl 4-amino-1-methylimidazole-2-carboxylate (8.10 g, 47.87 mmol, 1.00 equiv) and DMAP (14.62 g, 119.66 mmol, 2.50 equiv) at 0° C. The resulting mixture was stirred at 35° C. for 17.0 hours. 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 vacuum. Ethyl 4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido}-1-methylimidazole-2-carboxylate (16.00 g, 85.48% yield) was obtained as a light yellow solid. LC / MS: C 18 H 25 Calculated mass of N5O5: 391.19, found: 392.30 [M+H] + .

[0825] Step 12: To a stirred solution of ethyl 4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido}-1-methylimidazole-2-carboxylate (16.00 g, 40.88 mmol, 1.00 equiv) in DCM (135.00 mL) was added TFA (45.00 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2.0 hours and then concentrated in vacuo. 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 in vacuo. Ethyl 4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate (16.00 g, crude material) was obtained as a brown solid. LC / MS: C 13 H 17 Calculated mass of N5O3: 291.13, found: 292.15 [M+H] + .

[0826] Step 13: A solution of ethyl 4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate (12.00 g, 41.19 mmol, 1.00 equiv) and 3-[(tert-butoxycarbonyl)amino]propionic 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 hour. The reaction was poured into ice water (400 mL) and the mixture was stirred for 15 minutes. The precipitated solid was collected by filtration, washed with water (3×150 mL), and dried under vacuum. The aqueous phase was extracted with EA (3×150 mL), and the combined organic phases were combined and washed with H 2 O (200 mL) and dried over anhydrous Na 2 SO 4 . The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography and eluted with PE / EA (1: 8). 17.00 g of ethyl 4- (4- {3- [ (tert-butoxycarbonyl) amino] propionamido} -1-methylpyrrole-2-amide) -1-methylimidazole-2-carboxylate (89.28% yield) was obtained as a yellow solid. LC / MS: C 21 H 30 Calculated mass of N6O6: 462.22, found: 463.35 [M+H] + .

[0827] Step 14: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3). Ethyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propionamido}-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate (12.00 g) was used to obtain 10.00 g of the desired product as a white solid (88.81% yield). LC / MS: C 19 H 26 Calculated mass of N6O6: 434.19, found: 435.25 [M+H] + .

[0828] Step 15: A solution of 4-(4-{3-[(tert-butoxycarbonyl)amino]propionamido}-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylic acid (10.00 g, 23.02 mmol, 1.00 equiv) and β-alanine ethyl ester hydrochloride (4.90 g, 31.90 mmol, 1.39 equiv), PyBOP (12.50 g, 24.02 mmol, 1.04 equiv), 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 NaSO. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with PE / EA (1:8) to give ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propionamido}-1-methylpyrrole-2-amido)-1-methylimidazol-2-yl]formamido}propanoate (12.00 g, 93.80%) as a yellow solid. LC / MS: C 24 H 35 Calculated mass of N7O7: 533.26, found: 534.30 [M+H] + .

[0829] Step 16: The procedure was the same as for ethyl 4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate (Example 2, Step 12). Ethyl 3-{[4-(4-{3-[(tert-butoxycarbonyl)amino]propionamido}-1-methylpyrrole-2-amido)-1-methylimidazol-2-yl]formamido}propanoate (12.00 g) was used to obtain 12.00 g of the desired product as a crude white solid. LC / MS: C 19 H 27 Calculated mass of N7O5: 433.21, found: 434.25 [M+H] + .

[0830] Step 17: The procedure was the same as for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Example 2, Step 12). 1-Methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (10.00 g) was used, and 13.60 g of the desired product was obtained as a yellow solid (88.61% yield). The desired product was obtained after purification by preparative HPLC as a light yellow solid. HRMS: C 53 H 65 N 21 O 12 Calculated mass: 1187.5122, found: 1188.5153 [M+H] + .

[0831] Step 18: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3), except that the reaction temperature was 35° C. Ethyl 3-[(1-methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazol-2-yl}formamido)propionamido]pyrrol-2-amido}imidazol-2-yl)formamido]propanoate (10.60 g) was used and 10.00 g of the desired product was obtained as a yellow solid. LC / MS: C 51 H 61 N 21 O 12 Calculated mass: 1159.48, found: 581.25 [M / 2+H] + .

[0832] Example 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-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl pyrrole-2-yl} formamido) butanamido] imidazol-2-yl} formamido) propionamido] pyrrole-2-amido} imidazol-2-carboxamido Synthesis of acid (PA-040-OH)

[0833] Process 3.

[0834]

[0835] Step 1: The procedure was the same as for ethyl 4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate (Example 2, Step 12). 2.00 g of the desired product was obtained as a white solid using ethyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propionamido}-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate (2.00 g). LC / MS: C 16 H 22 Calculated mass of N6O4: 362.17, found: 363.25 [M+H] + .

[0836] Step 2: The procedure was the same as for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Example 2, Step 9), except that the solvent was DMA. 1-Methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (3.00 g) was used, and 4.30 g of the desired product was obtained as a yellow solid (96.84% yield). LC / MS: C 50 H 60 N 20 O 11 Calculated mass: 1116.48, found: 1117.60 [M+H] + .

[0837] Step 3: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3), except that the reaction temperature was 40°C and the reaction time was 5.0 hours. 1-Methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazol-2-yl}formamido)propionamido]pyrrol-2-amido}imidazole-2-carboxylic acid ethyl ester (4.20 g) was used to obtain 4.00 g of the desired product as a yellow solid (97.97% yield). LC / MS: C 48 H 56 N 20 O 11Calculated mass: 1088.44, found: 1089.55 [M+H] + .

[0838] Example 4. 3-[(4-{4-[3-({4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-methyl-4-[1- Methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazole-2- [amido]pyrrol-2-yl}formamido)butyramido]-1-methylimidazol-2-yl}formamido)propionamido]-1-methyl Synthesis of [1-(2-pyrrole-2-amido)-1-methylimidazol-2-yl)formamido]propionic acid (PA-004-NHBoc-OH)

[0839] Process 4.

[0840]

[0841] Step 1: The procedure was the same as for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Example 2, Step 9). (2R)-2-[(tert-butoxycarbonyl)amino]-4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}butanoic acid (3.00 g) was used, and 3.50 g of the desired product was obtained as a yellow solid. LC / MS: C 31 H 37 Calculated mass of N5O7: 591.27, found: 592.25 [M+H] + .

[0842] Step 2: To a 50 ml flask was added ethyl 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}butanamido]-1-methylimidazole-2-carboxylate (500.00 mg, 0.85 mmol, 1.00 equiv), DMF (5.00 mL), and piperidine (1.00 mL). The reaction was stirred at room temperature for 30 minutes. The piperidine was removed, and the reaction mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 column; mobile phase, CH3CN / water (0.5% NH4HCO3), 10% to 50% gradient over 30 minutes; detector, UV 254 nm. The fractions were combined and concentrated to give ethyl 4-[(2R)-4-amino-2-[(tert-butoxycarbonyl)amino]butanamido]-1-methylimidazole-2-carboxylate (250.00 mg, 96.10%) as a yellow oil. LC / MS: C 16 H 27 Calculated mass of N5O5: 369.20, found: 370.35 [M+H] + .

[0843] Step 3: The procedure was the same as for 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylic acid ethyl ester (Example 2, Step 9). 4-[(2R)-4-amino-2-[(tert-butoxycarbonyl)amino]butanamido]-1-methylimidazole-2-carboxylic acid ethyl ester (200.00 mg) was used to obtain 200.00 mg of the desired product as a yellow solid (68.39% yield). LC / MS: C 41 H 53 N 15 O 10 Calculated mass: 915.41, found: 916.75 [M+H] + .

[0844] Step 4: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3), 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 hour. 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]-1-methylimidazole-2-carboxylic acid ethyl ester (570 mg) was used, and 370.00 mg of the desired product was obtained as a yellow solid (66.90% yield). LC / MS: C 39 H 49 N 15 O 10 Calculated mass: 887.38, found: 888.85 [M+H] + .

[0845] Step 5: The procedure was the same as for 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylic acid ethyl ester (Example 2, Step 9). Using 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]-1-methylimidazole-2-carboxylic acid (380.00 mg), 521.00 mg of the desired product was obtained as a white solid (91.75% yield). The desired compound was obtained as a white solid after purification by preparative HPLC. HRMS: C 58 H 74 N 22 O 14 Calculated mass: 1302.5755, found: 1303.5867 [M+H] + .

[0846] Step 6: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3), except that the reaction temperature was room temperature. 3-[(4-{4-[3-({4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]-1-methylimidazol-2-yl}formamido)propionamido]-1-methylpyrrole-2-amido}-1-methylimidazol-2-yl)formamido]propanoic acid ethyl ester (150.00 mg) was used to obtain 146.00 mg of the desired product as a white solid. LC / MS: C 56 H 70 N 22 O 14 Calculated mass: 1274.54, found: 638.85 [M / 2+H] + .

[0847] Example 5. 3-[(4-{4-[3-({4-[(2R)-2-acetamido-4-({1-methyl-4-[1-methyl-4-(3- {[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl [pyrrole-2-yl}formamido)butyramido]-1-methylimidazol-2-yl}formamido)propionamido]-1-methylpyrrole-2-yl Synthesis of [amino]-1-methylimidazol-2-yl]formamido]propionic acid (PA-004-NHAc-OH)

[0848] Process 5.

[0849]

[0850] Step 1: The procedure was the same as for ethyl 4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate (Example 2, Step 12), but after concentration, the crude material was used directly in the next step without further purification. Ethyl 3-[(4-{4-[3-({4-[(2R)-2-amino-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]-1-methylimidazol-2-yl}formamido)propionamido]-1-methylpyrrole-2-amido}-1-methylimidazol-2-yl)formamido]propanoate (319.00 mg) was used, and 300.00 mg of the desired product was obtained as a brown solid. After purification by preparative HPLC, the desired compound was obtained as a white solid. HRMS: C 53 H 66 N 22 O 12 Calculated mass: 1202.5231, found: 1203.5302 [M+H] + .

[0851] Step 2: At 0°C, add 3-[(4-{4-[3-({4-[(2R)-2-amino-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]-1-methylimidazol-2-yl}formamido)propionamido] To a stirred solution of ethyl]-1-methylpyrrole-2-amido}-1-methylimidazol-2-yl)formamido]propanoate (294.50 mg, 0.25 mmol, 1.00 equiv) in DCM (6.00 mL) was added AcO (0.23 mL, 2.45 mmol, 10.00 equiv) and EtN (0.34 mL, 2.45 mmol, 10.00 equiv) in portions. The resulting mixture was stirred at room temperature for 1.0 hour and then concentrated in vacuo. The crude product was purified by reverse phase column using the following conditions: column, C18; mobile phase, ACN / water (0.5% TFA), 10% to 50% gradient over 30 minutes; detector, UV 254 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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]-1-methylimidazol-2-yl}formamido)propionamido]-1-methylpyrrol-2-amido}-1-methylimidazol-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: 1244.5336, found: 1245.5392 [M+H] + .

[0852] Step 3: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3), except that the reaction temperature was room temperature. (R)-ethyl 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)propionamido)-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)butanamido)-1-methyl-1H-imidazole-2-carboxamido)propionamido)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-imidazole-2-carboxamido)propanoate (190.00 mg) was used and 91.50 mg of the desired product was obtained as a white solid (50.12% yield). LC / MS: C 53 H 64 N 22 O 13 Calculated mass: 1216.50, found: 609.80 [M / 2+H] + .

[0853] Example 6. 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-methylimidazol-2-amide)pyrrol-2-yl]formamido}propionamido)imidazol-2-yl amino] pyrrol-2-yl} formamido) butyramido] imidazole-2-amido} pyrrol-2-yl) formamido] propionamido} imidazole Synthesis of 2-oxazole-2-amido)pyrrole-2-carboxylic acid (PA-049-OH)

[0854] Process 6.

[0855]

[0856] Step 1: The procedure was the same as for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Example 2, Step 9). 4-[(tert-Butoxycarbonyl)amino]-1-methylpyrrole-2-carboxylic acid (2.07 g) was used to obtain 3.00 g of the desired product as a yellow solid. LC / MS: C 26 H 34 Calculated mass of N8O7: 570.26, found: 571.30 [M+H] + .

[0857] Step 2: The procedure was the same as for ethyl 4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate (Example 2, Step 12), but after concentration, the crude material was used directly in the next step without further purification. Methyl 4-{4-[3-({4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-yl}formamido)propionamido]-1-methylimidazole-2-amido}-1-methylpyrrole-2-carboxylate (355.00 g) was used to obtain 350.00 mg of methyl 4-(4-{3-[(4-amino-1-methylpyrrole-2-yl)formamido]propionamido}-1-methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate as a brown oil. LC / MS: C 21 H 26 Calculated mass of N8O5: 470.20, found: 471.45 [M+H] + .

[0858] Step 3: The procedure was the same as for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Example 2, Step 9). 1-Methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (450.00 g) was used to obtain 790.00 mg of the desired product as a white solid (95.77% yield). LC / MS: C 55 H 64 N 22 O 12 Calculated mass: 1224.51, found: 1225.85 [M+H] + .

[0859] Step 4: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3), except that the reaction solvent was MeOH / THF = 1:1. 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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazol-2-amido}pyrrol-2-yl)formamido]propionamido}imidazol-2-amido)pyrrole-2-carboxylic acid methyl ester (300.00 mg) was used to obtain 290.00 mg of the desired product as a white solid (68.45% yield). LC / MS: C 54 H 62 N 22 O 12 Calculated mass: 1210.49, found: 1211.80 [M+H] + .

[0860] Example 7. 4-{3-[(4-{4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-[(1-methyl-4-{1-methyl- 4-[1-methyl-4-(1-methylpyrrole-2-amido)pyrrole-2-amido]imidazol-2-amido}pyrrol-2-yl)formamide 1-methylimidazole-2-amide}-1-methylpyrrol-2-yl)formamido]propionamido}-1-methylimidazole Synthesis of oxazole-2-carboxylic acid (PA-044-NHBoc)

[0861] Process 7.

[0862]

[0863] Step 1: The procedure was the same as for 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylic acid ethyl ester (Example 2, Step 9). 4-[(2R)-4-amino-2-[(tert-butoxycarbonyl)amino]butanamido]-1-methylimidazole-2-carboxylic acid ethyl ester (250.00 mg) was used to obtain 470.00 mg of the desired product as a white solid (82.30% yield). LC / MS: C 39 H 49 N 13 Calculated mass of O9: 843.38, found: 844.70 [M+H] + .

[0864] Step 2: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3), except that the reaction temperature was 50°C and the reaction time was 1.0 hour. 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-[(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylpyrrole-2-amido)pyrrole-2-amido]imidazol-2-amido}pyrrol-2-yl)formamido]butanamido]-1-methylimidazole-2-carboxylic acid ethyl ester (460.00 mg) was used to obtain 370.00 mg of the desired product as a white solid (83.20% yield). LC / MS: C 37 H 45 N 13 Calculated mass of O9: 815.35, found: 816.60 [M+H] + .

[0865] Step 3: The procedure was the same as for ethyl 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Example 2, Step 9). 4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-[(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylpyrrole-2-amido)pyrrol-2-amido]imidazol-2-amido}pyrrol-2-yl)formamido]butanamido]-1-methylimidazole-2-carboxylic acid (370.00 mg) was used to obtain 500.00 mg of the desired product as a red solid (95.02% yield). LC / MS: C 53 H 65 N 19 O 12 Calculated mass: 1159.51, found: 1161.05 [M+H] + .

[0866] Step 4: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3), except that the reaction time was 1.0 hour. 4-{3-[(4-{4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-[(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylpyrrole-2-amido)pyrrole-2-amido]imidazol-2-amido}pyrrol-2-yl)formamido]butanamido]-1-methylimidazol-2-amido}-1-methylpyrrol-2-yl)formamido]propionamido}-1-methylimidazole-2-carboxylic acid ethyl ester (300.00 mg) was used to obtain 240.00 mg of the desired product as a yellow solid (81.98% yield). LC / MS: C 51 H 61 N 19 O 12 Calculated mass: 1131.47, found: 1133.05 [M+H] + .

[0867] Example 8. 4-{4-[(2S)-2-[(tert-Butoxycarbonyl)amino]-4-{[1-methyl-4-(3-{[1-methyl-4- (1-Methylimidazol-2-yl)pyrrol-2-yl]formamido}propionamido)imidazol-2-yl]formamido}butanamide Synthesis of 1-methylpyrrole-2-amide}-1-methylimidazole-2-carboxylic acid (PA-023)

[0868] Process 8.

[0869]

[0870] Step 1: The procedure was the same as for 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylic acid ethyl ester (Example 2, Step 9), except that the reaction time was 2.0 hours. 4-(3-aminopropionamido)-1-methylimidazole-2-carboxylic acid ethyl ester (1.50 g) was used, and 2.00 g of the desired product was obtained as an off-white solid (68.09% yield). LC / MS: C 21 H 26 Calculated mass of N8O5: 470.20, found: 471.40 [M+H] + .

[0871] Step 2: The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propionamido]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3), except that the reaction temperature was room temperature and the reaction time was 2.0 hours. 1-Methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazole-2-carboxylic acid ethyl ester (2.00 g) was used to obtain 1.80 g of 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazole-2-carboxylic acid (95.71% yield) as an off-white solid. LC / MS: C 19 H 22 Calculated mass of N8O5: 442.17, found: 443.10 [M+H] + .

[0872] Step 3: The procedure was the same as for 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylic acid ethyl ester (Example 2, Step 9), except that the reaction time was 2.0 hours. 4-{4-[(2S)-4-amino-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}butanamido]-1-methylpyrrole-2-amido}-1-methylimidazole-2-carboxylic acid ethyl ester (1.60 g) was used, and 1.90 g of the desired product was obtained as a yellow solid (70.20% yield). LC / MS: C 51 H 55 N 15 O 10 Calculated mass: 1037.43, found: 1038.45 [M+H] + .

[0873] 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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-yl]formamido}butanamido]-1-methylpyrrole-2-amido}-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 34H 41 N 15 Calculated mass of O8: 787.33, found: 788.40 [M+H] + .

[0874] Step 5: To a mixture of 4-{4-[(2S)-2-amino-4-{[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-yl]formamido}butanamido]-1-methylpyrrole-2-amido}-1-methylimidazole-2-carboxylic acid (1.40 g, 1.78 mmol, 1.00 equiv) 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 equiv) and DMAP (0.02 g, 0.18 mmol, 0.10 equiv). The reaction was stirred at room temperature for 3.0 h, and then H2O (30 mL) was added. The resulting mixture was filtered through a pad of celite, 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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-yl]formamido}butanamido]-1-methylpyrrole-2-amido}-1-methylimidazole-2-carboxylic acid (1.20 g, 76.05% yield) as a yellow solid. LC / MS: C 39 H 49 N 15 O 10 Calculated mass: 887.38, found: 888.45 [M+H] + .

[0875] Step 6: The procedure was the same as for 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylate (Example 2, Step 9), except that the reaction time was 2.0 hours. 4-{4-[(2S)-2-[(tert-Butoxycarbonyl)amino]-4-{[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-yl]formamido}butanamido-1-methylpyrrole-2-amido}-1-methylimidazole-2-carboxylic acid (1.20 g) was used and 1.10 g of the desired product was obtained as a yellow solid (71.01% yield). LC / MS: C52 H 63 N 19 O 12 Calculated mass: 1145.49, found: 1146.50 [M+H] + .

[0876] Step 7: The procedure is the same as for 4-[4-(4-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-4-[(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylimidazol-2-amido)pyrrole-2-amido]pyrrole-2-amido}imidazol-2-yl)formamido]butanamido]-1-methylpyrrole-2-amido}-1-methylimidazol-2-amido)-1-methylpyrrole-2-amido]-1-methylpyrrole-2-carboxylic acid. Methyl 4-[4-(4-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-4-{[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-yl]formamido}butanamido]-1-methylpyrrole-2-amido}-1-methylimidazol-2-amido)-1-methylpyrrole-2-amido]-1-methylpyrrole-2-carboxylate (1.00 g) was used and 400.00 mg of the desired product was obtained as a white solid (39.16% yield). LC / MS: C 51 H 61 N 19 O 12 Calculated mass: 1131.47, found: 1132.65 [M+H] + .

[0877] Synthesis of Representative Compounds of the Invention

[0878] Example 9. Synthesis of Compound B-1

[0879] Process 9.

[0880]

[0881] To 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-methyl-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)propionamido)-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)butanamido)-1H-imidazole-2-carboxamido)propionamido)-1H-pyrrole-2-carboxamido)-1H-imidazole-2-carboxamido)propanoic acid (intermediate polyamide (PA-04)) (1.00 equiv) in DMF (3.00 mg) were added propan-1-amine (1.05 equiv), PyBOP (1.20 equiv) and DIEA (2.94 equiv); and the resulting mixture was stirred at room temperature for 1.0 h. The reaction mixture was purified by preparative HPLC to give 49.00 mg of the desired product as a white solid (25.17% yield). HRMS: C 54 H 68 N 22 O 11 Calculated mass: 1200.5438, found: 1201.5473 [M+H] + .

[0882] Example 10. Synthesis of Compound B-3

[0883] Process 10.

[0884]

[0885] Step 1: The procedure was the same as in Example 9 (Compound B-1). 3-[(4-{4-[3-({4-[(2R)-2-[(tert-butoxycarbonyl)amino]-4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]-1-methylimidazol-2-yl}formamido)propionamido]-1-methylpyrrole-2-amido}-1-methylimidazol-2-yl)formamido]propanoic acid (20.00 mg) was used to give 20.00 mg of the desired product as a white solid (96.88% yield). LC / MS: C 59 H 77 N 23 O 13 Calculated mass: 1315.61, found: 1316.70 [M+H] + .

[0886] Step 2: The procedure was the same as in Example 2, Step 16, except that the crude product was purified by preparative HPLC. Tert-butyl N-[(1R)-1-[(1-methyl-2-{[2-({1-methyl-5-[(1-methyl-2-{[2-(propylcarbamoyl)ethyl]carbamoyl}imidazol-4-yl)carbamoyl]pyrrol-3-yl}carbamoyl)ethyl]carbamoyl}imidazol-4-yl)carbamoyl]-3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)propyl]carbamate (20.00 g) was used, and 6.10 mg of the desired product was obtained as a white solid (32.53% yield). HRMS: C 54 H 69 N 23 O 11 Calculated mass: 1215.5547, found: 1216.5581 [M+H] + .

[0887] Example 11. Synthesis of Compound B-79

[0888] Process 11.

[0889]

[0890] The synthesis was the same as in Example 9 (Compound B-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-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazol-2-yl}formamido)propionamido]pyrrol-2-amido}imidazol-2-yl)formamido]propanoic acid (120.00 mg) was used to give 60.60 mg of the desired product as a white solid (37.83% yield).

[0891] Example 12. Synthesis of Compounds B-29 and B-156

[0892] Process 12.

[0893]

[0894] Step 1: To a 250 ml flask was added tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (4.00 g, 14.85 mmol, 1.00 equiv), DMF (80 mL), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (4.00 g, 14.85 mmol, 1.00 equiv) and K2CO3 (10.26 g, 74.24 mmol, 5.00 equiv) and stirred at 80 ° C for 17.0 hours. The reaction was quenched with ice water (300 mL) and the precipitated solid was collected by filtration, washed with water (3×50 mL) and dried under vacuum. tert-Butyl 4-[1-(4-nitrophenyl)piperidin-4-yl]piperazine-1-carboxylate (4.7 g, crude) was obtained as a yellow solid. LC / MS: C 20 H 30 Calculated mass of N4O4: 390.23, found: 391.20 [M+H] + .

[0895] Step 2: The procedure was the same as in Example 2, except that the reaction time was 4.0 hours. 4-[1-(4-nitrophenyl)piperidin-4-yl]piperazine-1-carboxylic acid tert-butyl ester (1.00 g) was used to obtain 0.70 g of the desired product as a yellow oil (94.14% yield). LC / MS: C 15 H 22 Calculated mass of N4O2: 290.17, found: 291.15 [M+H] + .

[0896] Step 3: Synthesis of compound B-29. The procedure was the same as in Example 9, except that the reaction time was 2.0 hours, and the reaction mixture was purified by preparative HPLC. 1-[1-(4-nitrophenyl)piperidin-4-yl]piperazine (30.03 mg) was used, and 20.10 mg of the desired product was obtained as a yellow solid (19.67% yield). HRMS: C 66 H 81 N 25 O 13 Calculated mass: 1431.6446, found: 1432.6538 [M+H] + .

[0897] Step 4: Synthesis of Compound 156. The procedure was the same as for ethyl 4-amino-1-methylimidazole-2-carboxylate (Example 1). 1-Methyl-4-{1-methyl-4-[3-({1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazol-2-yl}formamido)propionamido]pyrrol-2-amido}-N-(3-{4-[1-(4-nitrophenyl)piperidin-4-yl]piperazin-1-yl}-3-oxopropyl)imidazole-2-carboxamide (17.00 mg) was used to give 7.90 mg of the desired product as an off-white solid (47.34% yield). HRMS: C 66 H 83 N 25 O 11 Calculated mass: 1401.6704, found: 1402.6823 [M+H] + .

[0898] Example 13. Synthesis of Compound B-367

[0899] Process 13.

[0900]

[0901] The procedure was the same as for N-(5-{[(3R)-3-amino-3-[(1-methyl-2-{[2-({1-methyl-5-[(1-methyl-2-{[2-(propylcarbamoyl)ethyl]carbamoyl}imidazol-4-yl)carbamoyl]pyrrol-3-yl}carbamoyl)ethyl]carbamoyl}imidazol-4-yl)carbamoyl]propyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazole-2-carboxamide (Example 10). HRMS: C 48 H 64 N 20 Calculated mass of O9: 1064.5165, found: 1065.5226 [M+H] + .

[0902] Example 14. Synthesis of Compound B-127

[0903] Process 14.

[0904]

[0905] Step 1: A mixture of 4-formylpiperidine-1-carboxylic acid benzyl ester (2.00 g, 8.09 mmol, 1.00 equiv) and piperazine-1-carboxylic acid tert-butyl ester (1.51 g, 8.08 mmol, 1.00 equiv) in DCM (20 mL) was stirred at room temperature for 30 minutes. NaBH(OAc) 3 (1.71 g, 8.08 mmol, 1.00 equiv) was then added, and the resulting mixture was stirred at room temperature for 16.0 hours. Next, the mixture was washed with 2×30 mL of NaOH aqueous solution (2 M), 2×30 mL of HCl aqueous solution (2 M), and 2×30 mL of brine. The washed mixture was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 2.70 g of the desired product as a yellow solid (79.95% yield). LC / MS: C 23 H 35 Calculated mass of N3O4: 417.26, found: 418.15 [M+H] + .

[0906] Step 2: The procedure was the same as in Example 1, except that the reaction time was 16.0 hours. 4-({1-[(benzyloxy)carbonyl]piperidin-4-yl}methyl)piperazine-1-carboxylic acid tert-butyl ester (3.00 g) was used to obtain 1.40 g of the desired product as a yellow solid (68.75% yield). LC / MS: C 15 H 29 Calculated mass of N3O2: 283.23, found: 284.15 [M+H] + .

[0907] Step 3: The procedure was the same as in Example 9 (Compound B-1), except that the reaction time was 2.0 hours. 4-(Piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (120.00 mg) was used to obtain 270.00 mg of the desired product as a yellow solid (44.73% yield). LC / MS: mass calculated, LC / MS: C 66 H 88 N 24 O 13 Calculated mass: 1424.70, found: 1425.50 [M+H] + .

[0908] Step 4: The procedure was the same as in Example 2, Step 12, except that the reaction time was 2.0 hours and the reaction mixture was purified by preparative HPLC. 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-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazol-2-yl}formamido)propionamido]pyrrol-2-amido}imidazol-2-yl)formamido]propionyl}piperidin-4-yl)methyl]piperazine-1-carboxylate (250.00 mg) was used to give 5.70 mg of the desired product as a light yellow solid (2.45% yield). LC / MS: calculated mass, HRMS: C 61 H 80 N 24 O 11 Calculated mass: 1324.64, found: 1325.65 [M+H] + .

[0909] Example 15. Synthesis of Compounds B-126, B-378 and B-379

[0910] Process 15.

[0911]

[0912] Step 1: To a stirred solution of CuCl (9.07 mg, 0.09 mmol, 0.20 equiv) in BuNH2 (0.50 mL) and H2O (1.50 mL) was added NH2OH.HCl (63.65 mg, 0.912 mmol, 2.00 equiv). The mixture was stirred at room temperature for 15 minutes, and then tert-butyl 4-(2-iodoethynyl)piperidine-1-carboxylate (153.51 mg, 0.46 mmol, 1.00 equiv) and 4-ethynylpiperidine (50.00 mg, 0.46 mmol, 1.00 equiv) in BuNH2 (0.50 mL) were added at 0°C. The resulting mixture was stirred at room temperature for 2.0 hours. The reaction mixture was then diluted with H2O (5.00 mL) and extracted with EA (3 x 2.00 mL). The combined organic layers were washed with NaCl (2.00 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (15:1) to give tert-butyl 4-[4-(piperidin-4-yl)but-1,3-diyn-1-yl]piperidine-1-carboxylate (122.00 mg, 74.08%) as a brown solid. LC / MS: C 19 H 28Calculated mass of N2O2: 316.22, found: 317.10 [M+H] + .

[0913] Step 2: Synthesis of compound B-378. The procedure is the same as Example 9 (Compound B-1). After the reaction, the mixture is poured into ice water, and the resulting solid is 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-amide)pyrrol-2-yl]formamido}propionamido)imidazol-2-amide]pyrrol-2-yl}formamido)butanamido]imidazol-2-yl}formamido)propionamido]pyrrole-2-amide}imidazol-2-yl)formamido]propionic acid (100.00 mg), 90.00 mg of the desired product (50.58% yield) is obtained as a white solid. HRMS: C 68 H 86 N 24 O 12 Calculated mass: 1457.6854, found: 1458.6929 [M+H] + .

[0914] Step 3: Synthesis of Compound B-126. The procedure was the same as in Example 2, Step 16, but the crude material was purified by preparative HPLC. 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-methylimidazol-2-amide)pyrrol-2-yl]formamido}propionamido)imidazol-2-amide]pyrrol-2-yl}formamido)butanamido]imidazol-2-yl}formamido)propionamido]pyrrol-2-amide}imidazol-2-yl)formamido]propionyl}piperidin-4-yl)butan-1,3-diyn-1-yl]piperidine-1-carboxylic acid tert-butyl ester (80.00 mg) was used to give 25.20 mg of the desired product as a yellow solid. HRMS: C 65 H 79 N 23 O 11 Calculated mass: 1357.6329, found: 1358.6396 [M+H] + .

[0915] Step 4: Synthesis of Compound B-379 The procedure was the same as in Example 5, Step 2, and the obtained solid was purified by preparative HPLC. Using 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)-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-diyn-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 (16.19% yield). HRMS: C 67 H 81 N 23 O 12 Calculated mass: 1399.6435, found: 1400.6460 [M+H] + .

[0916] Example 16. Synthesis of Compound B-137

[0917] Process 16.

[0918]

[0919] Step 1: The procedure was the same as in Example 2, Step 16. 4-(2-iodoethynyl)piperidine-1-carboxylic acid tert-butyl ester (2.80 g) was used to obtain 2.80 g of a crude product as a yellow solid. LC / MS: C7H 10 Calculated mass of IN: 234.99, found: 235.95 [M+H] + .

[0920] Step 2: The procedure was the same as for tert-butyl 4-[4-(piperidin-4-yl)butan-1,3-diyn-1-yl]piperidine-1-carboxylate (Example 15, Step 1), but the crude product was used directly in the next step. 4-(2-iodoethynyl)piperidine (500.00 mg) was used to give 400.00 mg of the desired product as a yellow solid. LCMS: C 15 H 22 Calculated mass of N2O2: 262.17, found: 263.30 [M+H] + .

[0921] Step 3: A solution of tert-butyl N-[5-(piperidin-4-yl)pentan-2,4-diyn-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 hours. 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 NaSO. 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-diyn-1-yl}piperidine-1-carboxylate (110.00 mg, 45.81% yield) as a white oil. LCMS: C 30 H 32 Calculated mass of N2O4: 484.24, found: 485.25 [M+H] + .

[0922] Step 4: The procedure was the same as in Example 2, Step 16. 9H-fluoren-9-ylmethyl 4-{5-[(tert-butoxycarbonyl)amino]penta-1,3-diyn-1-yl}piperidine-1-carboxylate (110.00 mg) was used to obtain 110.00 mg of the desired product as a yellow oil. LCMS: C 25 H 24 Calculated mass of N2O2: 384.18, found: 385.25 [M+H] + .

[0923] Step 5: 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-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazol-2-yl}formamido)propionamido]pyrrol-2-amido}imidazol-2-yl)formamido]propanoic acid (270.00 mM) was added. g, 0.23 mmol, 0.81 equiv) and 9H-fluoren-9-ylmethyl 4-(5-aminopentan-1,3-diyn-1-yl)piperidine-1-carboxylate (110.00 mg, 0.29 mmol, 1.00 equiv), PyBOP (150.00 mg, 0.29 mmol, 1.01 equiv) and DIEA (160.00 mg, 1.24 mmol, 4.33 equiv) in DMF (3.00 mL) were stirred at room temperature for 1.0 hour. Piperidine (1.0 mL) was then added, and the reaction mixture was stirred at room temperature for an additional 1.0 hour. The reaction was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN / water (0.05% TFA), gradient from 5% to 48% 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.

[0924] The crude product (70 mg) was purified by preparative HPLC using 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 to 44% B, 44% B in 10 min; Wavelength: 254 nm; RT1 (min): 9.72. The fractions were combined and lyophilized to give 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)-N-(1-methyl-5-{[3-({1-methyl-2-[(2-{[1-methyl-5-({1-methyl-2-[(2-{[5-(piperidin-4-yl)pentan-2,4-diyn-1-yl]carbamoyl}ethyl)carbamoyl]imidazol-4-yl}carbamoyl)pyrrol-3-yl]carbamoyl}ethyl)carbamoyl]imidazol-4-yl}carbamoyl)propyl]carbamoyl}pyrrol-3-yl)imidazole-2-carboxamide (12.60 mg, 18.00 yield) as a white solid. HRMS (ESI): C 61 H 73 N 23 O 11Calculated mass: 1303.5860, found: 1304.5942 [M+H] + .

[0925] Example 17. Synthesis of Compound B-150

[0926] Process 17.

[0927]

[0928] Step 1: 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) was added 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) at room temperature. The resulting mixture was stirred at room temperature for 4.0 hours. Pd / C was then filtered off, and the resulting mixture was quenched with water (100 mL), extracted with EA (100 mL), and the aqueous phase was adjusted to pH 3 to 5 with 2M HCl and then extracted with EA (3*100 ml). The organic phases were combined, washed with NaCl solution (100 mL), dried over Na2SO4 (filtered off), and concentrated. (2S)-2-[(tert-Butoxycarbonyl)amino]-5-(2,2,2-trifluoroacetamido)pentanoic acid (12.00 g crude material) was obtained as an orange oil. LC / MS: C 12 H 19 Calculated mass of F3N2O5: 328.12, Found: 351.10 [M+Na] + .

[0929] 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) was added 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) at room temperature. The resulting mixture was stirred at room temperature for 4.0 hours. Pd / C was then filtered off, and the resulting mixture was quenched with water (100 mL), extracted with EA (100 mL), and the aqueous phase was adjusted to pH = 3 to 5 by 2M HCl, then extracted with EA (3×100 ml), the organic phases were combined and washed with NaCl solution (100 mL), dried over Na2SO4 (filtered off), and the organic phase was concentrated. (2S)-2-[(tert-Butoxycarbonyl)amino]-5-(2,2,2-trifluoroacetamido)pentanoic acid was obtained as an orange oil (12.00 g crude material).

[0930] 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 and allowed to warm 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 allowed to warm 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 (2S)-2-{[(2,2-dimethylpropanoyl)oxy]amino}-5-(2,2,2-trifluoroacetamido)pentanoic acid benzyl ester (780.00 mg, 52.22%) as a yellow oil. LC / MS: C 19 H 25 Calculated mass of F3N2O5: 418.17, Found: 441.30 [M+Na] + .

[0931] Step 4: The procedure was the same as in Example 2, except that the solvent used was CH2Cl2. (2S)-2-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroacetamido)pentanoic acid benzyl ester (700.00 mg) was used to obtain 440.00 mg of the desired product as a brown oil. LC / MS: C 14 H 17 Calculated mass of F3N2O3: 318.12, found: 319.30 [M+H] + .

[0932] 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. (2S)-2-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroacetamido)pentanoic acid (477.00 mg) was used to obtain 550.00 mg of the desired product as a white solid (34.37% yield).

[0933] 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 under an atmosphere of H for 17.0 hours. 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 of F6N4O7: 538.19, Found: 561.35 [M+Na] + .

[0934] 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 (65.27% yield). LC / MS: C 23 H 36 Calculated mass of F6N8O6: 634.27, Found: 657.30 [M+Na] + .

[0935] 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 (467.66 mg, 4.41 mmol, 10.00 equiv). The reaction was then stirred at 55°C for 17.0 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN / water (0.05% NH4HCO3), gradient from 10% to 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-carbamoylbutyl]carbamoyl}-4-carbamoylbutyl]carbamate as a colorless oil (230.00 mg, 98.98% yield). LC / MS: C 21 H 42 N 12 Calculated mass of O4: 526.34, found: 527.35 [M+H] + .

[0936] Step 9: The procedure was the same as in Example 2, Step 16. Using tert-butyl N-[(1S)-1-{[(1S)-1-[(4-azidobutyl)carbamoyl]-4-carbamoylbutyl]carbamoyl}-4-carbamoylbutyl]carbamate (60.00 mg), 60.00 mg of the desired product was obtained as a crude brown oil. LC / MS: C 16 H 34 N 12 Calculated mass of O2: 426.29, found: 427.50 [M+H] + .

[0937] Example 18. Synthesis of Compound B-76

[0938] Process 18.

[0939]

[0940] The procedure was the same as Example 5, Step 2, and the obtained crude material was purified by preparative HPLC. Using N-{5-[(3-{[2-({2-[(5-{[2-({2-[(17-amino-3,6,9,12,15-pentaoxaheptadecan-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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazole-2-carboxamide (500.00 mg), 158.90 mg of the desired product was obtained as a white solid (30.30% yield). HRMS: C 65 H 89 N 23 O 17 Calculated mass: 1463.6807, found: 1464.6862 [M+H] + .

[0941] Example 19. Synthesis of Compound B-296

[0942] Process 19.

[0943]

[0944] Step 1: The procedure was the same as for 1-methyl-4-[4-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)butanamido]imidazole-2-carboxylic acid ethyl ester (Example 2, Step 9). Using 3-({4-[4-(3-{[4-(4-{[1-(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl)-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl]formamido}butanamido)-1-methylimidazol-2-yl]formamido}propionamido)-1-methylpyrrol-2-amido]-1-methylimidazol-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 Calculated mass: 1530.74, found: 766.75 [M / 2+H] + .

[0945] Step 2: The procedure was the same as for compound B-1 in Example 9. Using 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} The mixture was stirred at 4 ℃ for 2 hours. The mixture was stirred at 4 ℃ for 3 hours. The mixture was stirred at 4 ℃ for 3 hours. The mixture was stirred at 4 ℃ for 3 hours. The mixture was stirred at 4 ℃ for 4 hours. The mixture was stirred at 4 ℃ for 5 hours. The mixture was stirred at 4 ℃ for 3 hours. The mixture was stirred at 4 ℃ for 5 hours. 75 H 96 N 24 O 15 Calculated mass: 1572.75, found: 787.65 [M / 2+H] + .

[0946] Step 3: The procedure was the same as in Example 2, Step 16, except that the reaction mixture was purified by preparative HPLC. N-{2-[2-(2-{[3-({2-[(2-{[5-({2-[(3-{4-[4-(1-acetylpiperidin-4-yl)butan-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

[0366] The mixture was stirred at 40 ℃ for 2 h. The mixture was stirred at 40 ℃ for 30 min. The mixture was stirred at 40 ℃ for 30 min. The mixture was stirred at 40 ℃ for 30 min. The mixture was stirred at 40 ℃ for 40 min ... 70 H 88 N 24 O 13 Calculated mass: 1472.6963, found: 1473.7025 [M+H] + .

[0947] Example 20. Synthesis of Compound B-435

[0948] Process 20.

[0949]

[0950] Step 1: To a stirred solution of (1-ethoxycyclopropyloxy)trimethylsilane (10.00 g, 57.37 mmol, 1.00 equiv) in toluene (100.00 mL) was added ethyl 2-(triphenyl-λ5-phosphinoyl)acetate (19.98 g, 57.37 mmol, 1.00 equiv) and benzoic acid (7.00 g, 57.37 mmol, 1.00 equiv) at room temperature. The reaction mixture was stirred at 90 ° C for 2.0 hours. The solid was filtered off. The filtrate was concentrated in vacuo to remove a portion of the solvent. The resulting mixture was used directly in the next step without further purification. LC / MS: C7H 10 Calculated mass of O2: 126.07, found: 127.10 [M+H] + .

[0951] Step 2: At 0 ° C, CH3NO2 (4.01 mL, 74.83 mmol, 2.36 equiv) and DBU (1.99 mL, 13.32 mmol, 0.42 equiv) were added dropwise to a stirred mixture of crude ethyl 2-cyclopropylidene acetate. The reaction mixture was stirred at room temperature for 6.0 hours. 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] ethyl acetate (3.00 g, 50.54%) as a light yellow oil. LC / MS: CH 13 Calculated mass of NO4: 187.08, Found: 188.20 [M+H] + .

[0952] 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 under a hydrogen atmosphere for 6.0 hours. The resulting mixture was filtered and the filter cake was washed with EtOH (10 mL x 5). The filtrate was concentrated under reduced pressure to give ethyl 2-[1-(aminomethyl)cyclopropyl]acetate (1.50 g, 59.54%) as a light yellow oil. LC / MS: CH 15 Calculated mass of NO2: 157.11, Found: 158.15 [M+H] + .

[0953] 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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]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 x 3). The combined organic layers were washed with water (30 mL x 3) and dried over anhydrous NaSO. 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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-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 of O7: 703.32, found: 704.25 [M+H] + .

[0954] Step 5: To a stirred mixture of ethyl 2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]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 2 M LiOH in water (2 M, 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 to 5 with 2 M HCl at 0°C. The precipitated solid was collected by filtration, washed with H2O (3×30 mL), and dried under vacuum. The desired product {1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]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 of O7: 675.29, found: 338.85 [M / 2+H] + .

[0955] Step 6: To a stirred mixture of {1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]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 in vacuo. The precipitated solid was collected by filtration and washed with water (30 mL×3), and dried in vacuo to give 1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazole-2-carboxylic acid ethyl ester (600.00 mg, 50.65%) as a pale yellow solid. LC / MS: C 38 H 46 N 14 Calculated mass of O8: 826.36, found: 827.40 [M+H] + .

[0956] Step 7: To a stirred mixture of ethyl 1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]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 2 M 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 HO (10 mL). The mixture was acidified to pH 3 to 5 with 2 M HCl at 0 °C. The precipitated solid was collected by filtration and washed with water (5 mL×5), and dried in vacuo to give 1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]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 of O8: 798.33, found: 799.35 [M+H] + .

[0957] Step 8: To 1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazole-2-carboxylic acid (170.00 mg, 0.21 mmol, 1.00 equiv), 4-[ ...carboxylic acid (170.00 mg, 0.21 mmol, 1.00 equiv)] To a stirred mixture of ethyl-[4-(3-aminopropionamido)-1-methylpyrrole-2-amido]-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). 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 x 3) and dried under vacuum. 1-Methyl-4-[1-methyl-4-(3-{[1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazol-2-yl]formamido}propionamido)pyrrol-2-amido]imidazole-2-carboxylic acid ethyl ester (200.00 mg, 82.21%) was obtained as a pale yellow solid. LC / MS: C 52 H 62 N 20 O 11 Calculated mass: 1142.49, found: 1143.50 [M+H] + .

[0958] 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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazol-2-yl]formamido}propionamido)pyrrol-2-amido]imidazole-2-carboxylate (180.00 mg, 0.16 mmol, 1.00 equiv) in MeOH (2.00 mL) and THF (10.00 mL) was added 2M LiOH in water (2.38 mL, 4.77 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 to 5 with 2M HCl at 0°C. The precipitated solid was collected by filtration and washed with water (5 mL×5) and dried in vacuo 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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazol-2-yl]formamido}propionamido)pyrrole-2-amido]imidazole-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: 1114.46, found: 1115.50 [M+H] + .

[0959] Step 10: To 1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(2-{1-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]cyclopropyl}acetamido)imidazol-2-yl]formamido}propionamide To a stirred mixture of [[N-([ ... B; wavelength: 254 nm; RT1 (min): 12; number of runs: 4) to give 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)-N-[1-methyl-5-({[1-({[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)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: 1155.5223, found: 1156.5264 [M+H] + . HPLC: 99.190% purity.

[0960] Example 21. Synthesis of Compound B-439

[0961] Process 21.

[0962]

[0963] Step 1: At room temperature, 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-phosphinoyl)acetate (10.17 g, 29.21 mmol, 1.00 equiv) in portions. The reaction mixture was stirred at room temperature for 16.0 hours. The reactant was subsequently quenched by adding 40 mL of water. The resulting solution was extracted with CH2Cl2 (50 mL × 3). The organic layers were combined, washed with sodium carbonate (aqueous solution) (50 mL × 2) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was applied to 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 of NO4: 241.13, Found: 242.20 [M+H] + . 1 HNMR (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).

[0964] 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) in portions at room temperature. The reaction mixture was stirred at room temperature for 16.0 hours. The resulting mixture was concentrated in vacuo. EA (30 mL) was added to the mixture. The resulting mixture was washed with 0.5N 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 of N2O6: 302.15, Found: 247.10 [M-56+H] + .

[0965] 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) was added Pd / C (1.00 g, 26% w / w) and TFA (0.10 mL) at room temperature. The flask was evacuated and flushed three times with nitrogen, followed by hydrogen. The mixture was stirred under a hydrogen atmosphere at room temperature for 16.0 hours. 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. tert-butyl 3-(aminomethyl)-3-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate (3.70 g, crude) was obtained as a colorless oil. LC / MS: C 13 H 24 Calculated mass of N2O4: 272.17, found: 273.05 [M+H] + .

[0966] 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 equiv) and 1-methyl-4-[1-methyl-4-(3-{[1-methyl-5-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrole-2-carboxylic acid (1.57 g, 2.78 mmol, 1.00 equiv) in DMF (20.00 mL) was added PyBOP (1.88 g, 3.62 mmol, 1.30 equiv) and DIEA (0.90 g, 6.95 mmol, 2.50 equiv) 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 x 3) and dried in vacuo. 3-{[(4-{4-[3-({5-[2-(dimethylamino)acetamido]-1-methylpyrrol-2-yl}formamido)propionamido]-1-methylimidazol-2-amide}-1-methylpyrrol-2-yl)formamido]methyl}-3-(2-ethoxy-2-oxoethyl)azetidine-1-carboxylic acid tert-butyl ester (2.00 g, 72.29%) was obtained as a yellow solid. LC / MS: C 38 H 50 N 12 Calculated mass of O9: 818.38, found: 819.50 [M+H] + .

[0967] Step 5: To a stirred solution of ethyl 3-{[4-(4-{3-[(4-{4-[(4-{4-[(2S)-2-hydroxy-3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido]-1-methylimidazol-2-amido}-1-methylpyrrol-2-yl)formamido]butanamido}-1-methylimidazol-2-yl)formamido]propionamido}-1-methylpyrrol-2-amido)-1-methylimidazol-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 2M 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 solvent was removed under reduced pressure. The residue was dissolved in H2O (20 mL). The mixture was acidified to pH 3 to 5 with 2M HCl at 0°C. The precipitated solid was collected by filtration and washed with H2O (3×30 mL) and dried in vacuo. 3-{[4-(4-{3-[(4-{4-[(2S)-2-hydroxy-3-{[1-methyl-4-(1-methylimidazol-2-amide)pyrrol-2-yl]formamido}propionamido]-1-methylimidazol-2-amide}-1-methylpyrrol-2-yl)formamido]butanamido}-1-methylimidazol-2-yl)formamido]propionamido}-1-methylpyrrole-2-amide)-1-methylimidazol-2-yl]formamido}propionic acid (1.50 g, 81.68%) was obtained as a yellow solid. LC / MS: C 36 H 46 N 12 Calculated mass of O9: 790.35, found: 791.45 [M+H] + .

[0968] Step 6: To a stirred mixture of [1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]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 containing DMF (22 mL) was purified by reverse phase column under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% TFA), gradient from 10% to 50% in 10 min; detector, UV 254 nm. 4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazole-2-carboxylic acid ethyl ester (1.50 g, 82.01%) was obtained as a yellow oil. LC / MS: C 43 H 55 N 15 O 10 Calculated mass: 941.43, found: 942.60 [M+H] + .

[0969] 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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazole-2-carboxylate (1.45 g, 1.54 mmol, 1.00 equiv) in MeOH (2.00 mL) and THF (10.00 mL) was added 2M LiOH in water (4.62 mL, 9.23 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 purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% TFA), gradient from 10% to 50% over 10 min; detector, UV 254 nm. 4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazole-2-carboxylic acid (1.30 g, 86.09%) was obtained as a yellow oil. LC / MS: C 41 H 51 N 15 O 10 Calculated mass: 913.39, found: 914.50 [M+H] + .

[0970] Step 8: To 4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazole-2-carboxylic acid (1.30 g, 1.42 mmol, 1 To a stirred mixture of ethyl 4-[4-(3-aminopropionamido)-1-methylpyrrole-2-amido]-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 hours. The reaction mixture was filtered, and the filtrate containing DMF (20.0 mL) was purified by reverse phase column using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% TFA), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. The fractions were combined and concentrated in vacuo. Ethyl 4-(4-{3-[(4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazol-2-yl)formamido]propionamido}-1-methylpyrrole-2-amido)-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: 1257.55, found: 630.10 [M / 2+H] + .

[0971] 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-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazol-2-yl)formamido]propionamido}-1-methylpyrrole-2-amido)-1-methylimidazole-2-carboxylate (1.00 g, 0.80 mmol, 1.00 equiv) in MeOH (5.00 mL) and THF (25.00 mL) was added 2M LiOH in water (2.38 mL, 4.77 mmol, 6.00 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure. The residue was purified by reverse phase column using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% TFA), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. 4-(4-{3-[(4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazol-2-yl)formamido]propionamido}-1-methylpyrrole-2-amido)-1-methylimidazole-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: 1229.52, found: 1230.55 [M+H] + .

[0972] Step 10: To 4-(4-{3-[(4-{2-[1-(tert-butoxycarbonyl)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]azetidin-3-yl]acetamido}-1-methylimidazol-2-yl)formamido]propionamido} To a stirred mixture of 1-methylpyrrole-2-amido)-1-methylimidazole-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). The reaction mixture was stirred at room temperature for 1.0 h. The reaction mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% TFA), 10% to 50% gradient over 10 min; detector, UV 254 nm. The fractions were combined and concentrated in vacuo. Tert-butyl 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)-3-[({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propionamido)imidazol-2-amido]pyrrol-2-yl}formamido)methyl]azetidine-1-carboxylate (40.00 mg, 46.53%) was obtained as a yellow oil. LC / MS: C 58 H 74 N 22 O 12 Calculated mass: 1270.59, found: 1271.65 [M+H] + .

[0973] Step 11: To 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- To a mixture of tert-butyl 4-(1-methyl-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)propionamido)-1H-imidazole-2-carboxamido)-1H-pyrrole-2-carboxamido)methyl)azetidine-1-carboxylate (35.00 mg, 0.03 mmol, 1.00 equiv) in CHCl (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 was purified by preparative HPLC using 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 to 31% B in 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-amido)pyrrol-2-yl]formamido}propionamido)-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)azetidin-3-yl]methyl}carbamoyl)pyrrol-3-yl]imidazole-2-carboxamide (2.20 mg, 6.39%) as a white solid. HRMS: C 53 H 66 N 22 O 10 Calculated mass: 1170.5332, found: 1171.5489 [M+H] + . HPLC: 93.582% purity.

[0974] Example 22. Synthesis of other compounds of the present invention

[0975] The compounds of the present application were prepared by methods analogous to Examples 1 to 22. A summary of the analytical data is presented in Table 3.

[0976] Table 3. Mass spectral data for compounds of the present disclosure.

[0977]

[0978]

[0979]

[0980]

[0981]

[0982] Biological Examples

[0983] Example B-1.EC 50 analyze

[0984] DM1 lesion reduction analysis method

[0985] Myotonic dystrophy type 1 patient fibroblasts (Coriell GM04602; 1600 CTG repeats) and wild-type fibroblasts (Coriell GM07492; control cells) were cultured in Gibco DMEM (1×) supplemented with 10% FBS and 1× penicillin / streptomycin, plus 4.5 g / L D-glucose, L-glutamine, and 110 mg / L sodium pyruvate. Cells were maintained in an incubator at 37°C and 5% CO2, with the medium refreshed every 48 to 72 hours.

[0986] Both cell lines were harvested using Tryp1-E at 90-95% confluence, pelleted at 500 × g for 5 minutes, and resuspended in fresh culture medium. DM1 fibroblasts were seeded in 200 μL of culture medium at a density of 5,000 cells / well in Agilent 96-well black culture plates; 8 wells were reserved for control fibroblasts. The plates were returned to the incubator and incubated at 37°C and 5% CO₂ for 24 hours.

[0987] Compounds were diluted from a 10 mM stock solution to 1 mM in DMSO and then diluted again to 6 μM (2× concentration) in culture medium. Culture medium was removed from all plates and cells were supplemented with 100 μL of culture medium. Cells were treated with an 8-point dose response, 1:3 dilutions, and a top dose of 3 μM by adding 100 μL of 6 μM (2× concentration) compound to 100 μL of culture medium containing cells. The plates were returned to the incubator and incubated for 48 hours at 37°C and 5% CO2.

[0988] After treatment, the compound was removed and the culture dish was washed with PBS, and then the cells were fixed in 75 μL of 4% PFA solution for 20 minutes at room temperature. The culture dish was washed twice with PBS and twice with 70% cold ethanol, and then permeabilized with 250 μL of 70% cold ethanol at -20°C for 24 to 72 hours.

[0989] After permeabilization, the plates were washed once with 30% formamide and 2×SSC buffer and rehydrated in the buffer for 15 minutes at room temperature. The cells were incubated overnight at 37° C. in 75 μL of hybridization solution containing 30% formamide, 2×SSC, 25 mg / mL dextran sulfate, 2.5 mg / mL BSA, 0.2 μg / mL herring sperm DNA, 2 mM vanadyl ribonucleoside complex, and 5 nM CAG10-Cy3 probe.

[0990] The culture dish was washed once with 2×SSC buffer containing 30% formamide, then washed twice with buffer and incubated at 37°C, 300 RPM for 30 minutes on a shaker. The cells were stained with 75 μL of 2.5 μg / mL DAPI in PBS for 5 minutes at room temperature. The dish was then washed twice with PBS and stored in 250 μL of PBS. The dish was sealed with adhesive foil and wiped with 70% ethanol.

[0991] Cells sampled from four areas of each well were imaged on a Cytation 5 with a 20× objective. Nuclei were captured in the DAPI channel, and foci were captured in the RFP channel. Plates were analyzed based on the average foci per nucleus per well. Active compounds were defined as those that showed a significant reduction in foci per nucleus in a dose-response manner compared to negative control cells.

[0992] Lesion reduction in FECD

[0993] F35T cells were cultured in a medium containing Opti-MEM (ThermoFisher) supplemented with 8% FBS, 20 μg / mL ascorbic acid, 200 mg / mL CaCl2, 0.08% chondroitin sulfate, 1× penicillin / streptomycin, 100 μg / mL bovine pituitary extract, 5 ng / mL epidermal growth factor, and 20 ng / mL nerve growth factor. During the entire culture period, the cells were maintained in an incubator at 37°C and 5% CO2. The culture medium was refreshed every 48 hours. Once the cells reached sufficient confluence, they were harvested and seeded in 96-well culture plates at a density of 5000 cells / well in 200 μL of supplemented Opti-MEM medium. The cells were returned to the incubator and allowed to stand at 37°C and 5% CO2 for 24 hours. The cells were then treated with compounds or negative controls in an 8-point dose response and incubated at 37°C and 5% CO2 for 48 hours. After treatment, cells were fixed with 4% PFA for 20 minutes at room temperature, followed by permeabilization with 70% ethanol. Cells were incubated at -20°C for a minimum of 1 hour and a maximum of 72 hours, after which the ethanol was removed and the cells washed with PBS. Cells were rehydrated with 30% formamide and 2×SSC buffer for 10 minutes at room temperature. Cells were then incubated overnight at 37°C in a hybridization solution containing 30% formamide, 2×SSC, 55 mg / mL dextran sulfate, 2.75 mg / mL bovine serum albumin, 0.2 μg / mL herring sperm DNA, 1% vanadyl ribonucleoside complex, and 0.05% 10 μM CAG10-Cy3 probe. Cells were washed twice with 2×SSC containing 30% formamide and incubated while shaking the second wash solution at 37°C and 200 rpm for 60 minutes. Cells were stained with 5 mg / mL DAPI (1:1000) in PBS for 5 minutes at room temperature. The cells were then washed with PBS and sealed with adhesive foil, with each well containing 150 μL of PBS in a final volume. Cells were imaged on a Cytation 5 and analyzed based on foci per nucleus. Active compounds were defined as those that showed a significant reduction in foci per nucleus compared to negative control cells in a dose-response manner.

[0994] 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.

[0995] Table 4. Representative biochemical data.

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, modifications, and substitutions may be contemplated by those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used to implement the present invention. It is intended that the following claims define the scope of the present invention and that methods and structures within the scope of these claims and their equivalents be encompassed thereby.

Claims

1. A transcriptional regulator molecule having a structure of formula (I) or a pharmaceutically acceptable salt thereof: in: W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl; Each Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are independently N or CH; L 1 C1-C 20 Alkylene or C2-C 20 heteroalkylene; Z is absent, -C(O)- or -C(=NH)-; R 4 C1-C6 alkyl, -OR 4b or -NR 4a R 4b ;in R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl; R 4b is an 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; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl; Each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace; Each R 3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in R 11a and R 11b Each is independently hydrogen, alkyl or PEG; R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; Each R 10 are 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; wherein R 10a and R 10b Each is independently hydrogen, alkyl or PEG; R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; and n1 and m1 are each independently 0 or 1.

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

3. A molecule according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each Y 1 , Y 3 and Y 6 For CH.

4. The molecule of claim 1, wherein the molecule or a pharmaceutically acceptable salt thereof has the structure of Formula (Ia): in: W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl; Each Y 5 are independently N or CH; L 1 C1-C 20 Alkylene or C2-C 20 heteroalkylene; Z is absent, -C(O)- or -C(=NH)-; R 4 C1-C6 alkyl, -OR 4b or -NR 4a R 4b ,in R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl; R 4b is an 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; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl; Each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace; Each R 3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in R 11a and R 11b Each is independently hydrogen, alkyl or PEG; R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; Each R 10 are 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, wherein R 10a and R 10b Each is independently hydrogen, alkyl or PEG; R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; and n1 and m1 are each independently 0 or 1.

5. A molecule according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L 1 C1-C 20 Alkylene or C2-C 20 heteroalkylene; Z is absent or -C(O)-; and R 4 For-NR 4a R 4b .

6. The molecule of claim 5, or a pharmaceutically acceptable salt thereof, wherein Z is absent.

7. The molecule of claim 5, or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)-.

8. A molecule according to any one of claims 5 to 7, or a pharmaceutically acceptable salt thereof, wherein L 1 C1-C 10 Alkylene.

9. The molecule according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein: R 4a is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl; and R 4b is an optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl.

10. The molecule according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R 4a is an optionally substituted C1-C 20 heteroalkyl; and R 4b is an optionally substituted C1-C 20 Heteroalkyl.

11. The molecule of claim 10, or a pharmaceutically acceptable salt thereof, wherein the heteroalkyl group is PEG 1-10 .

12. The molecule according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 4a is an optionally substituted C1-C6 alkyl group; and R 4b is an optionally substituted C1-C6 alkyl group.

13. The molecule according to claim 1, wherein the molecule or a pharmaceutically acceptable derivative thereof has a structure of formula (II): in: W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl; Each Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are independently N or CH; L 3 C1-C 20 Alkylene, C2-C 20 Heteroalkylene or (AA) 1-10 ;in Each AA is independently a naturally occurring amino acid; V is absent, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl; Each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace; Each R 3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in R 11a and R 11b Each is independently hydrogen, alkyl or PEG; R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; Each R 10 are 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; wherein R 10a and R 10b Each is independently hydrogen, alkyl or PEG; R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; n1 and m1 are each independently 0 or 1; and x1 is from 0 to 10.

14. The molecule according to claim 13, or a pharmaceutically acceptable salt thereof, wherein each Y 2 , Y 4 , Y 7 and Y 8 is N.

15. A molecule according to claim 13 or 14, or a pharmaceutically acceptable salt thereof, wherein each Y 1 , Y 3 and Y 6 For CH.

16. A molecule according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein each R 3b is hydrogen; and each R 3a are independently selected from hydrogen, -NR 11a R 11b and -NHC(O)R 12 .

17. A molecule according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein each R 3a is hydrogen; and each R 3b are independently selected from hydrogen, -NR 11a R 11b and -NHC(O)R 12 .

18. A molecule according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein each R 3a and each R 3b For hydrogen.

19. A molecule according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein both R 3a Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group; and each R 3b For hydrogen.

20. A molecule according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein both R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group; and each R 3a For hydrogen.

21. A molecule according to any one of claims 1 to 20, 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 are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C1-C 50 Haloalkyl or optionally substituted PEG 1-50 ; each of which is optionally replaced by one or more R 10 replace.

22. A molecule according to any one of claims 1 to 20, 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 are 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 ; each of which is optionally replaced by one or more R 10 replace.

23. A molecule according to any one of claims 1 to 20, 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 Independently C1-C 10 alkyl, each of which is optionally substituted by one or more R 10 replace.

24. A molecule according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein 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 replaced by one or more R 10 Replace; and R 2c , R 2e and R 2h Each of which is independently unsubstituted C1-C 10 alkyl.

25. The molecule according to claim 24, or a pharmaceutically acceptable salt thereof, wherein R 2c , R 2e and R 2h Each of them is a methyl group.

26. A molecule according to claim 24 or 25, or a pharmaceutically acceptable salt thereof, wherein each R 2a , R 2b and R 2g are independently unsubstituted C1-C 10 alkyl.

27. The molecule of claim 26, or a pharmaceutically acceptable salt thereof, wherein each R 2a , R 2b and R 2g It is methyl.

28. The molecule of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein n1 is 1.

29. The molecule of claim 13, wherein the molecule or a pharmaceutically acceptable salt thereof has the structure of Formula (IIa): in: W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl; Each Y 5 are independently N or CH; L 3 C1-C 20 Alkylene, C2-C 20 Heteroalkylene or AA 1-10 ;in Each AA is independently a naturally occurring amino acid; V is absent, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl; R 2d is hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace; R 3a is hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in R 11a and R 11b Each is independently hydrogen, alkyl or PEG; R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; Each R 10 are 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; wherein R 10a and R 10b Each is independently hydrogen, alkyl or PEG; R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; m1 is 0 or 1; and x1 is from 0 to 10.

30. A molecule according to any one of claims 13 to 29, or a pharmaceutically acceptable salt thereof, wherein V is optionally substituted C3-C8 cycloalkyl, optionally substituted 4 to 8 membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5 to 10 membered heteroaryl.

31. The molecule of claim 30, or a pharmaceutically acceptable salt thereof, wherein V is optionally substituted C3-C8 cycloalkyl or optionally substituted 4 to 8 membered heterocycloalkyl.

32. A molecule according to claim 30 or 31, or a pharmaceutically acceptable salt thereof, wherein V is an optionally substituted 4 to 8 membered heterocycloalkyl.

33. The molecule or pharmaceutically acceptable salt of claim 32 wherein V is piperazine, piperidine or morpholine.

34. The molecule according to any one of claims 13 to 29, or a pharmaceutically acceptable salt thereof, wherein V or a pharmaceutically acceptable salt thereof has the structure of formula (C): in: B 1 For-CR 5a R 5b -、-O-、-NR 5b -, -S-, -S(O)- or -S(O)2-; or B 1 for in R 5a is hydrogen, -OH or an optionally substituted C1-C 20 alkyl; R 5b is hydrogen, optionally substituted C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Heteroalkyl, -C(O)OR 6 or -C(O)R 6 ;or R 5a and R 5b together with the nitrogen atom to which it is attached, form an optionally substituted 4- to 8-membered heterocycloalkyl; R 6 is hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 10 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, or optionally substituted phenyl; Ring B is absent, is optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl; L 2 is absent, is C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene; and q1 and q2 are each independently 0, 1 or 2.

35. The molecule according to any one of claims 13 to 29, or a pharmaceutically acceptable salt thereof, wherein V or a pharmaceutically acceptable salt thereof has the structure of formula (C-1): in: Ring B is optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl; L 2 does not exist, is a C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene bond, alkylene or alkynylene; B 1 is CH or N; and q1 and q2 are each independently 0, 1 or 2.

36. The molecule of any one of claims 13 to 29, wherein V or a pharmaceutically acceptable salt thereof has the structure of formula (C-2): in: B 1 and B 2 are each independently CH or N; and B 3 For-CR 7a R 7b -, -O-, -S-, -S(O)-, -S(O)2- or -NR 7b -;in 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 to 6 membered heterocycloalkyl, or optionally substituted phenyl; and L 2 It does not exist and is C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene.

37. The molecule or pharmaceutically acceptable salt thereof of any one of claims 13 to 29, wherein V or a pharmaceutically acceptable salt thereof has the structure of formula (C-3): in: B 2 is CH or N; B 3 For-CR 7a R 7b -, -O-, -S-, -S(O)-, -S(O)2- or -NR 7b -;in 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 ;and 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- to 6-membered heterocycloalkyl, or optionally substituted phenyl; R 9a is hydrogen, optionally substituted C1-C 20 Alkylene or optionally substituted PEG 1-20 ; Each R 9 are independently hydrogen or C1-C3 alkyl; and s2 is 1 to 3.

38. The molecule of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 For-NR 4a R 4b , where R 4a and R 4b Together with the nitrogen to which it is attached it forms an optionally substituted 4- to 8-membered heterocycloalkyl.

39. The molecule of claim 38, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted piperidine, an optionally substituted piperidine or an optionally substituted morpholine.

40. The molecule of claim 13, wherein the molecule or a pharmaceutically acceptable salt thereof has the structure of formula (III): in: B 1 For-CR 5a R 5b -、-O-、-NR 5b -, -S-, -S(O)- or -S(O)2-; or B 1 for in R 5a is hydrogen, -OH or an optionally substituted C1-C 20 alkyl; R 5b 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 6 or C(O)R 6 ;or R 5a and R 5b together with the nitrogen atom to which it is attached, form an optionally substituted 4- to 8-membered heterocycloalkyl; R 6 is hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 20 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, or optionally substituted phenyl; Ring B is absent, is optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl; L 2 does not exist, is C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene; W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl; Z does not exist or is C(O); Each Y 5 are independently N or CH; R 2d is hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace; R 3a is hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in R 11a and R 11b Each is independently hydrogen, alkyl or PEG; R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; Each R 10 are 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; wherein R 10a and R 10b Each is independently hydrogen, alkyl or PEG; R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; m1 is 0 or 1; q1 and q2 are each independently 0 to 2; and x1 is from 0 to 10.

41. The molecule of claim 40, or a pharmaceutically acceptable salt thereof, wherein q1 is 1 and q2 is 1.

42. A molecule according to claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein B 1 -O- or -NR 5b -.

43. A molecule according to claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein B 1 For-CR 5a R 5b -.

44. A molecule according to claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein B 1 for 45. The molecule of claim 44, or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted C3-C6 cycloalkyl or optionally substituted 4 to 6 membered heterocycloalkyl.

46. ​​The molecule of claim 45, or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted piperidine or optionally substituted piperazine.

47. A molecule according to any one of claims 44 to 46, or a pharmaceutically acceptable salt thereof, wherein L 2 It is C1-C4 alkylene or C2-C4 alkynylene.

48. The molecule of claim 47, or a pharmaceutically acceptable salt thereof, wherein L 2 It is a C2-C4 alkynylene group.

49. The molecule according to any one of claims 44 to 46, or a pharmaceutically acceptable salt thereof, wherein L 2 Does not exist.

50. The molecule of any one of claims 40 to 49, or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)-.

51. The molecule of any one of claims 40 to 49, or a pharmaceutically acceptable salt thereof, wherein Z is absent.

52. The molecule of any one of claims 13 to 51, or a pharmaceutically acceptable salt thereof, wherein x1 is 1.

53. The molecule of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein m1 is 0.

54. A molecule according to any one of claims 24 to 53, or a pharmaceutically acceptable salt thereof, wherein each R 2d 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 replaced by one or more R 10 replace.

55. A molecule according to any one of claims 24 to 53, or a pharmaceutically acceptable salt thereof, wherein each R 2d is independently optionally substituted C1-C 10 Alkyl, which is optionally substituted by one or more R 10 replace.

56. A molecule according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein each R 10 are independently -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.

57. The molecule of claim 56, or a pharmaceutically acceptable salt thereof, wherein each R 10 are independently -N3, -NR 10a R 10b 、-C(O)NR 10a R 10b 、-NHC(O)R 10c or an optionally substituted 5-membered heteroaryl.

58. A molecule according to claim 54 or 55, or a pharmaceutically acceptable salt thereof, wherein R 2d For unsubstituted C1-C 10 alkyl.

59. The molecule of claim 58, or a pharmaceutically acceptable salt thereof, wherein R 2d It is methyl.

60. A transcriptional regulator molecule having a structure of formula (IV) or a pharmaceutically acceptable salt thereof: in: W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl; W 2 is hydrogen, optionally substituted C1-C 20 Alkyl or optionally substituted C1-C 20 heteroalkyl; R w is hydrogen or optionally substituted C1-C 20 alkyl; or W 2 and R w Together with the nitrogen to which it is attached, it forms a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl; Each Y 5 are independently N or CH; Each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace; Each R 3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in R 11a and R 11b Each is independently hydrogen, alkyl or PEG; R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; Each R 10 are 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; wherein R 10a and R 10b Each is independently hydrogen, alkyl or PEG; R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; and n1 and m1 are each independently 0 or 1.

61. The molecule of claim 60, or a pharmaceutically acceptable salt thereof, wherein W 2 and R w Together with the nitrogen to which it is attached, it forms a partially or fully unsaturated optionally substituted 4- to 8-membered heterocycloalkyl.

62. The molecule of claim 60, wherein the molecule or a pharmaceutically acceptable salt thereof has the structure of formula (V): in: B 1 For-CR 5a R 5b -、-O-、-NR 5b -, -S-, -S(O)- or -S(O)2-; or B 1 for in R 5a is hydrogen, -OH or an optionally substituted C1-C 20 alkyl; R 5b 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 Heteroaryl, -C(O)OR 6 or -C(O)R 6 ;or R 5a and R 5b together with the nitrogen atom to which it is attached, form an optionally substituted 4- to 8-membered heterocycloalkyl; R 6 is hydrogen, optionally substituted C1-C 20 Alkyl, optionally substituted C1-C 10 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, or optionally substituted phenyl; Ring B is absent, is optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- to 10-membered heteroaryl; L 2 does not exist, is C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene; W 1 is hydrogen or -N=C(N(R 1e )2)2, where each R 1e are independently hydrogen or C1-C3 alkyl; Each Y 5 are independently N or CH; Each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C2-C 50 Alkenyl, optionally substituted C2-C 50 Alkynyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C2-C 50 Heteroalkenyl, optionally substituted C2-C 50 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 ; each of which is optionally replaced by one or more R 10 replace; Each R 3a and R 3b are independently hydrogen, halogen, -NR 11a R 11b or -NHC(O)R 12 ,in R 11a and R 11b Each is independently hydrogen, alkyl or PEG; R 12 is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; or two R 3a or two R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; Each R 10 are 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; wherein R 10a and R 10b Each is independently hydrogen, alkyl or PEG; R 10c is alkyl, PEG, cycloalkyl, heterocycloalkyl or phenyl; n1 and m1 are each independently 0 or 1; and q1 and q2 are each independently 0 to 2.

63. The molecule of claim 62, or a pharmaceutically acceptable salt thereof, wherein q1 is 1 and q2 is 1.

64. A molecule according to claim 62 or 63, or a pharmaceutically acceptable salt thereof, wherein B 1 -O- or -NR 5b -.

65. A molecule according to claim 62 or 63, or a pharmaceutically acceptable salt thereof, wherein B 1 For-CR 5a R 5b -.

66. A molecule according to claim 62 or 63, or a pharmaceutically acceptable salt thereof, wherein B 1 for 67. The molecule of claim 66, or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted C3-C6 cycloalkyl or optionally substituted 4 to 6 membered heterocycloalkyl.

68. The molecule of claim 67, or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted piperidine or optionally substituted piperazine.

69. The molecule of any one of claims 66 to 68, or a pharmaceutically acceptable salt thereof, wherein L 2 It is C1-C4 alkylene or C2-C4 alkynylene.

70. The molecule of any one of claims 66 to 68, or a pharmaceutically acceptable salt thereof, wherein L 2 Does not exist.

71. The molecule of any one of claims 60 to 70, or a pharmaceutically acceptable salt thereof, wherein each R 3b is hydrogen; and each R 3a are independently selected from hydrogen, -NR 11a R 11b and -NHC(O)R 12 .

72. The molecule of any one of claims 60 to 70, or a pharmaceutically acceptable salt thereof, wherein each R 3a is hydrogen; and each R 3b are independently selected from hydrogen, -NR 11a R 11b and -NHC(O)R 12 .

73. The molecule of any one of claims 60 to 70, or a pharmaceutically acceptable salt thereof, wherein each R 3a and each R 3b For hydrogen.

74. A molecule according to any one of claims 60 to 70, or a pharmaceutically acceptable salt thereof, wherein both R 3a Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group; and each R 3b For hydrogen.

75. A molecule according to any one of claims 60 to 70, or a pharmaceutically acceptable salt thereof, wherein both R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group; and each R 3a For hydrogen.

76. The molecule of any one of claims 60 to 75, 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 are independently hydrogen, optionally substituted C1-C 50 Alkyl, optionally substituted C1-C 50 Heteroalkyl, optionally substituted C1-C 50 Haloalkyl or optionally substituted PEG 1-50 ; each of which is optionally replaced by one or more R 10 replace.

77. The molecule of any one of claims 60 to 75, 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 are 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 ; each of which is optionally replaced by one or more R 10 replace.

78. The molecule of any one of claims 60 to 75, 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 Independently C1-C 10 alkyl, each of which is optionally substituted by one or more R 10 replace.

79. The molecule of any one of claims 60 to 75, or a pharmaceutically acceptable salt thereof, wherein 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 replaced by one or more R 10 Replace; and R 2c , R 2e and R 2h Each of which is independently unsubstituted C1-C 10 alkyl.

80. The molecule of claim 79, or a pharmaceutically acceptable salt thereof, wherein R 2c , R 2e and R 2h Each of them is a methyl group.

81. A molecule according to claim 79 or 80, or a pharmaceutically acceptable salt thereof, wherein each R 2a , R 2b and R 2g are independently unsubstituted C1-C 10 alkyl.

82. The molecule of claim 81, or a pharmaceutically acceptable salt thereof, wherein each R 2a , R 2b and R 2g It is methyl.

83. The molecule of claim 79, or a pharmaceutically acceptable salt thereof, wherein each R 2d is independently optionally substituted C1-C 10 Alkyl, which is optionally substituted by one or more R 10 replace.

84. The molecule of any one of claims 60 to 79 or 83, or a pharmaceutically acceptable salt thereof, wherein each R 10 are independently -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.

85. The molecule of claim 84, or a pharmaceutically acceptable salt thereof, wherein each R 10 are independently -N3, -NR 10a R 10b 、-C(O)NR 10a R 10b 、-NHC(O)R 10c or an optionally substituted 5-membered heteroaryl.

86. The molecule of claim 79, or a pharmaceutically acceptable salt thereof, wherein R 2d For unsubstituted C1-C 10 alkyl.

87. The molecule of claim 86, or a pharmaceutically acceptable salt thereof, wherein R 2d It is methyl.

88. The molecule of any one of claims 60 to 87, or a pharmaceutically acceptable salt thereof, wherein n1 is 1.

89. The molecule of any one of claims 60 to 88, or a pharmaceutically acceptable salt thereof, wherein m1 is 0.

90. The molecule of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein W 1 For hydrogen.

91. A transcriptional regulator molecule selected from Table 2 or a pharmaceutically acceptable salt thereof.

92. A pharmaceutical composition comprising a molecule according to any one of claims 1 to 91, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

93. A method of binding to a nucleotide repeat sequence CTG, the method comprising contacting a molecule according to any one of claims 1 to 91 or a pharmaceutically acceptable salt thereof with a nucleotide comprising the repeat sequence CTG.

94. 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 according to any one of claims 1 to 91.

95. A method of treating Fuchs endothelial dystrophy or Fuchs corneal endothelial dystrophy (FECD) in a subject in need thereof, the method comprising administering to the subject an effective amount of a molecule according to any one of claims 1 to 91.

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