Compounds and methods for treating Friedreich's ataxia

Abstract

The present disclosure relates to compounds and methods for regulating the expression of fxn and treating diseases and conditions in which fxn plays an active role. The compounds can be transcriptional modulator molecules having a first end, a second end, and an oligomeric backbone, a) the first end comprising a DNA binding moiety capable of non-covalently binding to the trinucleotide repeat sequence GAA, b) the second end comprising a protein binding moiety that binds to a regulatory molecule that regulates the expression of a gene comprising the nucleotide repeat sequence GAA, and c) the oligomeric backbone comprising a linker between the first end and the second end.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Patent Application No. 63 / 297,090, filed January 6, 2022, and U.S. Patent Application No. 63 / 382,854, filed November 8, 2022, which are incorporated by reference in their entireties herein.

[0002] Disclosed herein are novel chimeric heterocyclic polyamide compounds and compositions and their applications as pharmaceuticals for the treatment of diseases. Methods of regulating the expression of fxn in a human or animal subject are also provided for the treatment of diseases such as Friedreich's ataxia. [Background technology]

[0003] The present disclosure relates to the treatment of inherited genetic disorders characterized by the over- or under-production of mRNA.

[0004] Friedreich's ataxia ("FA" or "FRDA") is an autosomal recessive neurodegenerative disorder caused by mutations in the frataxin gene ("fxn"), which encodes the protein frataxin ("FXN"), an iron-binding mitochondrial protein involved in electron transport and metabolism. In most subjects with FA, a GAA trinucleotide repeat (approximately 66 to more than 1000 trinucleotides) is contained in the first intron of fxn, and this overexpansion is responsible for the observed pathology. Overexpansion of the GAA repeat results in reduced expression of FXN.

[0005] Friedreich's ataxia is characterized by progressive degeneration of the nervous system, especially sensory neurons. In addition, cardiac myocytes and pancreatic beta cells are susceptible to frataxin depletion. Symptoms usually appear by age 18, but later diagnosis of FA is not uncommon. Patients with FA develop neurodegeneration of large sensory neurons and spinocerebellar tracts, as well as cardiomyopathy and diabetes. Clinical symptoms of FA include ataxia, gait ataxia, muscle weakness, loss of upper body muscle strength, loss of balance, lack of reflexes in the lower limbs and tendons, loss of sensation, especially to vibration, impaired position sense, impaired perception of temperature, touch, and pain, hearing and visual impairments, including distortion of color vision and involuntary eye movements, irregular foot shape, including pes cavus and varus, hearing loss, dysarthria, dysphagia, respiratory problems, scoliosis, diabetes, glucose and carbohydrate intolerance, hypertrophic cardiomyopathy, arrhythmias, myocardial fibrosis, and cardiac dysfunction, including heart failure. Currently, there is no cure for FA, and medical treatment is limited to spinal and cardiac surgical interventions, as well as therapies to assist with balance, coordination, movement, and speech. Summary of the Invention

[0006] 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 the conversion of genetic information into cellular components. Some regulatory molecules are known to regulate the production of mRNA, and when directed to fxn, can regulate the production of fxn mRNA that causes Friedreich's ataxia, thus reversing the progression of the disease.

[0007] The present disclosure provides compounds and methods for recruiting regulatory molecules to the vicinity of fxn. The compounds disclosed herein comprise (a) a recruiting moiety that will bind to the regulatory molecule, and (b) a DNA binding moiety that will selectively bind to fxn. The compounds will counteract expression of defective fxn in the following manner: (1) The DNA-binding moiety would selectively bind to the characteristic GAA trinucleotide repeat sequence of fxn; (2) Thus, the DNA-binding moiety and the bound recruiting moiety would be held in close proximity to fxn. (3) the recruiting moiety now proximal to fxn will recruit regulatory molecules proximal to genes; and (4) Regulatory molecules would regulate expression and thus counter the production of defective fxn by direct interaction with the gene.

[0008] The above mechanism would provide an effective treatment for Friedreich's ataxia caused by the expression of defective fxn genes. Therefore, correcting the expression of defective fxn genes represents a promising method for the treatment of Friedreich's ataxia.

[0009] The present disclosure provides recruitment moieties that will bind to regulatory molecules. Small molecule inhibitors of the regulatory molecules serve as templates for the design of the recruitment moieties, as these inhibitors typically act through non-covalent binding to the regulatory molecules.

[0010] The present disclosure further provides DNA-binding moieties that will selectively bind to one or more copies of the GAA trinucleotide repeat characteristic of a defective fxn gene. The selective binding of the DNA-binding moiety to fxn, made possible by the high GAA number associated with the defective fxn, targets the recruiting moiety to the vicinity of the gene, recruiting regulatory molecules to a position where they upregulate gene transcription.

[0011] The DNA binding moiety will include a polyamide segment that will selectively bind to the target GAA sequence. Polyamides have been designed by Dervan (U.S. Pat. Nos. 9,630,950 and 8,524,899) and others that can selectively bind to selected DNA sequences. These polyamides sit in the minor groove of double helical DNA and form hydrogen bond interactions with Watson-Crick base pairs. Polyamides that selectively bind to specific DNA sequences can be designed by linking monoamide building blocks according to established chemical rules. One building block is provided for each DNA base pair, and each building block non-covalently and selectively binds to one of the DNA base pairs: A / T, T / A, G / C, and C / G. Following this guideline, trinucleotides will be linked to the molecule with three amide units, i.e., triamides. In general, these polyamides will orient in either direction of the DNA sequence, so that the 5'-GAA-3' trinucleotide repeat sequence of fxn can be targeted by polyamides selectively to either GAA or AAG. Additionally, polyamides that bind complementary sequences, in this case TTC or CTT, also bind to the trinucleotide repeat sequence of fxn and can be used as well.

[0012] In principle, longer DNA sequences can be targeted with higher specificity and / or higher affinity by combining more monoamide building blocks into longer polyamide chains. Ideally, the binding affinity for polyamides is simply equal to the sum of each individual monoamide / DNA base pair interaction. However, in practice, due to rather strong geometric mismatches between polyamide and DNA structures, longer polyamide sequences do not bind to longer DNA sequences as tightly as would be expected from simple additive contributions. The geometric mismatches between longer polyamide sequences and longer DNA sequences induce unfavorable geometric distortions that subtract from the otherwise expected binding affinity.

[0013] Thus, the present disclosure provides DNA segments comprising triamides connected by flexible spacers that relieve geometric distortions that would otherwise reduce the binding affinity of larger polyamide sequences.

[0014] Disclosed herein are compounds that contain polyamides that can bind to one or more copies of the trinucleotide repeat sequence GAA and regulate the expression of defective fxn genes. Treating a subject with these compounds can counteract the expression of defective fxn genes, which can reduce the occurrence, severity, and / or frequency of symptoms associated with Friedreich's ataxia. Certain compounds disclosed herein can provide higher binding affinity and / or selectivity than previously observed for this class of compounds.

[0015] In one aspect, disclosed herein is a compound listed in Table 3, or a pharma- ceutically acceptable salt thereof.

[0016] In another aspect, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0017] In another aspect, disclosed herein is a method of modulating expression of fxn, comprising contacting fxn with a disclosed compound, or a pharma- ceutically acceptable salt thereof.

[0018] In another aspect, disclosed herein is a method of treating a disease or condition caused by expression of defective fxn in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease is FA.

[0019] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while showing specific embodiments, are provided by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from the detailed description.

[0020] Incorporation by Reference 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. In the event that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over such conflicting material. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Disclosed herein are compounds (i.e., transcriptional modulator molecules) that contain a DNA binding moiety that can selectively bind to one or more copies of the GAA trinucleotide repeat characteristic of a defective fxn gene. The compounds also contain a moiety that binds to a regulatory protein. Selective binding of a target gene can bring the regulatory protein into close proximity to the target gene and thus downregulate transcription of the target gene. The compounds disclosed herein provide higher binding affinity and selectivity than previously observed for this class of compounds and may be more effective in treating diseases associated with defective fxn genes.

[0022] The compounds described herein can recruit regulatory molecules to modulate the expression of the defective fxn gene and effectively treat and / or alleviate symptoms associated with diseases such as Friedreich's ataxia.

[0023] compound The compounds disclosed herein have useful activity for regulating the transcription of target genes having one or more GAA repeats (e.g., fxn) and may be used to treat or prevent diseases or conditions in which the target gene (e.g., fxn) plays an active role. Thus, in a broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharma- ceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for regulating the expression of fxn. Other embodiments provide methods for treating fxn-mediated disorders in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or composition according to the present disclosure. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition alleviated by the modulation of the expression of fxn.

[0024] Some embodiments relate to compounds having a first end, a second end, and an oligomeric backbone, where a) the first end comprises a DNA binding moiety capable of non-covalently binding to the nucleotide repeat sequence GAA, b) the second end comprises a protein binding moiety that binds to a regulatory molecule that regulates expression of a gene that comprises the nucleotide repeat sequence GAA, and c) the oligomeric backbone comprises a linker between the first end and the second end. In some embodiments, the second end is a Brd4 binding moiety. In some embodiments, the second end is not a Brd4 binding moiety.

[0025] In certain embodiments, the compound has the structure of formula (I): XLY Formula (I), or a salt thereof, wherein X comprises a recruiting moiety capable of binding to a regulatory moiety in the nucleus; Y comprises a DNA recognition moiety capable of non-covalently binding to one or more copies of the trinucleotide repeat sequence GAA; L is a linker.

[0026] In some embodiments, the recruitment moiety can be non-covalently or covalently associated with the control moiety. In some embodiments, the recruitment moiety can be non-covalently associated with the control moiety.

[0027] In certain embodiments, the regulatory molecule is selected from a bromodomain-containing protein.

[0028] In some embodiments, the first terminus is Y, the second terminus is X, and the oligomer backbone is L.

[0029] In certain embodiments, the compound has the structure of formula (II): XL-(Y 1 -Y 2 -Y 3 ) n -Y 0 Formula (II), or a salt thereof, wherein X comprises a recruitment moiety capable of binding to a regulatory molecule in the nucleus; L is a linker, Y 1 , Y 2 , and Y 3 are internal subunits, each of which is a heterocyclic or heteroaryl ring or C 1 -C 6 a linear aliphatic segment, each of which is chemically bonded to its two neighbors; Y 0 is a terminal subunit comprising a moiety selected from a heterocyclic or heteroaryl ring or a linear aliphatic segment, chemically linked to its single neighbor; Each subunit can non-covalently bind to an individual nucleotide within the GAA repeat, n is an integer between 1 and 200, (Y 1 -Y 2 -Y 3 ) n -Y 0combine to form a DNA recognition moiety that is capable of non-covalently binding to one or more copies of the trinucleotide sequence GAA.

[0030] In some embodiments, the compound of structural formula (II) comprises a subunit for each individual nucleotide in the GAA repeat sequence.

[0031] In some embodiments, each internal subunit has an amino (-NH-) group and a carboxy (-CO-) group.

[0032] In some embodiments, the compound of structural formula (II) contains an amide (-NHCO-) ​​bond between each pair of internal subunits.

[0033] In some embodiments, the compound of structural formula (II) comprises an amide (-NHCO-) ​​bond between L and the left-most internal subunit.

[0034] In some embodiments, the compound of structural formula (II) comprises an amide bond between the rightmost internal subunit and the terminal subunit.

[0035] In some embodiments, each subunit independently comprises a moiety selected from a heterocycle and an aliphatic chain.

[0036] In some embodiments, the aliphatic chain is 1 -C 6 A linear aliphatic chain. In certain embodiments, the aliphatic chain has the structural formula -(CH 2 ) m -, and m is selected from 1, 2, 3, 4, and 5. In certain embodiments, the aliphatic chain has -CH 2 CH 2 -It is.

[0037] In some embodiments, the heteroaryl is a monocyclic, bicyclic or polycyclic heteroaryl. In some embodiments, the heteroaryl is a monocyclic heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. In some embodiments, each heteroaryl comprises a heteroatom independently selected from N, O, or S. In some embodiments, each heteroaryl is independently selected from pyrrole, imidazole, thiazole, oxazole, thiophene, and furan.

[0038] In some embodiments, each internal subunit independently comprises:

[0039] [ka]

[0040] [ka] -NH-benzopyrazinylene-CO-, -NH-phenylene-CO-, -NH-pyridinylene-CO-, -NH-piperidinylene-CO-, -NH-pyrimidinylene-CO-, -NH-anthracenylene-CO-, -NH-quinolinylene-CO-, and

[0041] [ka] wherein Z is selected from H, NH 2 , C 1-6 Alkyl or C 1-6 Alkyl NH 2 It is.

[0042] In some embodiments, n is 1 or greater and 100 or less. In certain embodiments, n is 1 or greater and 50 or less. In certain embodiments, n is 1 or greater and 20 or less. In certain embodiments, n is 1 or greater and 10 or less. In certain embodiments, n is 1 or greater and 5 or less. In certain embodiments, n is an integer 1 or greater and 3 or less. In certain embodiments, n is selected from 1 and 2. In certain embodiments, n is 1.

[0043] In some embodiments, n is an integer between 1 and 5, inclusive.

[0044] In some embodiments, n is an integer between 1 and 3, inclusive.

[0045] In some embodiments, n is an integer between 1 and 2, inclusive.

[0046] In some embodiments, n is 1.

[0047] In some embodiments, L is C 1 -C 6 Contains a linear aliphatic segment.

[0048] In some embodiments, L is (CH 2 OCH 2 ) m wherein m is an integer between 1 and 20 inclusive. In some further embodiments, m is an integer between 1 and 10 inclusive. In certain further embodiments, m is an integer between 1 and 5 inclusive.

[0049] In some embodiments, the compound has the structure of formula (III): XL-(Y 1 -Y 2 -Y 3 )-(WY 1 -Y 2 -Y 3 ) n -Y 0 Formula (III), or a salt thereof, wherein X comprises a recruitment moiety capable of binding to a regulatory molecule in the nucleus; L is a linker, Y 1 , Y 2 , and Y 3 are internal subunits, each of which is a heterocyclic or heteroaryl ring or C 1 -C 6 a linear aliphatic segment, each of which is chemically bonded to its two neighbors; Y 0 is a terminal subunit comprising a moiety selected from a heterocyclic or straight chain aliphatic segment, chemically linked to its single neighbor; Each subunit can non-covalently bind to an individual nucleotide within the GAA repeat, W is a spacer, n is an integer between 1 and 200, (Y 1 -Y 2 -Y 3 )-(WY 1 -Y 2 -Y 3 ) n -Y 0 combine to form a DNA recognition moiety that can non-covalently bind to one or more copies of the trinucleotide repeat sequence GAA.

[0050] In some embodiments, Y 1 -Y 2 -Y 3 teeth,

[0051] [ka] ("β-Py-Im").

[0052] In certain embodiments, Y 1 -Y 2 -Y 3 teeth,

[0053] [ka] ("β-Im-Im").

[0054] In some embodiments, Y 1 -Y 2 -Y 3 is Im-Py-β.

[0055] In some embodiments, Y 1 -Y 2 -Y 3 is Im-Im-β.

[0056] In some embodiments, each Y 1 -Y 2 -Y 3 is independently selected from β-Py-Im and β-Im-Im.

[0057] In some embodiments, at most one Y 1 -Y 2 -Y 3 is β-Im-Im.

[0058] In some embodiments of a compound of structural formula (III), n is 1 or greater and 100 or less. In certain embodiments of a compound of structural formula (III), n is 1 or greater and 50 or less. In certain embodiments of a compound of structural formula (III), n is 1 or greater and 20 or less. In certain embodiments of a compound of structural formula (III), n is 1 or greater and 10 or less. In certain embodiments of a compound of structural formula (III), n is 1 or greater and 5 or less. In certain embodiments of a compound of structural formula (III), n is selected from 1 and 2. In certain embodiments of a compound of structural formula (III), n is 1.

[0059] In some embodiments, the compound has the structure of formula (IV):

[0060] [ka] or a salt thereof, wherein X comprises a recruitment moiety capable of binding to a regulatory molecule in the nucleus; Y 0 is a terminal subunit comprising a moiety selected from a heterocyclic or straight chain aliphatic segment, chemically linked to its single neighbor; n is an integer greater than or equal to 1 and less than or equal to 200.

[0061] In some embodiments of a compound of structural formula (IV), n is greater than or equal to 1 and less than or equal to 10. In certain embodiments of a compound of structural formula (IV), n is greater than or equal to 1 and less than or equal to 5. In certain embodiments of a compound of structural formula (IV), n is selected from 1 and 2. In certain embodiments of a compound of structural formula (IV), n is 1.

[0062] In some embodiments, the compound has the structure of formula (V):

[0063] [ka] or a salt thereof, wherein X comprises a recruiting moiety capable of covalently binding to a regulatory molecule in the nucleus; W is a spacer, Y 0 is a terminal subunit comprising a moiety selected from a heterocyclic or straight chain aliphatic segment, chemically linked to its single neighbor; n is an integer greater than or equal to 1 and less than or equal to 200.

[0064] In some embodiments of a compound of Structural Formula (V), n is equal to or greater than 1 and equal to or less than 10. In certain embodiments of a compound of Structural Formula (V), n is equal to or greater than 1 and equal to or less than 5. In certain embodiments of a compound of Structural Formula (V), n is selected from 1 and 2. In certain embodiments of a compound of Structural Formula (V), n is 1.

[0065] In some embodiments of the compound of Structural Formula (V), W is -NHCH 2 -(CH 2 OCH 2 ) p -CH 2 CO-, and p is an integer of 1 or more and 4 or less.

[0066] First end - DNA binding site The first end interacts with and binds to the minor groove of the gene, particularly the GAA sequence. In one embodiment, the compound of the present disclosure provides a polyamide sequence for the interaction of a single polyamide subunit with each base pair in the GAA repeat sequence. In one embodiment, the compound of the present disclosure provides a turn component (e.g., an aliphatic amino acid portion) to allow the compound to bind to GAA in a hairpin, with each nucleotide pair interacting with two subunits of the polyamide.

[0067] In one aspect, the molecules of the disclosure are more likely to bind to the repeated GAA of fxn than to GAA elsewhere in the DNA of the subject due to the higher number of GAA repeats associated with fxn.

[0068] In one embodiment, the compounds of the present disclosure provide more than one copy of a polyamide sequence for non-covalent binding to GAA. In one embodiment, the compounds of the present disclosure bind to fxn with higher affinity than the corresponding compounds that contain a single polyamide sequence.

[0069] In one embodiment, the compounds of the present disclosure provide more than one copy of a polyamide sequence for non-covalent attachment to GAA, where the individual polyamide sequences in the compound are linked by a spacer W, as defined above. The spacer W allows the compound to adjust its geometry as needed to alleviate geometric distortions that would otherwise affect non-covalent attachment of longer polyamide sequences.

[0070] In certain embodiments, the DNA recognition or binding moiety binds to the minor groove of DNA.

[0071] In certain embodiments, the DNA recognition or binding moiety comprises a polymeric sequence of monomers, where each monomer in the polymer selectively binds to a specific DNA base pair.

[0072] In certain embodiments, the DNA recognition or binding moiety comprises a polyamide moiety.

[0073] In certain embodiments, the DNA recognition or binding moiety comprises a polyamide portion comprising heteroaromatic monomers, each of which is non-covalently bound to a particular nucleotide, and each of which is bound to its neighbor or neighbors via amide bonds.

[0074] In certain embodiments, the DNA recognition moiety binds to a sequence that comprises at least 1000 trinucleotide repeats. In certain embodiments, the DNA recognition moiety binds to a sequence that comprises at least 500 trinucleotide repeats. In certain embodiments, the DNA recognition moiety binds to a sequence that comprises at least 200 trinucleotide repeats. In certain embodiments, the DNA recognition moiety binds to a sequence that comprises at least 100 trinucleotide repeats. In certain embodiments, the DNA recognition moiety binds to a sequence that comprises at least 50 trinucleotide repeats. In certain embodiments, the DNA recognition moiety binds to a sequence that comprises at least 20 trinucleotide repeats.

[0075] The form of the polyamide selected may vary based on the target gene. The first end may comprise a polyamide selected from the group consisting of linear polyamide, hairpin polyamide, H-pin polyamide, overlapping polyamide, slip polyamide, cyclic polyamide, tandem polyamide, and extended polyamide. In some embodiments, the first end comprises a linear polyamide. In some embodiments, the first end comprises a hairpin polyamide.

[0076] The binding affinity between the polyamide and the target gene can be adjusted based on the composition of the polyamide. In some embodiments, the polyamide can bind to DNA with an affinity of less than about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, or about 50 nM. In some embodiments, the polyamide can bind to DNA with an affinity of less than about 300 nM. In some embodiments, the polyamide can bind to DNA with an affinity of less than about 200 nM. In some embodiments, the polyamide can bind to DNA with an affinity of more than about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, or about 1 nM. In some embodiments, the polyamide can bind to DNA with an affinity in the range of about 1-600 nM, 10-500 nM, 20-500 nM, 50-400 nM, or 100-300 nM.

[0077] The binding affinity between a polyamide and a target DNA can be determined using quantitative footprint titration experiments, which are carried out at either 24° C. or 37° C. using either standard polyamide assay solution conditions or approximate intracellular solution conditions to determine the dissociation constant, K, of the polyamide for the target sequence. d This involves measuring

[0078] The binding affinity between the control protein and the ligand on the second terminus can be determined using an assay suitable for the particular protein. The experiment can be performed using the dissociation constant K of the ligand for the protein. d and involves using either standard protein assay solution conditions or approximating intracellular solution conditions.

[0079] In some embodiments, the first terminus comprises -NH-QC(=O)-, where Q is an optionally substituted C 6-10 In some embodiments, Q is an optionally substituted C6-10 In some embodiments, Q is an optionally substituted 5-10 membered heteroarylene group. In some embodiments, Q is an optionally substituted 5-10 membered heteroarylene group. In some embodiments, the 5-10 membered heteroarylene group is selected from the group consisting of H, OH, halogen, C 1-10 Alkyl, NO 2 ,CN,NR'R'',C 1-6 Haloalkyl, C 1-6 Alkoxyl, C 1-6 Haloalkoxy, (C 1 -C 6 Alkoxy)C 1 -C 6 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 7 Carbocyclyl, 4-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, (C 3 -C 7 Carbocyclyl)C 1 -C 6 Alkyl, (4-10 membered heterocyclyl)C 1 -C 6 Alkyl, (C 6 -C 10 Aryl)C 1 -C 6 Alkyl, (C 6 -C 10 Aryl)C 1 -C 6 Alkoxy, (5-10 membered heteroaryl)C 1 -C 6 Alkyl, (C 3 -C 7 (4-10 membered heterocyclyl)amines, (C 6 -C 10 (aryl)amine, (5-10 membered heteroaryl)amine, acyl, C-carboxy, O-carboxy, C-amide, N-amide, S-sulfonamide, N-sulfonamide, -SR ’, C(═O)OH, or C(═O)NR′R″, wherein each R′ and R″ is independently H, C 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl, C 1 -C 10 It is alkoxyl.

[0080] In some embodiments, the first end comprises at least three aromatic carboxamide moieties selected to correspond to the nucleotide repeat sequence GAA, and at least one aliphatic amino acid residue selected from the group consisting of glycine, β-alanine, γ-aminobutyric acid, 2,4-diaminobutyric acid, and 5-aminovaleric acid, In some embodiments, the first end comprises at least one β-alanine subunit.

[0081] In some embodiments, the monomer elements are independently selected from the group consisting of optionally substituted pyrrole carboxamide monomers, optionally substituted imidazole carboxamide monomers, optionally substituted C-C linked heteromonocyclic / heterobicyclic moieties, and β-alanine.

[0082] In some embodiments, the first end comprises a polyamide having a structure of Formula (A-2), or a pharma- ceutically acceptable salt thereof:

[0083] [ka] During the ceremony, m 1 is 1 to 4, n 1 is between 0 and 2, Each Y 1 , Y 2 , Y 3 , and Y 4 is independently CH or N; each Z 1 , Z 2 , Z 3 , and Z 4are independently O, S, or NR 1D and Each L 3 is optionally replaced by C 1 -C 6 Alkylene, optionally substituted C 3 -C 7 cycloalkylene, optionally substituted 3- to 7-membered heterocyclene, or optionally substituted 5- to 6-membered heteroarylene; Each R 30 is hydrogen or C 1 -C 6 is alkyl, or Each R 30 and L 3 are bonded together with the atoms to which they are attached to form a 4- to 7-membered heterocyclic ring; W 1 is hydrogen, optionally substituted C 1 -C 6 Alkyl, -NR 1E -C(=O)-NR 1E R 1F , -C(=O)-NR 1E R 1F , or (AA) 1-10 and W 2 is hydrogen, optionally substituted C 1 -C 6 Alkyl, -C(=O)-NR 1E R 1F , or (AA) 1-10 and Each R 1D and R 1E are independently hydrogen, deuterium, optionally substituted C 1 -C 50 Alkyl, optionally substituted C 1 -C 50 Heteroalkyl, or optionally substituted (PEG) 1-50 and R 1F is optionally substituted with hydrogen, deuterium, 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, (PEG) 1-20or one or more AA, Each AA is independently a naturally occurring amino acid.

[0084] In some embodiments, each L 3 is optionally replaced by C 1 -C 6 In some embodiments, L is alkylene. 3 is one or more hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 3 -C 6 C optionally substituted with a cycloalkyl or 4- to 7-membered heterocycloalkyl ring 2 , C 3 , C 4 , or C 5 In some embodiments, L is alkylene. 3 is one or more hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 3 -C 6 C optionally substituted with a cycloalkyl or 4- to 7-membered heterocycloalkyl ring 2 Or C 3 In some embodiments, L is alkylene. 3 is one or two hydrogens, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 3 -C 6 C optionally substituted with a cycloalkyl or 4- to 7-membered heterocycloalkyl ring 2 It is alkylene.

[0085] In some embodiments, each L 3 is independently 3 -C7 In some embodiments, L is cycloalkylene. 3 is a cyclobutylene, a cyclopentylene ring, a cyclohexylene, or a cycloheptylene ring. 3 is cyclobutylene. In some embodiments, L 3 is cyclopentylene. In some embodiments, L 3 is cyclohexylene.

[0086] In some embodiments, each L 3 is a 3- to 7-membered heterocyclene. 3 is a 4-, 5-, or 6-membered heterocyclene.

[0087] In some embodiments, each R 30 is independently hydrogen. In some embodiments, each R 30 is independently 1 -C 6 It is an alkyl.

[0088] In some embodiments, L 3 and R 30 are joined together with the atoms to which they are attached to form a 4- to 7-membered heterocyclic ring. In some embodiments, the ring is a 4-membered heterocyclic ring. In some embodiments, the ring is a 5-membered heterocyclic ring. In some embodiments, the ring is a 6-membered heterocyclic ring. In some embodiments, the ring is a 7-membered heterocyclic ring.

[0089] In some embodiments, the first end comprises a polyamide having a structure of Formula (A-3):

[0090] [ka] During the ceremony, m 1 is 1 to 4, n 1 is between 0 and 2, Each Y 1 , Y2 , Y 3 , and Y 4 is independently CH or N; each Z 1 , Z 2 , Z 3 , and Z 4 are independently O, S, or NR 1D and W 1 is hydrogen, optionally substituted C 1 -C 6 Alkyl, -NR 1E -C(=O)-NR 1E R 1F , -C(=O)-NR 1E R 1F , or (AA) 1-10 and W 2 is hydrogen, optionally substituted C 1 -C 6 Alkyl, -C(=O)-NR 1E R 1F , or (AA) 1-10 and Each R 1D and R 1E are independently hydrogen, deuterium, optionally substituted C 1 -C 50 Alkyl, optionally substituted C 1 -C 50 Heteroalkyl, or optionally substituted (PEG) 1-50 and R 1F is optionally substituted with hydrogen, deuterium, 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, optionally substituted (PEG) 1-20 or one or more AA, Each AA is independently selected from β-alanine, lysine, and arginine.

[0091] In some embodiments, each L 3 are the same. In some embodiments, each L 3 is different.

[0092] In some embodiments, the first end comprises a polyamide having a structure of formula (A-4), or a pharma- ceutically acceptable salt thereof:

[0093] [ka] During the ceremony, n 1 is between 0 and 2, Each Y 1 , Y 2 , Y 3 , and Y 4 is independently CH or N; each Z 1 , Z 2 , Z 3 , and Z 4 are independently O, S, or NR 1D and Each L 3 is optionally replaced by C 3 -C 7 cycloalkylene, optionally substituted 3- to 7-membered heterocyclene, or optionally substituted 5- to 6-membered heteroarylene; Each R 30 is hydrogen or C 1 -C 6 is alkyl, or Each R 30 and L 3 are bonded together with the atoms to which they are attached to form a 4- to 7-membered heterocyclic ring; W 1 is hydrogen, optionally substituted C 1 -C 6 Alkyl, -NR 1E -C(=O)-NR 1E R 1F , -C(=O)-NR 1E R 1F , or (AA) 1-10 and W 2 is hydrogen, optionally substituted C 1 -C 6 Alkyl, -C(=O)-NR 1E R1F , or (AA) 1-10 and Each R 1D and R 1E are independently hydrogen, deuterium, optionally substituted C 1 -C 50 Alkyl, optionally substituted C 1 -C 50 Heteroalkyl, or optionally substituted (PEG) 1-50 and R 1F is optionally substituted with hydrogen, deuterium, 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, (PEG) 1-20 or one or more AA, Each AA is independently a naturally occurring amino acid.

[0094] In some embodiments, the linker moiety is W 2 In some embodiments, the W 2 is optionally replaced by C 1 -C 6 Alkyl, -C(=O)-NR 1E R 1F , or (AA) 1-10 In some embodiments, W 2 is -C(=O)-NR 1E R 1F In some embodiments, W 2 is -C(=O)NHCH 2 CH 2 In some embodiments, W 2 is hydrogen.

[0095] In some embodiments, W 2 is (AA) 1-10 In some embodiments, each AA is independently β-alanine. In some embodiments, AA comprises one β-alanine. In some embodiments, AA comprises two β-alanines.

[0096] In some embodiments, the first end comprises a polyamide having a structure of formula (A-5), or a pharma- ceutically acceptable salt thereof:

[0097] [ka]

[0098] In some embodiments, each R 1D and R 1E are independently hydrogen, optionally substituted C 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, or optionally substituted (PEG) 1-20 In some embodiments, each R 1D and R 1E are independently hydrogen, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 1 -C 10 Heteroalkyl, or optionally substituted (PEG) 1-20 It is.

[0099] In some embodiments, each R 1D are independently optionally substituted C 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, or optionally substituted (PEG) 1-20 each of which is optionally substituted with amido, alkyl, alkynyl, azido, amino, halogen, haloalkyl, hydroxy, nitro, oxo (=O), phosphorus hydroxide, or PEG. 1D are independently -CN, -NH 2 , -N 3 , -OH, CF 3 , -OP(=O)(OH) 2 , -OP(=O)(OCH3 ) 2 , -OP(=O)(OCH 3 )(OH) or -OP(=O) 2 Optionally substituted with OH, optionally substituted with C 1 -C 20 In some embodiments, each R 1D are independently (PEG) 1-50 In some embodiments, each R 1D are independently -C(=O)-NR 2A R 2B or -NR 2A R 2B And each R 2A and R 2B are independently hydrogen, C 1 -C 50 Alkyl, or (PEG) 1-50 It is.

[0100] In some embodiments, each Z 1 , Z 2 , Z 3 , and Z 4 is independently, NR 1D and R 1D is optionally replaced by C 1 -C 20 Alkyl or optionally substituted C 1 -C 20 It is heteroalkyl.

[0101] In some embodiments, each Z 1 , Z 2 , Z 3 , and Z 4 is an independent NCH 3 It is.

[0102] In some embodiments, each Z 1 , Z 2 , Z 3 , and Z 4 are independently NH.

[0103] In some embodiments, the first end comprises a polyamide having a structure of formula (A-6), or a pharma- ceutically acceptable salt thereof:

[0104] [ka]

[0105] In some embodiments, each Y 1 and Y 3 is N, and each Y 2 and Y 4 is independently CH or N. In some embodiments, each Y 2 and Y 4 is independently CH. In some embodiments, each Y 2 and Y 4 is independently N. In some embodiments, Y 2 is CH and Y 4 is N. In some embodiments, Y 2 is N and Y 4 is CH.

[0106] In some embodiments, each unit m 1 and n 1 are different or the same. In some embodiments, each unit m 1 In some embodiments, each unit m 1 are the same. In some embodiments, each unit n 1 In some embodiments, each unit n 1 is the same.

[0107] In some embodiments, m 1 is 2 or 3, n 1 is 0 or 1.

[0108] In some embodiments, m 1 is 2. In some embodiments, m 1 is 1.

[0109] In some embodiments, n 1 is 0. In some embodiments, n 1 is 1.

[0110] In some embodiments, the linker moiety is W 1 In some embodiments, W is connected to the DNA binding moiety via 1 is optionally replaced by C 1 -C 6 Alkyl, or -C(=O)-NR 1E R 1F In some embodiments, W 1 is -C(=O)-NR 1E R 1F and R 1E is hydrogen and R 1F is hydrogen, optionally substituted C 1 -C 10 Alkyl, or optionally substituted (PEG) 1-20 It is.

[0111] In some embodiments, W 1 is hydrogen.

[0112] In some embodiments, the first end comprises a polyamide having a structure of Formula (A-7), or a pharma- ceutically acceptable salt thereof:

[0113] [ka] During the ceremony, m 1 is 1 to 4, n 1 is between 0 and 2, Each Y 1 , Y 2 , Y 3 , and Y 4 is independently CH or N; each Z 1 , Z 2 , Z 3 , and Z 4 are independently O, S, or NR 1D and W 1 is hydrogen, optionally substituted C 1 -C 6 Alkyl, -NR 1E -C(=O)-NR 1E R 1F , -C(=O)-NR 1E R 1F , or (AA) 1-10 and W 2 is hydrogen, optionally substituted C 1 -C 6 Alkyl, -C(=O)-NR 1E R 1F , or (AA) 1-10 where: Each R 1D and R 1E are independently hydrogen, deuterium, optionally substituted C 1 -C 50 Alkyl, optionally substituted C 1 -C 50 Heteroalkyl, or optionally substituted (PEG) 1-50 and R 1F is optionally substituted with hydrogen, deuterium, 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, (PEG) 1-20 or one or more AA, each AA is independently a naturally occurring amino acid; Each R 1H , R 1J , R 1K , and R 1L are independently hydrogen, deuterium, halogens, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 is hydroxyalkyl, or R 1H and R 1J or R 1Land R 1K are bonded together with the carbon atom to which they are attached, C 3 -C 6 It forms a cycloalkyl or 4- to 7-membered heterocycloalkyl ring.

[0114] In some embodiments, each R 1H , R 1J , R 1K , and R 1L are independently hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments, each R 1H , R 1J , R 1K , and R 1L are independently hydrogen, halogen, or C 1 -C 6 In some embodiments, each R 1H , R 1J , R 1K , and R 1L is independently halogen. In some embodiments, each R 1H , R 1J , R 1K , and R 1L is independently 1 -C 6 In some embodiments, each R 1H , R 1J , R 1K , and R 1L are independently hydrogen.

[0115] In some embodiments, R 1H and R 1J or R 1L and R 1K are bonded together with the atoms to which they are attached, C 3 -C 6In some embodiments, R 1H and R 1J or R 1L and R 1K are bonded together with the atoms to which they are attached, C 3 -C 6 In some embodiments, R 1H and R 1J or R 1L and R 1K are joined together with the atoms to which they are attached to form a 4- to 7-membered heterocycloalkyl ring.

[0116] In some embodiments, the first end comprises a polyamide having a structure of formula (A-8), or a pharma- ceutically acceptable salt thereof:

[0117] [ka] During the ceremony, each v 1 and v 2 are independently 1 to 3, m 1 is 1 to 4, n 1 is between 0 and 2, Each Y 1 , Y 2 , Y 3 , and Y 4 is independently CH or N; each Z 1 , Z 2 , Z 3 , and Z 4 are independently O, S, or NR 1D and W 1 is hydrogen, optionally substituted C 1 -C 6 Alkyl, -NR 1E -C(=O)-NR 1E R 1F , -C(=O)-NR 1E R 1F , or (AA) 1-10 and W 2 is hydrogen, optionally substituted C 1 -C 6 Alkyl, -C(=O)-NR 1E R 1F , or (AA) 1-10 where: Each R 1D and R 1E are independently hydrogen, deuterium, optionally substituted C 1 -C 50 Alkyl, optionally substituted C 1 -C 50 Heteroalkyl, or optionally substituted (PEG) 1-50 and R 1F is optionally substituted with hydrogen, deuterium, 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, (PEG) 1-20 or one or more AA, Each AA is independently a naturally occurring amino acid.

[0118] In some embodiments, each v 1 is independently 1. In some embodiments, each v 1 is independently 2. In some embodiments, each v 1 is independently 3. In some embodiments, each v 2 is independently 1. In some embodiments, each v 2 is independently 2. In some embodiments, each v 2 is independently 3.

[0119] In some embodiments, the first end comprises a polyamide having a structure of formula (A-9), or a pharma- ceutically acceptable salt thereof:

[0120] [ka]

[0121] In some embodiments, the first end comprises a polyamide having a structure of formula (A-10), or a pharma- ceutically acceptable salt thereof:

[0122] [ka]

[0123] In some embodiments, the first end comprises a polyamide having a structure of formula (A-11), or a pharma- ceutically acceptable salt thereof:

[0124] [ka] , where each v 1 and v 2 However, independently, they are 1 to 3.

[0125] In some embodiments, the first end comprises a polyamide having a structure of formula (A-12), or a pharma- ceutically acceptable salt thereof:

[0126] [ka] , in the formula, Each R 1H , R 1J , R 1K , and R 1L are independently hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 is hydroxyalkyl, or R 1H and R 1J or R 1L and R 1K are bonded together with the carbon atom to which they are attached, C 3 -C 6 It forms a cycloalkyl or 4- to 7-membered heterocycloalkyl ring.

[0127] In some embodiments, the first end comprises a polyamide having a structure of formula (A-13), or a pharma- ceutically acceptable salt thereof:

[0128] [ka] , where each v 3 and v 4 However, independently, they are 1 to 3.

[0129] The DNA recognition or binding moiety is

[0130] [ka]

[0131] [ka] -NH-benzopyrazinylene-CO-, -NH-phenylene-CO-, -NH-pyridinylene-CO-, -NH-piperidinylene-CO-, -NH-pyrimidinylene-CO-, -NH-anthracenylene-CO-, -NH-quinolinylene-CO-, optionally substituted heterocycles having 5 to 10 rings,

[0132] [ka] and wherein the formula is: Each R a are independently H, optionally substituted C 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, optionally substituted C 1 -C 20 haloalkyl, or optionally substituted C 1 -C 20 is alkylamino, Each R bare independently H, halogen, -OH, optionally substituted C 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, optionally substituted C 1 -C 20 Haloalkyl, optionally substituted C 1 -C 20 Hydroxyalkyl or optionally substituted C 1 -C 20 It is an alkylamino.

[0133] The DNA recognition or binding moiety is

[0134] [ka]

[0135] [ka] -NH-benzopyrazinylene-CO-, -NH-phenylene-CO-, -NH-pyridinylene-CO-, -NH-piperidinylene-CO-, -NH-pyrimidinylene-CO-, -NH-anthracenylene-CO-, -NH-quinolinylene-CO-, and

[0136] [ka] wherein Z is H, NH 2 , C 1-6 Alkyl or C 1-6 Alkyl NH 2 It is.

[0137] In some embodiments, Py is

[0138] [ka] and Im is

[0139] [ka] and Hp is

[0140] [ka] and Th is

[0141] [ka] and Pz is

[0142] [ka] and Nt is

[0143] [ka] and Tn is

[0144] [ka] and Nh is

[0145] [ka] and iNt is

[0146] [ka] and iIm is

[0147] [ka] and HpBi is

[0148] [ka] and ImBi is

[0149] [ka] And PyBi is

[0150] [ka] and Dp is

[0151] [ka] and -NH-benzopyrazinylene-CO- is

[0152] [ka] and -NH-phenylene-CO- is

[0153] [ka] and -NH-pyridinylene-CO- is

[0154] [ka] and -NH-piperidinylene-CO- is

[0155] [ka] and -NH-pyrazinylene-CO- is

[0156] [ka] and -NH-naphthalene-CO- is

[0157] [ka] and -NH-quinolinylene-CO- is

[0158] [ka] It is.

[0159] In some embodiments, the first terminus comprises one or more subunits selected from the group consisting of optionally substituted N-methylpyrrole, optionally substituted N-methylimidazole, and β-alanine.

[0160] The first end of the compounds described herein has a high binding affinity to sequences with multiple repeats of GAA and binds to the target nucleotide repeat preferentially over other nucleotide repeats or nucleotide sequences. In some embodiments, the first end has a higher binding affinity to sequences with multiple repeats of GAA than sequences with repeats of CGG. In some embodiments, the first end has a higher binding affinity to sequences with multiple repeats of GAA than sequences with repeats of CCG. In some embodiments, the first end has a higher binding affinity to sequences with multiple repeats of GAA than sequences with repeats of CCTG. In some embodiments, the first end has a higher binding affinity to sequences with multiple repeats of GAA than sequences with repeats of TGGAA. In some embodiments, the first end has a higher binding affinity to sequences with multiple repeats of GAA than sequences with repeats of GGGGCC. In some embodiments, the first end has a higher binding affinity to sequences with multiple repeats of GAA than sequences with repeats of CAG. In some embodiments, the first end has a higher binding affinity for sequences with multiple repeats of GAA than for sequences with repeats of CTG.

[0161] The preferential binding between the first end and the target nucleotide repeats causes the transcription modulator molecules described herein to localize around regions with multiple repeats of GAA. In some embodiments, the localized concentration of the first end of the molecules described herein is higher near sequences with multiple repeats of GAA than near sequences with repeats of CGG. In some embodiments, the localized concentration of the first end of the molecules described herein is higher near sequences with multiple repeats of GAA than near sequences with repeats of CCG. In some embodiments, the localized concentration of the first end of the molecules described herein is higher near sequences with multiple repeats of GAA than near sequences with repeats of CCTG. In some embodiments, the localized concentration of the first end of the molecules described herein is higher near sequences with multiple repeats of GAA than near sequences with repeats of TGGAA. In some embodiments, the localized concentration of the first end of the molecules described herein is higher near sequences with multiple repeats of GAA than near sequences with repeats of GGGGCC. In some embodiments, the localized concentration of the first end of the molecules described herein is higher near the sequence with multiple GAA repeats than near the sequence with CTG repeats.In some embodiments, the localized concentration of the first end of the molecules described herein is higher near the sequence with multiple GAA repeats than near the sequence with CAG repeats.

[0162] The first end is localized to a sequence having multiple repeats of GAA and binds to the target nucleotide repeat preferentially over other nucleotide repeats. In some embodiments, the sequence has at least 2, 3, 4, 5, 8, 10, 12, 15, 20, 25, 30, 40, 50, 100, 200, 300, 400, or 500 repeats of GAA. In certain embodiments, the sequence comprises at least 1000 nucleotide repeats of GAA. In certain embodiments, the sequence comprises at least 500 nucleotide repeats of GAA. In certain embodiments, the sequence comprises at least 200 nucleotide repeats of GAA. In certain embodiments, the sequence comprises at least 100 nucleotide repeats of GAA. In certain embodiments, the sequence comprises at least 50 nucleotide repeats of GAA. In certain embodiments, the sequence comprises at least 20 nucleotide repeats of GAA.

[0163] In one aspect, compounds of the disclosure are capable of binding to the repeat GAA of fxn in preference to GAA elsewhere in the DNA of a subject.

[0164] Polyamides consisting of preselected combinations of subunits can selectively bind DNA in the minor groove. In their hairpin structure, antiparallel juxtaposed pairs of two aromatic amino acids bind to the DNA sequence with the polyamide rings packed specifically for each DNA base. N-methylpyrrole (Py) prefers T, A, and C bases except G, N-methylimidazole (Im) is a G-reading factor, and 3-hydroxyl-N-methylpyrrole (Hp) is specific for thymine bases. Nucleotide base pairs can be recognized using different pairings of amino acid subunits using the pairing principles shown in Tables 1A and 1B below. For example, Im / Py pairing symmetry reads G·C, Py / Im pairing reads 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.

[0165] In some embodiments, the first end comprises Im corresponding to the nucleotide G, Py or beta corresponding to the nucleotide A, Py corresponding to the nucleotide A, where Im is an N-alkylimidazole, Py is an N-alkylpyrrole, and beta is β-alanine. In some embodiments, the first end comprises Im / Py corresponding to the nucleotide pair G / C, Py / beta or Py / Py corresponding to the nucleotide pair A / T, where Im is an N-alkylimidazole (e.g., N-methylimidazole), Py is an N-alkylpyrrole (e.g., N-methylpyrrole), and beta is β-alanine.

[0166] [Table 1-1]

[0167] [Table 1-2]

[0168] [Table 1-3]

[0169] [Table 2-1]

[0170] [Table 2-2]

[0171] The monomer subunits of the polyamide can be linked together based on the pairing principles shown in Tables 1A and 1B. The monomer subunits of the polyamide can be linked together based on the pairing principles shown in Tables 1C and 1D.

[0172] Table 1C shows examples of monomeric subunits that can be linked to a particular nucleotide. The first end can include a polyamide described as having several monomeric subunits linked together with monomeric subunits selected from each column. For example, the polyamide can include Im-β-Py linked to GAA, where Im is selected from the first G column, β is selected from the A column, and Py is selected from the second A column. The polyamide can be any combination of subunits selected from each column of Table 1C that link to the subunits of GAA, where the subunits are linked together according to the GAA order.

[0173] In addition, polyamides can also include partial or multiple sets of 5 subunits, for example, 1.5, 2, 2.5, 3, 3.5, or 4 sets of 3 subunits. Polyamides can include 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, and 16 monomer subunits. Multiple sets can be linked together by W. In addition to 5 or 10 subunits, polyamides can also include 1 to 4 additional subunits that can link multiple sets of 5 subunits.

[0174] A polyamide can include monomer subunits that link 2, 3, 4, or 5 nucleotides of GAA. For example, a polyamide can link GA, AA, GAA, AAG, AGA, GAAG, AAGA, GAAGA, or GAAGAA. A polyamide can include monomer subunits that link 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides of GAA repeats. The nucleotides can be linked by W.

[0175] When a monomer subunit is located as a terminal unit, it does not have a terminal amine, carbonyl, or carboxylic acid group. The terminal amine or carboxylic acid group is replaced with a hydrogen. For example, Py, when used as a terminal unit, is

[0176] [ka] (for example,

[0177] [ka] ) wherein Im, when located as a terminal unit, is

[0178] [ka] (for example,

[0179] [ka] In addition, when Py or Im is used as a terminus, Py and Im are each represented by the formula: PyT

[0180] [ka] (for example,

[0181] [ka] ) and ImT

[0182] [ka] (for example,

[0183] [ka] ) can be replaced with

[0184] Linear polyamides can have non-limiting examples including, but not limited to, β-Py-Im, Im-Py-β-Im-Py-β-Im-Py, Im-Py-β-Im-Py-Py-Im-β, Im-Py-Py-Im-Py-β-Im-β, and any combination thereof.

[0185] [Table 3]

[0186] Because the target gene can contain multiple repeats of GAA, the subunits can be linked together to bind at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in one or more GAA repeats (e.g., GAAGAAGAAGAA). For example, the polyamide can bind to the GAA repeats by binding to a partial copy, a full copy, or multiple repeats of GAA, such as GA, AA, GAA, AAG, AGA, GAAG, AAGA, GAAGA, or GAAGAA. For example, the polyamide can include Im-Py-β-W-Py-β-Py that binds to GAA and its complementary nucleotides on double-stranded DNA, where the Im / Py pair binds to G·C, the Py / β pair binds to A·T, and the β / Py pair binds to G·A. Another example is Im-Py-β-Im-W-β-Py-β-Py, which binds to GAAG and its complementary nucleotide on double-stranded DNA, with the Im / Py pair binding to G·C, the Py / β pair binding to A·T, the β / Py pair binding to G·A, and the Im / β pair binding to G·C. Another example is Im-Py-β-Im-gAB-Im-Py, which binds to a portion of the complementary nucleotides (ACG) on double-stranded DNA, with Im binding to G, Py binding to A, β / Py binding to A·T, and Im / Im binding to G·C.

[0187] Some additional examples of polyamides include, but are not limited to, Im-Py-Py-Im-gAB-Py-Im-Im-Py, Im-Py-Py-Im-gAB-Py-Im-Im-PyT, Im-Py-Py-Im-gAB-Py-Im-Im-β, Im-Py-Py-Im-gAB-Py-Im-Im-β-G, Im-β-β-Py-Im-gAB-Py-Im-Im-β, Im-β-Py-Im-gAB-Py-Im-Im-β-G, Im-β-Py-Im-gAB-Py-Im-Im-Py, Im-β-Py-Im-gAB-Py-Im-Im-PyT, Py-Py-Im-β-gAB-Im-Py-Im-Im, Py-Py-Im-β-gAB-Im-Py-Im-ImT, Py-Py-Im-Py-gAB-Im-Py-Im-Im, Py-Py-Im-Py-gAB-Im-Py-Im-ImT, Py-Py-Im-β-gAB-Im-β-Im-Im, Py-Py-Im-β-gAB-Im-β-Im-ImT, Py-Py-Im-Py-gAB-Im-β-Im-Im, Py-Py-Im-Py-gAB-Im-β-Im-ImT, Im-β-Py-gAB-Im-Im-Py, Im-β-Py-gAB-Im-Im-PyT, Im-β-Py-gAB-Im-Im-β, Im-β-Py-gAB-Im-Im-β-G, Im-Py-Py-gAB-Im-Im-β, Im-Py-Py-gAB-Im-Im-β-G, Im-Py-Py-gAB-Im-Im-Py, Im-Py-Py-gAB-Im-Im-PyT, Im-p-Py-gAB-Im-Im-Py, and Im-β-Py-gAB-Im-Im-PyT, where G can be hydrogen, alkyl, alkenyl, alkynyl, or -C(=O)-R B and can be B hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, or C 1 -C 6 alkynyl group. In some embodiments, the hairpin polyamide has a structure of Im-Py-β-Im-gAB-Im-Py, Im-Py-β-Im-gAB-Im-Py-β-Im, Py-β-Im-gAB-Im-Py-β-Im, or β-Im-gAB-Im-Py-β-Im.

[0188] Second end - Regulatory binding site In some embodiments, the second end comprises a protein-binding moiety capable of binding to a regulatory molecule that regulates expression of a gene comprising one or more copies of the trinucleotide repeat sequence GAA.

[0189] In some embodiments, the regulatory molecule is selected from nucleosome remodeling factors ("NURF"), bromodomain PHD finger transcription factors ("BPTF"), ten-eleven translocation enzymes ("TET"), methylcytosine dioxygenases ("TET1"), DNA demethylases, helicases, acetyltransferases, CREB binding proteins ("CBP"), P300, O-linked β-N-acetylglucosamine transferases ("OGT"), P300-CBP associated factors ("PCAF"), histone methyltransferases, histone demethylases, chromodomains, cyclin-dependent kinase-9 ("CDK9"), octamer-binding transcription factors ("OCT1"), histone acetyltransferases ("HAT"), host cell factor-1 ("HCF1"), and histone deacetylases ("HDAC").

[0190] In some embodiments, the protein-binding moiety binds to a regulatory molecule selected from the group consisting of CBP, P300, OGT, CAF, CDK9, NURF, BPTF, TET, TET1, HAT, HDAC, HCF1, OCT1, P-TEFb, cyclin-T1, PRC2, DNA-demethylases, helicases, acetyltransferases, histone-deacetylases, and methylated histone lysine proteins.

[0191] In some embodiments, the second end comprises a moiety that binds OGT or CBP, hi some embodiments, the protein-binding moiety is a residue of a compound that binds OGT or CBP.

[0192] In some embodiments, the second end comprises a bromodomain binding moiety. In some embodiments, the bromodomain binding moiety is a BRD2, BRD3, BRD4, or BRDT binding moiety. In some embodiments, the bromodomain binding moiety is a BRD4 binding moiety.

[0193] In some embodiments, the regulatory molecule is a bromodomain-containing protein selected from BRD2, BRD3, BRD4, and BRDT.

[0194] In some embodiments, the regulatory molecule is BRD4. In certain embodiments, the recruiting moiety is a BRD4 activator.

[0195] In some embodiments, the regulatory molecule regulates histone rearrangement.

[0196] In some embodiments, the regulatory molecule modulates glycosylation, phosphorylation, alkylation, or acylation of histones.

[0197] In some embodiments, the regulatory molecule is a transcription factor.

[0198] In some embodiments, the regulatory molecule is an RNA polymerase.

[0199] In some embodiments, the regulatory molecule is a moiety that regulates the activity of an RNA polymerase.

[0200] In some embodiments, the recruitment moiety binds to a regulatory molecule but does not inhibit the activity of the regulatory molecule. In some embodiments, the recruitment moiety binds to a regulatory molecule and inhibits the activity of the regulatory molecule. In some embodiments, the recruitment moiety binds to a regulatory molecule and increases the activity of the regulatory molecule.

[0201] In certain embodiments, the recruitment moiety binds to an active site of a regulatory molecule. In certain embodiments, the recruitment moiety binds to a regulatory site of a regulatory molecule.

[0202] The binding affinity between the regulatory protein and the second end can be adjusted based on the composition of the molecule or the type of protein. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, or about 50 nM. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 300 nM. In some embodiments, the second end binds to the regulatory molecule with an affinity of less than about 200 nM. In some embodiments, the second end can bind to the regulatory molecule with an affinity of more than about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, or about 1 nM. In some embodiments, the second end can bind to the regulatory molecule with an affinity in the range of about 1-600 nM, 10-500 nM, 20-500 nM, 50-400 nM, 100-300 nM, or 50-200 nM.

[0203] In some embodiments, the second terminus is a ligand.

[0204] In some embodiments, the second terminus comprises pyrrolopyridinone. In some embodiments, the pyrrolopyridinone is substituted with an optionally substituted oxydibenzyl. In some embodiments, the second terminus comprises an optionally substituted 4-(2-phenoxyphenyl)-6λ 2 -pyrrolo[2,3-c]pyridin-7(1H)-one.

[0205] In some embodiments, the second end comprises a compound having the structure of Formula (B), or a pharma- ceutically acceptable salt thereof:

[0206] [ka] During the ceremony, Y is -CH 2 NH-, CH 2 -O-, -NH-, or -O-; R 17is hydrogen or C 1 -C 6 is alkyl, R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , optionally replaced by -C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Haloalkyl or optionally substituted C 1 -C 6 is hydroxyalkyl, or R 18 But -NR A R B and R 25 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Hydroxyalkyl, -SO 2 R A , or -NHSO 2 R A and R 32 is hydrogen or optionally substituted C 1 -C 6 is alkyl, R 34 is hydrogen, halogen, -OH, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 is hydroxyalkyl, R 35 is hydrogen, optionally substituted C 1 -C6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or an optionally substituted 5-6 membered monocyclic aryl or heteroaryl; Each R A and R B are independently hydrogen, deuterium, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 is heteroalkyl, y 1 But, 1 to 3, The bond to the linker is R 18 or R 35 In either case.

[0207] In some embodiments, the bond to the linker is R 18 In some embodiments, the bond to the linker is at R 35 In.

[0208] In some embodiments, the second end comprises a compound having a structure of formula (B-1), or a pharma- ceutically acceptable salt thereof:

[0209] [ka] During the ceremony, Ring E is absent or an optionally substituted 5- to 6-membered monocyclic aryl or heteroaryl, or an optionally substituted 4- to 8-membered heterocycle; Y is -CH 2 NH-, CH 2 -O-, -NH-, or -O-; R 17 is hydrogen or C 1 -C 6 is alkyl, R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , optionally replaced by -C 1-C 6 Alkyl, optionally substituted C 1 -C 6 Haloalkyl or optionally substituted C 1 -C 6 is hydroxyalkyl, or R 18 But -NR A R B and R 25 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Hydroxyalkyl, -SO 2 R A , or -NHSO 2 R A and R 32 is hydrogen or optionally substituted C 1 -C 6 is alkyl, R 34 is hydrogen, halogen, -OH, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 is hydroxyalkyl, Each R A and R B are independently hydrogen, deuterium, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 is heteroalkyl, y 1 However, the numbers are 1 to 3.

[0210] In some embodiments, the second end comprises a compound having the structure of formula (B-2), or a pharma- ceutically acceptable salt thereof:

[0211] [ka] During the ceremony, Ring E is absent or an optionally substituted 5- to 6-membered monocyclic aryl or heteroaryl, or an optionally substituted 4- to 8-membered heterocycle; Y is -CH 2 NH-, CH 2 -O-, -NH-, or -O-; R 17 is hydrogen or C 1 -C 6 is alkyl, R 18 is a halogen, R 19a is halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 is hydroxyalkyl, R 19b is optionally substituted with hydrogen, halogen, 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 is hydroxyalkyl, R 25a is hydrogen or optionally substituted C 1 -C 6 is alkyl, R 32 is hydrogen or optionally substituted C 1 -C 6 It is an alkyl.

[0212] In some embodiments, Ring E is an optionally substituted 5- or 6-membered monocyclic aryl or heteroaryl, each aryl or heteroaryl being optionally substituted with alkyl, amino, halogen, hydroxy, hydroxyalkyl, or PEG. In some embodiments, Ring E is optionally substituted with one or more R 33 , and each R 33 is deuterium, halogen, hydroxyl, amino, nitro, optionally substituted C 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, optionally substituted C 1 -C 20 Haloalkyl, optionally substituted C 1 -C 6 Hydroxyalkyl, or optionally substituted (PEG) 1-20 are independently selected from

[0213] In some embodiments, ring E is phenyl. In some embodiments, ring E is a 6-membered heteroaryl. In some embodiments, ring E is pyridine, pyrazine, or triazine. In some embodiments, ring E is pyridine. In some embodiments, ring E is pyrazine. In some embodiments, ring E is triazine. In some embodiments, ring E is 5-membered heteroaryl. In some embodiments, ring E is pyrazole. In some embodiments, ring E is triazole, pyrrole, imidazole, oxazole, oxadiazole, thiazole, or thiadiazole. In some embodiments, ring E is triazole. In some embodiments, ring E is imidazole or pyrrole. In some embodiments, oxazole or oxadiazole. In some embodiments, ring E is thiazole or thiadiazole.

[0214] In some embodiments, ring E is one or more of -OH, -(OCH 2 CH 2 ) m -OH or -(OCH2 CH 2 ) m -O-(C 1 -C 6 In some embodiments, Ring E is phenyl substituted with one or more -OH. In some embodiments, Ring E is substituted with -(OCH 2 CH 2 ) m In some embodiments, ring E is phenyl substituted with one or more -(OCH 2 CH 2 ) m -O-(C 1 -C 6 phenyl substituted with alkyl.

[0215] In some embodiments, m is 1 to 10. In some embodiments, m is 2 to 10. In some embodiments, m is 3 to 10. In some embodiments, m is 4 to 10. In some embodiments, m is 5 to 10. In some embodiments, m is 6 to 10. In some embodiments, m is 7 to 10. In some embodiments, m is 8 to 10. In some embodiments, m is 9 to 10.

[0216] In some embodiments, m is 1 to 9. In some embodiments, m is 2 to 9. In some embodiments, m is 3 to 9. In some embodiments, m is 4 to 9. In some embodiments, m is 5 to 9. In some embodiments, m is 6 to 9. In some embodiments, m is 7 to 9. In some embodiments, m is 8 to 9.

[0217] In some embodiments, m is 1 to 8. In some embodiments, m is 2 to 8. In some embodiments, m is 3 to 8. In some embodiments, m is 4 to 8. In some embodiments, m is 5 to 8. In some embodiments, m is 6 to 8. In some embodiments, m is 7 to 8.

[0218] In some embodiments, m is 1 to 7. In some embodiments, m is 2 to 7. In some embodiments, m is 3 to 7. In some embodiments, m is 4 to 7. In some embodiments, m is 5 to 7. In some embodiments, m is 6 to 7.

[0219] In some embodiments, m is 1 to 6. In some embodiments, m is 2 to 6. In some embodiments, m is 3 to 6. In some embodiments, m is 4 to 6. In some embodiments, m is 5 to 6.

[0220] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0221] In some embodiments, ring E is absent.

[0222] In some embodiments, Y is -CH 2 In some embodiments, Y is -CH 2 In some embodiments, Y is -NH-. In some embodiments, Y is -NH-. In some embodiments, Y is -O-.

[0223] In some embodiments, R 17 is hydrogen. In some embodiments, R 17 is C 1 -C 6 In some embodiments, R 17 is methyl, ethyl, or propyl. In some embodiments, R 17is methyl. In some embodiments, R 17 is ethyl. In some embodiments, R 17 is propyl.

[0224] In some embodiments, R 18 and R 19 are each independently hydrogen, CN, or NO 2 In some embodiments, R 18 and R 19 each independently represents a halogen or an optionally substituted C 1 -C 6 In some embodiments, R 18 and R 19 is, independently at each occurrence, bromo, chloro, fluoro, methyl, or ethyl. In some embodiments, R 18 and R 19 is independently at each occurrence fluoro or methyl.

[0225] In some embodiments, R 18 is halogen. In some embodiments, R 18 is chloro, bromo, or fluoro. In some embodiments, R 18 is chloro. In some embodiments, R 18 is bromo. In some embodiments, R 18 is fluoro.

[0226] In some embodiments, R 19a is halogen, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 In some embodiments, R 19a is halogen or optionally substituted C 1 -C 6 In some embodiments, R 19a is chloro, bromo, fluoro, or methyl. In some embodiments, R 19ais fluoro or methyl. In some embodiments, R 19a is chloro. In some embodiments, R 19a is bromo. In some embodiments, R 19a is fluoro. In some embodiments, R 19a is methyl.

[0227] In some embodiments, R 19b is hydrogen, halogen or optionally substituted C 1 -C 6 In some embodiments, R 19b is chloro, bromo, fluoro, or methyl. In some embodiments, R 19b is chloro. In some embodiments, R 19b is bromo. In some embodiments, R 19b is fluoro or methyl. In some embodiments, R 19b is fluoro. In some embodiments, R 19b is methyl. In some embodiments, R 19b is hydrogen.

[0228] In some embodiments, R 25 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, or optionally substituted C 1 -C 6 and hydroxyalkyl, each of which is optionally substituted with amido, alkyl, alkynyl, azido, amino, halogen, haloalkyl, hydroxy, nitro, oxo (=O), phosphorus hydroxide, or PEG.

[0229] In some embodiments, R 25is optionally replaced by C 1-6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl or optionally substituted C 1 -C 6 In some embodiments, R 25 is C 1 -C 6 Alkyl or C 1 -C 6 Heteroalkyl, each of which is -CN, -NH 2 , -N 3 , -OH, CF 3 , -OP(=O)(OH) 2 , or -O(CH 2 )OP(=O)(OH) 2 is optionally replaced by .

[0230] In some embodiments, R 25 -NHSO 2 R A where R A is C 1 -C 6 In some embodiments, R 25 -NHSO 2 Et. In some embodiments, R 25 -NHSO 2 In some embodiments, R 25 -SO 2 R A where R A is C 1 -C 6 In some embodiments, R 25 -SO 2 Et. In some embodiments, R 25 -SO 2 It's me.

[0231] In some embodiments, R 25 teeth,

[0232] [ka] It is.

[0233] In some embodiments, R 25a is optionally replaced by C 1-6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl or optionally substituted C 1 -C 6 In some embodiments, R 25a is C 1 -C 6 Alkyl or C 1-6 Heteroalkyl, each of which is -CN, -NH 2 , -N 3 , -OH, CF 3 , -OP(=O)(OH) 2 , -C(=O)(CH 2 ) 2 P(=O)(OH) 2 , or -(CH 2 )OP(=O)(OH) 2 In some embodiments, R 25a is hydrogen, methyl, ethyl, -OP(=O)(OH) 2 , or -(CH 2 )OP(=O)(OH) 2 It is.

[0234] In some embodiments, R 32 is optionally substituted with haloalkyl, phosphorus hydroxide 1 -C 6 In some embodiments, R 32 is -OP(=O)(OH) 2 C replaced by 1 -C 6 In some embodiments, R 32 is unsubstituted C 1 -C 6 In some embodiments, R 32 is methyl, ethyl, or tert-butyl. In some embodiments, R 32is methyl. In some embodiments, R 32 is ethyl. In some embodiments, R 32 is tert-butyl. In some embodiments, R 32 is hydrogen.

[0235] In some embodiments, y 1 is 1. In some embodiments, y 1 is 2. In some embodiments, y 1 is 3.

[0236] In some embodiments, the second end comprises the structure of formula (B-3):

[0237] [ka] During the ceremony, R 17 is hydrogen or C 1 -C 6 is alkyl, R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , optionally replaced by -C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Haloalkyl or optionally substituted C 1 -C 6 is hydroxyalkyl, or R 18 But -NR A R B and R 25 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C6 Alkynyl, optionally substituted C 1 -C 6 Hydroxyalkyl, -SO 2 R A , or -NHSO 2 R A and R 32 is hydrogen or optionally substituted C 1 -C 6 is alkyl, R 33a , R 33b , and R 33c each independently is selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, optionally substituted C 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, optionally substituted C 1 -C 20 Haloalkyl, optionally substituted C 1 -C 6 Hydroxyalkyl, or optionally substituted (PEG) 1-20 Selected from Each R A and R B are independently hydrogen, deuterium, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 is heteroalkyl, y 1 However, the numbers are 1 to 3.

[0238] In some embodiments, R 33a , R 33b , and R 33c each independently represents hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, or optionally substituted (PEG) 1-20 In some embodiments, R 33a , R33b , and R 33c are each independently hydrogen, halogen, or optionally substituted (PEG) 1-20 In some embodiments, R 33a , R 33b , and R 33c are each hydrogen.

[0239] In some embodiments, R 33a is halogen, hydroxyl, optionally substituted C 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, or optionally substituted (PEG) 1-20 and R 33b and R 33c are each hydrogen. In some embodiments, R 33a is optionally substituted (PEG) 1-20 and R 33b and R 33c are each hydrogen.

[0240] In some embodiments, the second end comprises a compound having the structure of formula (B-4), or a pharma- ceutically acceptable salt thereof:

[0241] [ka]

[0242] In some embodiments, the second end comprises a compound having the structure of formula (B-5), or a pharma- ceutically acceptable salt thereof:

[0243] [ka]

[0244] In some embodiments, the second end comprises a compound having the structure of formula (B-6) or (B-7), or a pharma- ceutically acceptable salt thereof:

[0245] [ka]

[0246] In some embodiments, the second end comprises a compound having the structure of formula (B-8), or a pharma- ceutically acceptable salt thereof:

[0247] [ka]

[0248] In some embodiments, the second end comprises a compound having the structure of formula (B-9), or a pharma- ceutically acceptable salt thereof:

[0249] [ka]

[0250] In some embodiments, the second end comprises a structure of formula (B-10) or (B-11), or a pharma- ceutically acceptable salt thereof:

[0251] [ka]

[0252] In some embodiments, the second end comprises a compound having the structure of formula (B-12), (B-13), or (B-14), or a pharma- ceutically acceptable salt thereof:

[0253] [ka]

[0254] In some embodiments, the second end comprises a compound having the structure of formula (B-15), or a pharma- ceutically acceptable salt thereof:

[0255] [ka] During the ceremony, Y is -CH 2 NH-, CH 2 -O-, -NH-, or -O-; R 17 is hydrogen or C 1 -C 6 is alkyl, R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , optionally replaced by -C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Haloalkyl or optionally substituted C 1 -C 6 is hydroxyalkyl, R 25 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Hydroxyalkyl, -SO 2 R A , or -NHSO 2 R A and R 32 is hydrogen or optionally substituted C 1 -C 6 is alkyl, R 34 is hydrogen, halogen, -OH, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 is hydroxyalkyl, R 35is hydrogen, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 haloalkyl, or an optionally substituted 5-6 membered monocyclic aryl or heteroaryl; R A is optionally substituted with hydrogen, deuterium, 1 -C 6 Alkyl or optionally substituted C 1 -C 6 is heteroalkyl, y 1 However, the numbers are 1 to 3.

[0256] In some embodiments, the second end comprises a compound having the structure of formula (B-16), or a pharma- ceutically acceptable salt thereof:

[0257] [ka] During the ceremony, Y is -CH 2 NH-, CH 2 -O-, -NH-, or -O-; R 17 is hydrogen or C 1 -C 6 is alkyl, R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , optionally replaced by -C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Haloalkyl or optionally substituted C 1 -C 6 is hydroxyalkyl, R 25 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 1 -C6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Hydroxyalkyl, -SO 2 R A , or -NHSO 2 R A and R 32 is hydrogen or optionally substituted C 1 -C 6 is alkyl, R 34 is hydrogen, halogen, -OH, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 is hydroxyalkyl, R 35 is hydrogen, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 haloalkyl, or an optionally substituted 5-6 membered monocyclic aryl or heteroaryl; R A is optionally substituted with hydrogen, deuterium, 1 -C 6 Alkyl or optionally substituted C 1 -C 6 is heteroalkyl, y 1 However, the numbers are 1 to 3.

[0258] In some embodiments, R 34 is hydrogen, halogen, or -OH. In some embodiments, R 34 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C1 -C 6 In some embodiments, R 34 is hydrogen.

[0259] In some embodiments, R 35 is optionally replaced by C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 In some embodiments, R 35 is optionally replaced by C 1 -C 6 In some embodiments, R 35 is methyl, ethyl, or iso-propyl. In some embodiments, R 35 is an optionally substituted 5-6 membered monocyclic aryl or heteroaryl.

[0260] In some embodiments, the second end comprises a compound having the structure of formula (B-17), or a pharma- ceutically acceptable salt thereof:

[0261] [ka] .

[0262] In some embodiments, the second end is

[0263] [ka]

[0264] [ka] or a pharma- ceutically acceptable salt thereof.

[0265] Linker-oligomer backbone The oligomeric backbone includes a linker connecting the first and second ends and brings the regulatory molecule into proximity with the target gene to modulate gene expression.

[0266] The length of the linker also depends on the type of regulatory protein and the target gene. In some embodiments, the linker has a length of less than about 50 angstroms. In some embodiments, the linker has a length of about 20-30 angstroms.

[0267] In some embodiments, the linker comprises between 5 and 50 chain atoms.

[0268] In some embodiments, the linker comprises a multimer having 2 to 50 spacing moieties, the spacing moieties being independently -((CR 3a R 3b ) x -O) y -, -((CR 3a R 3b ) x -NR 4a ) y -, -((CR 3a R 3b ) x -CH=CH-(CR 3a R 3b ) x -O) y -, optionally replaced by -C 1 -C 12 Alkyl, optionally substituted C 2 -C 10 Alkenyl, optionally substituted C 2 -C 10 Alkynyl, optionally substituted C 6 -C 10 Arylene, optionally substituted C 3 -C 7 Cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 4- to 10-membered heterocycloalkylene, amino acid residue, -O-, -C(=O)NR 4a -, -NR 4a C(=O)-, -C(=O)-, -NR 1-, -C(=O)O-, -O-, -S-, -S(=O)-, -SO 2 -, -SO 2 NR 4a -, -NR 4a SO 2 -, -P(=O)OH-, and any combination thereof; each x is independently 2 to 4; each y is independently 1 to 10; Each R 3a and R 3b are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, optionally substituted alkylamido, sulfonyl, optionally substituted thioalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl; Each R 4a are independently hydrogen or optionally substituted C 1 -C 6 It is an alkyl.

[0269] In some embodiments, the oligomer backbone is -(T 1 -V 1 ) a -(T 2 -V 2 ) b -(T 3 -V 3 ) c -(T 4 -V 4 ) d -(T 5 -V 5 ) e -, wherein a, b, c, d, and e are each independently 0 or 1, and the sum of a, b, c, d, and e is 1 to 5; T 1 , T 2 , T 3, T 4 , and T 5 each independently represents an optionally substituted C 1 -C 12 Alkylene, optionally substituted alkenylene, optionally substituted alkynylene, (EA) w , (EDA) m , (PEG) n , (modified PEG) n , (AA) p , -(CR 2a OH) h -, optionally replaced by C 6 -C 10 Arylene, optionally substituted C 3 -C 7 is selected from cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 4- to 10-membered heterocycloalkylene, acetal groups, disulfides, hydrazines, carbohydrates, beta-lactams, and esters, wherein w is an integer from 1 to 20; m is an integer from 1 to 20; n is an integer from 1 to 30; p is an integer from 1 to 20; h is an integer from 1 to 12; The EA has the following structure:

[0270] [ka] EDA has the following structure:

[0271] [ka] In the formula, each q is independently an integer from 1 to 6, each x is independently an integer from 1 to 4, and each r is independently 0 or 1; (PEG) n But -(CR 2a R 2b -CR 2a R 2b -O) n-CR 2a R 2b -having the structure (Modified PEG) n However, (PEG) n At least one of -(CR 2a R 2b -CR 2a R 2b -O)-(CH 2 -CR 2a =CR 2a -CH 2 -O)- or -(CR 2a R 2b -CR 2a R 2b -S)-, AA is an amino acid residue, V 1 , V 2 , V 3 , V 4 , and V 5 each independently represents a bond, -CO-, or -NR 1a -,-CONR 1a -, -NR 1a CO-, -CONR 1a C 1-4 Alkyl-, -NR 1a CO-C 1-4 Alkyl-, -C(=O)O-, -OC(=O)-, -O-, -S-, -S(=O)-, -SO 2 -, -SO 2 NR 1a -, -NR 1a SO 2 -, and -P(=O)OH-, Each R 1a are independently hydrogen or optionally substituted C 1-6 is alkyl, Each R 2a and R 2bis independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamido, substituted alkylamido, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0272] In some embodiments, a, b, c, d, and e are each independently 0 or 1, and the sum of a, b, c, d, and e is 1. In some embodiments, a, b, c, d, and e are each independently 0 or 1, and the sum of a, b, c, d, and e is 2. In some embodiments, a, b, c, d, and e are each independently 0 or 1, and the sum of a, b, c, d, and e is 3. In some embodiments, a, b, c, d, and e are each independently 0 or 1, and the sum of a, b, c, d, and e is 4. In some embodiments, a, b, c, d, and e are each independently 0 or 1, and the sum of a, b, c, d, and e is 5.

[0273] In some embodiments, n is 3 to 9. In some embodiments, n is 4 to 8. In some embodiments, n is 5 or 6.

[0274] In some embodiments, T 1 , T 2 , T 3 , and T 4 , and T 5 are each independently 1 -C 12 ) Alkyl, Substituted (C 1 -C 12 ) alkyl, (EA) w , (EDA) m , (PEG) n , (modified PEG) n , (AA) p , -(CR2a OH) h -, phenyl, substituted phenyl, piperidine-4-amino (P4A), para-amino-benzyloxycarbonyl (PABC), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), meta-amino-benzyloxy (MABO), para-aminobenzyl, acetal group, disulfide, hydrazine, carbohydrate, beta-lactam, ester, (AA) p -MABC-(AA) p , (AA) p -MABO-(AA) p , (AA) p -PABO-(AA) p , and (AA) p -PABC-(AA) p In some embodiments, piperidine-4-amino (P4A) is selected from:

[0275] [ka] where R 1a is H or C 1 -C 6 It is an alkyl.

[0276] In some embodiments, T 1 , T 2 , T 3 , T 4 , and T 5 are each independently 1 -C 12 Alkyl, substituted C 1 -C 12 Alkyl, (EA) w , (EDA) m , (PEG) n , (modified PEG) n , (AA) p , -(CR 2a OH) h -, optionally replaced by C 6 -C 10arylene, 4-10 membered heterocycloalkene, and optionally substituted 5-10 membered heteroarylene. In some embodiments, EA has the structure:

[0277] [ka] EDA has the following structure:

[0278] [ka]

[0279] In some embodiments, for EA and EDA, x is 2 to 3 and q is 1 to 3. In some embodiments, R 1a is H or C 1 -C 6 It is an alkyl.

[0280] In some embodiments, T 4 Or T 5 is optionally replaced by C 6 -C 10 It is Arylene.

[0281] In some embodiments, T 4 Or T 5 is phenylene or substituted phenylene. In some embodiments, T 4 Or T 5 is phenylene or -C 1-6 In some embodiments, T is phenylene substituted with 1 to 3 substituents selected from alkyl, halogen, OH, or amine. 4 Or T 5 is 5-10 membered heteroarylene or substituted heteroarylene. In some embodiments, T 4 Or T 5 is a 4-10 membered heterocylcene or substituted heterocyclene. In some embodiments, T 4 Or T5 is C 1 -C 6 It is a heteroarylene or heterocyclene optionally substituted with 1 to 3 substituents selected from alkyl, halogen, OH, or amine.

[0282] In some embodiments, T 1 , T 2 , T 3 , T 4 , and T 5 , and V 1 , V 2 , V 3 , V 4 , and V 5 is selected from Table 2 below.

[0283] [Table 4]

[0284] In some embodiments, the linker is

[0285] [ka] or any combination thereof, r is an integer from 1 to 10, preferably from 3 to 7, and X is O, S, or NR 1a In some embodiments, X is O or NR 1a In some embodiments, X is O.

[0286] In some embodiments, the linker is

[0287] [ka] or any combination thereof, and at least one -(CH 2 -CH 2 -O)- is -((CR 1a R 1b ) x -CH=CH-(CR1a R 1b ) x -O)-, or any combination thereof; W' is absent, (CH 2 ) 1-5 , -(CH 2 ) 1-5 O, (CH 2 ) 1-5 -C(=O)NH-(CH 2 ) 1-5 -O, (CH 2 ) 1-5 -C(=O)NH-(CH 2 ) 1-5 , -(CH 2 ) 1-5 -NHC(=O)-(CH 2 ) 1-5 -O, or -(CH 2 ) 1-5 -NHC(=O)-(CH 2 ) 1-5 - and E 3 is optionally replaced by C 6 -C 10 arylene group, optionally substituted 4- to 10-membered heterocycloalkylene, or optionally substituted 5- to 10-membered heteroarylene, X is O, S, or NH, and each R 1a and R 1b are independently H or C 1 -C 6 alkyl, r is an integer from 1 to 10, and x is an integer from 1 to 15. In some embodiments, X is O. In some embodiments, X is NH. In some embodiments, E 3 is C 1 -C 6 C optionally substituted with 1 to 3 substituents selected from alkyl, halogen, OH, or amine 6 -C 10 It is an arylene group.

[0288] In some embodiments, E 3 is phenylene or substituted phenylene.

[0289] In some embodiments, the linker is

[0290] [ka] Includes.

[0291] In some embodiments, the linker is -X(CH 2 ) m (CH 2 CH 2 O) n where X is -O-, -NH-, or -S-, m is 0 or greater, and n is at least 1.

[0292] In some embodiments, the linker comprises at the second end

[0293] [ka] Including R c is a bond, -N(R 1a )-, -O-, and -S-; R d is -N(R 1a )-, -O-, and -S-; R e are independently hydrogen and optionally substituted C 1 -C 6 alkyl; R 1a is H or C 1 -C 6 It is an alkyl.

[0294] In some embodiments, the linker is

[0295] [ka] C 1 -C 12 Alkyl, arylene, cycloalkylene, heteroarylene, heterocycloalkylene, -O-, -C(=O)NR 1a -, -C(=O)-, -NR 1a -, -(CH 2 CH2 CH 2 O) y - and -(CH 2 CH 2 CH 2 NR 1a ) y -, wherein each d and y is independently 1 to 10; 1a are independently hydrogen or C 1 -C 6 In some embodiments, d is 4 to 8.

[0296] In some embodiments, the linker is

[0297] [ka] wherein each d is independently 3 to 7. In some embodiments, d is 4 to 6. In other embodiments, d is 5 to 9.

[0298] In some embodiments, the linker is -N(R 1a )(CH 2 ) x N(R 1b )(CH 2 ) x N-, wherein R 1a and R 1b are each independently hydrogen or optionally substituted C 1 -C 6 alkyl, and each x is independently an integer ranging from 1 to 6.

[0299] In some embodiments, the linker is -(CH 2 -C(=O)N(R'')-(CH 2 ) q -N(R')-(CH 2 ) q -N(R'')C(=O)-(CH 2 ) x -C(=O)N(R'')-A 2 -, -(CH 2 )x -C(=O)N(R'')-(CH 2 CH 2 O) y (CH 2 ) x -C(=O)N(R'')-A 2 -, -C(=O)N(R'')-(CH 2 ) q -N(R')-(CH 2 ) q -N(R'')C(=O)-(CH 2 ) x -A 2 -, -(CH 2 ) x -O-(CH 2 CH 2 O) y -(CH 2 ) x -N(R'')C(=O)-(CH 2 ) x -A 2 - or -N(R'')C(=O)-(CH 2 )-C(=O)N(R'')-(CH 2 ) x -O(CH 2 CH 2 O) y (CH 2 ) x -A 2 wherein R' is methyl, R'' is hydrogen, each x and y is independently an integer from 1 to 10, each q is independently an integer from 2 to 10, and each A 2 is independently a bond, optionally substituted C 1 -C 12 Alkyl, optionally substituted C 6 -C 12 Arylene, optionally substituted C 3 -C 7 It is selected from cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, and optionally substituted 4- to 10-membered heterocycloalkylene.

[0300] In some embodiments, the linker is -(CH 2 CH 2 -O)x1 -or-(CH 2 CH 2 -O) x2 -A 2 -(CH 2 CH 2 -O) x3 -, wherein A 2 is an optionally substituted 4-10 membered heterocycloalkylene or spirocyclene, and each x 1 , x 2 , and x 3 are independently an integer from 1 to 15.

[0301] In some embodiments, A 2 teeth,

[0302] [ka] In some embodiments, A 2 teeth,

[0303] [ka] In some embodiments, A 2 teeth,

[0304] [ka] In some embodiments, A 2 teeth,

[0305] [ka] It is.

[0306] In some embodiments, A 2 comprises a moiety having the structure:

[0307] [ka] During the ceremony, X 2 is absent or -C(=O)-, R 26 is optionally replaced by C 1 -C 50 Alkyl or optionally substituted C 1 -C 50 It is heteroalkyl.

[0308] In some embodiments, X 2 is -C(=O)-. In some embodiments, X 2 is absent.

[0309] In some embodiments, R 26 is C 1 -C 50 In some embodiments, R 26 is C 1 -C 40 In some embodiments, R 26 is C 1 -C 30 In some embodiments, R 26 is C 1 -C 20 In some embodiments, R 26 is C 1 -C 10 In some embodiments, R 26 is C 1 -C 50 In some embodiments, R 26 is C 1 -C 40 In some embodiments, R 26 is C 1 -C 30 In some embodiments, R 26 is C 1 -C 20 In some embodiments, R 26 is C 1-C 10 Heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG).

[0310] In some embodiments, the linker is -C(=O)-, -NR 1a -, C 1 -C 12 Alkyl, -C(=O)NR 1a - and -NR 1a C(═O)—, wherein each R 1a are independently hydrogen or optionally substituted C 1 -C 12 Alkylene, optionally substituted C 2 -C 10 Alkenylene, optionally substituted C 2 -C 10 Alkynylene, optionally substituted C 6 -C 10 Arylene, optionally substituted C 3 -C 7 cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, and optionally substituted 4- to 10-membered heterocycloalkylene.

[0311] In some embodiments, the linker is -C(=O)-, -NR 1a -, -C(=O)NR 1a -, -NR 1a C(=O)-, -C(=O)NR 1a C 1 -C 4 Alkyl-, -NR 1a C(=O)-C 1 -C 4 Alkyl, -C(=O)O-, -OC(=O)-, -O-, -S-, -S(=O)-, -SO 2 -, -SO 2 NR 1a -, -NR 1 SO 2 -, -P(=O)OH-, -((CH 2 ) x -O)-, -((CH 2 )y -NR 1a )-, optionally replaced by C 1 -C 12 Alkylene, optionally substituted C 2 -C 10 Alkenylene, optionally substituted C 2 -C 10 Alkynylene, optionally substituted C 6 -C 10 Arylene, optionally substituted C 3 -C 7 attached to the first terminus by a group selected from cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, and optionally substituted 4- to 10-membered heterocycloalkylene; each x is independently 1 to 4, each y is independently 1 to 4, and each R 1a are independently hydrogen or optionally substituted C 1 -C 6 It is an alkyl.

[0312] In some embodiments, the linker is -C(=O)-, -NR 1a -, C 1-12 Alkyl, -C(=O)NR 1a - and -NR 1a and attached to the first end by a group selected from C(=O).

[0313] In some embodiments, the linker is -C(=O)-, -NR 1a -, -C(=O)NR 1a -, -NR 1a C(=O)-, -C(=O)NR 1a C 1 -C 4 Alkyl-, -NR 1a C(=O)-C 1 -C 4 Alkyl, -C(=O)O-, -OC(=O)-, -O-, -S-, -S(=O)-, -SO 2 -, -SO 2 NR 1a -, -NR 1 SO 2 -, -P(=O)OH-, -((CH 2 )x -O)-, -((CH 2 ) y -NR 1a )-, optionally replaced by -C 1 -C 12 Alkylene, optionally substituted C 2 -C 10 Alkenylene, optionally substituted C 2 -C 10 Alkynylene, optionally substituted C 6 -C 10 Arylene, optionally substituted C 3 -C 7 attached to the second terminus by a group selected from cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, and optionally substituted 4- to 10-membered heterocycloalkylene; each x is independently 1 to 4, each y is independently 1 to 4, and each R 1a are independently hydrogen or optionally substituted C 1 -C 6 It is an alkyl.

[0314] In some embodiments, the linker is -C(=O)-, -NR 1a -, -C(=O)NR 1a -, -NR 1a C(=O)-, -((CH 2 ) x -O)-, -((CH 2 ) y -NR 1a )-, -O-, optionally substituted -C 1 -C 12 Alkyl, optionally substituted C 6 -C 10 Arylene, optionally substituted C 3 -C 7 attached to the second terminus by a group selected from cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, and optionally substituted 4- to 10-membered heterocycloalkylene; each x is independently 1 to 4, each y is independently 1 to 4, and each R 1 are independently hydrogen or optionally substituted C 1 -C 6It is an alkyl.

[0315] In some embodiments, the linker is attached to the second terminus with a group selected from an optionally substituted 4-10 membered heterocycloalkylene.

[0316] In some embodiments, the linker is attached to the second end by a moiety that comprises the structure of formula (C-1), or a pharma- ceutically acceptable salt thereof:

[0317] [ka] During the ceremony, Ring D is absent, optionally substituted arylene, or optionally substituted heterocycloalkylene; L 1 is absent or optionally substituted alkylene, optionally substituted C 2 -C 10 Alkenylene or optionally substituted C 2 -C 10 is alkynylene, each X 3 and X 4 is independently CH or N; p 1 and p 2 are each independently 0 to 3; ** indicates the bond to the second end.

[0318] In some embodiments, ring D is absent. In some embodiments, ring D is C 4 -C 7 It is a heterocycloalkylene.

[0319] In some embodiments, X 3 is N. In some embodiments, X 3 is CH.

[0320] In some embodiments, X 4 is N. In some embodiments, X 4 is CH.

[0321] In some embodiments, the linker is attached to the second end by a moiety that comprises the structure of formula (C-2), or a pharma- ceutically acceptable salt thereof:

[0322] [ka] During the ceremony, L 1 is absent or optionally substituted alkylene, optionally substituted C 2 -C 10 Alkenylene or optionally substituted C 2 -C 10 is alkynylene, X 4 is independently CH or N; each X 5 and X 6 is independently N or CH; ** indicates the bond to the second end.

[0323] In some embodiments, X 4 and X 5 Each of X is independently N or CH; 6 is N.

[0324] In some embodiments, L 1 is absent.

[0325] In some embodiments, L 1 is -(CR 1G R 1G ) x -(Alkylene) 2 -(CR 1G R 1G ) y -, wherein x and y are each independently 0 or 1; 1G is hydrogen or C 1 -C 3 It is an alkyl.

[0326] In some embodiments, L 1 is C1 -C 3 Alkylene, C 2 -C 4 Alkenylene or C 2 -C 4 It is alkynylene.

[0327] In some embodiments, L 1 is -CH 2 -, -CH 2 CH 2 In some embodiments, L is -, -C≡C-, or -C≡CC≡C-. 1 is -CH 2 -or-CH 2 CH 2 In some embodiments, L 1 is -C≡C-. In some embodiments, L 1 is -C≡CC≡C-.

[0328] In some embodiments, the linker is attached to the second end with a moiety that comprises the structure of formula (C-3):

[0329] [ka] During the ceremony, p 1 and p 2 are each independently 0 to 3; r 1 But, 1 to 3, R 27 is optionally replaced by C 1 -C 50 Alkyl, optionally substituted C 1 -C 50 Heteroalkyl, -C(=O)(C 1 -C 50 alkyl) or -C(=O)(C 1 -C 50 heteroalkyl), each alkyl and heteroalkyl being optionally substituted; Each R 1G are independently hydrogen or C 1-C 3 is alkyl, ** indicates the bond to the second end.

[0330] In some embodiments, R 27 is optionally replaced by C 1 -C 50 Alkyl or optionally substituted C 1 -C 50 In some embodiments, R 27 is -C(=O)(C 1 -C 50 alkyl) or -C(=O)(C 1 -C 50 heteroalkyl), wherein each alkyl and heteroalkyl is optionally substituted.

[0331] In some embodiments, R 27 is C 1 -C 50 In some embodiments, R 27 is C 1 -C 40 In some embodiments, R 27 is C 1 -C 30 In some embodiments, R 27 is C 1 -C 20 In some embodiments, R 27 is C 1 -C 10 In some embodiments, R 27 is C 1 -C 50 In some embodiments, R 27 is C 1 -C 40 In some embodiments, R 27 is C 1 -C 30 In some embodiments, R 27 is C 1 -C 20In some embodiments, R 27 is C 1 -C 10 Heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG).

[0332] In some embodiments, each R 1G is independently hydrogen. In some embodiments, each R 1G is independently 1 -C 3 In some embodiments, C 1 -C 3 Alkyl is methyl, ethyl, or propyl. In some embodiments, each R 1G is independently methyl.

[0333] In some embodiments, p 1 is 0, 1, or 2. In some embodiments, p 1 is 0. In some embodiments, p 1 is 1. In some embodiments, p 1 is 2.

[0334] In some embodiments, r 1 is 1 or 2. In some embodiments, r 1 is 1. In some embodiments, r 1 is 2.

[0335] In some embodiments, the linker is

[0336] [ka] and ** indicates the bond to the second terminal.

[0337] In some embodiments, the linker is

[0338] [ka] and ** indicates the bond to the second terminal.

[0339] In some embodiments, the compound comprises a moiety having the structure of formula (D-1), or a pharma- ceutically acceptable salt thereof:

[0340] [ka] During the ceremony, Ring E is absent or an optionally substituted 5- to 6-membered monocyclic aryl or heteroaryl, or an optionally substituted 4- to 8-membered heterocycle; Y is -CH 2 NH-, CH 2 -O-, -NH-, or -O-; L A is optionally substituted alkylene, optionally substituted heteroalkylene, or optionally substituted PEG; L B However, absent or

[0341] [ka] and Ring D is absent, optionally substituted arylene, or optionally substituted heterocycloalkylene; L 1 is absent or optionally substituted alkylene, optionally substituted C 2 -C 10 Alkenylene or optionally substituted C 2 -C 10 is alkynylene, each X 3 and X 4 is independently CH or N; p 1 and p 2 are each independently 0 to 3; ** indicates the point of attachment to ring E or Y; each X 3 and X 4 is independently CH or N; R 17 is hydrogen or C 1 -C 6 is alkyl, R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , optionally replaced by -C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Haloalkyl or optionally substituted C 1 -C 6 is hydroxyalkyl, or R 18 But -NR A R B and R 25 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Hydroxyalkyl, -SO 2 R A , or -NHSO 2 R A and R 32 is hydrogen or optionally substituted C 1 -C 6 is alkyl, R 34 is hydrogen, halogen, -OH, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C1 -C 6 is hydroxyalkyl, Each R A and R B are independently hydrogen, deuterium, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 is heteroalkyl, y 1 But, 1 to 3, The * indicates the bond to the first end.

[0342] In some embodiments, L B is absent.

[0343] In some embodiments, L B teeth,

[0344] [ka] It is.

[0345] In some embodiments, the compound comprises a moiety having the structure of formula (D-2):

[0346] [ka] During the ceremony, Ring D is absent, optionally substituted arylene, or optionally substituted heterocycloalkylene; Ring E is absent or an optionally substituted 5- to 6-membered monocyclic aryl or heteroaryl, or an optionally substituted 4- to 8-membered heterocycle; Y is -CH 2 NH-, CH 2 -O-, -NH-, or -O-; L A is optionally substituted alkylene, optionally substituted heteroalkylene, or optionally substituted PEG; L 1 is absent or optionally substituted alkylene, optionally substituted C 2 -C 10 Alkenylene or optionally substituted C 2 -C 10 is alkynylene, each X 3 and X 4 is independently CH or N; R 17 is hydrogen or C 1 -C 6 is alkyl, R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , optionally replaced by -C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Haloalkyl or optionally substituted C 1 -C 6 is hydroxyalkyl, or R 18 But -NR A R B and R 25 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Hydroxyalkyl, -SO 2 R A , or -NHSO 2 R A and R 32 is hydrogen or optionally substituted C 1 -C 6 is alkyl, R34 is hydrogen, halogen, -OH, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 is hydroxyalkyl, Each R A and R B are independently hydrogen, deuterium, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 is heteroalkyl, p 1 and p 2 are each independently 0 to 3; y 1 But, 1 to 3, The * indicates the bond to the first end.

[0347] In some embodiments, the compound comprises a moiety having the structure of formula (D-3):

[0348] [ka] During the ceremony, Ring D is absent, optionally substituted arylene, or optionally substituted heterocycloalkylene; Y is -CH 2 NH-, CH 2 -O-, -NH-, or -O-; L A is optionally substituted alkylene, optionally substituted heteroalkylene, or optionally substituted PEG; L 1 is absent or optionally substituted alkylene, optionally substituted C 2 -C 10 Alkenylene or optionally substituted C 2 -C 10 is alkynylene, each X 3 and X 4 is independently CH or N; R 17 is hydrogen or C 1 -C 6 is alkyl, R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , optionally replaced by -C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Haloalkyl or optionally substituted C 1 -C 6 is hydroxyalkyl, or R 18 But -NR A R B and R 25 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Hydroxyalkyl, -SO 2 R A , or -NHSO 2 R A and R 32 is hydrogen or optionally substituted C 1 -C 6 is alkyl, Each R 33 are independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, and optionally substituted C 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, optionally substituted C1 -C 20 Haloalkyl, optionally substituted C 1 -C 6 Hydroxyalkyl, or optionally substituted (PEG) 1-20 is selected from R 34 is hydrogen, halogen, -OH, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 is hydroxyalkyl, Each R A and R B are independently hydrogen, deuterium, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 is heteroalkyl, p 1 and p 2 are each independently 0 to 3; y 2 But, 1 to 3, y 1 But, 1 to 3, The * indicates the bond to the first end.

[0349] In some embodiments, the compound comprises a moiety having the structure of formula (D-4):

[0350] [ka] During the ceremony, Y is -CH 2 NH-, CH 2 -O-, -NH-, or -O-; L A is optionally substituted alkylene, optionally substituted heteroalkylene, or optionally substituted PEG; R 17 is hydrogen or C 1-C 6 is alkyl, R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , optionally replaced by -C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Haloalkyl or optionally substituted C 1 -C 6 is hydroxyalkyl, or R 18 But -NR A R B and R 25 is optionally replaced by C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Hydroxyalkyl, -SO 2 R A , or -NHSO 2 R A and R 32 is hydrogen or optionally substituted C 1 -C 6 is alkyl, Each R 33 are independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, and optionally substituted C 1 -C 20 Alkyl, optionally substituted C 1 -C 20 Heteroalkyl, optionally substituted C 1 -C 20 Haloalkyl, optionally substituted C 1 -C 6 Hydroxyalkyl, or optionally substituted (PEG)1-20 is selected from R 34 is hydrogen, halogen, -OH, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 is hydroxyalkyl, Each R A and R B are independently hydrogen, deuterium, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 is heteroalkyl, y 2 But, 1 to 3, y 1 But, 1 to 3, The * indicates the bond to the first end.

[0351] In some embodiments, L A is optionally replaced by C 1 -C 20 Alkylene or optionally substituted C 2 -C 20 Heteroalkylene, optionally substituted C 2 -C 4 Alkynylene, or optionally substituted PEG 1-20 wherein each is optionally substituted with alkyl, amino, cyano, haloalkyl, or oxo (=O).

[0352] In some embodiments, L A teeth,

[0353] [ka] where n 3is 7, 8, 9, 10, 11, 12, 13, 14, or 15, * indicates the attachment to the first terminus, and ** indicates the point of attachment to the phenyl. A teeth,

[0354] [ka] where n 3 is 9, 10, 11, 12, 13, 14, or 15, * indicates the attachment to the first terminus, and ** indicates the point of attachment to the phenyl. 3 is 7. In some embodiments, n 3 is 8. In some embodiments, n 3 is 9. In some embodiments, n 3 is 10. In some embodiments, n 3 is 11. In some embodiments, n 3 is 12.

[0355] In some embodiments, the compound comprises a moiety having the structure of formula (D-5), or a pharma- ceutically acceptable salt thereof:

[0356] [ka] .

[0357] In some embodiments, the compound comprises a moiety having the structure of formula (D-6):

[0358] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6alkyl), and m is 1 to 20.

[0359] In some embodiments, the compound comprises a moiety having the structure of formula (D-7):

[0360] [ka] In the formula, n is 1 to 20.

[0361] In some embodiments, the compound comprises a moiety having the structure of formula (D-8):

[0362] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), m is 1 to 20, and n is 1 to 20.

[0363] In some embodiments, the compound comprises a moiety having the structure of formula (D-9):

[0364] [ka] In the formula, m is 1 to 20, and n is 1 to 20.

[0365] In some embodiments, the compound comprises a moiety having the structure of formula (D-10), or a pharma- ceutically acceptable salt thereof:

[0366] [ka] .

[0367] In some embodiments, the compound comprises a moiety having the structure of formula (D-11), or a pharma- ceutically acceptable salt thereof:

[0368] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), and m is 1 to 20.

[0369] In some embodiments, the compound comprises a moiety having the structure of formula (D-12):

[0370] [ka] In the formula, n is 1 to 20.

[0371] In some embodiments, the compound comprises a moiety having the structure of formula (D-13):

[0372] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), m is 1 to 20, and n is 1 to 20.

[0373] In some embodiments, the compound comprises a moiety having the structure of formula (D-14):

[0374] [ka] In the formula, m is 1 to 20, and n is 1 to 20.

[0375] In some embodiments, the compound comprises a moiety having the structure of formula (D-15), or a pharma- ceutically acceptable salt thereof:

[0376] [ka]

[0377] In some embodiments, the compound comprises a moiety having the structure of formula (D-16):

[0378] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), and m is 1 to 20.

[0379] In some embodiments, the compound comprises a moiety having the structure of formula (D-17):

[0380] [ka] In the formula, n is 1 to 20.

[0381] In some embodiments, the compound comprises a moiety having the structure of formula (D-18):

[0382] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), m is 1 to 20, and n is 1 to 20.

[0383] In some embodiments, the compound comprises a moiety having the structure of formula (D-19):

[0384] [ka] In the formula, m is 1 to 20, and n is 1 to 20.

[0385] In some embodiments, the compound comprises a moiety having the structure of formula (D-20), or a pharma- ceutically acceptable salt thereof:

[0386] [ka] .

[0387] In some embodiments, the compound comprises a moiety having the structure of formula (D-21):

[0388] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), and m is 1 to 20.

[0389] In some embodiments, the compound comprises a moiety having the structure of formula (D-22):

[0390] [ka] In the formula, n is 1 to 20.

[0391] In some embodiments, the compound comprises a moiety having the structure of formula (D-23):

[0392] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), m is 1 to 20, and n is 1 to 20.

[0393] In some embodiments, the compound comprises a moiety having the structure of formula (D-24):

[0394] [ka] In the formula, m is 1 to 20, and n is 1 to 20.

[0395] In some embodiments, the compound comprises a moiety having the structure of formula (D-25), or a pharma- ceutically acceptable salt thereof:

[0396] [ka]

[0397] In some embodiments, the compound comprises a moiety having the structure of formula (D-26):

[0398] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), and m is 1 to 20.

[0399] In some embodiments, the compound comprises a moiety having the structure of formula (D-27):

[0400] [ka] In the formula, n is 1 to 20.

[0401] In some embodiments, the compound comprises a moiety having the structure of formula (D-28):

[0402] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), m is 1 to 20, and n is 1 to 20.

[0403] In some embodiments, the compound comprises a moiety having the structure of formula (D-29):

[0404] [ka] In the formula, m is 1 to 20, and n is 1 to 20.

[0405] In some embodiments, the compound comprises a moiety having the structure of formula (D-30), or a pharma- ceutically acceptable salt thereof:

[0406] [ka]

[0407] In some embodiments, the compound comprises a moiety having the structure of formula (D-31), or a pharma- ceutically acceptable salt thereof:

[0408] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), and m is 1 to 20.

[0409] In some embodiments, the compound comprises a moiety having the structure of formula (D-32):

[0410] [ka] In the formula, n is 1 to 20.

[0411] In some embodiments, the compound comprises a moiety having the structure of formula (D-33):

[0412] [ka] In the formula, RE -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), m is 1 to 20, and n is 1 to 20.

[0413] In some embodiments, the compound comprises a moiety having the structure of formula (D-34):

[0414] [ka] In the formula, m is 1 to 20, and n is 1 to 20.

[0415] In some embodiments, the compound comprises a moiety having the structure of formula (D-35), or a pharma- ceutically acceptable salt thereof:

[0416] [ka]

[0417] In some embodiments, the compound comprises a moiety having the structure of formula (D-36):

[0418] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), and m is 1 to 20.

[0419] In some embodiments, the compound comprises a moiety having the structure of formula (D-37):

[0420] [ka] In the formula, n is 1 to 20.

[0421] In some embodiments, the compound comprises a moiety having the structure of formula (D-38):

[0422] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), m is 1 to 20, and n is 1 to 20.

[0423] In some embodiments, the compound comprises a moiety having the structure of formula (D-39):

[0424] [ka] In the formula, m is 1 to 20, and n is 1 to 20.

[0425] In some embodiments, the compound comprises a moiety having the structure of formula (D-40), or a pharma- ceutically acceptable salt thereof:

[0426] [ka]

[0427] In some embodiments, the compound comprises a moiety having the structure of formula (D-41), or a pharma- ceutically acceptable salt thereof:

[0428] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), and m is 1 to 20.

[0429] In some embodiments, the compound comprises a moiety having the structure of formula (D-42):

[0430] [ka] In the formula, n is 1 to 20.

[0431] In some embodiments, the compound comprises a moiety having the structure of formula (D-43):

[0432] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), m is 1 to 20, and n is 1 to 20.

[0433] In some embodiments, the compound comprises a moiety having the structure of formula (D-44):

[0434] [ka] In the formula, m is 1 to 20, and n is 1 to 20.

[0435] In some embodiments, the compound comprises a moiety having the structure of formula (D-45), or a pharma- ceutically acceptable salt thereof:

[0436] [ka]

[0437] In some embodiments, the compound comprises a moiety having the structure of formula (D-46):

[0438] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), and m is 1 to 20.

[0439] In some embodiments, the compound comprises a moiety having the structure of formula (D-47):

[0440] [ka] In the formula, n is 1 to 20.

[0441] In some embodiments, the compound comprises a moiety having the structure of formula (D-48):

[0442] [ka] In the formula, RE -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), m is 1 to 20, and n is 1 to 20.

[0443] In some embodiments, the compound comprises a moiety having the structure of formula (D-49):

[0444] [ka] In the formula, m is 1 to 20, and n is 1 to 20.

[0445] In some embodiments, the compound comprises a moiety having the structure of formula (D-50), or a pharma- ceutically acceptable salt thereof:

[0446] [ka]

[0447] In some embodiments, the compound comprises a moiety having the structure of formula (D-51), or a pharma- ceutically acceptable salt thereof:

[0448] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), and m is 1 to 20.

[0449] In some embodiments, the compound comprises a moiety having the structure of formula (D-52):

[0450] [ka] In the formula, n is 1 to 20.

[0451] In some embodiments, the compound comprises a moiety having the structure of formula (D-53):

[0452] [ka] In the formula, R E -OH, -(OCH 2 CH 2 ) m -OH or -(OCH 2 CH2) m -O(C 1 -C 6 alkyl), m is 1 to 20, and n is 1 to 20.

[0453] In some embodiments, the compound comprises a moiety having the structure of formula (D-54):

[0454] [ka] In the formula, m is 1 to 20, and n is 1 to 20.

[0455] In some embodiments, L A is optionally replaced by C 2 -C 20 Heteroalkylene or optionally substituted PEG 1-20 each optionally substituted with alkyl, amino, cyano, haloalkyl, or oxo (=O). In some embodiments, L A is C 2 -C 20In some embodiments, L is heteroalkylene. A PEG 1-20 and in some embodiments, L A is -NH(CH 2 CH 2 -O) n -or-(CH 2 CH 2 -O) n -, where n is 1 to 20. In some embodiments, L A is C 2 -C 20 In some embodiments, L is heteroalkylene. A PEG 1-20 and in some embodiments, L A is -NH(CH 2 CH 2 -O) n In some embodiments, L A is -(CH 2 CH 2 -O) n -It is.

[0456] In some embodiments, n is 1 to 15. In some embodiments, n is 7 to 15. In some embodiments, n is 8 to 15. In some embodiments, n is 9 to 15. In some embodiments, n is 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0457] Also provided are embodiments in which any of the above embodiments may be combined with any one or more of these embodiments, provided that the combinations are not mutually exclusive.

[0458] As used herein, two embodiments are "mutually exclusive" if one is defined as being distinct from the other. For example, an embodiment in which two groups are linked to form a cycloalkyl is mutually exclusive from an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is CH 2The embodiment where is is mutually exclusive with the embodiment where the same group is NH.

[0459] In some embodiments, the compound of formula (I) is a compound selected from Table 3, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is a compound selected from Table 3.

[0460] In some embodiments, non-limiting examples of compounds described herein are shown in Table 3 (next page).

[0461] [Table 5-1]

[0462] [Table 5-2]

[0463] [Table 5-3]

[0464] Further forms of the compound In some aspects, the compounds disclosed herein have one or more stereocenters, each of which exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as appropriate mixtures thereof. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form diastereomeric compound / salt pairs, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, resolution of the enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is accomplished by chromatography, or by forming diastereomeric salts, and then separating 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. In one aspect, stereoisomers are obtained by stereoselective synthesis.

[0465] The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 13 C.14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, and 125 I can be mentioned.

[0466] As used herein, the term "isotopic variant" refers to a compound that contains a proportion of an isotope that is greater than the natural abundance at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound may be radiolabeled, i.e., contain one or more radioactive isotopes, or may be, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15( 15 In compounds where such isotopic substitutions are made, the following atoms, if present, may be labeled with non-radioactive isotopes, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 2 13 C or any nitrogen 15 It will be understood that the alkyl groups may be altered to include N, and the presence and location of such atoms would be within the skill of one of ordinary skill in the art to determine.

[0467] How to use The present disclosure also relates to a method of modulating the transcription of fxn comprising contacting fxn with a compound described herein. Changes in cell phenotype, cell proliferation, transcription of fxn, production of mRNA from transcription of fxn, translation of fxn, changes in biochemical output produced by a protein encoded by fxn, or non-covalent binding of a protein encoded by fxn with a natural binding partner may be monitored. Such methods may be disease treatment modalities, biological assays, cellular assays, biochemical assays, etc.

[0468] The compounds described herein recruit regulatory molecules to modulate the expression of the defective fxn gene, effectively treating and / or alleviating symptoms associated with diseases such as Friedreich's ataxia.

[0469] Also provided herein is a method for treating a disease mediated by the transcription of fxn, comprising administering to a patient in need of treatment thereof a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0470] In some aspects, the disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof.

[0471] In some aspects, the disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0472] In some aspects, the disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the disclosure, or a pharma- ceutically acceptable salt thereof.

[0473] In some aspects, the disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0474] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[0475] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease or disorder disclosed herein.

[0476] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0477] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0478] In some embodiments, the disease or disorder is associated with transcription of fxn.

[0479] In some embodiments, the disease is Friedreich's ataxia.

[0480] Also provided is the use of the compounds disclosed herein for the treatment of a disease mediated by the transcription of fxn.

[0481] Also provided herein is a method of modulating the transcription of fxn, comprising contacting fxn with a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0482] Also provided herein is a method for achieving an effect in a patient comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, wherein the effect is selected from improved neurosensation, improved vision, improved balance, improved gait, reduced sensitivity to glucose, and reduced sensitivity to carbohydrates.

[0483] In some embodiments, the compounds described herein can mediate and / or reduce one or more of muscle atrophy, ataxia, fasciculation, or dementia.

[0484] In some embodiments, the disease or disorder is muscle atrophy.

[0485] In some embodiments, the disease or disorder is ataxia.

[0486] In some embodiments, the disease or disorder is fasciculation.

[0487] In some embodiments, the disease or disorder is dementia.

[0488] Certain compounds of the present disclosure may be effective in treating subjects whose genotype has 5 or more repeats of GAA. Certain compounds of the present disclosure may be effective in treating subjects whose genotype has 10 or more repeats of GAA. Certain compounds of the present disclosure may be effective in treating subjects whose genotype has 20 or more repeats of GAA. Certain compounds of the present disclosure may be effective in treating subjects whose genotype has 50 or more repeats of GAA. Certain compounds of the present disclosure may be effective in treating subjects whose genotype has 100 or more repeats of GAA. Certain compounds of the present disclosure may be effective in treating subjects whose genotype has 200 or more repeats of GAA. Certain compounds of the present disclosure may be effective in treating subjects whose genotype has 500 or more repeats of GAA.

[0489] Also provided are methods of modulating fxn-mediated function in a subject comprising administering a therapeutically effective amount of a compound disclosed herein.

[0490] In certain embodiments, ex vivo therapeutic methods are provided. Ex vivo methods typically include cells, organs, and / or tissues that are removed from a subject. The cells, organs, and / or tissues can be, for example, incubated with an agent under appropriate conditions. The contacted cells, organs, and / or tissues are typically returned to the donor, placed in a recipient, or stored for future use. Thus, the compound is typically present in a pharma- ceutically acceptable carrier.

[0491] In certain embodiments, administration of the pharmaceutical composition modulates expression of fxn within 6 hours of treatment. In certain embodiments, administration of the pharmaceutical composition modulates expression of fxn within 24 hours of treatment. In certain embodiments, administration of the pharmaceutical composition modulates expression of fxn within 72 hours of treatment.

[0492] In certain embodiments, administration of the pharmaceutical composition causes a 2-fold increase in expression of fxn. In certain embodiments, administration of the pharmaceutical composition causes a 5-fold increase in expression of fxn. In certain embodiments, administration of the pharmaceutical composition causes a 10-fold increase in expression of fxn. In certain embodiments, administration of the pharmaceutical composition causes a 20-fold increase in expression of fxn.

[0493] In certain embodiments, administration of the pharmaceutical composition causes a 20% decrease in the expression of fxn. In certain embodiments, administration of the pharmaceutical composition causes a 50% decrease in the expression of fxn. In certain embodiments, administration of the pharmaceutical composition causes an 80% decrease in the expression of fxn. In certain embodiments, administration of the pharmaceutical composition causes a 90% decrease in the expression of fxn. In certain embodiments, administration of the pharmaceutical composition causes a 95% decrease in the expression of fxn. In certain embodiments, administration of the pharmaceutical composition causes a 99% decrease in the expression of fxn.

[0494] In some embodiments, administration of the pharmaceutical composition reduces expression of fxn to within 25% of the expression level observed in a healthy individual. In some embodiments, administration of the pharmaceutical composition reduces expression of fxn to within 50% of the expression level observed in a healthy individual. In some embodiments, administration of the pharmaceutical composition reduces expression of fxn to within 75% of the expression level observed in a healthy individual. In some embodiments, administration of the pharmaceutical composition reduces expression of fxn to within 90% of the expression level observed in a healthy individual.

[0495] Pharmaceutical Compositions and Administration Also provided are methods of modulating fxn-mediated function in a subject comprising administering a therapeutically effective amount of a compound disclosed herein.

[0496] Also provided are pharmaceutical compositions comprising a compound disclosed herein together with a pharma- ceutically acceptable carrier.

[0497] In certain embodiments, the pharmaceutical composition is formulated for oral administration.

[0498] In certain embodiments, the pharmaceutical composition is formulated for intravenous injection or infusion.

[0499] In certain embodiments, the oral pharmaceutical composition is selected from a tablet and a capsule.

[0500] In certain embodiments, ex vivo therapeutic methods are provided. Ex vivo methods typically include cells, organs, or tissues that are removed from a subject. The cells, organs, or tissues can be, for example, incubated with an agent under appropriate conditions. The contacted cells, organs, or tissues are typically returned to the donor, placed in a recipient, or stored for future use. Thus, the compound is typically present in a pharma-ceutically acceptable carrier.

[0501] In certain embodiments, the compound is effective at a concentration of less than about 5 μM. In certain embodiments, the compound is effective at a concentration of less than about 1 μM. In certain embodiments, the compound is effective at a concentration of less than about 400 nM. In certain embodiments, the compound is effective at a concentration of less than about 200 nM. In certain embodiments, the compound is effective at a concentration of less than about 100 nM. In certain embodiments, the compound is effective at a concentration of less than about 50 nM. In certain embodiments, the compound is effective at a concentration of less than about 20 nM. In certain embodiments, the compound is effective at a concentration of less than about 10 nM.

[0502] Combinations and Combined Therapies In certain cases, it may be appropriate to administer at least one of the compounds described herein (or a pharma- ceutically acceptable salt thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient when receiving one of the compounds described herein is hypertension, it may be appropriate to administer an antihypertensive drug in combination with the first therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., the adjuvant itself may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein with another therapeutic agent (including a treatment regimen) that has a therapeutic benefit. By way of example only, in the treatment of diabetes involving administration of one of the compounds described herein, an increased therapeutic benefit may be provided by providing the patient with another diabetes medication. In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be the addition of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0503] Specific non-limiting examples of possible combination therapies include the use of certain compounds of the present disclosure together with ACE inhibitors.

[0504] In either case, the multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, integrated form or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be administered in multiple doses, or both may be administered as multiple doses. If not simultaneously, the timing between the multiple doses may be any period ranging from a few minutes to four weeks.

[0505] Thus, in another aspect, certain embodiments provide a method for treating a fxn-mediated disorder in a human or animal subject in need of such treatment, comprising administering to the subject an amount of a compound disclosed herein in combination with at least one additional agent known in the art for treating the disorder effective to reduce or prevent the disorder in the subject. In a related aspect, certain embodiments provide a therapeutic composition comprising at least one compound disclosed herein in combination with one or more additional agents for treating a fxn-mediated disorder.

[0506] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. More preferred animals include horses, dogs, and cats.

[0507] definition As used herein, the following terms have the meanings indicated.

[0508] It is understood that a particular radical naming convention can include either a monoradical or a diradical, depending on the context. For example, if a substituent requires two points of attachment to the remainder of the molecule, it is understood that the substituent is a diradical. For example, a substituent identified as an alkyl requiring two points of attachment includes -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 Other radical naming conventions explicitly state that the radical is a diradical, such as "alkylene," "alkenylene," "arylene," "heteroarylene," etc.

[0509] When two R groups are said to form a ring "together with the atoms to which they are attached" (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring), it means that the collective unit of the atoms and the two R groups is the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, the following substructure exists:

[0510] [ka] R 1 and R 2 is defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl, which is 1 and R 2 may be selected from hydrogen or alkyl, or alternatively, the moiety has the structure:

[0511] [ka] wherein ring A is the depicted nitrogen-containing heteroaryl ring.

[0512] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," what is meant is that the collective unit of the atoms, intervening bonds, and two R groups is the recited ring. For example, the substructure

[0513] [ka] R 1 and R 2 is defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2When together with the atom to which they are attached form an aryl or carbocyclyl, it is R 1 and R 2 may be selected from hydrogen or alkyl, or alternatively, the moiety has the structure:

[0514] [ka] wherein A is an aryl ring or carbocyclyl containing the depicted double bond.

[0515] When a substituent is depicted as a diradical (i.e., having two points of attachment to the rest of the molecule), it is understood that the substituent may be attached in any orientation unless otherwise indicated. Thus, for example, -AE-, or

[0516] [ka] Substituents drawn as include those where A is attached to the rightmost attachment point of the molecule as well as those oriented so that A is attached to the leftmost attachment point of the molecule.

[0517] The range of values ​​is disclosed and "n 1 …~n 2 " or "n 1 …~n 2 When the expression "between" is used, 1 and n 2are numbers, and unless otherwise specified, this notation is intended to include the numbers themselves and the range therebetween. The range may be integral or continuous between them, and may include both end values. As an example, carbon is an integer unit, so the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons. For comparison, as an example, the range "1 to 3 μM (micromolar)" is intended to include 1 μM, 3 μM, and all values ​​therebetween to any significant figure (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0518] As used herein, the term "about" is intended to qualify the numerical value it modifies and to indicate such value as a variable within a margin of error. When a specific error, such as a standard deviation to the average value given in a chart or table of data, is not recited, the term "about" should be understood to mean a range that encompasses the recited value, and also by rounding up or down to that numerical value to take into account significant numerical values.

[0519] The term "polyamide" refers to a polymer of linkable units chemically linked by amide (i.e., CONH) bonds, and optionally includes a chemical probe attached thereto. Polyamides can be synthesized by stepwise condensation of carboxylic acids (COOH) with amines (RR'NH) using methods known in the art. Alternatively, polyamides can be formed using in vitro enzymatic reactions or by using microbial fermentation.

[0520] The term "linkable unit" refers to methylimidazole, methylpyrrole, and linear and branched chain aliphatic functional groups, optionally containing nitrogen substituents (e.g., methylene, ethylene, propylene, butylene, etc.), and chemical derivatives thereof. The aliphatic functional groups of the linkable unit can be provided, for example, by condensation of beta-alanine or dimethylaminopropylamine during the synthesis of the polyamide by methods well known in the art.

[0521] The term "linker" refers to a chain of at least 10 contiguous atoms. In certain embodiments, the linker comprises 20 or fewer non-hydrogen atoms. In certain embodiments, the linker comprises 40 or fewer non-hydrogen atoms. In certain embodiments, the linker comprises 60 or fewer non-hydrogen atoms. In certain embodiments, the linker comprises an atom selected from C, H, N, O, and S. In certain embodiments, all non-hydrogen atoms are chemically bonded to either two adjacent atoms in the linker, or one adjacent atom in the linker and the terminus of the linker. In certain embodiments, the linker forms an amide bond with at least one of the two other groups to which it is attached. In certain embodiments, the linker forms an ester or ether bond with at least one of the two other groups to which it is attached. In certain embodiments, the linker forms a thioester or thioether bond with at least one of the two other groups to which it is attached. In certain embodiments, the linker forms a direct carbon-carbon bond with at least one of the two other groups to which it is attached. In certain embodiments, the linker forms an amine or amide bond with at least one of the two other groups to which it is attached. In certain embodiments, the linker is -(CH 2 OCH 2 In certain embodiments, the linker comprises a -(CH(CH 3 )OCH 2 In certain embodiments, the linker comprises R N =C 1-4 For alkyl, -(CH 2 NR N CH 2 ) units. In certain embodiments, the linker comprises an arylene, cycloalkylene, or heterocycloalkylene moiety.

[0522] The term "spacer" refers to a chain of at least five contiguous atoms. In certain embodiments, a spacer comprises 10 or fewer non-hydrogen atoms. In certain embodiments, a spacer comprises an atom selected from C, H, N, O, and S. In certain embodiments, a spacer forms an amide bond with the two other groups to which it is attached. In certain embodiments, a spacer is -(CH 2 OCH 2 In certain embodiments, the spacer comprises R N =C 1-4 For alkyl, -(CH 2 NR N CH 2 ) units. In certain embodiments, the spacer comprises at least one positive charge at physiological pH.

[0523] The term "curve element" refers to a chain of about 4-10 contiguous atoms. In certain embodiments, the curve element includes atoms selected from C, H, N, O, and S. In certain embodiments, the curve element forms amide bonds with the two other groups to which it is attached. In certain embodiments, the curve element includes at least one positive charge at physiological pH.

[0524] The terms "nucleic acid" and "nucleotide" refer to ribonucleotides and deoxyribonucleotides and their analogs well known in the art.

[0525] The term "oligonucleotide sequence" refers to a plurality of nucleic acids having a defined sequence and length (e.g., 2, 3, 4, 5, 6, or more nucleotides). The term "oligonucleotide repeat" refers to a contiguous extension of an oligonucleotide sequence.

[0526] The term "transcription" is well known in the art and refers to the synthesis of RNA (i.e., ribonucleic acid) by DNA-directed RNA polymerase. The term "modulating transcription" refers to a change in the level of transcription, which can be measured by methods well known in the art, for example, by assaying the transcription product, mRNA. In certain embodiments, modulation is an increase in transcription. In other embodiments, modulation is a decrease in transcription.

[0527] The term "contacting" refers to bringing a compound (e.g., a transcriptional molecular molecule of the present disclosure) into close proximity with a desired target gene. Contacting may result in binding to the target moiety or may result in a conformational change in the target moiety.

[0528] The term "acyl," as used herein, alone or in combination, refers to a carbonyl bound to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom bound to the carbonyl is carbon. An "acetyl" group is -C(=O)CH 3 An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0529] As used herein, the term "alkenyl", alone or in combination, refers to a straight or branched chain hydrocarbon radical having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkenyl will contain 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, such as ethenylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise noted, the term "alkenyl" can include "alkenylene" groups.

[0530] The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether radical, where the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0531] The term "alkyl", as used herein, alone or in combination, refers to a straight or branched chain alkyl radical containing 1 to 20 carbon atoms. In certain embodiments, the alkyl will contain 1 to 10 carbon atoms. In further embodiments, the alkyl will contain 1 to 8 carbon atoms. An alkyl group may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl, and the like. The term "alkylene", as used herein, alone or in combination, refers to methylene (-CH 2 "Alkyl" refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon bonded at two or more positions, such as -. Unless otherwise noted, the term "alkyl" can include "alkylene" groups.

[0532] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups can be mono- or di-alkylated to form, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like groups.

[0533] The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[0534] As used herein, the term "alkylthio", alone or in combination, refers to an alkylthioether (RS-) radical, where the term alkyl is as defined above and the sulfur may be singly or doubly oxidized. Examples of suitable alkylthioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0535] The term "alkynyl", as used herein, alone or in combination, refers to a straight or branched chain hydrocarbon radical having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkynyl contains 2 to 6 carbon atoms. In further embodiments, the alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise noted, the term "alkynyl" can include "alkynylene" groups.

[0536] The terms "amido" and "carbamoyl", as used herein, alone or in combination, refer to an amino group, as described below, attached to the parent molecular moiety through a carbonyl group, or vice versa. The term "C-amido", as used herein, alone or in combination, refers to a -C(=O)N(RR') group, where R and R' are as defined herein or as defined by the specifically enumerated "R" group designated. The term "N-amido", as used herein, alone or in combination, refers to a RC(=O)N(R')- group, where R and R' are as defined herein or as defined by the specifically enumerated "R" group designated. The term "acylamino", as used herein, alone or in combination, encompasses an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH 3 C(=O)NH-).

[0537] As used herein, the term “amide” alone or in combination refers to —C(═O)NRR′, where R and R ’ is independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form a heterocycloalkyl, any of which may be optionally substituted. Amides may be formed by direct condensation of a carboxylic acid with an amine or by using an acid chloride. Additionally, coupling reagents are known in the art and include carbodiimide-based compounds such as DCC and EDCI.

[0538] As used herein, the term "amino", alone or in combination, means -NRR ’ In the formula, R and R ’is independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form a heterocycloalkyl, any of which may be optionally substituted.

[0539] As used herein, the term "aryl", alone or in combination, refers to a carbocyclic aromatic system containing one, two, or three rings, such polycyclic ring systems being fused together. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl. The term "arylene" encompasses aromatic groups such as phenylene, naphthylene, anthracenylene, and phenanthrylene.

[0540] The terms "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkenyl group.

[0541] The terms "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkoxy group.

[0542] The terms "arylalkyl" or "aralkyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkyl group.

[0543] The terms "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkynyl group.

[0544] The terms "arylalkanoyl" or "aralkanoyl" or "aroyl," as used herein, alone or in combination, refer to acyl radicals derived from aryl substituted alkanecarboxylic acids, such as, for example, benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0545] The term aryloxy, as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

[0546] As used herein, the terms “benzo” and “benz”, alone or in combination, refer to the divalent radical C derived from benzene. 6 H 4 = Examples include benzothiophene and benzimidazole.

[0547] The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-), which may be attached to the parent molecular moiety through either the nitrogen or the acid terminus, and may be optionally substituted as defined herein.

[0548] As used herein, the term "O-carbamyl," alone or in combination, refers to a -OC(O)NRR' group, with R and R' as defined herein.

[0549] The term "N-carbamyl," as used herein, alone or in combination, refers to an ROC(O)NR'- group, with R and R' as defined herein.

[0550] As used herein, the term "carbonyl" alone includes formyl [-C(=O)H] and in combination is a -C(O)- group.

[0551] As used herein, the term "carboxyl" or "carboxy" refers to -C(=O)OH, or the corresponding "carboxylate" anion, such as in a carboxylate salt. An "O-carboxy" group refers to a RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(=O)OR group, where R is as defined herein.

[0552] The term "cyano," as used herein, alone or in combination, refers to --CN.

[0553] As used herein, "cycloalkyl" or, alternatively, "carbocycle", alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, each cyclic moiety containing 3 to 12 carbon atom ring members, and may be an optionally substituted benzo-fused ring system, as defined herein. In certain embodiments, the cycloalkyl will contain 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic" and "tricyclic" are intended to include fused ring systems, e.g., decahydronaphthalene, octahydronaphthalene, as well as polycyclic (multi-center) both saturated or partially unsaturated types. The latter type of isomer is commonly exemplified by bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0554] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties joined at a carbon atom.

[0555] The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties joined at a carbon atom.

[0556] The terms "halo" or "halogen," as used herein, alone or in combination, refer to fluorine, chlorine, bromine, or iodine.

[0557] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0558] As used herein, the term "haloalkyl", alone or in combination, refers to an alkyl radical having the meaning defined above, in which one or more hydrogens are replaced by halogen. Specifically encompassed are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. As an example, monohaloalkyl radicals can have iodo, bromo, chloro, or fluoro atoms within the radical. Dihalo and polyhaloalkyl radicals can have two or more of the same halo atoms, or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. For example, fluoromethylene (-CFH-), difluoromethylene (-CF 2 -), chloromethylene (-CHCl-), etc.

[0559] As used herein, the term "heteroalkyl," alone or in combination, refers to a stable linear or branched chain, or combination thereof, that is fully saturated or contains one to three degrees of unsaturation, consisting of the specified number of carbon atoms and one to three heteroatoms selected from N, O, and S, where the N and S atoms can be optionally oxidized, and the N heteroatom can be optionally quaternized. The heteroatoms can be placed at any interior position of the heteroalkyl group. Up to two heteroatoms can be, for example, -CH 2-NH-OCH 3 The two may be consecutive.

[0560] As used herein, the term "heteroaryl", alone or in combination, refers to a 3-15 membered unsaturated heteromonocycle or fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic and contains at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl will contain 1-4 heteroatoms as ring members. In further embodiments, the heteroaryl will contain 1-2 heteroatoms as ring members. In certain embodiments, the heteroaryl will contain 5-7 atoms. The term also encompasses fused polycyclic groups in which a heterocycle is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0561] As used herein, the terms "heterocycloalkyl" and, interchangeably, "heterocycle", alone or in combination, refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic), monocyclic, bicyclic, or tricyclic heterocyclic group, each containing at least one heteroatom as a ring member, where each heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl will contain 1-4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl will contain 1-2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl will contain 3-8 ring members in each ring. In further embodiments, the heterocycloalkyl will contain 3-7 ring members in each ring. In still further embodiments, the heterocycloalkyl will contain 5-6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and fused carbocyclic and benzofused ring systems, and additionally, both terms include systems in which a heterocycle is fused to an aryl group, as defined herein, or an additional heterocyclic group. Examples of heterocyclic groups include tetrahydroisoquinoline, aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.

[0562] The term "hydrazinyl," as used herein, alone or in combination, refers to two amino groups joined by a single bond, ie, --NN--.

[0563] The term "hydroxy," as used herein, alone or in combination, refers to --OH.

[0564] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

[0565] The term "imino," as used herein, alone or in combination, refers to =N-.

[0566] The term "iminohydroxy," as used herein, alone or in combination, refers to =N(OH) and =NO-.

[0567] The phrase "in the backbone" refers to the longest contiguous or adjacent chain of carbon atoms beginning from the point of attachment of a group to a compound or molecule of any one of the formulas disclosed herein.

[0568] The term "isocyanato" refers to a -NCO group.

[0569] The term "isothiocyanato" refers to the group -NCS.

[0570] The phrase "linear chain of atoms" refers to the longest linear chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0571] As used herein, the term “lower”, alone or in combination, unless otherwise defined, includes 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl).

[0572] The term "lower aryl" as used herein, alone or in combination, means phenyl or naphthyl, either of which, if provided, may be optionally substituted.

[0573] The term "lower heteroaryl," as used herein, alone or in combination, means either 1) a monocyclic heteroaryl containing 5 or 6 ring members, of which 1 to 4 of the ring members can be heteroatoms selected from N, O, and S, or 2) a bicyclic heteroaryl in which each of the fused rings contains 5 or 6 ring members and between them contains 1 to 4 heteroatoms selected from N, O, and S.

[0574] As used herein, "lower cycloalkyl," alone or in combination, refers to a monocyclic cycloalkyl having 3 to 6 ring members (i.e., C 3 -C 6 Lower cycloalkyl may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0575] The term “lower heterocycloalkyl,” as used herein, alone or in combination, means a monocyclic heterocycloalkyl having 3 to 6 ring members, 1 to 4 of which are N, O, and S (i.e., C 3 -C 6 The heteroatom may be selected from the group consisting of lower heterocycloalkyl, heterocycloalkyl, and heterocycloalkyl. Examples of lower heterocycloalkyl include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyl may be unsaturated.

[0576] As used herein, the term "lower amino," alone or in combination, refers to --NRR', where R and R' are independently selected from hydrogen and lower alkyl, either of which may be optionally substituted.

[0577] The term "mercaptyl" as used herein, alone or in combination, refers to an RS-group, where R is as defined herein.

[0578] As used herein, the term "nitro", alone or in combination, means -NO 2 Refers to...

[0579] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to --O--.

[0580] The term "oxo" as used herein, alone or in combination, refers to =O.

[0581] The term "perhaloalkoxy" refers to an alkoxy group where all of the hydrogen atoms have been replaced with halogen atoms.

[0582] The term "perhaloalkyl," as used herein, alone or in combination, refers to an alkyl group in which all of the hydrogen atoms have been replaced with halogen atoms.

[0583] As used herein, the terms "sulfonate," "sulfonic acid," and "sulfonic," alone or in combination, refer to the --SO group when sulfonic acid is used in salt formation. 3 H group and its anion.

[0584] The term "sulfanyl" as used herein, alone or in combination, refers to --S--.

[0585] The term "sulfinyl" as used herein, alone or in combination, refers to -S(O)-.

[0586] As used herein, the term "sulfonyl," alone or in combination, refers to -S(O) 2 - refers to.

[0587] The term "N-sulfonamide" refers to RS(=O) 2 It refers to the group NR'--, where R and R' are as defined herein.

[0588] The term "S-sulfonamide" refers to -S(=O) 2 It refers to the group NRR', where R and R' are as defined herein.

[0589] The terms "thia" and "thio", as used herein, alone or in combination, refer to an -S- group or ethers where the oxygen is replaced by a sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0590] The term "thiol", as used herein, alone or in combination, refers to a -SH group.

[0591] As used herein, the term "thiocarbonyl" alone includes thioformyl-C(S)H and in combination is a -C(S)- group.

[0592] The term "N-thiocarbamyl" refers to the group ROC(S)NR', ​​with R and R' as defined herein.

[0593] The term "O-thiocarbamyl" refers to an OC(S)NRR' group, with R and R' as defined herein.

[0594] "The term "thiocyanato" refers to a CNS group.

[0595] The term "trihalomethanesulfonamide" means X 3 CS(O) 2 It refers to an NR group, where X is a halogen and R is as defined herein.

[0596] The term "trihalomethanesulfonyl" means X 3 CS(O) 2 group, where X is a halogen.

[0597] The term "trihalomethoxy" means X 3It refers to a CO group, where X is a halogen.

[0598] As used herein, the term "trisubstituted silyl", alone or in combination, refers to a silicone group substituted at its three free valences with a group listed herein under the definition of substituted amino. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, etc.

[0599] Any definition herein can be used in combination with any other definition to describe a composite structural group.By convention, the element following such a definition is the one that is attached to the parent moiety.For example, the composite group alkylamide represents an alkyl group that is attached to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group that is attached to the parent molecule via an alkyl group.

[0600] When a group is defined to be "null", what is meant is that the group is absent.

[0601] The term "optionally substituted" means that the preceding group can be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may include, but are not limited to, one or more substituents independently selected from the following groups or the set of specific specified groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3 , S.H., S.C.H. 3 , C(O)CH 3 , CO 2 CH 3 , CO 2 H, pyridinyl, thiophene, furanyl, lower carbamates, and lower ureas. If structurally feasible, two substituents may be linked together to form a fused 5-, 6-, or 7-membered carbocyclic or heterocyclic ring of 0-3 heteroatoms, e.g., methylenedioxy or ethylenedioxy. An optionally substituted group can be unsubstituted (e.g., -CH 2 CH 3 ), full substitutions (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F), or any level between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ). When substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. When a substituent is modified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents for a particular moiety may be defined as desired, and in these cases, the optional substitutions will often be as defined immediately following the phrase "optionally substituted with."

[0602] As used herein, a substituent is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise indicated, when a group is deemed to be "substituted", the group is independently selected from the group C 1 -C 6 Alkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl, C 1 -C 6 Heteroalkyl, C 3 -C 7 Carbocyclyl (Halo, C 1 -C 6 Alkyl, C 1 -C6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 optionally substituted with haloalkoxy, C 3 -C 7 -Carbocyclyl-C 1 -C 6 -Alkyl (halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 optionally substituted with haloalkoxy), 3-10 membered heterocyclyl (halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 (optionally substituted with haloalkoxy), 3-10 membered heterocyclyl-C 1 -C 6 -Alkyl (halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 aryl (halo, optionally substituted with haloalkoxy); 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 aryl (optionally substituted with haloalkoxy); 1 -C 6 )Alkyl(Halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C1 -C 6 Haloalkyl and C 1 -C 6 Optionally substituted with haloalkoxy), 5-10 membered heteroaryl (halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 optionally substituted with haloalkoxy; 5-10 membered heteroaryl (C 1 -C 6 )Alkyl(Halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 (optionally substituted with haloalkoxy), halo, cyano, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxy(C 1 -C 6 ) alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo (C 1 -C 6 ) alkyl (e.g., -CF 3 ), Haro(C 1 -C 6 ) alkoxy (e.g., -OCF 3 ), C 1 -C 6 Alkylthio, arylthio, amino, amino(C 1 -C 6) alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," that group can be substituted with the above substituents.

[0603] The term R or R', unless otherwise defined, appears alone and without a number designation and refers to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups may be optionally substituted as defined herein. Regardless of whether an R group has a number designation, R, R', and R n All R groups, including those in which n=(1, 2, 3, ... n), all substituents, and all terms, should be understood to be independent of all others in terms of selection from the group. When any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than once within a formula or generic structure, its definition at each occurrence is independent of its definition at every other occurrence. Those skilled in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position within a chain of elements from either end as written. For example, an unsymmetrical group, such as -C(O)N(R)-, may be attached to the parent moiety at either the carbon or the nitrogen.

[0604] Asymmetric centers exist in the compounds or molecules disclosed herein. These centers are designated by the symbols "R" or "S", depending on the arrangement of the substituents around the chiral carbon atom. It is to be understood that the present disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of a compound or molecule can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparation of a mixture of enantiomeric products, followed by conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatographic techniques, direct separation of the enantiomers on a chiral chromatographic column, or any other suitable method known in the art. Starting compounds or molecules of a particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, compounds or molecules disclosed herein can exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entogen (E), and zusanmen (Z) isomers, as well as the appropriate mixtures thereof. Additionally, compounds or molecules may exist as tautomers, and all tautomeric isomers are provided by the present disclosure. Additionally, compounds or molecules disclosed herein may exist in unsolvated or solvated forms with pharma- ceutically acceptable solvents, such as water, ethanol, and the like. In general, solvated forms are considered equivalent to unsolvated forms.

[0605] The term "bond" refers to a covalent bond between two atoms, or two moieties where the atoms connected by the bond are considered to be part of a larger substructure. Unless otherwise specified, the bond may be a single bond, a double bond, or a triple bond. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may or may not be present at that position.

[0606] As used herein, the term "disease" is intended to be generally synonymous with, and is used interchangeably with, the terms "disorder," "syndrome," and "condition" (as in medical conditions), in that all reflect an abnormal condition of the human or animal body, or parts thereof, that impairs normal functioning, are typically defined by identifying signs and symptoms, and reduce the duration or quality of a human or animal's life.

[0607] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule with a fixed ratio of active ingredients, or in multiple separate capsules for each active ingredient. In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in the treatment of the condition or disorder described herein.

[0608] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used in the treatment of a disease or disorder or for the implementation of a clinical endpoint.

[0609] The term "therapeutically acceptable" refers to those compounds or molecules (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, or allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for the intended use.

[0610] As used herein, reference to "treatment" of a patient is intended to include prevention. Treatment may also be preemptive in nature, i.e., include prevention of disease. Prevention of disease may include complete protection from disease, such as in the case of prevention of infection by a pathogen, or may include prevention of disease progression. For example, prevention of disease may not mean completely eliminating the effects associated with the disease at any level, but instead may mean preventing symptoms of the disease to a clinically significant or detectable level. Prevention of disease may also mean prevention of disease progression to a later stage of the disease.

[0611] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, domestic animals such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0612] The term "prodrug" refers to a compound or molecule that is more active in vivo. Certain compounds or molecules disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the compounds. Additionally, prodrugs can be converted to the compounds by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some cases, they may be easier to administer than the compound or parent drug. They may be bioavailable, for example, by oral administration, whereas the parent drug is not bioavailable. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, including those that rely on hydrolytic cleavage or oxidative activation of the prodrug. Examples of prodrugs include, but are not limited to, compounds that are administered as an ester (the "prodrug"), but are subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of the compounds.

[0613] The compounds or molecules disclosed herein can exist as therapeutically acceptable salts. The present disclosure includes the compounds or molecules listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts are usually pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may also be useful in the preparation and purification of the compound or molecule in question. Basic addition salts are also formed and are pharmaceutically acceptable. For a more complete discussion of salt preparation and selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0614] Basic addition salts can be prepared during the final isolation and purification of a compound or molecule by reacting a carboxyl group with a suitable base, such as the hydroxide, carbonate, bicarbonate of a metal cation, or with ammonia, or with an organic primary, secondary, or tertiary amine.Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations, such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine.Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0615] Other carrier materials and modes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. Preferred unit dosage formulations are those that contain an effective dose, as recited herein below, or an appropriate fraction thereof, of active ingredient.

[0616] It will be understood that in addition to the ingredients particularly mentioned above, the above formulations may include other agents conventional in the art having regard to the type of formulation in question, e.g., those suitable for oral administration may include flavoring agents.

[0617] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0618] The compound or molecule may be administered in various ways, for example, orally, topically, or by injection. The exact amount of compound administered to a patient is the responsibility of the attending physician. The specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination, the exact disease being treated, and the severity of the indication or condition being treated. In addition, the route of administration may vary depending on the symptoms and their severity. The above considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks. EXAMPLES

[0619] The following examples are given for the purpose of illustrating various embodiments of the present disclosure and are not intended to limit the present disclosure in any manner. The examples, together with the methods described herein, are representative of currently preferred embodiments and are exemplary and are not intended as limitations on the scope of the present disclosure. Modifications therein and other uses encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.

[0620] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments described herein may be used. The following claims define the scope of the disclosure, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0621] Compound synthesis The compounds of the present disclosure can be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes and experimental procedures are presented for illustrative purposes and are not intended to be limiting. The starting materials used to prepare the compounds of the present disclosure are commercially available or can be prepared using routine methods known in the art.

[0622] List of abbreviations Ac 2 O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; Bu 3 SnH = tributyltin hydride; CD 3 OD = deuterated methanol; CDCl 3 = deuterated chloroform;CDI = 1,1'-carbonyldiimidazole;DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene;DCM = dichloromethane;DEAD = diethyl azodicarboxylate;DIBAL-H = di-isobutylaluminum hydride;DIEA = DIPEA = N,N-diisopropylethylamine;DMAP = 4-dimethylaminopyridine;DMF = N,N-dimethylformamide;DMSO-d 6 = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EDC.HCl = EDCI.HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et 2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = hours; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanamine; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-PrOH = isopropanol; LAH = lithium aluminum hydride; LiHMDS = lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeOH = methanoic acid ol;MP-carbonate resin = macroporous triethylammonium methyl polystyrene carbonate resin;MsCl = mesyl chloride;MTBE = methyl tertiary butyl ether;MW = microwave irradiation;n-BuLi = n-butyl lithium;NaHMDS = sodium bis(trimethylsilyl)amide;NaOMe = sodium methoxide;NaOtBu = sodium t-butoxide;NBS = N-bromosuccinimide;NCS = N-chlorosuccinimide;NMP = N-methyl-2-pyrrolidone;Pd(Ph 3 ) 4 = Tetrakis(triphenylphosphine)palladium(0); Pd 2 (dba) 3 = Tris(dibenzylideneacetone)dipalladium(0); PdCl 2 (PPh 3 ) 2 = Bis(triphenylphosphine)palladium(II) dichloride;PG = Protecting group;Prep-HPLC = Preparative high performance liquid chromatography;PyBop = (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate;Pyr = Pyridine;RT = Room temperature;RuPhos = 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl;sat. = Saturated;ss = Saturated solution;t-BuOH = tert-butanol;T3P = Propylphosphonic anhydride;TBS = TBDMS = tert-butyldimethylsilyl;TBSCl = TBDMSCl = tert-butyldimethylchlorosilane;TEA = Et 3N=triethylamine; TFA=trifluoroacetic acid; TFAA=trifluoroacetic anhydride; THF=tetrahydrofuran; Tol=toluene; TsCl=tosyl chloride; XPhos=2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0623] Synthesis of representative polyamides Example 1. Synthesis of 3-([1-methyl-4-[3-([1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido]propanamido)imidazol-2-amido]pyrrol-2-yl]formamido)propanamido]imidazol-2-yl]formamido)propanoic acid (PA01-OH)

[0624] [ka]

[0625] Step 1: Synthesis of ethyl 4-amino-1-methylimidazole-2-carboxylate 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 cooled to 5° C. for 2 hours. 2 The mixture was stirred at room temperature under atmospheric pressure 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: 7 H 11 N 3 O 2 Calculated mass: 169.09, measured mass: 170.10 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ:7.37(s,1H),4.29-4.34(m,2H),3.94(s,3H),1.31(t,J=7.2Hz,3H).

[0626] Step 2: Synthesis of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylate To a 500 mL flask was added 3-[(tert-butoxycarbonyl)amino]propanoic acid (22.45 g, 118.65 mmol, 0.90 equiv), DMF (180.00 mL). The mixture was cooled to 0° C., then HATU (75.18 g, 197.71 mmol, 1.50 equiv) and DIEA (51.11 g, 395.43 mmol, 3.00 equiv) were added, the mixture was stirred for 10.0 min, then ethyl 4-amino-1-methylimidazole-2-carboxylate (22.30 g, 131.81 mmol, 1.00 equiv) was added in portions. The reaction was stirred at room temperature for 1.0 h. The reaction was quenched with ice water (600 mL) and the solution was stirred for 15.0 min. The precipitated solid was collected by filtration, washed with water (3×50 mL) and dried under vacuum to give ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylate (34.50 g, 76.90%) as a pale yellow solid. LC / MS: C 15 H 24 N 4 O 5 Calculated mass: 340.17, Measured mass: 341.20 [M+H] + . 1 H NMR(400MHz,DMSO-d6) δ:10.63(s,1H),7.52(s,1H),6.80(t,J=5.6Hz,1H),4.23-4.28(m,2H),3.90(s,3 H),3.15-3.20(m,2H),2.42(t,J=7.2Hz,2H),1.37(s,9H),1.29(t,J=7.2Hz,3H).

[0627] Step 3: Synthesis of 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid To a stirred solution of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylate (34.50 g, 101.36 mmol, 1.00 equiv) in MeOH (200.00 mL) was added LiOH solution (2 M, 202.00 mL, 4.00 equiv) dropwise at room temperature. The resulting mixture was stirred at 45° C. for 2.0 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by H 2 The mixture was acidified with 2M HCl to pH 3-5. The precipitated solid was collected by filtration and diluted with H 2 2H 3O (3×30 mL) and dried under vacuum to give 4-[3-[(Tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (30.00 g, 94.77%) as a white solid. LC / MS: C 13 H 20 N 4 O 5 Calculated mass: 312.14, Measured mass: 313.15 [M+H] + . 1 H NMR(300MHz,DMSO-d6) δ:10.53(s,1H),7.48(s,1H),6.79(t,J=5.4Hz,1H),3.89(s,3H),3.15-3.22(m,2H),2.43(t,J=7.2Hz,2H),1.37(s,9H).

[0628] Step 4: Synthesis of methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazol-2-amido)-1-methylpyrrole-2-carboxylate CH 3To a stirred solution of 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (16.00 g, 51.23 mmol, 1.00 equiv) in CN (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) in portions at 0° C. The resulting mixture was stirred at room temperature for 2.0 h. The precipitated solid was collected by filtration and diluted with CH 3 Washed with CN (3×20 mL) and dried under vacuum to give methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazol-2-amido)-1-methylpyrrole-2-carboxylate (19.00 g, 82.70%) as a white solid. LC / MS: C 20 H 28 N 6 O 6 Calculated mass for: 448.21, Measured mass: 449.25[M+H]+. 1 H NMR(300MHz,DMSO-d6) δ:10.24(s,1H),10.11(s,1H),7.52(s,1H),7.33(s,1H),6.99(s,1H),6.82(t,J=5.1Hz,1H), 3.94(s,3H),3.85(s,3H),3.74(s,3H),3.16-3.23(m,2H),2.47(t,J=6.9Hz,2H),1.38(s,9H).

[0629] Step 5: Synthesis of methyl 4-[4-(3-aminopropanamido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate hydrochloride A solution of methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-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 2.0 h. The resulting mixture was concentrated under vacuum to give methyl 4-[4-(3-aminopropanamido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate (19.00 g crude) as a yellow solid. LC / MS: C 15 H 21 CIN 6 O 4 Calculated mass for: 348.15, Measured mass: 349.05[M+H]+. 1 H NMR (300MHz, CD 3 OD) δ:7.37(s,2H),6.91(s,1H),4.03(s,3H),3.88(s,3H),3.79(s,3H),3.09(t,J=6.6Hz,2H),2.64(t,J=6.6Hz,2H).

[0630] Step 6: Synthesis of methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazol-2-yl)formamido]propanoate To a 1000 ml flask was added 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (11.00 g, 35.22 mmol, 1.00 equiv), DMF (300.00 mL), the mixture was cooled to 0° C., then HATU (20.09 g, 52.83 mmol, 1.50 equiv), DIEA (18.21 g, 140.88 mmol, 4.00 equiv) were added dropwise, the mixture was stirred for 10 min, and methyl 3-aminopropanoate (3.63 g, 35.22 mmol, 1.00 equiv) was added in portions. The reaction was stirred at room temperature for 1.0 h. The reaction mixture was poured into water / ice (600 mL) and the solid was filtered and dried under vacuum. The aqueous phase was extracted with EA (3×200 mL) and the organic phases were combined and washed with H 2Wash with 2×O (1×200 mL) and NaCl (1×200 mL), and then rinse with anhydrous Na 2 SO 4 The mixture was dried at 4° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with pure EA. The fractions were combined and concentrated. Methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazol-2-yl)formamido]propanoate (13.00 g, 87.95%) was obtained as a yellow solid. LC / MS: C 17 H 27 N 5 O 6 Calculated mass: 397.20, Measured mass: 398.20 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ:10.28(s,1H),7.92(t,J=6.0Hz,1H),7.37(s,1H),6.77(t,J=6.0Hz,1H),3.88(s,3H),3.59(s,3H ),3.42-3.47(m,2H),3.13-3.18(m,2H),2.56(t,J=6.0Hz,2H),2.42(t,J=6.0Hz,2H),1.35(s,9H).

[0631] Step 7: Synthesis of methyl 3-[[4-(3-aminopropanamido)-1-methylimidazol-2-yl]formamido]propanoate hydrochloride A solution of methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazol-2-yl)formamido]propanoate (11.00 g, 27.678 mmol, 1.00 equiv) in HCl / 1,4-dioxane (4 M, 110.00 mL) was stirred at room temperature for 1.0 h. The resulting mixture was concentrated in vacuo to give methyl 3-[[4-(3-aminopropanamido)-1-methylimidazol-2-yl]formamido]propanoate hydrochloride (11.00 g, crude) as a yellow oil. LC / MS: C 12 H 19 N 5 O 4Calculated mass: 297.14, Measured mass: 298.20 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ:10.57(s,1H),7.92(t,J=6.0Hz,1H),7.37(s,1H),3.89(s,3H),3.59(s,3H), 3.43-3.47(m,2H),2.97-3.05(m,2H),2.57-2.71(m,2H),2.56(t,J=6.0Hz,2H).

[0632] Step 8: Synthesis of methyl 1-methyl-4-(1-methylimidazol-2-amido)pyrrole-2-carboxylate 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) in small portions at 0° C. The resulting mixture was stirred at room temperature for 17.0 h. The reaction was poured into water / ice (450 mL). The precipitated solid was collected by filtration and diluted with H 2 2H 2 O (3×50 mL) and dried under vacuum. Methyl 1-methyl-4-(1-methylimidazol-2-amido)pyrrole-2-carboxylate (16.50 g, 78.37%) was obtained as a white solid. LC / MS: C 12 H 14 N 4 O 3 Calculated mass: 262.11, measured mass: 263.15 [M+H] + . 1 H NMR (300MHz, DMSO-d 6 ) δ:10.54(s,1H),7.54(s,1H),7.40(s,1H),7.04(s,2H),3.99(s,3H),3.85(s,3H),3.74(s,3H).

[0633] Step 9: Synthesis of 1-methyl-4-(1-methylimidazol-2-amido)pyrrole-2-carboxylic acid To a stirred solution of methyl 1-methyl-4-(1-methylimidazol-2-amido)pyrrole-2-carboxylate (16.50 g, 62.91 mmol, 1.00 equiv) in MeOH (100.00 mL) was added LiOH solution (2 M, 158.00 mL, 5.00 equiv) dropwise at room temperature. The resulting mixture was stirred at 45° C. for 2.0 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by H 2 The mixture was acidified with 2M HCl to pH 3-5. The precipitated solid was collected by filtration and diluted with H 2 2H 2 O (3×30 mL) and dried under vacuum. 1-Methyl-4-(1-methylimidazol-2-amido)pyrrole-2-carboxylic acid (12.00 g, 76.84%) was obtained as a white solid. LC / MS: C 11 H 12 N 4 O 3 Calculated mass: 248.09, Measured mass: 249.10 [M+H] + . 1 H NMR (300MHz, DMSO-d 6 ) δ:10.52(s,1H),7.48(s,1H),7.41(s,1H),7.06(s,1H),6.99(s,1H),3.99(s,3H),3.82(s,3H).

[0634] Step 10: Synthesis of methyl 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido]propanamido)imidazol-2-amido]pyrrole-2-carboxylate To a stirred solution of 1-methyl-4-(1-methylimidazol-2-amido)pyrrole-2-carboxylic acid (9.00 g, 36.255 mmol, 1.00 equiv) in DMF (150.00 mL) was added HATU (20.68 g, 54.38 mmol, 1.50 equiv), DIEA (14.06 g, 108.77 mmol, 3.00 equiv), and methyl 4-[4-(3-aminopropanamido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate (13.89 g, 39.872 mmol, 1.10 equiv) in portions at 0° C. The resulting mixture was stirred at room temperature for 17.0 h. The reaction was poured into water / ice (450 mL) at 0° C. The precipitated solid was collected by filtration, washed with HO (3 x 50 mL) and dried under vacuum to give methyl 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido]propanamido)imidazol-2-amido]pyrrole-2-carboxylate (14.00 g, 63.54%) as a yellow solid. LC / MS: C 26 H 30 N 10 O 6 Calculated mass for: 578.23, Measured mass: 579.10[M+H]+. 1 H NMR (300MHz, DMSO-d 6 ) δ:10.53(s,1H),10.29(s,1H),10.11(s,1H),8.10(t,J=5.4Hz,1H),7.52(s,1H),7.47(s,2H),7.25(s,1H),7.17(s,1H),6.99( s,1H),6.97(s,1H),3.99(s,3H),3.95(s,3H),3.84(s,3H),3.82(s,3H),3.69(s,3H),3.42-3.49(m,2H),2.60(t,J=7.2Hz,2H).

[0635] Step 11: Synthesis of 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido]propanamido)imidazole-2-afoldamido]pyrrole-2-carboxylic acid To a solution of methyl 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido]propanamido)imidazol-2-amido]pyrrol-2-yl]formamidocarboxylate (14.00 g, 24.20 mmol, 1.00 equiv.) in MeOH (70.00 mL) was added LiOH solution (2 M, 72.00 mL, 6.00 equiv.). The mixture was stirred at 45° C. for 2.0 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by H 2 The mixture was acidified with 2M HCl to pH 3-5. The precipitated solid was collected by filtration and diluted with H 2 2H NMR (Hz) δ: 1.00-1.50 (4H, 1H, 2H, 1 ... 25 H 28 N 10 O 6 Calculated mass: 564.22, measured mass: 565.15 [M+H] + . 1 H NMR(300MHz,DMSO-d6) δ:10.72(s,1H),10.32(s,1H),10.08(s,1H),8.14(t,J=6.0Hz,1H),7.51(s,1H),7.47(s,2H),7.27(s,1H),7.23( s,1H),6.98(s,1H),6.94(s,1H),4.00(s,3H),3.95(s,3H),3.82(s,6H),3.44-3.46(m,2H),2.60(t,J=6.6Hz,2H).

[0636] Step 12: Synthesis of methyl 3-([1-methyl-4-[3-([1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido]propanamido)imidazol-2-amido]pyrrol-2-yl]formamido)propanamido]imidazol-2-yl]formamido)propanoate To a stirred solution of 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido]propanamido)imidazole-2-amido]pyrrole-2-carboxylic acid (12.00 g, 21.26 mmol, 1.00 equiv.) in DMF (100.00 mL), HATU (12.12 g, 31.88 mmol, 1.50 equiv.), DIEA (8.24 g, 63.77 mmol, 3.00 equiv.), and methyl 3-[[4-(3-aminopropanamido)-1-methylimidazol-2-yl]formamido]propanoate (6.95 g, 23.38 mmol, 1.10 equiv.) were added in small portions at 0° C. The resulting mixture was stirred at room temperature for 2.0 h. The reaction was poured into water / ice (300 mL) at 0° C. The precipitated solid was collected by filtration, washed with H2O (3×30 mL) and dried under vacuum. Methyl 3-([1-methyl-4-[3-([1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide]propanamide)imidazol-2-amido]pyrrol-2-yl]formamide)propanamide]imidazol-2-yl]formamide)propanoate (13.00 g, 64.77%) was obtained as a yellow solid. LC / MS: C 37 H 45 N 15 O 9 Calculated mass for: 843.35, Measured mass: 844.55[M+H]+. 1H NMR(300MHz,DMSO-d6) δ:10.41(s,1H),10.37(s,1H),10.32(s,1H),9.96(s,1H),8.08(s,2H),7.96(s,1H),7.46(s,1H),7.42(s,1H),7.38(s,1H),7.24( s,2H),7.03(s,1H),6.98(s,1H),6.93(s,1H),4.13(s,3H),3.98(s,3H),3.95(s,3H),3.81(s,9H),3.60(s,6H),2.57-2.69(m,6H).

[0637] Step 13: Synthesis of 3-([1-methyl-4-[3-([1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido]propanamido)imidazol-2-amido]pyrrol-2-yl]formamido)propanamido]imidazol-2-yl]formamido)propanoic acid To a solution of methyl 3-([1-methyl-4-[3-([1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide]propanamide)imidazol-2-amido]pyrrol-2-yl]formamide)propanamide]imidazol-2-yl]formamide)propanoate (10.00 g, 10.59 mmol, 1.00 equiv) in MeOH (60.00 mL), 2 M LiOH (21.20 mL, 42.40 mmol, 4.00 equiv) was added and the resulting mixture was stirred at 45 °C for 2.0 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (60 mL). The mixture was acidified with 2 M HCl to pH 3-5. The precipitated solid was collected by filtration and washed with water (3 x 20 mL). The solid was dried under vacuum. This gave 3-([1-methyl-4-[3-([1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido]propanamido)imidazol-2-amido]pyrrol-2-yl]formamido)propanamido]imidazol-2-yl]formamido)propanoic acid (8.70 g, 84.14%) as a brown solid. LC / MS: C 36 H 43 N 15 O 9 Calculated mass for: 829.34, Measured mass: 830.25[M+H]+. 1 H NMR (300MHz, DMSO-d 6 ) δ:10.46(s,1H),10.39(s,1H),10.31(s,1H),9.93(s,1H),8.05-8.10(m,2H),7.87(t,J=6.0Hz,1H),7.42-7.46(m,3H),7.20-7.23(m,2H) ,7.07(s,1H),6.90-6.95(m,2H),3.95(s,3H),3.92(s,3H),3.89(s,3H),3.79(s,3H),3.78(s,3H),3.38-3.41(m,6H),2.44-2.59(m,6H).

[0638] Example 2. Synthesis of 1-methyl-4-(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-amido]pyrrol-2-amido}imidazol-2-amido)pyrrole-2-carboxylic acid (PA-047)

[0639] [ka]

[0640] Step 1: Synthesis of ethyl 4-[4-[(tert-butoxycarbonyl)amino]-1-methylpyrrol-2-amido]-1-methylimidazole-2-carboxylate 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 h. After reaction, the reaction was poured into 500 mL of ice / water. The precipitated solid was collected by filtration, washed with water (3×50 mL), and dried under vacuum. This gave ethyl 4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido}-1-methylimidazole-2-carboxylate (16.00 g, 85.48% yield) as a pale yellow solid. LC / MS: C 18 H 25 N 5 O 5 Calculated mass: 391.19, Measured mass: 392.30 [M+H] + .

[0641] Step 2: Synthesis of 4-[4-[(tert-butoxycarbonyl)amino]-1-methylpyrrol-2-amido]-1-methylimidazole-2-carboxylic acid The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Example 1, step 3), but the reaction temperature was room temperature and the reaction time was 1.0 h. 970.00 mg of ethyl 4-[4-[(tert-butoxycarbonyl)amino]-1-methylpyrrol-2-amido]-1-methylimidazole-2-carboxylate was used to obtain 638.00 mg of 4-[4-[(tert-butoxycarbonyl)amino]-1-methylpyrrol-2-amido]-1-methylimidazole-2-carboxylic acid as a yellow solid (yield 64.36%). LC / MS: C 16 H 21 N 5 O 5 Calculated mass: 363.15, measured mass: 364.15 [M+H] + .

[0642] Step 3: Synthesis of methyl 4-(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido}-1-methylimidazol-2-amido)-1-methylpyrrole-2-carboxylate 4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amide}-1-methylimidazole-2-carboxylic acid (6.00 g, 16.51 mmol, 1.00 equiv.) was dissolved in DMF (60.00 mL). PyBOP (8.59 g, 16.51 mmol, 1.00 equiv.), methyl 4-amino-1-methylpyrrole-2-carboxylate (2.55 g, 16.51 mmol, 1.00 equiv.), and DIEA (6.40 g, 49.536 mmol, 3.00 equiv.) were added sequentially to the solution at 0° C. The mixture was allowed to warm to room temperature and stirred for 1.0 h. After the reaction was complete, the mixture was added dropwise to ice water (150 mL). The solid formed was filtered, washed with water (2×15 mL) and dried under vacuum to give methyl 4-(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido}-1-methylimidazol-2-amido)-1-methylpyrrole-2-carboxylate (7.10 g, 86.08%) as a red-brown solid. LC / MS: C 23 H29 N 7 O 6 Calculated mass: 499.21, measured mass: 500.15 [M+H] + .

[0643] Step 4: Synthesis of methyl 4-[4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate To a stirred solution of methyl 4-(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido}-1-methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate (250.00 mg, 0.500 mmol, 1.00 equiv) in DCM (2.50 mL) was added TFA (0.50 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1.0 h. The resulting mixture was concentrated under vacuum to give methyl 4-[4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2-amido]-1-methylpyrrole-2-carboxylate (250.00 mg, crude) as a tan oil. LC / MS: C 18 H 21 N 7 O 4 Calculated mass: 399.17, Measured mass: 400.35 [M+H] + .

[0644] Step 5: Synthesis of methyl 1-methyl-4-(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-amido]pyrrol-2-amido}imidazol-2-amido)pyrrole-2-carboxylate To a stirred solution of 1-methyl-4-(1-methylimidazol-2-amido)pyrrole-2-carboxylic acid (156.62 mg, 0.63 mmol, 0.90 equiv) in DMF (2.00 mL) was added PyBOP (361.16 mg, 0.69 mmol, 1.00 equiv), methyl 4-[4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate (280.00 mg, 0.70 mmol, 1.00 equiv), and DIEA (453.02 mg, 3.51 mmol, 5.00 equiv) in small portions at 0° C. The resulting mixture was stirred at room temperature for 1.0 h. The reaction mixture was directly purified by reverse phase column with the following conditions: column, C18 column; mobile phase, ACN in water (0.05% TFA), 5% to 70% gradient in 50 min; detector, UV 254 nm. Fractions were combined and concentrated. Methyl 1-methyl-4-(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylimidazole-2-amido)pyrrol-2-amido]pyrrol-2-amido}imidazole-2-amido)pyrrole-2-carboxylate (240.00 mg, 51.65% yield) was obtained as a white solid. LC / MS: C 29 H 31 N 11 O 6 Calculated mass: 629.25, Measured mass: 630.25 [M+H] + .

[0645] Step 6: Synthesis of 1-methyl-4-(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-amido]pyrrol-2-amido}imidazol-2-amido)pyrrole-2-carboxylic acid The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Example 1, step 3). Using 240.00 mg of methyl 1-methyl-4-(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylimidazole-2-amido)pyrrol-2-amido]pyrrol-2-amido}imidazole-2-amido)pyrrole-2-carboxylate, 178.00 mg of 1-methyl-4-(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylimidazole-2-amido)pyrrol-2-amido]pyrrol-2-amido}imidazole-2-amido)pyrrole-2-carboxylic acid was obtained as a white solid (62.96% yield). LC / MS: C 28 H 29 N 11 O 6 Calculated mass: 615.23, measured mass: 616.25 [M+H] + .

[0646] Example 3. Synthesis of 1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylic acid (PA-048)

[0647] [ka]

[0648] Step 1: Synthesis of 2-(1-methylimidazol-2-yl)-3H-1,3-benzodiazole-5-carboxylic acid The procedure was the same as (Example 1, step 7), but the reaction time was 1.0 h. Using 2.00 g of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylate, 2.00 g of crude ethyl 4-(3-aminopropanamido)-1-methyl-1H-imidazole-2-carboxylate was obtained as an off-white solid. LC / MS: C 10 H 16 N 4 O 3 Calculated mass: 240.12, measured mass: 241.10 [M+H] + .

[0649] Step 2: Ethyl 1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1- Synthesis of methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]pyrrol-2-yl}formamido)propanamido]imidazole-2-carboxylate The procedure was the same as for methyl 4-(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido}-1-methylimidazol-2-amido)-1-methylpyrrole-2-carboxylate (Example 2, step 3). Using 270.00 mg of 1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrole-2-carboxylic acid, 460.00 mg of ethyl 1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylate was obtained as an off-white solid (96.45% yield). LC / MS: C 35 H 42 N 14 O 8Calculated mass: 786.33, Measured mass: 809.60 [M+Na] + .

[0650] Step 3: Synthesis of 1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylic acid The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Example 1, step 3). 470.00 mg of ethyl 1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylate was used to give 400.00 mg of 1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylic acid as an off-white solid (74.41% yield). LC / MS: C 33 H 38 N 14 O 8 Calculated mass: 758.30, measured mass: 759.55 [M+H] + .

[0651] Example 4. Synthesis of 1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]-1H-pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylic acid (PA-048-Des)

[0652] [ka]

[0653] Step 1: Synthesis of ethyl 4-amino-1H-pyrrole-2-carboxylate The procedure was the same as for ethyl 4-amino-1-methylimidazole-2-carboxylate (Example 1, step 1), but the reaction time was 18.0 h. 5.00 g of ethyl 4-nitro-1H-pyrrole-2-carboxylate was used to give 4.00 g of ethyl 4-amino-1H-pyrrole-2-carboxylate as a brown solid (95.56% yield). LC / MS: C 7 H 10 N 2 O 2 Calculated mass: 154.07, measured mass: 155.25 [M+H] + .

[0654] Step 2: Synthesis of ethyl 4-amino-1H-pyrrole-2-carboxylate To a 100 mL flask was added 1-methylimidazole-2-carboxylic acid (0.82 g, 6.49 mmol, 1.00 equiv), DMF (20.00 mL), ethyl 4-amino-1H-pyrrole-2-carboxylate (1.00 g, 6.486 mmol, 1.00 equiv), DIEA (3.36 g, 26.01 mmol, 4.01 equiv), the mixture was stirred at room temperature for 5.0 min, then PyBOP (4.39 g, 8.43 mmol, 1.30 equiv) was added and the reaction was stirred at room temperature for 1.0 h. The reaction was quenched by the addition of water (60 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE:EA=1:1) to give ethyl 4-(1-methylimidazol-2-amido)-1H-pyrrole-2-carboxylate (1.50 g, 88.17%) as a light green solid. LC / MS: C 12 H 14N 4 O 3 Calculated mass: 262.11, measured mass: 263.25 [M+H] + .

[0655] Step 3: Synthesis of 4-(1-methylimidazol-2-amido)-1H-pyrrole-2-carboxylic acid The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Example 1, step 9), but the reaction temperature was 30° C. and the reaction solvent was MeOH / THF (2:1). 2.00 g of ethyl 4-(1-methylimidazole-2-amido)-1H-pyrrole-2-carboxylate was used to obtain 2.00 g of crude 4-(1-methylimidazole-2-amido)-1H-pyrrole-2-carboxylic acid as a brown solid. LC / MS: C 10 H 10 N 4 O 3 Calculated mass: 234.08, measured mass: 235.05 [M+H] + .

[0656] Step 4: Synthesis of ethyl 1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxylate The procedure was the same as for ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4, step 2). Using 1.60 g of 4-(1-methylimidazol-2-amido)-1H-pyrrole-2-carboxylic acid, 1.10 g of ethyl 1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxylate was obtained as a brown solid (35.28% yield). LC / MS: C 20 H 24 N 8 O 5 Calculated mass: 456.19, measured mass: 457.30 [M+H] + .

[0657] Step 5: Synthesis of 1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxylic acid The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid (Example 1, step 9), but the reaction time was 1.0 h and the reaction solvent was MeOH / THF (1:1). Using 1.10 g of ethyl 1-methyl-4-(3-{[4-(1-methylimidazol-2-amide)-1H-pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxylate, 760.00 mg of 1-methyl-4-(3-{[4-(1-methylimidazol-2-amide)-1H-pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxylic acid was obtained as a white solid (73.62% yield). LC / MS: C 18 H 20 N 8 O 5 Calculated mass: 428.16, Measured mass: 429.15 [M+H] + .

[0658] Step 6: Synthesis of ethyl 4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]-1H-pyrrole-2-carboxylate The procedure was the same as for methyl 4-(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrol-2-amido}-1-methylimidazol-2-amido)-1-methylpyrrole-2-carboxylate (Example 3, step 2). 760.00 mg of 1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxylic acid was used to obtain 1.00 g of crude ethyl 4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]-1H-pyrrole-2-carboxylate as a brown solid. LC / MS: C 25 H 28 N 10 O 6 Calculated mass: 564.22, measured mass: 565.45 [M+H] + .

[0659] Step 7: Synthesis of 4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazol-2-amide]-1H-pyrrole-2-carboxylic acid The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Example 1, step 3), but the reaction temperature was 40° C. and the reaction time was 1.0 h. Using 1.00 g of ethyl 4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamido}propanamido)imidazole-2-amido]-1H-pyrrole-2-carboxylate, 930.00 mg of crude 4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamido}propanamido)imidazole-2-amido]-1H-pyrrole-2-carboxylic acid was obtained as a brown solid. LC / MS: C 23 H 24 N 10 O 6Calculated mass: 536.19, measured mass: 537.20 [M+H] + .

[0660] Step 8: Synthesis of ethyl 1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]-1H-pyrrol-2-yl}formamido)propanamido]imidazole-2-carboxylate To a 100 mL flask was added 4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamido}propanamido)imidazole-2-amido]-1H-pyrrole-2-carboxylic acid (650.00 mg, 1.21 mmol, 1.00 equiv), DMF (10.00 mL), ethyl 4-(3-aminopropanamido)-1-methylimidazole-2-carboxylate (292.00 mg, 1.22 mmol, 1.00 equiv), EDCI (1161.00 mg, 6.06 mmol, 5.00 equiv) and the mixture was stirred at room temperature for 5.0 minutes, then DMAP (740.00 mg, 6.06 mmol, 5.00 equiv) was added and the reaction was stirred at room temperature for 17.0 hours. The reaction was poured into ice water (30 mL), the precipitated solid was collected by filtration, washed with water (3 x 10 mL), dried under vacuum, and the crude product was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.05% TFA) in water, 10% to 50% gradient in 50 min; detector, UV 254 nm. Fractions were combined and concentrated. This gave ethyl 1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]-1H-pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylate (320.00 mg, 34.81%) as a brown solid. LC / MS: C 33 H 38 N 14 O 8 Calculated mass: 758.30, measured mass: 759.55 [M+H]+ .

[0661] Step 9: Synthesis of 1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]-1H-pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylic acid (PA-048-Des) The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino]propanamide]-1-methylimidazole-2-carboxylic acid (Example 1, Step 3), but the reaction temperature was room temperature. Using 310.00 mg of ethyl 1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]-1H-pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylate, 170.00 mg of crude 1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]-1H-pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylic acid was obtained as a brown solid. LC / MS: C 31 H 34 N 14 O 8 Calculated mass: 730.27, Measured mass: 731.55 [M+H] + .

[0662] Example 5. Synthesis of 1-methyl-4-[(1r,3r)-3-{1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-amido}cyclobutanamide]imidazole-2-carboxylic acid (PA-048-P6CB)

[0663] [ka]

[0664] Step 1: Synthesis of ethyl 1-methyl-4-[(1r,3r)-3-[(tert-butoxycarbonyl)amino]cyclobutanamido]imidazole-2-carboxylate The procedure was the same as for methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazol-2-yl)formamido]propanoate. Using 200.00 mg of (1r,3r)-3-[(tert-butoxycarbonyl)amino]cyclobutane-1-carboxylic acid, 330.00 mg of ethyl 1-methyl-4-[(1r,3r)-3-[(tert-butoxycarbonyl)amino]cyclobutanamido]imidazole-2-carboxylate was obtained as an orange solid (96.93% yield). LC / MS: C 17 H 26 N 4 O 5 Calculated mass: 366.19, measured mass: 367.25 [M+H] + .

[0665] Step 2: Synthesis of ethyl 1-methyl-4-[(1r,3r)-3-aminocyclobutanamido]imidazole-2-carboxylate The procedure was the same as for methyl 4-[4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2-amido]-1-methylpyrrole-2-carboxylate (Example 2, step 3). 145.00 mg of ethyl 1-methyl-4-[(1r,3r)-3-[(tert-butoxycarbonyl)amino]cyclobutanamido]imidazole-2-carboxylate was used to obtain 145.00 mg of crude ethyl 1-methyl-4-[(1r,3r)-3-aminocyclobutanamido]imidazole-2-carboxylate as a yellow oil. LC / MS: C 12 H 18 N 4 O 3 Calculated mass: 266.14, Measured mass: 267.10 [M+H] + .

[0666] Step 3: Synthesis of ethyl 1-methyl-4-[(1r,3r)-3-{1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]pyrrol-2-amido}cyclobutanamido]imidazole-2-carboxylate The procedure was the same as for methyl 4-(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido}-1-methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate (Example 2, step 3). Using 105.00 mg of ethyl 1-methyl-4-[(1r,3r)-3-aminocyclobutanamide]imidazole-2-carboxylate, 250.00 mg of ethyl 1-methyl-4-[(1r,3r)-3-{1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazole-2-amido)pyrrol-2-yl]formamide}propanamide)imidazole-2-amido]pyrrol-2-amido}cyclobutanamide]imidazole-2-carboxylate was obtained as a pale yellow solid (78.15% yield). LC / MS:C 37 H 44 N 14 O 8 Calculated mass: 812.35, measured mass: 813.50 [M+H] + .

[0667] Step 4: Synthesis of 1-methyl-4-[(1r,3r)-3-{1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-amido}cyclobutanamide]imidazole-2-carboxylic acid (PA-048-P6CB) The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Example 1, step 3). Using 250.00 mg of ethyl 1-methyl-4-[(1r,3r)-3-{1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-amido}cyclobutanamide]imidazole-2-carboxylate, 210.00 mg of 1-methyl-4-[(1r,3r)-3-{1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-amido}cyclobutanamide]imidazole-2-carboxylic acid was obtained as a pale yellow solid (87.00% yield). LC / MS: C 35 H 40 N 14 O 8 Calculated mass: 784.32, measured mass: 785.40 [M+H] + .

[0668] Example 6. Synthesis of 3-(3-(1-methyl-4-(3-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-1H-imidazole-2-carboxamide)-1H-pyrrole-2-carboxamide)propanamide)-1H-imidazole-2-carboxamide)-1H-pyrrole-2-carboxamide)propanamide)-1H-imidazole-2-carboxamide)propanamide)propanoic acid (PA-001-b)

[0669] [ka]

[0670] Following a procedure similar to that of reported Example 1, 3-(3-(1-methyl-4-(3-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-1H-imidazole-2-carboxamide)-1H-pyrrole-2-carboxamide)propanamide)-1H-imidazole-2-carboxamide)-1H-pyrrole-2-carboxamide)propanamide)-1H-imidazole-2-carboxamide)propanamide)propanoic acid (PA-01-b).

[0671] Synthesis of representative ligands Example 7. Synthesis of 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid

[0672] [ka]

[0673] Step 1: Synthesis of 4-bromo-7-methoxy-1-(4-methylbenzenesulfonyl)pyrrolo[2,3-c]pyridine To a solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (5.00 g, 22.12 mmol, 1.00 equiv) in DMF (20.00 mL) was added NaH (60%, 796.46 mg, 33.19 mmol, 1.50 equiv) in small portions at 0° C. The reaction was then stirred for 15.0 min, followed by the addition of TsCl (6.30 g, 33.19 mmol, 1.50 equiv) at 0° C. The resulting mixture was stirred at room temperature for an additional 2.0 h. The mixture was poured into ice water (60 mL). The solid was filtered and diluted with H 2 2H 2 O (10 mL) and dried to give 4-bromo-7-methoxy-1-(4-methylbenzenesulfonyl)pyrrolo[2,3-c]pyridine (7.50 g, 83.98% yield) as a white solid. LCMS: C 15 H 13 BrN 2 O 3Calculated mass for S: 379.98, Measured mass: 380.95, 382.95 [M+H, M+2+H] + .

[0674] Step 2: Synthesis of ethyl 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate To a solution of 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (6.30 g, 16.58 mmol, 1.00 equiv) in THF (80.00 mL), LDA (2 M in THF, 12.50 mL, 24.87 mmol, 1.50 equiv) was added dropwise at -78 °C and the mixture was stirred at -78 °C to -50 °C for 1.0 h, followed by the dropwise addition of ClCOOEt (2.69 g, 24.87 mmol, 1.50 equiv). After 2.0 h, the reaction mixture was diluted with saturated NH 4 Cl(aq) and the residue was extracted with EA (3×300 mL). The organic phases were combined and washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA=10:1 to give ethyl 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (7.00 g, 90.11% yield) as a white solid. LCMS: C 18 H 17 BrN 2 O 5 Calculated mass for S: 452.00, Measured mass: 453.00, 455.00 [M+H, M+2+H] + .

[0675] Step 3: Synthesis of ethyl 4-bromo-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate CH 3To a stirred solution of ethyl 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (4.00 g, 8.850 mmol, 1.00 equiv) in CN (80.00 mL) was added TMSCl (1.45 g, 13.28 mmol, 1.50 equiv) and NaI (2.00 g, 13.28 mmol, 1.50 equiv) in N 2 The mixture was stirred at room temperature for 1.0 hour, then H 2 2H2O (238.95 mg, 13.28 mmol, 1.50 equiv) was added dropwise at 65° C. The mixture was stirred at 65° C. for 2.0 h. The reaction mixture was cooled to room temperature. The precipitate was filtered, washed with water (50 mL) and dried in vacuum. Ethyl 4-bromo-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (4.30 g, crude) was obtained as a brown solid. LCMS: C 17 H 15 BrN 2 O 5 Calculated mass for S: 437.99, Measured mass: 438.95, 440.95 [M+H, M+2+H] + .

[0676] Step 4: Synthesis of ethyl 4-bromo-6-methyl-1-(4-methylbenzenesulfonyl)-7-oxopyrrolo[2,3-c]pyridine-2-carboxylate To a solution of ethyl 4-bromo-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (4.30 g, 9.82 mmol, 1.00 equiv) in DMF (20.00 mL) was added Cs 2 CO 3 (3.83 g, 11.78 mmol, 1.20 equiv) was added and MeI (1.67 g, 11.78 mmol, 1.20 equiv) was added dropwise to the reaction. The reaction mixture was cooled to 5° C. 2 The mixture was stirred at room temperature for 17.0 hours under atmospheric pressure. The mixture was poured into ice water (60 mL). The solid was filtered and 22H 2 O (10 mL) and dried to give ethyl 4-bromo-6-methyl-1-(4-methylbenzenesulfonyl)-7-oxopyrrolo[2,3-c]pyridine-2-carboxylate (4.30 g, crude) as a brown solid. LCMS: C 18 H 17 BrN 2 O 5 Calculated mass for S: 452.00, Measured mass: 453.15, 455.15 [M+H, M+2+H] + .

[0677] Step 5: Synthesis of ethyl 6-methyl-1-(4-methylbenzenesulfonyl)-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-c]pyridine-2-carboxylate To a solution of ethyl 4-bromo-6-methyl-1-(4-methylbenzenesulfonyl)-7-oxopyrrolo[2,3-c]pyridine-2-carboxylate (1.00 g, 2.21 mmol, 1.00 equiv) in THF (30.00 mL), bis(pinacolato)diboron (1.12 g, 4.41 mmol, 2.00 equiv), KOAc (650.00 mg, 6.62 mmol, 3.00 equiv), X-Phos Pd G2 (175.00 mg, 0.22 mmol, 0.10 equiv), and X-Phos (106.00 mg, 0.22 mmol, 0.10 equiv) were added N 2 The resulting mixture was added under atmospheric pressure. 2 The mixture was stirred at 75° C. for 17.0 hours under atmospheric pressure. The mixture was concentrated and diluted with 40 mL of H 2 O was added to the residue, then the mixture was extracted with EA (3×40 mL), the combined organic phases were washed with NaCl solution (40 mL) and Na 2 SO 4 The solid was filtered and the filtrate was concentrated to give ethyl 6-methyl-1-(4-methylbenzenesulfonyl)-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-c]pyridine-2-carboxylate (2.20 g, crude) as a yellow solid. The crude product was used directly in the next step. LCMS: C 21 H25 BN 2 O 5 Calculated mass for S: 500.18, Measured mass: 501.10 [M+H] + .

[0678] Step 6: Synthesis of 2-(4-fluoro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 2-bromo-5-fluoro-1,3-dimethylbenzene (5.00 g, 24.62 mmol, 1.00 equiv) in THF (15.00 mL), n-BuLi (2.5 M, 14.77 mL, 36.94 mmol, 1.50 equiv) was added 2 The mixture was stirred at -78°C for 3.0 hours, and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.87 g, 36.94 mmol, 1.50 equiv) was added dropwise at -78°C. The resulting mixture was allowed to warm to room temperature and stirred for 3.0 hours. After reaction, the reaction was quenched with water (20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 2-(4-fluoro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.70 g, crude) as a pale yellow oil. The crude product was used directly in the next step without further purification. LC / MS: C 14 H 20 BFO 2 Calculated mass: 250.15, measured mass: 251.30 [M+1] + .

[0679] Step 7: Synthesis of 4-fluoro-2,6-dimethylphenol To a stirred solution of 2-(4-fluoro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.70 g, 26.79 mmol, 1.00 equiv) in THF (20.00 mL) was added NaOH (1.61 g, 40.25 mmol, 1.50 equiv) and H 2 O2 (9.99 mL, 428.59 mmol, 16.00 equiv.) 2 The mixture was added dropwise under atmospheric pressure at -10°C. The resulting mixture was stirred at room temperature for 17.0 h. After the reaction, the mixture was acidified to pH = 1 with HCl (aqueous 2M). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated NaHCO 3 (aqueous) (1 x 10 mL), and saturated Na 2 S 2 O 3 (aqueous) (1 × 10 mL), and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (12:1) to give 4-fluoro-2,6-dimethylphenol (2.70 g, 66.88% yield) as a white solid. 1 HNMR(400MHz,DMSO) δ:8.12(s,1H),6.73(d,J=9.3Hz,2H),2.16(s,6H).

[0680] Step 8: Synthesis of methyl 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzoate To a stirred solution of 4-fluoro-2,6-dimethylphenol (2.70 g, 19.26 mmol, 1.00 equiv.) and methyl 3-bromo-4-fluorobenzoate (4.94 g, 21.20 mmol, 1.10 equiv.) in DMSO (20.00 mL) was added Cs 2 CO 3 (9.41 g, 28.90 mmol, 1.50 equiv) was added at room temperature. The resulting mixture was stirred at 80° C. for 2.0 h. After reaction, the reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were combined and washed with anhydrous Na 2 SO 4The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (12:1) to give methyl 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzoate (6.80 g, 94.95% yield) as a white solid. LC / MS: C 16 H 14 BrFO 3 Calculated mass: 352.01, measured mass: 353.15 [M+H] + .

[0681] Step 9: Synthesis of 2-[3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl]propan-2-ol To a stirred solution of methyl 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzoate (2.00 g, 5.66 mmol, 1.00 equiv) in THF (10.00 mL) was added bromo(methyl)magnesium (3.00 M in 2-Me-THF, 11.33 mL, 33.98 mmol, 6.00 equiv) with N 2 The resulting mixture was added under atmospheric pressure at 0°C. 2 The mixture was stirred at 0° C. for 1.0 hour under atmospheric conditions. After the reaction, the reaction product was diluted with saturated NH 4 The mixture was quenched by adding Cl(aq) (10 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (10:1) to give 2-[3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl]propan-2-ol (1.80 g, 77.40% yield) as a white solid. LC / MS: C 17 H 18 BrFO 2 Calculated mass: 352.05, measured mass: 335.00 [M-OH] + .

[0682] Step 10: Synthesis of ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-1-(4-methylbenzenesulfonyl)-7-oxopyrrolo[2,3-c]pyridine-2-carboxylate Dioxane (16.00 mL) and H 2 To a stirred solution of 2-[3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl]propan-2-ol (500.00 mg, 1.42 mmol, 1.00 equiv.) and ethyl 6-methyl-1-(4-methylbenzenesulfonyl)-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-c]pyridine-2-carboxylate (1.42 g, 2.83 mmol, 2.00 equiv.) in 2O (4.00 mL) was added Pd 2 (dba) 3 .CHCl 3 (129.62mg, 0.14mmol, 0.10eq), K 3 PO 4 (901.39 mg, 4.25 mmol, 3.00 equiv.) and 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane (82.00 mg, 0.28 mmol, 0.20 equiv.) were added to N 2 The resulting mixture was added under atmospheric pressure. 2 The mixture was stirred at 75° C. under atmospheric pressure for 1.0 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 37° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with hexane / EtOAc (1:1) to give ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-1-(4-methylbenzenesulfonyl)-7-oxopyrrolo[2,3-c]pyridine-2-carboxylate (620.00 mg, 48.76% yield) as a white solid. LC / MS: C 35 H 35 FN 2O 7 Calculated mass for S: 646.21, Measured mass: 647.20 [M+H] + .

[0683] Step 11: Synthesis of 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid To a stirred solution / mixture of ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-1-(4-methylbenzenesulfonyl)-7-oxopyrrolo[2,3-c]pyridine-2-carboxylate (600.00 mg, 0.93 mmol, 1.00 equiv.) in MeOH (15.00 mL) was added KOH (2 M, 3.71 mL, 7.42 mmol, 8.00 equiv.) at room temperature. The resulting mixture was stirred at 40° C. for 4.0 h. After reaction, the resulting mixture was concentrated under vacuum. The residue was then dissolved in water (10 mL) and acidified to pH 3 with HCl (2 M aqueous). The precipitated solid was collected by filtration and washed with water (3×10 mL). The solid was concentrated under vacuum to give 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (390.00 mg, 64.26% yield) as a white solid. LC / MS: C 26 H 25 FN 2 O 5 Calculated mass: 464.17, Measured mass: 465.15 [M+H] + .

[0684] Example 8. Synthesis of 1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridine-2-carboxylic acid

[0685] [ka]

[0686] Step 1: Synthesis of ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate To a stirred solution of ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-1-(4-methylbenzenesulfonyl)-7-oxopyrrolo[2,3-c]pyridine-2-carboxylate (3.40 g, 5.26 mmol, 1.00 equiv.) in ethyl alcohol (50.00 mL), sodium ethoxide (894.40 mg, 13.14 mmol, 2.50 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for 2.0 hours. After reaction, the reaction was poured into citric acid solution (3.32 g, 3.00 equiv., 125 mL). The resulting mixture was then extracted with EtOAc (3×150 mL). The combined organic layers were washed with water (2×50 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was washed with diethyl ether (3×10 mL) to give ethyl 4-[2-(4-fluoro-2,6-)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (2.00 g, 71.78% yield) as a white solid. LCMS: C 28 H 29 FN 2 O 5 Calculated mass: 492.21, Measured mass: 493.40 [M+H] + .

[0687] Step 2: Synthesis of ethyl 1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridine-2-carboxylate The procedure was the same as for ethyl 1-(5-bromopentyl)-4-[(tert-butoxycarbonyl)amino]pyrrole-2-carboxylate, but the reaction time was 2.0 hours. Using 500.00 mg of ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate, 500.00 mg of ethyl 1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridine-2-carboxylate was obtained as a white solid (94.61% yield). LC / MS: C 30 H 33 FN 2 O 5 Calculated mass: 520.24, measured mass: 521.35 [M+H] + .

[0688] Step 3: Synthesis of 1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridine-2-carboxylic acid The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid, but the reaction solvent was MeOH / THF (1:5). 500.00 mg of ethyl 1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridine-2-carboxylate was used to obtain 514.00 mg of crude 1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridine-2-carboxylic acid as a pale yellow solid. LC / MS: C 28 H 29 FN 2 O 5Calculated mass: 492.21, measured mass: 493.15 [M+H] + .

[0689] Example 9. Synthesis of 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid

[0690] [ka]

[0691] Step 1: Synthesis of ethyl 4-bromo-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate To a stirred solution of ethyl 6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (10.00 g, 45.41 mmol, 1.00 equiv.) in tetrahydrofuran (150.00 mL) was added NBS (8.08 g, 45.41 mmol, 1.00 equiv.) and p-TsOH (3.91 g, 22.70 mmol, 0.50 equiv.). The resulting mixture was stirred at room temperature for 1.0 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (0-10% MeOH / DCM) to give ethyl 4-bromo-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (13.00 g, 95.71% yield) as a yellow solid. LC / MS: C 11 H 11 BrN 2 O 3 Calculated mass: 298.00, Measured mass: 299.00, 301.00 [M+H, M+2+H] + .

[0692] Step 2: Synthesis of ethyl 6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate To a stirred solution of ethyl 4-bromo-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (13.00 g, 43.46 mmol, 1.00 equiv.) in dioxane (150.00 mL) was added bis(pinacolato)diboron (22.07 g, 86.92 mmol, 2.00 equiv.), Pd 2 (dba) 3 .CHCl 3 (4.00 g, 4.36 mmol, 0.10 equiv), and AcOK (8.53 g, 86.92 mmol, 2.00 equiv) were added. The final reaction mixture was irradiated in a microwave at 120° C. for 1.0 h. The reaction was run on a 1.0 g scale and repeated 13 times. The reaction mixtures were then combined and treated together. 150 mL of H 2 O was added and the resulting mixture was extracted with EA (3×150 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (50-70% EA / PE) to give ethyl 6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (10.00 g, 66.47% yield) as a yellow solid. LC / MS: C 17 H 23 BN 2 O 5 Calculated mass: 346.17, Measured mass: 347.20 [M+H] + .

[0693] Step 3: Synthesis of 5-fluoro-2-(4-methanesulfonyl-2-nitrophenoxy)-1,3-dimethylbenzene The procedure was the same as for methyl 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzoate, except that the reaction temperature was 120° C. and the reaction time was 1.0 h. Using 2.00 g of 4-fluoro-2,6-dimethylphenol, 4.60 g of the desired product was obtained as an off-white solid (94.05% yield). 1H NMR(300MHz,DMSO-d6) δ:8.60(s,1H),8.07(d,J=9.0Hz,1H),7.16(d,J=9.0Hz,2H),6.88(d,J=9.0Hz,1H),3.31(s,3H),2.09(s,6H).

[0694] Step 4: Synthesis of 2-(2,4-difluorophenoxy)-5-methanesulfonylaniline To a stirred solution of 1-(2,4-difluorophenoxy)-4-methanesulfonyl-2-nitrobenzene (500.00 mg, 1.52 mmol, 1.00 equiv) in THF (10.00 mL) was added Pd / C (100.00 mg, 20% w / w). The mixture was heated to 100° C. using a hydrogen balloon. 2 Hydrogenated at room temperature under atmosphere for 17.0 h. The resulting mixture was filtered and the filter cake was washed with EA (3×20 mL). The filtrate was concentrated under reduced pressure to give 2-(2,4-difluorophenoxy)-5-methanesulfonylaniline (450.00 mg, crude) as a pale yellow oil. The crude product was used directly in the next step without further purification. LC / MS: C 15 H 16 FNO 3 Calculated mass for S: 309.08, Measured mass: 310.10 [M+H] + .

[0695] Step 5: Synthesis of 5-fluoro-2-(2-iodo-4-methanesulfonylphenoxy)-1,3-dimethylbenzene To a stirred solution of 2-(4-fluoro-2,6-dimethylphenoxy)-5-methanesulfonylaniline (500.00 mg, 1.62 mmol, 1.00 equiv) in dioxane (5.00 mL) was added concentrated hydrogen chloride (1.00 mL) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 10.0 min. To the above mixture was added sodium nitrite (133.81 mg, 1.94 mmol, 1.20 equiv) at 0° C. The resulting mixture was stirred at 0° C. for an additional 1.0 h. To the above mixture was added KI (536.60 mg, 3.23 mmol, 2.00 equiv) at 0° C. The resulting mixture was stirred at 40° C. for an additional 17.0 h. After reaction, the reaction was quenched with water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (1×10 mL) and then with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to give 5-fluoro-2-(2-iodo-4-methanesulfonylphenoxy)-1,3-dimethylbenzene (250.00 mg, 31.65% yield) as a pale yellow oil. LC / MS: C 15 H 14 FIO 3 Calculated mass for S: 419.97, Measured mass: 442.95 [M+Na] + .

[0696] Step 6: Synthesis of ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate To a stirred solution of 5-fluoro-2-(2-iodo-4-methanesulfonylphenoxy)-1,3-dimethylbenzene (380.00 mg, 0.90 mmol, 1.00 equiv) in toluene (6.00 mL) and water (1.50 mL) was added ethyl 6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (469.56 mg, 1.36 mmol, 1.50 equiv), K 3 PO 4(383.88 mg, 1.81 mmol, 2.00 equiv.), and Pd(dtbpf)Cl 2 (58.93 mg, 0.09 mmol, 0.10 equiv.) 2 The resulting mixture was added under atmospheric pressure. 2 The mixture was stirred at 70° C. under atmospheric pressure for 2.0 hours. After the reaction, the reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (1×5 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (0-100%) to give ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (250.00 mg, 52.86% yield) as a dark yellow solid. LC / MS: C 26 H 25 FN 2 O 6 Calculated mass for S: 512.14, Measured mass: 513.30 [M+H] + .

[0697] Step 7: Synthesis of 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid To a stirred solution of ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (240.00 mg, 0.47 mmol, 1.00 equiv.) in tetrahydrofuran (1.00 mL) and water (5.00 mL), caustic soda (74.91 mg, 1.87 mmol, 4.00 equiv.) was added at room temperature. The resulting mixture was stirred at 70° C. for 2.0 hours. After the reaction, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL). The mixture was acidified to pH 4 with HCl (aqueous 2 M). The precipitated solid was collected by filtration, washed with water (3×5 mL), and dried under vacuum. This gave 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (170.00 mg, 73.44% yield) as a pale yellow solid. LC / MS: C 24 H 21 FN 2 O 6 Calculated mass for S: 484.11, Measured mass: 485.10 [M+H] + .

[0698] Example 10. Synthesis of 4-[5-(ethanesulfonyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid

[0699] [ka]

[0700] Step 1: Synthesis of 2-bromo-4-(ethanesulfonyl)-1-fluorobenzene H 2 SO 4To a stirred solution of fluoreszone (1.00 g, 5.31 mmol, 1.00 equiv) in (6.00 mL) was added NBS (1.04 g, 5.84 mmol, 1.10 equiv). The resulting mixture was stirred at room temperature for 16.0 h. The resulting mixture was poured into ice water (20 mL). The precipitated solid was collected by filtration, washed with PE (50 mL) and dried to give 2-bromo-4-(ethanesulfonyl)-1-fluorobenzene (890.00 mg, 62.71% yield) as a yellow solid. LC / MS: C 8 H 8 BrFO 2 Calculated masses for S: 265.94, 267.05, 268.95[M+H,M+H+2].

[0701] Step 2: Synthesis of 2-[2-bromo-4-(ethanesulfonyl)phenoxy]-5-fluoro-1,3-dimethylbenzene The procedure was the same as for methyl 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzoate (Example 9, Step 2), but the reaction temperature was 110° C., the reaction time was 1.0 h, and the crude product was used in the next step without purification. Using 870.00 mg of 1,3-dibromo-5-(ethanesulfonyl)-2-fluorobenzene, 950.00 mg of 2-[2-bromo-4-(ethanesulfonyl)phenoxy]-5-fluoro-1,3-dimethylbenzene was obtained as a yellow solid (97.56% yield). LC / MS: C 16 H 16 BrFO 3 Calculated mass for S: 386.00, Measured mass: 387.05, 389.05 [M+H, M+2+H] + .

[0702] Step 3: Synthesis of 2-[2-bromo-4-(ethanesulfonyl)phenoxy]-5-fluoro-1,3-dimethylbenzene The procedure was the same as for ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Example 9, step 6), but the reaction temperature was 75° C. and the reaction time was 1.0 h. Using 950.00 mg of 2-[2-bromo-4-(ethanesulfonyl)phenoxy]-5-fluoro-1,3-dimethylbenzene, 870.00 mg of ethyl 4-[5-(ethanesulfonyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate was obtained as a yellow solid (67.35% yield). LC / MS: C 27 H 27 FN 2 O 6 Calculated mass for S: 526.15, Measured mass: 527.35 [M+H] + .

[0703] Step 4: Synthesis of 4-[5-(ethanesulfonyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid. Using 860.00 mg of ethyl 4-[5-(ethanesulfonyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate, 590.00 mg of 4-[5-(ethanesulfonyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid was obtained as a yellow solid (72.46% yield). LC / MS: C 25 H 23 FN 2 O 6 Calculated mass for S: 498.12, Measured mass: 499.25 [M+H] + .

[0704] Example 11. Synthesis of 4-[2-(2,4-difluorophenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid

[0705] [ka]

[0706] Step 1: Synthesis of 1-(2,4-difluorophenoxy)-4-methanesulfonyl-2-nitrobenzene To a stirred solution of 2,4-difluorophenol (1.78 g, 13.68 mmol, 1.00 equiv) in DMSO (50.00 mL) was added 1-fluoro-4-methanesulfonyl-2-nitrobenzene (3.00 g, 13.682 mmol, 1.00 equiv), and K 2 CO 3 (1.89 g, 13.68 mmol, 1.00 equiv) was added. The resulting mixture was stirred at 120° C. for 1.0 h. The reaction mixture was poured into ice water (120 mL) and extracted with EA (3×150 mL). The organic phases were combined and diluted with H 2 HO (100 mL) and NaCl (100 mL), and then rinsed with anhydrous Na 2 SO 4 The solid was filtered and the filtrate was concentrated to give 1-(2,4-difluorophenoxy)-4-methanesulfonyl-2-nitrobenzene (4.20 g, 88.56% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ) δ:8.61(s,1H),8.15(d,J=8.8Hz,1H),7.55-7.66(m,2H),7.24-7.30(m,2H),3.34(s,3H).

[0707] Step 2: Synthesis of 2-(2,4-difluorophenoxy)-5-methanesulfonylaniline The procedure was the same as for 2-(2,4-difluorophenoxy)-5-methanesulfonylaniline, but the reaction time was 1.0 h. 500.00 mg of 1-(2,4-difluorophenoxy)-4-methanesulfonyl-2-nitrobenzene was used to give 420.00 mg of 2-(2,4-difluorophenoxy)-5-methanesulfonylaniline as a colorless oil. LC / MS: C 13 H 11 F 2 NO 3 Calculated mass for S: 299.04, Measured mass: 300.05 [M+H] + .

[0708] Step 3: Synthesis of 1-(2,4-difluorophenoxy)-2-iodo-4-methanesulfonylbenzene The procedure was the same as for 5-fluoro-2-(2-iodo-4-methanesulfonylphenoxy)-1,3-dimethylbenzene, but the reaction time was 1.0 h after adding KI. Using 420.00 mg of 5-fluoro-2-(2-iodo-4-methanesulfonylphenoxy)-1,3-dimethylbenzene, 440.00 mg of 1-(2,4-difluorophenoxy)-2-iodo-4-methanesulfonylbenzene was obtained as a yellow solid (78.57% yield). 1 H NMR (400MHz, DMSO-d 6 ) δ:8.38(s,1H),7.86 d,J=8.4Hz,1H),7.50-7.61(m,1H),7.41-7.49(m,1H),7.15-7.25(m,1H),6.90(d,J=8.8Hz,1H),3.26(s,3H).

[0709] Step 4: Synthesis of ethyl 4-[2-(2,4-difluorophenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate The procedure was the same as for ethyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Example 9, step 6), but the reaction temperature was 75° C. and the reaction time was 1.0 h. Using 420.00 mg of 1-(2,4-difluorophenoxy)-2-iodo-4-methanesulfonylbenzene, 340.00 mg of ethyl 4-[2-(2,4-difluorophenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate was obtained as a white solid (62.11% yield). LC / MS: C 24 H 20 F 2 N 2 O 6 Calculated mass for S: 502.10, Measured mass: 503.25 [M+H] + .

[0710] Step 5: Synthesis of 4-[2-(2,4-difluorophenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid The procedure was the same as for 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylic acid (Example 1, step 3), but the reaction time was 1.0 h. Using 320.00 mg of ethyl 4-[2-(2,4-difluorophenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate, 290.00 mg of 4-[2-(2,4-difluorophenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid was obtained as a white solid (92.15% yield). LC / MS: C 22 H 16 F 2 N 2 O 6 Calculated mass for S: 474.07, Measured mass: 475.20 [M+H] + .

[0711] Example 12. Synthesis of 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-methoxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid

[0712] [ka]

[0713] In a 25 mL flask, 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (200.00 mg, 0.43 mmol, 1.00 equiv.), MeOH (4.00 mL), and H 2 SO 4 (0.20 mL) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was cooled to room temperature with NaHCO 3 The pH was adjusted to 7-8 with ethyl acetate and the aqueous layer was extracted with EtOAc (4×10 mL). The combined organic layers were washed with brine (2×10 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. This gave 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-methoxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (220.00 mg, crude) as a white solid. LC / MS: C 27 H 27 FN 2 O 5 Calculated mass: 478.19, Measured mass: 479.35 [M+H] + .

[0714] Synthesis of Representative Compounds of the Disclosure Example 13. Synthesis of N-[26-(4-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]-1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxamide (compound 7)

[0715] [ka]

[0716] Step 1: Synthesis of benzyl N-(4-{[26-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]pyrrol-2-yl}formamido)propanamido]imidazol-2-yl}formamido)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]oxy}phenyl)carbamate The procedure was the same as for methyl 1-methyl-4-(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-amido]pyrrol-2-amido}imidazol-2-amido)pyrrole-2-carboxylate. 150.00 mg of benzyl N-{4-[(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)oxy]phenyl}carbamate was used to obtain 325.00 mg of the desired product as a white solid (97.63% yield). LC / MS: C 65 H 86 N 16 O 18Calculated mass: 1378.63, Measured mass: 1379.65 [M+H] + .

[0717] Step 2: Synthesis of N-[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]-1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxamide The procedure was the same as for 9H-fluoren-9-ylmethyl N-[2-({2-[(5-{[2-({2-[(2-{[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl]-1-methylpyrrol-3-yl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamate. Using 380.00 mg of benzyl N-(4-{[26-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazol-2-yl}formamide)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]oxy}phenyl)carbamate, 350.00 mg of crude desired product was obtained as a brown oil. LC / MS: C 57 H 80 N 16 O 16 Calculated mass: 1244.59, Measured mass: 1245.70 [M+H] + .

[0718] Step 3: Synthesis of compound 7 The procedure was carried out by reacting N-(5-{[2-({2-[(2-{[26-(4-{1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl ]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide (Example 20). Using 250.00 mg of N-[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]-1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxamide, 29.90 mg of the desired product was obtained as a white solid (8.64% yield). HRMS: C 83 H 103 FN 18 O 20 Calculated mass: 1690.7580, Measured mass: 1691.7722 [M+H] + .

[0719] Example 14. Synthesis of N-[26-(4-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]-1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]-1H-pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxamide (compound 9)

[0720] [ka]

[0721] Step 1: Synthesis of benzyl N-(4-{[26-({1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]-1H-pyrrol-2-yl}formamido)propanamido]imidazol-2-yl}formamido)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]oxy}phenyl)carbamate The procedure was the same as for methyl 4-(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrol-2-amido}-1-methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate (Example 2, step 3). 160.00 mg of 1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazole-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazole-2-amido]-1H-pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxylic acid was used to obtain 260.00 mg of crude benzyl N-(4-{[26-({1-methyl-4-[3-({4 -[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]-1H-pyrrol-2-yl}formamido)propanamido]imidazol-2-yl}formamido)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]oxy}phenyl)carbamate was obtained as a brown solid. LC / MS: C 63 H 82 N 16 O 18 Calculated mass: 1350.60, measured mass: 676.85 [M / 2+H] + .

[0722] Step 2: Synthesis of N-[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]-1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]-1H-pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxamide The procedure was the same as for 9H-fluoren-9-ylmethyl N-[2-({2-[(5-{[2-({2-[(2-{[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamate, but the reaction time was 17.0 h. Using 250.00 mg of benzyl N-(4-{[26-({1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]-1H-pyrrol-2-yl}formamido)propanamido]imidazol-2-yl}formamido)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]oxy}phenyl)carbamate, 170.00 mg of crude desired product was obtained as a brown solid. LC / MS: C 55 H 76 N 16 O 16 Calculated mass: 1216.56, measured mass: 609.80 [M / 2+H] + .

[0723] Step 3: Synthesis of compound 9 The procedure was the same as for N-(5-{[2-({2-[(2-{[26-(4-{1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxamide. Using 160.00 mg of N-[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]-1-methyl-4-[3-({4-[1-methyl-4-(3-{[4-(1-methylimidazol-2-amido)-1H-pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]-1H-pyrrol-2-yl}formamide)propanamide]imidazole-2-carboxamide, 30.30 mg of the desired product was obtained as a white solid (13.71% yield). HRMS: C 81 H 99 FN 18 O 20 Calculated mass: 1662.7267, Measured mass: 1663.7394 [M+H] + .

[0724] Example 15. N-(5-{[2-({2-[(2-{[26-(4-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-amide}-2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)phenoxy)-3,6,9,12,15,18, Synthesis of 21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide (compound 4)

[0725] [ka]

[0726] Step 1: Synthesis of 2-(benzyloxy)-5-nitrophenol To a stirred solution of 4-nitrocatechol (1.00 g, 6.45 mmol, 1.00 equiv) in DMF (10.00 mL) was added NaH (60%, 0.15 g, 6.45 mmol, 1.00 equiv) in portions over 10.0 min at -20 °C. The resulting mixture was stirred at room temperature for 1.0 h. To the above mixture was added benzyl bromide (0.77 mL, 4.51 mmol, 0.70 equiv) in DMF (10.00 mL) dropwise over 30.0 min at -20 °C. The resulting mixture was stirred at room temperature for an additional 17.0 h. The reaction mixture was quenched with water and extracted with DCM (3 x 5 mL). The combined organic layers were combined and concentrated. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (10:1) to give 2-(benzyloxy)-5-nitrophenol (0.75 g, 45.54% yield) as a yellow oil. LC / MS: 13 H 11 NO 4 Calculated mass: 245.06, measured mass: 244.05 [MH]+ .

[0727] Step 2: Synthesis of 19-[2-(benzyloxy)-5-nitrophenoxy]-2,5,8,11,14,17-hexaoxanonadecane The procedure was the same as for tert-butyl (S)-2-(4-(4-(16-((2-(1H-indol-3-yl)ethyl)amino)hexadecanamido)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate. Using 400.00 mg of 2-(benzyloxy)-5-nitrophenol, 670.00 mg of 19-[2-(benzyloxy)-5-nitrophenoxy]-2,5,8,11,14,17-hexaoxanonadecane was obtained as a pale yellow oil (78.45% yield). LC / MS: C 26 H 37 NO 10 Calculated mass: 523.24, measured mass: 541.20 [M+H 2 O] + .

[0728] Step 3: Synthesis of 2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenol 19-[2-(benzyloxy)-5-nitrophenoxy]-2,5,8,11,14,17-hexaoxanonadecane (670.00 mg, 1.280 mmol, 1.00 equiv) was dissolved in TFA (2.00 mL). The resulting mixture was stirred at 70° C. for 2.0 h. The resulting mixture was concentrated under reduced pressure to give 2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenol (670.00 mg, crude) as a light brown oil. LC / MS: C 19 H 31 NO 10 Calculated mass: 433.19, Measured mass: 456.25 [M+Na] + .

[0729] Step 4: Synthesis of tert-butyl N-{26-[2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamate The procedure was the same as for tert-butyl (S)-2-(4-(4-(16-((2-(1H-indol-3-yl)ethyl)amino)hexadecanamido)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate, but the reaction time was 40.0 h. Using 550.00 mg of 2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenol, 700.00 mg of tert-butyl N-{26-[2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamate was obtained as a pale yellow oil (59.38% yield). LC / MS: C 42 H 76 N 2 O 20 Calculated mass: 928.49, measured mass: 946.40 [M+H 2 O] + .

[0730] Step 5: Synthesis of 26-[2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-amine The procedure was the same as for methyl 4-[4-(4-amino-1-methylpyrrol-2-amido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate (Example 2, step 3). Using 410.00 mg of tert-butyl N-{26-[2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamate gave 410.00 mg of 26-[2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-amine as a brown oil. LC / MS: C 37 H 68 N 2 O 18 Calculated mass: 828.44, Measured mass: 829.75 [M+H] + .

[0731] Step 6: Synthesis of N-[5-({2-[(2-{[2-({26-[2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide The procedure was the same as for methyl 4-(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido}-1-methylimidazol-2-amido)-1-methylpyrrole-2-carboxylate (Example 2, step 3). 360.00 mg of 26-[2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-amine was used to prepare 650.00 mg of N-[5-({2-[(2-{[2-({26-[2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenoxy]-3,6,9,12,1 5,18,21,24-Octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was obtained as a light brown solid (91.22% yield). LC / MS: C 73 H 109 N 17 O 26 Calculated mass: 1639.77, measured mass: 821.65 [M / 2+H] + .

[0732] Step 7: Synthesis of N-[5-({2-[(2-{[2-({26-[4-amino-2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)phenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide The procedure was the same as for 9H-fluoren-9-ylmethyl N-[2-({2-[(5-{[2-({2-[(2-{[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamate, but the reaction solvent was MeOH. 720.00 mg of N-[5-({2-[(2-{[2-({26-[2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was used to prepare 500.00 mg of N-[5-({2-[(2-{[2-({26-[4-amino-2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)phenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxylate was obtained as a light brown solid (70.74% yield). LC / MS: C 73 H 111 N 17 O 24 Calculated mass: 1609.79, measured mass: 806.65 [M / 2+H] + .

[0733] Step 8: Synthesis of compound 4 The procedure was carried out by reacting N-(5-{[2-({2-[(2-{[26-(4-{1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl ]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide (Example 20).300.00 mg of N-[5-({2-[(2-{[2-({26-[4-amino-2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)phenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl] ethyl 36.30 mg of N-(5-{[2-({2-[(2-{[26-(4-{4-[2-(4-fluoro-2,6-dimethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was used to synthesize 36.30 mg of N-(5-{[2-({2-[(2-{[26-(4-{4-[2-(4-fluoro-2,6-dimethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide. ethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-amido}-2-(2,5,8,11,14,17-hexaoxanonadecane-19-yloxy)phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl )carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was obtained as an off-white solid (8.89% yield). HRMS: C. 99 H 134 FN 19 O 28 Calculated mass: 2055.9629, Measured mass: 2056.9525 [M+H] + .

[0734] Example 16. N-{5-[(2-{[2-({2-[(26-{4-[({4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-yl}formamido)methyl]-1,2,3-triazol-1-yl}-3,6,9,12,15,18,21,24-octyl Synthesis of 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide (compound 5)

[0735] [ka]

[0736] Step 1: Synthesis of tert-butyl N-{[1-(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)-1,2,3-triazol-4-yl]methyl}carbamate To a stirred solution of tert-butyl N-(prop-2-yn-1-yl)carbamate (318.52 mg, 2.052 mmol, 3.00 equiv) in DMF (6.00 mL) was added CuSO 4 .5H 2O (85.41 mg, 0.342 mmol, 0.50 equiv), sodium ascorbate (68.11 mg, 0.342 mmol, 0.50 equiv), and 26-azido-3,6,9,12,15,18,21,24-octaoxahexacosan-1-amine (300.00 mg, 0.684 mmol, 1.00 equiv) were added in small portions at 0 °C. The resulting mixture was stirred at room temperature for 1.0 h. The reaction mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05% TFA), 35% to 45% gradient in 20 min; detector, UV 254 nm. The fractions were combined and concentrated. Tert-butyl N-{[1-(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)-1,2,3-triazol-4-yl]methyl}carbamate (190.00 mg, 46.78%) was obtained as a yellow oil. LC / MS: C 26 H 51 N 5 O 10 Calculated mass: 593.36, measured mass: 594.55 [M+H] + .

[0737] Step 2: Synthesis of tert-butyl N-[(1-{26-[3-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazol-2-yl}formamide)propanamide]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}-1,2,3-triazol-4-yl)methyl]carbamate The procedure was the same as for methyl 1-methyl-4-(1-methyl-4-{1-methyl-4-[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-amido]pyrrol-2-amido}imidazol-2-amido)pyrrole-2-carboxylate. 240.00 mg of 3-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazol-2-yl}formamide)propanoic acid was used to prepare 450.00 mg of tert-butyl N-[(1-{26-[3-({1-methyl-4-[3-({1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide]imidazol-2-yl}formamide]propanoic acid. -4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]pyrrol-2-yl}formamido)propanamido]imidazol-2-yl}formamido)propanamido]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}-1,2,3-triazol-4-yl)methyl]carbamate was obtained as a yellow oil (crude). LC / MS: C 62 H 92 N 20 O 18 Calculated mass: 1404.69, Measured mass: 1406.00 [M+H] + .

[0738] Step 3: Synthesis of N-[5-({2-[(2-{[2-({26-[4-(aminomethyl)-1,2,3-triazol-1-yl]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxamide The procedure was the same as for methyl 4-[4-(4-amino-1-methylpyrrol-2-amido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate (Example 2, step 4). 200.00 mg of tert-butyl N-[(1-{26-[3-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]pyrrol-2-yl}formamido)propanamido]imidazol-2-yl}formamido)propanamido]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}-1,2,3-triazol-4-yl)methyl]carbamate was used. Obtained 0.00 mg of crude N-[5-({2-[(2-{[2-({26-[4-(aminomethyl)-1,2,3-triazol-1-yl]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide as a yellow oil. LC / MS: C 57 H 84 N 20 O 16 Calculated mass: 1304.64, Measured mass: 1305.95 [M+H] + .

[0739] Step 4: Synthesis of compound 5 The procedure was carried out by reacting N-(5-{[2-({2-[(2-{[26-(4-{1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl ]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide (Example 20). 180.00 mg of N-[5-({2-[(2-{[2-({26-[4-(aminomethyl)-1,2,3-triazol-1-yl]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1 29.80 mg of N-{5-[(2-{[2-({2-[(26-{4-[({4-[2-(4-fluoro-2,6-dimethyl- ethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-yl}formamido)methyl]-1,2,3-triazol-1-yl}-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)carbamoyl]ethyl}carbamoyl)-1-methylimidazol-4-yl]carbamoyl}ethyl)carbamoyl]-1-methylpyrrol-3-yl}-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was obtained as a white solid (12.30% yield). HRMS: C 83 H 107 FN22 O 20 Calculated mass: 1750.8016, Measured mass: 1751.8142 [M+H] + .

[0740] Example 17. N-{5-[(2-{[2-({2-[(26-{4-[({4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-yl}formamido)methyl]phenoxy}-3,6,9,12,15,18,21,24-octaoxahexyl Synthesis of 3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxamide (compound 6)

[0741] [ka]

[0742] Step 1: Synthesis of benzyl N-[(4-hydroxyphenyl)methyl]carbamate In a 100 mL flask, add 4-(aminomethyl)phenol (500.00 mg, 4.060 mmol, 1.00 equiv), THF (8.00 mL), and H 2 O (8.00 mL) was added. The resulting mixture was cooled to 0 °C and treated with NaHCO 3(444.00 mg, 5.285 mmol, 1.30 equiv) was added, followed by dropwise addition of benzyl chloroformate (693.00 mg, 4.062 mmol, 1.0 equiv) and stirred at 0° C. for 10.0 min, then the reaction was stirred at room temperature for 1.0 h. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (1×10 mL), brine (1×10 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was triturated with heptane to give benzyl N-[(4-hydroxyphenyl)methyl]carbamate (680 mg, crude) as an off-white solid. LC / MS: C 15 H 15 NO 3 Calculated mass: 257.11, Measured mass: 280.10 [M+Na] + .

[0743] Step 2: Synthesis of benzyl N-{[4-({26-[(tert-butoxycarbonyl)amino]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}oxy)phenyl]methyl}carbamate The procedure was the same as for tert-butyl (S)-2-(4-(4-(16-((2-(1H-indol-3-yl)ethyl)amino)hexadecanamido)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (Example 15, step 2). Using 300.00 mg of benzyl N-[(4-hydroxyphenyl)methyl]carbamate, 720.00 mg of benzyl N-{[4-({26-[(tert-butoxycarbonyl)amino]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}oxy)phenyl]methyl}carbamate was obtained as a yellow oil (82.02% yield). LC / MS:C 38 H 60 N 2 O 13 Calculated mass: 752.41, Measured mass: 753.70 [M+H] + .

[0744] Step 3: Synthesis of benzyl N-({4-[(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)oxy]phenyl}methyl)carbamate The procedure was the same as for methyl 4-[4-(3-aminopropanamido)-1-methylimidazol-2-amido]-1-methylpyrrole-2-carboxylate hydrochloride, except that the reaction solvent was 4M HCl in dioxane / DCM (1:1) and the reaction time was 1.0 h. Using 690.00 mg of benzyl N-{[4-({26-[(tert-butoxycarbonyl)amino]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}oxy)phenyl]methyl}carbamate, 700.0 mg of crude benzyl N-({4-[(26-amino-3,6,12,15,18,21,24-octaoxahexacosan-1-yl)oxy]phenyl}methyl)carbamate was obtained as a yellow oil. LC / MS: C 33 H 52 N 2 O 11 Calculated mass: 652.36, measured mass: 653.55 [M+H] + .

[0745] Step 4: Synthesis of benzyl N-{[4-({26-[3-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]pyrrol-2-yl}formamido)propanamido]imidazol-2-yl}formamido)propanamido]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}oxy)phenyl]methyl}carbamate The procedure was the same as for methyl 4-(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido}-1-methylimidazol-2-amido)-1-methylpyrrole-2-carboxylate (Example 2, step 3). 690.00 mg of benzyl N-{4-[(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)oxy]phenyl}methyl)carbamate was used to obtain 1.30 g of crude benzyl N-{[4-({26-[3-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)-1-methylimidazol-2-amido)-1-methylimidazol-2-amido)-1-methylimidazol-2-carboxylate. Imidazol-2-amido)pyrrol-2-yl}formamido}propanamido)imidazol-2-amido]pyrrol-2-yl}formamido)propanamido]imidazol-2-yl}formamido)propanamido]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}oxy)phenyl]methyl}carbamate was obtained as a yellow solid. LC / MS: C 69 H 93 N 17 O 19 Calculated mass: 1463.68, measured mass: 733.45 [M / 2+H] + .

[0746] Step 5: Synthesis of N-[5-({2-[(2-{[2-({26-[4-(aminomethyl)phenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide The procedure was the same as for 9H-fluoren-9-ylmethyl N-[2-({2-[(5-{[2-({2-[(2-{[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamate, but the reaction temperature was 40° C. and the reaction time was 17.0 h. 900.00 mg of benzyl N-{[4-({26-[3-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]pyrrol-2-yl}formamido)propanamido]imidazol-2-yl}formamido)propanamido]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}oxy)phenyl]methyl}carbamate was used to prepare 800. Obtained 0.00 mg of crude N-[5-({2-[(2-{[2-({26-[4-(aminomethyl)phenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide as a yellow oil. LC / MS: C 61 H 87 N 17 O 17 Calculated mass: 1329.65, measured mass: 666.40 [M / 2+H] + .

[0747] Step 6: Synthesis of compound 6 The procedure was carried out by reacting N-(5-{[2-({2-[(2-{[26-(4-{1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxopyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl ]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide (Example 20). 200.00 mg of N-[5-({2-[(2-{[2-({26-[4-(aminomethyl)phenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was used to synthesize 25.90 mg of N-{5-[(2-{[2-({2-[(26-{4-[({4-[2-(4-fluoro-2,6-di Methylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-yl}formamido)methyl]phenoxy}-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)carbamoyl]ethyl}carbamoyl)-1-methylimidazol-4-yl]carbamoyl}ethyl)carbamoyl]-1-methylpyrrol-3-yl}-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was obtained as a white solid (9.39% yield). HRMS: C 87 H 110 FN 19 O 21Calculated mass: 1775.8108, Measured mass: 1776.8272 [M+H + .

[0748] Example 18. N-(5-{[2-({2-[(2-{[26-(4-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-methoxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosane-1- Synthesis of 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide (compound 1)

[0749] [ka]

[0750] The procedure was the same as for ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4, step 2), using 60.00 mg of 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-methoxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid to obtain 47.40 mg of N-(5-{[2-({2-[(2-{[26-(4-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-methoxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid). Oxo-1H-pyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was obtained as a white solid (20.95% yield). HRMS: C 87 H 110 FN 19 O 21 Calculated mass: 1775.8108, Measured mass: 1776.8225 [M+H] + .

[0751] Example 19. 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-N-(4-((1-(1-methyl-4-(3-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-1H-imidazole-2-carboxamide)-1H-pyrrole-2-carboxamide)propanamide)-1H-imidazo Synthesis of 1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carboxamido)propanamido)-1H-imidazol-2-yl)-1,5-dioxo-9,12,15,18,21,24,27,30-octaoxa-2,6-diazatriacontan-32-yl)oxy)phenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (compound 15)

[0752] [ka]

[0753] The procedure was the same as for ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4, step 2). 0.43 g of 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid was used to prepare 1 g of N-(5-{[2-({2-[(2-{[26-(4-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-methoxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid). -amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was obtained as a white solid (22.58% yield). HRMS: C86 H 108 FN 19 O 21 Calculated mass: 1761.7951, measured mass: 1762.9204 [M+H] + .

[0754] Example 20. Synthesis of N-(5-{[2-({2-[(2-{[26-(4-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-methanesulfonylphenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxamide (compound 2)

[0755] [ka]

[0756] The procedure was the same as for ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4, step 2). 150.00 mg of N-(5-{[2-({2-[(2-{[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was used to obtain 50.50 mg of the desired product as a white solid (24.13% yield). HRMS: C 84 H 104 FN 19 O 22Calculated mass: 1781.7308, measured mass: 1782.7370 [M+H] + .

[0757] Example 21. Synthesis of N-(5-{[2-({2-[(2-{[26-(4-{4-[5-(ethanesulfonyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxamide (compound 3)

[0758] [ka]

[0759] The procedure was the same as for ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 2, step 2). 70.00 mg of 4-[5-(ethanesulfonyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid was used to obtain 6.70 mg of the desired product as a white solid (2.48% yield). HRMS: C 85 H 106 FN 19 O 22 Calculated mass for S: 1795.7464, Measured mass: 1796.7515 [M+H] + .

[0760] Example 22. 1-Methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)-N-(1-methyl-5-{[(1r,3r)-3-[(2-{[26-(4-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]- Synthesis of 6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-amido}phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]cyclobutyl]carbamoyl}pyrrol-3-yl)imidazole-2-carboxamide (compound 8)

[0761] [ka]

[0762] Step 1: Synthesis of benzyl N-(4-{[26-({1-methyl-4-[(1r,3r)-3-{1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazol-2-amido]pyrrol-2-amido}cyclobutanamido]imidazol-2-yl}formamido)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]oxy}phenyl)carbamate The procedure was the same as for ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4, step 2). 140.00 mg of 1-methyl-4-[(1r,3r)-3-{1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-amido}cyclobutanamide]imidazole-2-carboxylic acid was used to obtain 240.00 mg of the desired product as a pale yellow solid (95.72% yield). LC / MS: C 67 H 88 N 16 O18 Calculated mass: 1404.65, Measured mass: 1405.95 [M+H] + .

[0763] Step 2: Synthesis of 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)-N-(1-methyl-5-{[(1r,3r)-3-[(2-{[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]cyclobutyl]carbamoyl}pyrrol-3-yl)imidazole-2-carboxamide The procedure was the same as for ethyl 4-amino-1-methylimidazole-2-carboxylate (Example 1, step 2), but the reaction time was 2.0 hours and the solvent was DMF. Using 240.00 mg of benzyl N-(4-{[26-({1-methyl-4-[(1r,3r)-3-{1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-amide}cyclobutanamide]imidazol-2-yl}formamide)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]oxy}phenyl)carbamate, 220.00 mg of crude desired product was obtained as a yellow oil. LC / MS: C 59 H 82 N 16 O 16 Calculated mass: 1270.61, measured mass: 636.60 [M / 2+H] + .

[0764] Step 3: Synthesis of compound 8 The procedure was the same as for ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4, step 2). 120.00 mg of 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)-N-(1-methyl-5-{[(1r,3r)-3-[(2-{[26-(4-aminophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]cyclobutyl]carbamoyl}pyrrol-3-yl)imidazole-2-carboxamide was used to obtain 54.80 mg of the desired product as a white solid (32.40% yield). HRMS: C 85 H 105 FN 18 O 20 Calculated mass: 1716.7737, Measured mass: 1717.7781 [M+H] + .

[0765] Example 23. N-(5-{[2-({2-[(2-{[26-(4-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-amide}-2-hydroxyphenoxy)-3,6,9,12,15,18,21.24-Octaoxahexacosa Synthesis of 3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxamide (compound 12)

[0766] [ka]

[0767] Step 1: Synthesis of 2-(benzyloxy)-1-fluoro-4-nitrobenzene To a stirred solution of 2-fluoro-5-nitrophenol (1.00 g, 6.365 mmol, 1.00 equiv) in DMF (15.00 mL) was added benzyl bromide (1.63 g, 9.547 mmol, 1.50 equiv) and K 2 CO 3 (2.64 g, 19.095 mmol, 3.00 equiv) was added. The resulting mixture was stirred at 50° C. for 1.0 h. The reaction mixture was poured into ice water (50 mL) and extracted with EA (3×80 mL). The organic phases were combined and diluted with H 2 HO (50 mL) and NaCl (50 mL), and then rinsed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0-10% EA / PE) to give ethyl 2-(benzyloxy)-1-fluoro-4-nitrobenzene (1.50 g, 95.32%) as a yellow solid.

[0768] Step 2: Synthesis of 2-(benzyloxy)-1-fluoro-4-nitrobenzene 2-(benzyloxy)-1-fluoro-4-nitrobenzene (INT-503-201) was synthesized using NaH (60% 1.00 equiv.) in DMF as solvent at 0 °C to room temperature, reaction time was 2.0 h. 100.00 mg of 2-(benzyloxy)-1-fluoro-4-nitrobenzene was used to obtain 290.00 mg of tert-butyl N-{26-[2-(benzyloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamate as a yellow oil (96.78% yield). LC / MS: C 36 H 56 N 2 O 14 Calculated mass: 740.37, Measured mass: 741.50 [M+H] + .

[0769] Step 3: Synthesis of 26-[2-(benzyloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosane-1-amine The procedure was the same as in Example 2, step 4. 240.00 mg of tert-butyl N-{26-[2-(benzyloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamate was used to obtain 240.00 mg of 26-[2-(benzyloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-amine as a yellow oil. LC / MS: C 31 H 48 N 2 O 12 Calculated mass: 640.32, measured mass: 641.55 [M+H] + .

[0770] Step 4: Synthesis of N-[5-({2-[(2-{[2-({26-[2-(benzyloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide The procedure was the same as in Example 2, step 5. 240.00 mg of 26-[2-(benzyloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosane-1-amine was used to prepare 500.00 mg of N-[5-({2-[(2-{[2-({26-[2-(benzyloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosane-1-amine]. 4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was obtained as a yellow solid (91.90% yield). LC / MS: C67 H 89 N 17 O 20 Calculated mass: 1451.64, measured mass: 727.45 [M / 2+H] + .

[0771] Step 5: Synthesis of N-(5-{[2-({2-[(2-{[26-(4-amino-2-hydroxyphenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide The procedure was the same as for ethyl 4-amino-1-methylimidazole-2-carboxylate (Example 1, step 3), but the reaction time was 2.0 hours and the solvent was DMF. 250.00 mg of N-[5-({2-[(2-{[2-({26-[2-(benzyloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)carbamoyl]ethyl}carbamoyl)-1-methylpyrrol-3-yl]-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide was used to obtain 25 Obtained 0.00 mg of crude N-(5-{[2-({2-[(2-{[26-(4-amino-2-hydroxyphenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide as a brown oil. LC / MS: C60 H 85 N 17 O 18 Calculated mass: 1331.62, measured mass: 667.30 [M / 2+H] + .

[0772] Step 6. 5-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-amide}-2-({26-[3-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazo Synthesis of 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate The procedure was the same as for ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4, step 2). 130.00 mg of N-(5-{[2-({2-[(2-{[26-(4-amino-2-hydroxyphenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4 -(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazole-2-carboxamide was used to prepare 70.00 mg of 5-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c] Pyridin-2-amido}-2-({26-[3-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamide}propanamide)imidazol-2-amido]pyrrol-2-yl}formamide)propanamide]imidazol-2-yl}formamide)propanamide]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}oxy)phenyl 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate was obtained as a white solid (32.24% yield). LC / MS:C 112 H 131 F 2 N 21 O 26 Calculated mass: 2223.95, measured mass: 1113.45 [M / 2+H] + .

[0773] Step 7: Synthesis of compound 12 5-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-2-amide}-2-({26-[3-({1-methyl-4-[3-({1-methyl-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amide)pyrrol-2-yl]formamide}propanamide)imidazol-2-amide]pyrrol-2-yl}formamide)propanamide in MeOH (2.00 mL) and THF (2.00 mL). To a stirred solution of 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (70.00 mg, 0.031 mmol, 1.00 equiv.), LiOH (2 M, 0.09 mL, 6.00 equiv.) was added and the resulting mixture was stirred at room temperature for 2.0 h. The mixture was concentrated under reduced pressure, the residue was dissolved in 5 mL of water, cooled to 0 °C, and the PH was adjusted to 3-5 with 2 M HCl. The precipitated solid was collected by filtration, washed with water (2 × 3 mL), and concentrated under vacuum. The crude was dissolved in DMF, filtered, and the filtrate (2.00 mL) was purified by preparative HPLC with the following conditions: Column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1%NH3.H 20), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 28% B to 53% B in 15 min, 53% B; wavelength: 254 nm; RT1 (min): 12.58; run number: 0. Fractions were combined and directly lyophilized to give N-(5-{[2-({2-[(2-{[26-(4-{4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-amide}-2-hydroxyphenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosane-1 -yl]carbamoyl}ethyl)carbamoyl]-1-methylimidazol-4-yl}carbamoyl)ethyl]carbamoyl}-1-methylpyrrol-3-yl)-1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-amido)pyrrol-2-yl]formamido}propanamido)imidazole-2-carboxamide (19.5 mg, 33.43%) was obtained as a white solid. HRMS: C 86 H 108 FN 19 O 22 Calculated mass: 1777.7900, Measured mass: 1778.7906 [M+H] + .

[0774] Example 24. 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-N-(4-((1-(1-methyl-4-(3-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-1H-imidazole-2-carboxamide)-1H-pyrrole-2-carboxamide)propanamide)-1H-imidazole-2- Synthesis of carboxamido)-1H-pyrrole-2-carboxamido)propanamido)-1H-imidazol-2-yl)-1,5,9-trioxo-13,16,19,22,25,28,31,34-octaoxa-2,6,10-triazahexatriacontan-36-yl)oxy)phenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (compound 10)

[0775] [ka]

[0776] The procedure was the same as for ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4, step 2). 191.00 mg of 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid was used to obtain 600 mg of the desired product as a white solid. HRMS: C 89 H 113 FN 20 O 22 Calculated mass: 1832.8322, measured mass: 1834.30[M+H] + .

[0777] Example 25. 4-((1-(1-methyl-4-(3-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-1H-imidazole-2-carboxamide)-1H-pyrrole-2-carboxamide)propanamide)-1H-imidazole-2-carboxamide)-1H-pyrrole-2-carboxamide)propanamide)-1H-imidazol-2-yl Synthesis of 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (compound 11)

[0778] [ka]

[0779] The procedure was the same as for ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4, step 2). 2.85 g of 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid DIEA salt was used to obtain 5.5 g of the desired product as a white solid. HRMS: C 80 H 96 FN 19 O 18 Calculated mass: 1630.70, measured mass: 1631.10 [M+H] + .

[0780] Example 26. 4-(2-(2,6-dimethyl-4-((1-(1-methyl-4-(3-(1-methyl-4-(1-methyl-4-(3-(1-methyl-4-(1-methyl-1H-imidazole-2-carboxamide)-1H-pyrrole-2-carboxamide)propanamide)-1H-imidazole-2-carboxamide)-1H-pyrrole-2-carboxamide)propanamide)-1H- Synthesis of imidazol-2-yl)-1,5-dioxo-9,12,15,18,21,24,27,30-octaoxa-2,6-diazatriacontan-32-yl)oxy)phenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (compound 17)

[0781] [ka]

[0782] Step 1: Synthesis of methyl 3-bromo-4-(2,6-dimethyl-4-nitrophenoxy)benzoate To a stirred mixture of 2-fluoro-1,3-dimethyl-5-nitrobenzene (5.80 g, 34.29 mmol, 1.00 equiv.) and methyl 3-bromo-4-hydroxybenzoate (8.71 g, 37.717 mmol, 1.1 equiv.) in DMSO (30.00 mL) was added Cs 2 CO 3 (13.41 g, 41.15 mmol, 1.20 equiv.) was added in portions. The mixture was stirred at 130° C. for 4 days. The resulting mixture was diluted with 100 mL of H 2 The combined organic layers were washed with brine (1×100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give methyl 3-bromo-4-(2,6-dimethyl-4-nitrophenoxy)benzoate (1.50 g, 10.36%) as an orange solid. 1 H NMR(400MHz,CDCl3) δ:8.38(s,1H),8.07(s,2H),7.85(d,J=8.8Hz,1H),6.36(d,J=8.4Hz,1H),3.93(s,3H),2.24(s,6H).

[0783] Step 2: Synthesis of methyl 4-(4-amino-2,6-dimethylphenoxy)-3-bromobenzoate To a stirred mixture of methyl 3-bromo-4-(2,6-dimethyl-4-nitrophenoxy)benzoate (1.50 g, 3.95 mmol, 1.00 equiv) in EtOH (20.00 mL) was added NH 4 Cl (2.11 g, 39.45 mmol, 10.00 equiv.) and H 2O (10.00 mL) was added at room temperature. The reaction was heated to 70° C., Fe (2.20 g, 39.45 mmol, 10.00 equiv) was added portionwise, and the resulting mixture was stirred at 70° C. for 1.0 h. The mixture was filtered, the filter cake was washed with ethanol (3×15 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give methyl 4-(4-amino-2,6-dimethylphenoxy)-3-bromobenzoate (1.30 g, 88.44%) as a brown solid. LC / MS: C 16 H 16 BrNO 3 Calculated mass: 349.03, Measured mass: 350.00, 352.00 [M+H, M+H+Na] +

[0784] Step 3: Synthesis of 3-bromo-4-(4-hydroxy-2,6-dimethylphenoxy)benzoate Methyl 4-(4-amino-2,6-dimethylphenoxy)-3-bromobenzoate (1.30 g, 3.71 mmol, 1.00 equiv.) was dissolved in H 2 O (10.00 mL) and 2M H 2 SO 4 (5.00 mL) of NaNO 2 (0.26 g, 3.71 mmol, 1.00 equiv.) was added. The mixture was stirred for 10 min, then Cu 2 O (0.27 g, 1.86 mmol, 0.50 equiv) was added in a batch and the mixture was stirred at 80° C. for 1.0 h. The mixture was then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (1×30 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give methyl 3-bromo-4-(4-hydroxy-2,6-dimethylphenoxy)benzoate (0.60 g, 41.42%) as an orange solid. LC / MS: C 16 H 15 Bro 4Calculated mass: 350.02, measured mass: 349.00, 351.00 [MH,M-H+2] -

[0785] Step 4: Synthesis of methyl 3-bromo-4-[4-({26-[(tert-butoxycarbonyl)amino]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}oxy)-2,6-dimethylphenoxy]benzoate To a mixture of methyl 3-bromo-4-(4-hydroxy-2,6-dimethylphenoxy)benzoate (600.00 mg, 1.71 mmol, 1.00 equiv) and tert-butyl N-(26-bromo-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)carbamate (984.96 mg, 1.71 mmol, 1.00 equiv) in ACN (10.00 mL), was added K 2 CO 3 (708.35 mg, 5.12 mmol, 3.00 equiv) was added in portions and the resulting mixture was stirred at 70 °C for 16.0 h. The mixture was then filtered, the filter cake was washed with MeCN (3 x 10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The fractions were combined and concentrated to give methyl 3-bromo-4-[4-({26-[(tert-butoxycarbonyl)amino]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}oxy)-2,6-dimethylphenoxy]benzoate (750.00 mg, 52.88%) as a yellow oil. LC / MS: C 39 H 60 BrNO 14 Calculated mass: 845.32, Measured mass: 846.30, 848.30 [M+H, M+H+2] +

[0786] Step 5: Synthesis of methyl 4-{4-[(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)oxy]-2,6-dimethylphenoxy}-3-bromobenzoate To a solution of methyl 3-bromo-4-[4-({26-[(tert-butoxycarbonyl)amino]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl}oxy)-2,6-dimethylphenoxy]benzoate (750.00 mg, 0.89 mmol, 1.00 equiv) in DCM (10.00 mL) was added TFA (2.00 mL) at room temperature and the mixture was stirred for 1.0 h. The resulting mixture was concentrated under reduced pressure to give methyl 4-{4-[(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)oxy]-2,6-dimethylphenoxy}-3-bromobenzoate (750.00 mg, crude) as a yellow oil. LC / MS: C 34 H 52 BrNO 12 Calculated mass: 745.27, Measured mass: 746.25, 478.25 [M+H, M+H+2] + .

[0787] Step 6: Synthesis of methyl 4-{4-[(26-{[(benzyloxy)carbonyl]amino}-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)oxy]-2,6-dimethylphenoxy}-3-bromobenzoate Cbz-Cl (319.85 mg, 1.87 mmol, 2.00 equiv.) was added via syringe to H 2 Methyl 4-{4-[(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)oxy]-2,6-dimethylphenoxy}-3-bromobenzoate (750.00 mg, 0.94 mmol, 1.00 equiv.) and Na in 2O (10.00 mL) and THF (3.00 mL). 2 CO 3 (149.04 mg, 1.41 mmol, 1.50 equiv) was added at 0 °C. The resulting mixture was stirred at room temperature for 18.0 h and then CH 2 Cl2 (3×30 mL). The combined organic layers were washed with brine (1×30 mL) and anhydrous Na 2 SO 4 The filtrate was dried at 40° C. for 1 hour and the filtrate was concentrated under reduced pressure to give methyl 4-{4-[(26-{[(benzyloxy)carbonyl]amino}-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)oxy]-2,6-dimethylphenoxy}-3-bromobenzoate (680.00 mg, 75.76%) as a yellow liquid. LC / MS: C 42 H 58 BrNO 14 Calculated mass: 879.30, Measured mass: 880.30, 882.30 [M+H, M+H+2] + .

[0788] Step 7: Synthesis of benzyl N-(26-{4-[2-bromo-4-(2-hydroxypropan-2-yl)phenoxy]-3,5-dimethylphenoxy}-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl)carbamate...

Claims

【Request Item 1】 【Chemistry 1-1】 【Chemistry 1-2】 [Chemistry 1-3] [Chemistry 1-4] [Chemistry 1-5] or a pharmaceutically acceptable salt thereof.

2. The compound is 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

3. The compound is 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

4. The compound is 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

5. The compound is 【Transformation 5】 or a pharmaceutically acceptable salt thereof.

6. The compound is 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

7. The compound is 【Transformation 7】 or a pharmaceutically acceptable salt thereof.

8. The compound is 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

9. The compound is 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

10. The compound is 【Chemistry 10】 or a pharmaceutically acceptable salt thereof.

11. The compound is 【Chemistry 11】 or a pharmaceutically acceptable salt thereof.

12. The compound is 【Chemistry 12】 or a pharmaceutically acceptable salt thereof.

13. The compound is 【Chemistry 13】 or a pharmaceutically acceptable salt thereof.

14. The compound is 【Chemistry 14】 or a pharmaceutically acceptable salt thereof.

15. The compound is 【Chemistry 15】 or a pharmaceutically acceptable salt thereof.

16. The compound is 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

17. The compound is 【Chemistry 17】 or a pharmaceutically acceptable salt thereof.

18. The compound is [Chemistry 18] or a pharmaceutically acceptable salt thereof.

19. The compound is 【Chemistry 19】 or a pharmaceutically acceptable salt thereof.

20. The compound is 【Chemistry 20】 or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising the compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of Friedreich's ataxia (FA) in a patient in need thereof.

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