WO2023133284A2 - Compounds and methods for treating friedreich's ataxia - Google Patents

Compounds and methods for treating friedreich's ataxia Download PDF

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Publication number
WO2023133284A2
WO2023133284A2 PCT/US2023/010331 US2023010331W WO2023133284A2 WO 2023133284 A2 WO2023133284 A2 WO 2023133284A2 US 2023010331 W US2023010331 W US 2023010331W WO 2023133284 A2 WO2023133284 A2 WO 2023133284A2
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optionally substituted
methyl
alkyl
compound
amido
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French (fr)
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WO2023133284A3 (en
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Aseem Ansari
Abhijit Bhat
Sean JEFFRIES
Pratik Shah
Chengzhi Zhang
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Design Therapeutics Inc
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Design Therapeutics Inc
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Priority to US18/726,567 priority Critical patent/US20250109132A1/en
Priority to IL314006A priority patent/IL314006A/en
Priority to CR20240321A priority patent/CR20240321A/es
Priority to PE2024001532A priority patent/PE20241730A1/es
Priority to CA3246468A priority patent/CA3246468A1/en
Priority to EP23737637.1A priority patent/EP4460302A4/en
Priority to JP2024540893A priority patent/JP2025502064A/ja
Priority to CN202380020304.1A priority patent/CN118695861A/zh
Priority to KR1020247025794A priority patent/KR20240138079A/ko
Priority to MX2024008474A priority patent/MX2024008474A/es
Application filed by Design Therapeutics Inc filed Critical Design Therapeutics Inc
Priority to AU2023205889A priority patent/AU2023205889A1/en
Publication of WO2023133284A2 publication Critical patent/WO2023133284A2/en
Publication of WO2023133284A3 publication Critical patent/WO2023133284A3/en
Anticipated expiration legal-status Critical
Priority to CONC2024/0010651A priority patent/CO2024010651A2/es
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/595—Polyamides, e.g. nylon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the disclosure relates to the treatment of inherited genetic diseases characterized by overproduction or underproduction of mRNA.
  • Friedreich’s ataxia (“FA” or “FRDA”) is an autosomal recessive neurodegenerative disorder caused by mutations in the frataxin gene (“ ⁇ xn”), which encodes the protein frataxin (“FXN”), an iron-binding mitochondrial protein involved in electron transport and metabolism.
  • ⁇ xn frataxin gene
  • FXN protein frataxin
  • a GAA trinucleotide repeat from about 66 to over 1000 trinucleotides is included in the first intron of ⁇ xn, and this hyperexpansion is responsible for the observed pathology.
  • Clinical symptoms of FA include ataxia, gait ataxia, muscle weakness, loss of upper body strength, loss of balance, lack of reflexes in lower limbs and tendons, loss of sensation, particularly to vibrations, impairment of position sense, impaired perception of temperature, touch, and pain, hearing and vision impairment, including distorted color vision and involuntary eye movements, irregular foot configuration, including pes cavus and inversion, hearing impairment, dysarthria, dysphagia, impaired breathing, scoliosis, diabetes, intolerance to glucose and carbohydrates, cardiac dysfunctions including hypertrophic cardiomyopathy, arrhythmia, myocardial fibrosis, and cardiac failure.
  • This disclosure utilizes regulatory molecules present in cell nuclei that control gene expression.
  • Eukaryotic cells provide several mechanisms for controlling gene replication, transcription, and/or translation. Regulatory molecules that are produced by various biochemical mechanisms within the cell can modulate the various processes involved in the conversion of genetic information to cellular components.
  • regulatory molecules are known to modulate the production of mRNA and, if directed to ⁇ xn, could modulate the production of ⁇ xn mRNA that causes Friedreich’s ataxia, and thus, reverse the progress of the disease.
  • the disclosure provides compounds and methods for recruiting a regulatory molecule into close proximity to ⁇ xn.
  • the compounds disclosed herein contain: (a) a recruiting moiety that will bind to a regulatory molecule, linked to (b) a DNA binding moiety that will selectively bind to ⁇ xn.
  • the compounds will counteract the expression of defective ⁇ xn in the following manner: (1) The DNA binding moiety will bind selectively the characteristic GAA trinucleotide repeat sequence of ⁇ xn; (2) The recruiting moiety, linked to the DNA binding moiety, will thus be held in proximity to ⁇ xn; (3) The recruiting moiety, now in proximity to ⁇ xn, will recruit the regulatory molecule into proximity with the gene; and (4) The regulatory molecule will modulate expression, and therefore counteract the production of defective ⁇ xn by direct interaction with the gene. [0008] The mechanism set forth above will provide an effective treatment for Friedreich’s ataxia, which is caused by the expression of defective ⁇ xn gene.
  • the disclosure provides recruiting moieties that will bind to regulatory molecules. Small molecule inhibitors of regulatory molecules serve as templates for the design of recruiting moieties, since these inhibitors generally act via noncovalent binding to the regulatory molecules. [0010] The disclosure further provides for DNA binding moieties that will selectively bind to one or more copies of the GAA trinucleotide repeat that is characteristic of the defective ⁇ xn gene.
  • the DNA binding moiety will comprise a polyamide segment that will bind selectively to the target GAA sequence.
  • Polyamides have been designed by Dervan (U.S. Patent 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 bonding interactions with the Watson-Crick base pairs.
  • Polyamides that selectively bind to particular 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, with each building block binding noncovalently and selectively to one of the DNA base pairs: A/T, T/A, G/C, and C/G.
  • trinucleotides will bind to molecules with three amide units, i.e. triamides.
  • these polyamides will orient in either direction of a DNA sequence, so that the 5'- GAA-3' trinucleotide repeat sequence of ⁇ xn can be targeted by the polyamides selective either for GAA or for AAG.
  • polyamides that bind to the complementary sequence in this case, TTC or CTT, will also bind to the trinucleotide repeat sequence of ⁇ xn and can be employed as well.
  • longer DNA sequences can be targeted with higher specificity and/or higher affinity by combining a larger number of monoamide building blocks into longer polyamide chains.
  • the binding affinity for a polyamide would simply be equal to the sum of each individual monoamide/DNA base pair interaction. In practice, however, due to the geometric mismatch between the fairly rigid polyamide and DNA structures, longer polyamide sequences do not bind to longer DNA sequences as tightly as would be expected from a simple additive contribution.
  • the disclosure therefore, provides DNA moieties that comprise triamides that are connected by flexible spacers.
  • the spacers alleviate the geometric strain that would otherwise decrease binding affinity of a larger polyamide sequence.
  • compounds that comprise a polyamide which can bind to one or more copies of the trinucleotide repeat sequence GAA, and can modulate the expression of the defective ⁇ xn gene. Treatment of a subject with these compounds may counteract the expression of the defective ⁇ xn gene, and this can reduce the occurrence, severity, and/or frequency of symptoms associated with Friedreich’s ataxia.
  • Certain compounds disclosed herein may provide higher binding affinity and/or selectivity than has been observed previously for this class of compound.
  • a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • a method of modulation of the expression of ⁇ xn comprising contacting ⁇ xn with a compound disclosed, or a pharmaceutically acceptable salt thereof.
  • a method of treating a disease or condition caused by expression of a defective ⁇ xn in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the disease is FA.
  • the compounds also contains moieties that bind to regulatory proteins.
  • the selective binding of the target gene can bring the regulatory protein into proximity to the target gene and thus downregulates transcription of the target gene.
  • the compounds disclosed herein provide higher binding affinity and selectivity than has been observed previously for this class of compounds and can be more effective in treating diseases associated with the defective ⁇ xn gene.
  • the compounds described herein can recruit the regulatory molecule to modulate the expression of the defective ⁇ xn gene and effectively treat and/or and alleviate the symptoms associated with diseases such as Friedreich ataxia.
  • compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for modulating the expression of ⁇ xn.
  • inventions provide methods for treating a ⁇ xn-mediated disorder in a patient in need of such treatment, comprising administering to said 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 ameliorated by the modulation of the expression of ⁇ xn.
  • Some embodiments relate to a compound having a first terminus, a second terminus, and oligomeric backbone, wherein: a) the first terminus comprises a DNA-binding moiety capable of noncovalently binding to a nucleotide repeat sequence GAA; b) the second terminus comprises a protein- binding moiety binding to a regulatory molecule that modulates an expression of a gene comprising the nucleotide repeat sequence GAA; and c) the oligomeric backbone comprising a linker between the first terminus and the second terminus.
  • the second terminus is a Brd4 binding moiety. In some embodiments, the second terminus is not a Brd4 binding moiety.
  • the compounds have the structure of Formula (I): X-L-Y Formula (I), or a salt thereof, wherein: X comprises a recruiting moiety is capable of binding to a regulatory moiety within the nucleus; Y comprises a DNA recognition moiety is capable of noncovalent binding to one or more copies of the trinucleotide repeat sequence GAA; and L is a linker.
  • the recruiting moiety is capable of noncovalent or covalent binding to a regulatory moiety.
  • the recruiting moiety is capable of noncovalent binding to a regulatory moiety.
  • the regulatory molecule is chosen from a bromodomain-containing protein.
  • the first terminus is Y
  • the second terminus is X
  • the oligomeric backbone is L.
  • the compounds have the structure of Formula (II): X-L-(Y 1 -Y 2 -Y 3 ) n -Y 0 Formula (II), or a salt thereof, wherein: X comprises a recruiting moiety that is capable of binding to a regulatory molecule within the nucleus; L is a linker; Y 1 , Y 2 , and Y 3 are internal subunits, each of which comprises a moiety chosen from a heterocyclic or heteroaryl ring or a C 1 -C 6 straight chain aliphatic segment, and each of which is chemically linked to its two neighbors; Y 0 is an end subunit which comprises a moiety chosen from a heterocyclic or heteroaryl ring or a straight chain aliphatic segment, which is chemically linked to its single neighbor; each subunit can nonco
  • the compounds of structural Formula (II) comprise a subunit for each individual nucleotide in the GAA repeat sequence.
  • each internal subunit has an amino (-NH-) group and a carboxy (-CO-) group.
  • the compounds of structural Formula (II) comprise amide (-NHCO-) bonds between each pair of internal subunits.
  • the compounds of structural Formula (II) comprise an amide (-NHCO-) bond between L and the left-most internal subunit.
  • the compounds of structural Formula (II) comprise an amide bond between the right-most internal subunit and the end subunit.
  • each subunit comprises a moiety that is independently chosen from a heterocycle and an aliphatic chain.
  • the aliphatic chain is a C 1 -C 6 straight chain aliphatic chain.
  • the aliphatic chain has structural formula -(CH 2 )m-, for m chosen from 1, 2, 3, 4, and 5.
  • the aliphatic chain is -CH 2 CH 2 -.
  • the heteroaryl is a monocyclic, bicyclic or polycyclic heteroaryl.
  • the heteroaryl is a monocyclic heteroaryl.
  • the heteroaryl is a 5- membered heteroaryl.
  • each heteroaryl contains a heteroatom independently chosen from N, O, or S. In some embodiments, each heteroaryl is independently chosen from pyrrole, imidazole, thiazole, oxazole, thiophene, and furan.
  • each internal subunit is independently selected from: benzopyrazinylene-CO-, -NH-phenylene-CO-, -NH-pyridinylene-CO-, -NH-piperidinylene-CO-, -NH- pyrimidinylene-CO-, -NH-anthracenylene-CO-, -NH-quinolinylene-CO-, and wherein Z is H, NH 2 , C 1-6 alkyl, or C 1-6 alkylNH 2 .
  • n is between 1 and 100, inclusive. In certain embodiments, n is between 1 and 50, inclusive. In certain embodiments, n is between 1 and 20, inclusive.
  • n is between 1 and 10, inclusive. In certain embodiments, n is between 1 and 5, inclusive. In certain embodiments, n is an integer between 1 and 3, inclusive. In certain embodiments, n is chosen from 1 and 2. In certain embodiments, n is 1. [0040] In some embodiments, n is an integer between 1 and 5, inclusive. [0041] In some embodiments, n is an integer between 1 and 3, inclusive. [0042] In some embodiments, n is an integer between 1 and 2, inclusive. [0043] In some embodiments, n is 1. [0044] In some embodiments, L comprises a C 1 -C 6 straight chain aliphatic segment.
  • L comprises (CH 2 OCH 2 )m; and m is an integer between 1 to 20, inclusive. In some further embodiments, m is an integer between 1 to 10, inclusive. In certain further embodiments, m is an integer between 1 to 5, inclusive.
  • the compounds have the structure of Formula (III): X-L-(Y 1 -Y 2 -Y 3 )-(W-Y 1 -Y 2 -Y 3 ) n -Y 0 Formula (III), or a salt thereof, wherein: X comprises a recruiting moiety that is capable of binding to a regulatory molecule within the nucleus; L is a linker; Y 1 , Y 2 , and Y 3 are internal subunits, each of which comprises a moiety chosen from a heterocyclic or heteroaryl ring or a C 1 -C 6 straight chain aliphatic segment, and each of which is chemically linked to its two neighbors; Y 0 is an end subunit which comprises a moiety chosen from a heterocyclic ring or a straight chain aliphatic segment, which is chemically linked to its single neighbor; each subunit can noncovalently bind to an individual nucleotide in the GAA repeat sequence; W is a spacer;
  • Y 1 -Y 2 -Y 3 is: [0048] In certain embodiments, Y 1 -Y 2 -Y 3 is: [0049] In some embodiments, Y 1 -Y 2 -Y 3 is Im-Py- ⁇ . [0050] In some embodiments, Y 1 -Y 2 -Y 3 is Im-Im- ⁇ . [0051] In some embodiments, each Y 1 -Y 2 -Y 3 is independently chosen from ⁇ -Py-Im and ⁇ -Im-Im. [0052] In some embodiments, at most one Y 1 -Y 2 -Y 3 is -Im-Im.
  • n is between 1 and 100, inclusive. In certain embodiments of the compound of structural Formula (III), n is between 1 and 50, inclusive. In certain embodiments of the compound of structural Formula (III), n is between 1 and 20, inclusive. In certain embodiments of the compound of structural Formula (III), n is between 1 and 10, inclusive. In certain embodiments of the compound of structural Formula (III), n is between 1 and 5, inclusive. In certain embodiments of the compound of structural Formula (III), n is chosen from 1 and 2. In certain embodiments of the compound of structural Formula (III), n is 1.
  • the compounds have the structure of Formula (IV): or a salt thereof, wherein: X comprises a recruiting moiety that is capable of binding to a regulatory molecule within the nucleus; Y 0 is an end subunit which comprises a moiety chosen from a heterocyclic ring or a straight chain aliphatic segment, which is chemically linked to its single neighbor; and n is an integer between 1 and 200, inclusive. [0055] In some embodiments of the compound of structural Formula (IV), n is between 1 and 10, inclusive. In certain embodiments of the compound of structural Formula (IV), n is between 1 and 5, inclusive. In certain embodiments of the compound of structural Formula (IV), n is chosen from 1 and 2.
  • n is 1.
  • the compounds have the structure of Formula (V): or a salt thereof, wherein: X comprises a recruiting moiety that is capable of binding to a regulatory molecule within the nucleus; and W is a spacer; Y 0 is an end subunit which comprises a moiety chosen from a heterocyclic ring or a straight chain aliphatic segment, which is chemically linked to its single neighbor; and n is an integer between 1 and 200, inclusive.
  • n is between 1 and 10, inclusive. In certain embodiments of the compound of structural Formula (V), n is between 1 and 5, inclusive.
  • n is chosen from 1 and 2. In certain embodiments of the compound of structural Formula (V), n is 1. [0058] In some embodiments of the compounds of structural Formula (V), wherein: W is -NHCH 2 -(CH 2 OCH 2 ) p -CH 2 CO-; and p is an integer between 1 and 4, inclusive.
  • First terminus – DNA binding moiety [0059] The first terminus interacts and binds with the gene, particularly with the minor grooves of the GAA sequence.
  • the compounds of the present disclosure provide a polyamide sequence for interaction of a single polyamide subunit to each base pair in the GAA repeat sequence.
  • the compounds of the present disclosure provide a turn component (e.g., aliphatic amino acid moiety), in order to enable hairpin binding of the compound to the GAA, in which each nucleotide pair interacts with two subunits of the polyamide.
  • a turn component e.g., aliphatic amino acid moiety
  • the compounds of the present disclosure are more likely to bind to the repeated GAA of ⁇ xn than to GAA elsewhere in the subject’s DNA, due to the high number of GAA repeats associated with ⁇ xn.
  • the compounds of the present disclosure provide more than one copy of the polyamide sequence for noncovalent binding to GAA.
  • the compounds of the present disclosure bind to ⁇ xn with an affinity that is greater than a corresponding compound that contains a single polyamide sequence.
  • the compounds of the present disclosure provide more than one copy of the polyamide sequence for noncovalent binding to the GAA, and the individual polyamide sequences in this compound are linked by a spacer W, as defined above.
  • the spacer W allows this compound to adjust its geometry as needed to alleviate the geometric strain that otherwise affects the noncovalent binding of longer polyamide sequences.
  • the DNA recognition or binding moiety binds in the minor groove of DNA.
  • the DNA recognition or binding moiety comprises a polymeric sequence of monomers, wherein each monomer in the polymer selectively binds to a certain DNA base pair.
  • the DNA recognition or binding moiety comprises a polyamide moiety.
  • the DNA recognition or binding moiety comprises a polyamide moiety comprising heteroaromatic monomers, wherein each heteroaromatic monomer binds noncovalently to a specific nucleotide, and each heteroaromatic monomer is attached to its neighbor or neighbors via amide bonds.
  • the DNA recognition moiety binds to a sequence comprising at least 1000 trinucleotide repeats.
  • the DNA recognition moiety binds to a sequence comprising at least 500 trinucleotide repeats. In certain embodiments, the DNA recognition moiety binds to a sequence comprising at least 200 trinucleotide repeats. In certain embodiments, the DNA recognition moiety binds to a sequence comprising at least 100 trinucleotide repeats. In certain embodiments, the DNA recognition moiety binds to a sequence comprising at least 50 trinucleotide repeats. In certain embodiments, the DNA recognition moiety binds to a sequence comprising at least 20 trinucleotide repeats. [0068] The form of the polyamide selected can vary based on the target gene.
  • the first terminus can include a polyamide selected from the group consisting of a linear polyamide, a hairpin polyamide, a H-pin polyamide, an overlapped polyamide, a slipped polyamide, a cyclic polyamide, a tandem polyamide, and an extended polyamide.
  • the first terminus comprises a linear polyamide.
  • the first terminus comprises a hairpin polyamide.
  • the polyamide is capable of binding the 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 50nM. In some embodiments, the polyamide is capable of binding the DNA with an affinity of less than about 300 nM. In some embodiments, the polyamide is capable of binding the DNA with an affinity of less than about 200 nM. In some embodiments, the polyamide is capable of binding the DNA with an affinity of greater than about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, or about 1 nM. In some embodiments, the polyamide is capable of binding the 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.
  • the binding affinity between the polyamide and the target DNA can be determined using a quantitative footprint titration experiment.
  • the experiment involves measuring the dissociation constant Kd of the polyamide for the target sequence at either 24 °C or 37 °C, and using either standard polyamide assay solution conditions or approximate intracellular solution conditions.
  • the binding affinity between the regulatory protein and the ligand on the second terminus can be determined using an assay suitable for the specific protein.
  • the experiment involves measuring the dissociation constant K d of the ligand for the protein and using either standard protein assay solution conditions or approximate intracellular solution conditions.
  • the 5-10 membered heteroarylene group is optionally substituted with 1-4 substituents selected from H, OH, halogen, C 1-10 alkyl, NO2, CN, NR'R", C 1-6 haloalkyl, C 1-6 alkoxyI.
  • the first terminus comprises at least three aromatic carboxamide moieties selected to correspond to the nucleotide repeat sequence GAA and at least one aliphatic amino acid residue chosen from the group consisting of glycine, ⁇ -alanine, y-aminobutyric acid, 2,4-diaminobutyric acid, and 5- aminovaleric acid.
  • the first terminus comprises at least one ⁇ -alanine subunit.
  • the monomer element is independently selected from the group consisting of optionally substituted pyrrole carboxamide monomer, optionally substituted imidazole carboxamide monomer, optionally substituted C-C linked heteromonocyclic/heterobicyclic moiety, and ⁇ -alanine.
  • the first terminus comprises a polyamide having the structure of Formula (A- 2), or a pharmaceutically acceptable salt thereof: Formula (A-2), wherein, m1 is 1-4; n1 is 0-2; 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 is independently O, S, or NR 1D ; each L 3 is an optionally substituted C 1 -C 6 alkylene, optionally substituted C 3 -C7 cycloalkylene, optionally substituted 3 to 7-membered heterocyclene, or optionally substituted 5 to 6-membered heteroarylene; each R 30 is hydrogen or a C 1 -C 6 alkyl; or each R 30 and L 3 join together with the atom(s) to which they are attached to form a 4- to 7-membered heterocyclic ring; W 1 is hydrogen, an optionally substituted C 1 -C 6 alkyl, or a pharmaceutically
  • each L 3 is an optionally substituted C 1 -C 6 alkylene.
  • L 3 is a C 2 , C 3 , C4, or C5 alkylene optionally substituted with 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 cycloalkyl or 4 to 7-membered heterocycloalkyl ring.
  • L 3 is a C 2 or C 3 alkylene optionally substituted with one or more hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4 to 7-membered heterocycloalkyl ring.
  • L 3 is a C 2 alkylene optionally substituted with one or two hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4 to 7-membered heterocycloalkyl ring.
  • each L 3 is independently C 3 -C 7 cycloalkylene.
  • L 3 is a cyclobutylene, cyclopentylene, cyclohexylene, or cycloheptylene ring. In some embodiments, L 3 is cyclobutylene. In some embodiments, L 3 is cyclopentylene. In some embodiments, L 3 is cyclohexylene. [0078] In some embodiments, each L 3 is 3 to 7-membered heterocyclene. In some embodiments, L 3 is a 4- membered, 5-membered, or 6-membered heterocyclene. [0079] In some embodiments, each R 30 is independently hydrogen. In some embodiments, each R 30 is independently C 1 -C 6 alkyl.
  • L 3 and R 30 join together with the atoms to which they are attached to form a 4- to 7-membered heterocyclic ring.
  • the ring is a 4-membered heterocyclic ring.
  • the ring is a 5-membered heterocyclic ring.
  • the ring is a 6- membebered heterocyclic ring.
  • the ring is a 7-membered heteroaromatic ring.
  • ni is 0-2; 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 is independently O, S, or NR 1D ; each L 3 is an 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 a C 1 -C 6 alkyl; or each R 30 and L 3 join together with the atom(s) to which they are attached to form a 4- to 7 -membered heterocyclic ring;
  • R 1F is hydrogen, deuterium, optionally substituted C 1 -C 20 alkyl, C 1 -C 20 heteroalkyl, (PEG) 1-20 , or one or more AA; and each AA is independently a naturally occurring amino acid.
  • the linker moiety is connected to the DNA binding moiety (i.e., a polyamide) at W2.
  • W 2 is hydrogen.
  • W 2 is (AA) 1-10 .
  • each AA is independently ⁇ -alanine.
  • AA comprises one p-alanine.
  • AA comprises two ⁇ -alanines.
  • the first terminus comprises a polyamide having the structure of Formula (A-5), or a pharmaceutically acceptable salt thereof: Formula (A-5).
  • each R 1D and R 1E is independently hydrogen, optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 heteroalkyl, or optionally substituted (PEG) 1-20 .
  • each R 1D and R 1E is independently hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 - C 10 heteroalkyl, or optionally substituted (PEG)1-20.
  • each R 1D is independently (PEG) 1-50 .
  • each Z 1 , Z 2 , Z 3 , and Z 4 is independently NR 1D , wherein R 1D is an optionally substituted C 1 -C 20 alkyl or optionally substituted C 1 -C 20 heteroalkyl.
  • each Z 1 , Z 2 , Z 3 , and Z 4 is independently NCH 3 .
  • each Z 1 , Z 2 , Z 3 , and Z 4 is independently NH.
  • the first terminus comprises a polyamide having the structure of Formula (A-6), or a pharmaceutically acceptable salt thereof: Formula (A-6).
  • each Y 1 and Y 3 are N; and each Y 2 and Y 4 are 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. [0094] In some embodiments, each unit m 1 and n 1 are different or the same. In some embodiments, each unit m 1 is different. In some embodiments, each unit m 1 is the same. In some embodiments, each unit n 1 is different. In some embodiments, each unit n 1 is the same.
  • m1 is 2 or 3; and n1 is 0 or 1.
  • m1 is 2. In some embodiments, m1 is 1.
  • n1 is 0. In some embodiments, n1 is 1.
  • the linker moiety is connected to the DNA binding moiety through W 1 .
  • each R 1H , R 1J , R 1K , and R 1L is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.
  • each R 1H , R 1J , R 1K , and R 1L is independently hydrogen, halogen, or C 1 -C 6 alkyl.
  • each R 1H , R 1J , R 1K , and R 1L is independently halogen.
  • each R 1H , R 1J , R 1K , and R 1L is independently C 1 -C 6 alkyl. In some embodiments, each R 1H , R 1J , R 1K , and R 1L is independently hydrogen. [00102] In some embodiments, R 1H and R 1J or R 1L and R 1K combine together with the atom to which they are attached to form a C 3 -C 6 cycloalkyl or 4 to 7-membered heterocycloalkyl ring. In some embodiments, R 1H and R 1J or R 1L and R 1K combine together with the atom to which they are attached to form a C 3 -C 6 cycloalkyl.
  • R 1H and R 1J or R 1L and R 1K combine together with the atom to which they are attached to form a 4 to 7-membered heterocycloalkyl ring.
  • each v 1 is independently 1. In some embodiments, each v 1 is independently 2. In some embodiments, each v 1 is independent 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. [00105] In some embodiments, the first terminus comprises a polyamide having the structure of Formula (A-9), or a pharmaceutically acceptable salt thereof: Formula (A-9). [00106] In some embodiments, the first terminus comprises a polyamide having the structure of Formula (A-10) or a pharmaceutically acceptable salt thereof: Formula (A-10).
  • the first terminus comprises a polyamide having the structure of Formula (A-11), or a pharmaceutically acceptable salt thereof: Formula (A-11), wherein, each v 1 and v 2 are independently 1-3.
  • the first terminus comprises a polyamide having the structure of Formula (A-12), or a pharmaceutically acceptable salt thereof: Formula (A-12), wherein, each R 1H , R 1J , R 1K , and R 1L is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl; or R 1H and R 1J or R 1L and R 1K combine together with the carbon atom to which they are attached to form a C 3 - C 6 cycloalkyl or 4 to 7-membered heterocycloalkyl ring.
  • the first terminus comprises a polyamide having the structure of Formula (A-13), or a pharmaceutically acceptable salt thereof: Formula (A-13), wherein, each v 3 and v 4 are independently 1-3.
  • the DNA recognition or binding moiety can include one or more subunits selected from the groups consisting of:
  • each R a is 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 alkylamino; and each R b is 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 alkylamino.
  • the DNA recognition or binding moiety can include one or more subunits selected from the group consisting of: benzopyrazinylene-CO-, -NH-phenylene-CO-, -NH-pyridinylene-CO-, -NH-piperidinylene-CO-, -NH- pyrimidinylene-CO-, -NH-anthracenylene-CO-, -NH-quinolinylene-CO-, and wherein Z is H, NH 2 , C 1-6 alkyl, or C 1-6 alkylNH 2 .
  • the first terminus comprises one or more subunits selected from the group alanine.
  • the first terminus in the compounds described herein has a high binding affinity to a sequence having multiple repeats of GAA and binds to the target nucleotide repeats preferentially over other nucleotide repeats or nucleotide sequences.
  • the first terminus has a higher binding affinity to a sequence having multiple repeats of GAA than to a sequence having repeats of CGG.
  • the first terminus has a higher binding affinity to a sequence having multiple repeats of GAA than to a sequence having repeats of CCG.
  • the first terminus has a higher binding affinity to a sequence having multiple repeats of GAA than to a sequence having repeats of CCTG.
  • the first terminus has a higher binding affinity to a sequence having multiple repeats of GAA than to a sequence having repeats of TGGAA. In some embodiments, the first terminus has a higher binding affinity to a sequence having multiple repeats of GAA than to a sequence having repeats of GGGGCC. In some embodiments, the first terminus has a higher binding affinity to a sequence having multiple repeats of GAA than to a sequence having repeats of CAG. In some embodiments, the first terminus has a higher binding affinity to a sequence having multiple repeats of GAA than to a sequence having repeats of CTG.
  • the transcription modulation molecules described herein become localized around regions having multiple repeats of GAA.
  • the local concentration of the first terminus of the molecules described herein is higher near a sequence having multiple repeats of GAA than near a sequence having repeats of CGG.
  • the local concentration of the first terminus of the molecules described herein is higher near a sequence having multiple repeats of GAA than near a sequence having repeats of CCG.
  • the local concentration of the first terminus of the molecules described herein is higher near a sequence having multiple repeats of GAA than near a sequence having repeats of CCTG.
  • the local concentration of the first terminus of the molecules described herein is higher near a sequence having multiple repeats of GAA than near a sequence having repeats of TGGAA. In some embodiments, the local concentration of the first terminus of the molecules described herein is higher near a sequence having multiple repeats of GAA than near a sequence having repeats of GGGGCC. In some embodiments, the local concentration of the first terminus of the molecules described herein is higher near a sequence having multiple repeats of GAA than near a sequence having repeats of CTG. In some embodiments, the local concentration of the first terminus of the molecules described herein is higher near a sequence having multiple repeats of GAA than near a sequence having repeats of CAG.
  • the first terminus is localized to a sequence having multiple repeats of GAA and binds to the target nucleotide repeats preferentially over other nucleotide repeats.
  • 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.
  • the sequence comprises at least 1000 nucleotide repeats of GAA.
  • the sequence comprises at least 500 nucleotide repeats of GAA.
  • the sequence comprises at least 200 nucleotide repeats of GAA.
  • the sequence comprises at least 100 nucleotide repeats of GAA.
  • the sequence comprises at least 50 nucleotide repeats of GAA.
  • the sequence comprises at least 20 nucleotide repeats of GAA.
  • the compounds of the present disclosure can bind to the repeated GAA of ⁇ xn than to GAA elsewhere in the subject’s DNA.
  • the polyamide composed of a pre-selected combination of subunits can selectively bind to the DNA in the minor groove.
  • antiparallel side-by-side pairings of two aromatic amino acids bind to DNA sequences, with a polyamide ring packed specifically against each DNA base.
  • N- Methylpyrrole (Py) favors T, A, and C bases, excluding G;
  • N-methylimidazole (Im) is a G-reader; and 3- hydroxyl-N-methylpyrrol (Hp) is specific for thymine base.
  • the nucleotide base pairs can be recognized using different pairings of the amino acid subunits using the paring principle shown in Table 1A and IB below.
  • an Im/Py pairing reads G C by symmetry
  • a Py/Im pairing reads C G
  • an Hp/Py pairing can distinguish T A from A T, G C, and C G
  • a Py/Py pairing nonspecifically discriminates both A T and T A from G C and C G.
  • the first terminus comprises Im corresponding to the nucleotide G; Py or beta corresponding to the nucleotide A; Py corresponding to the nucleotide A, wherein Im is N-alkyl imidazole, Py is N-alkyl pyrrole, and beta is P-alanine.
  • the first terminus comprises Im/Py to correspond to the nucleotide pair G/C, Py/beta or Py/Py to correspond to the nucleotide pair A/T, and wherein Im is N-alkyl imidazole (e.g., N-methyl imidazole), Py is N-alkyl pyrrole (e.g., N-methyl pyrrole), and beta is ⁇ -alanine.
  • Im is N-alkyl imidazole (e.g., N-methyl imidazole)
  • Py is N-alkyl pyrrole (e.g., N-methyl pyrrole)
  • beta is ⁇ -alanine.
  • HpBi, ImBi, and PyBi function as a conjugate of two monomer subunits and bind to two nucleotides.
  • the binding property of HpBi, ImBi, and PyBi corresponds to Hp-Py, Im-Py, and Py-Py respectively.
  • Table 1B Base pairing for hairpin polyamide.
  • the monomer subunits of the polyamide can be strung together based on the pairing principles shown in Table 1A and Table IB.
  • the monomer subunits of the polyamide can be strung together based on the pairing principles shown in Table 1C and Table ID.
  • Table 1C shows an example of the monomer subunits that can bind to the specific nucleotide.
  • the first terminus can include a polyamide described having several monomer subunits stung together, with a monomer subunit selected from each row.
  • the polyamide can include Im- ⁇ -Py that binds to GAA, with Im selected from the first G column, ⁇ from the A column, and Py from the second A column.
  • the polyamide can be any combinations that bind to the subunits of GAA, with a subunit selected from each column in Table 1C, wherein the subunits are strung together following the GAA order.
  • the polyamide can also include a partial or multiple sets of the five subunits, such as 1.5, 2, 2.5, 3, 3.5, or 4 sets of the three subunits.
  • the polyamide can include 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, and 16 monomer subunits. The multiple sets can be joined together by W.
  • the polyamide can also include 1-4 additional subunits that can link multiple sets of the five subunits.
  • the polyamide can include monomer subunits that bind to 2, 3, 4, or 5 nucleotides of GAA.
  • the polyamide can bind to GA, AA, GAA, AAG, AGA, GAAG, AAGA, GAAGA or GAAGAA.
  • the polyamide can include monomer subunits that bind to 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides of GAA repeats.
  • the nucleotides can be joined by W.
  • the monomer subunit when positioned as a terminal unit, does not have an amine, carbonyl, or a carboxylic acid group at the terminal.
  • the amine or carboxylic acid group in the terminal is replaced by a hydrogen.
  • Py when used as a terminal unit, is understood to have the structure of and Im, when positioned as a terminal unit, is understood to have the structure of .
  • Py and Im can be respectively replaced by PyT (e.g.,
  • Table 1C Examples of monomer subunits in a linear polyamide that binds to GAA.
  • the second terminus comprises a protein-binding moiety that is capable of binding to a regulatory molecule that modulates an expression of a gene comprising one or more copies of the trinucleotide repeat sequence GAA.
  • the regulatory molecule is chosen from a nucleosome remodeling factor (“NURF”), a bromodomain PHD finger transcription factor (“BPTF”), a ten-eleven translocation enzyme (“TET”), methylcytosine dioxygenase (“TET1”), a DNA demethylase, a helicase, an acetyltransferase, a CREB binding protein (“CBP”), a P300, an O-linked P-N-acetylglucosamine-transferase (“OGP’), a P300- CBP-associated-factor (“PCAF”), histone methyltransferase, histone demethylase, chromodomain, a cyclin- dependent-kinase-9 (“CDK9”), an octamer-binding-transcription-factor (“OCTI”), a histone acetyltransferase (“HAT”), a host-cell-factor- 1
  • NURF nucleosome
  • the protein-binding moiety binds to the regulatory molecule that is selected from the group consisting of a CBP, a P300, a OGT, a CAF, a CDK9, a NURF, a BPTF, a TET, a TET1, HAT, a HDAC, a HCF1, an OCTI, a P-TEFb, a cyclin-Tl, a PRC2, a DNA-demethylase, a helicase, an acetyltransferase, a histone-deacetylase, and a methylated histone lysine protein.
  • the regulatory molecule that is selected from the group consisting of a CBP, a P300, a OGT, a CAF, a CDK9, a NURF, a BPTF, a TET, a TET1, HAT, a HDAC, a HCF1, an OCTI, a P-TEFb, a
  • the second terminus comprises a moiety that binds to OGT or CBP.
  • the protein binding moiety is a residue of a compound that binds to OGT or CBP.
  • the second terminus comprises a bromodomain binding moiety.
  • the bromodomain binding moiety is a BRD2, BRD3, BRD4, or BRDT binding moiety.
  • the bromodomain binding moiety is a BRD4 binding moiety.
  • the regulatory molecule is a bromodomain-containing protein chosen from BRD2, BRD3, BRD4, and BRDT.
  • the regulatory molecule is BRD4.
  • the recmiting moiety is a BRD4 activator.
  • the regulatory molecule modulates the rearrangement of histones.
  • the regulatory molecule modulates the glycosylation, phosphorylation, alkylation, or acylation of histones.
  • the regulatory molecule is a transcription factor.
  • the regulatory molecule is an RNA polymerase.
  • the regulatory molecule is a moiety that regulates the activity of RNA polymerase.
  • the recmiting moiety binds to the regulatory molecule but does not inhibit the activity of the regulatory molecule. In some embodiments, the recmiting moiety binds to the regulatory molecule and inhibits the activity of the regulatory molecule. In some embodiments, the recmiting moiety binds to the regulatory molecule and increases the activity of the regulatory molecule.
  • the recmiting moiety binds to the active site of the regulatory molecule.
  • the recruiting moiety binds to a regulatory site of the regulatory molecule.
  • the binding affinity between the regulatory protein and the second terminus can be adjusted based on the composition of the molecule or type of protein.
  • the second terminus binds 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 50nM.
  • the second terminus binds the regulatory molecule with an affinity of less than about 300 nM.
  • the second terminus binds the regulatory molecule with an affinity of less than about 200 nM. In some embodiments, the second terminus is capable of binding the regulatory molecule with an affinity of greater than about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, or about 1 nM. In some embodiments, the second terminus is capable of binding 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.
  • the second terminus is a ligand.
  • the second terminus comprises a pyrrolopyridinone.
  • the pyrrolopyridinnone is substituted with an optionally substituted oxydibeneze.
  • the second terminus comprises an optionally substituted 4-(2-phenoxyphenyl)-6A. 2 -pyrrolo
  • the second terminus comprises a compound having the structure of Formula (B), or a pharmaceutically acceptable salt thereof:
  • Y is -CH2NH-, CH 2 O-, -NH-, or -0-;
  • R 17 is hydrogen or C 1 -C 6 alkyl
  • R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO2, optionally substituted - C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 hydroxyalkyl; or R 18 is -NR A R B ;
  • R 25 is an optionally substituted 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 -NHS0 2 R A ;
  • R 32 is hydrogen or an optionally substituted C 1 -C 6 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 hydroxyalkyl
  • R 35 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted 5-6-membered monocyclic aryl or heteroaryl
  • each R A and R B is independently hydrogen, deuterium, an optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl
  • y 1 is 1-3; and wherein attachment to the linker is at either R 18 or at R 35 .
  • the attachment to the linker is at R 18 . In some embodiments the attachment to the linker is at R 35 .
  • the second terminus comprises a compound having the structure of Formula (B-1), or a pharmaceutically acceptable salt thereof: Formula (B-1), wherein, Ring E is absent or an optionally substituted 5-6-membered monocyclic aryl or heteroaryl or optionally substituted 4-8-membered heterocycle; Y is -CH 2 NH-, CH 2 O-, -NH-, or -O-; R 17 is hydrogen or C 1 -C 6 alkyl; R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , optionally substituted - C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 hydroxyalkyl; or R 18 is -NR A R B ; R 25 is an optionally substituted 5-6-membered monocyclic
  • the second terminus comprises a compound having the structure of Formula (B-2), or a pharmaceutically acceptable salt thereof: Formula (B-2), wherein, Ring E is absent or an optionally substituted 5-6-membered monocyclic aryl or heteroaryl or optionally substituted 4-8-membered heterocycle; Y is -CH 2 NH-, CH 2 O-, -NH-, or -O-; R 17 is hydrogen or C 1 -C 6 alkyl; R 18 is 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 hydroxyalkyl; R 19b is hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 hydroxyalkyl; R 25a is hydrogen or an optionally
  • Ring E is an optionally substituted 5 or 6-membered monocyclic aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with alkyl, amino, halogen, hydroxy, hydroxyalkyl, or PEG.
  • Ring E is optionally substituted with one or more R 33 , wherein each R 33 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, an 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 .
  • Ring E is phenyl.
  • Ring E is a 6-membered heteroaryl.
  • Ring E is pyridine, pyrazine, or triazine.
  • Ring E is pyridine. In some embodiments, Ring E is pyrazine. In some embodiments, Ring E is triazine. In some embodiments, Ring E is a 5-membered heteroaryl. In some embodiments, Ring E is a pyrazole. In some embodiments, Ring E is a triazole, pyrrole, imidazole, oxazole, oxadiazole, thiazole, or thiadiazole. In some embodiments, Ring E is a triazole. In some embodiments, Ring E is an imidazole or pyrrole. In some embodiments, an oxazole or oxadiazole.
  • Ring E is a thiazole or thiadiazole.
  • Ring E is phenyl substituted with one or more -OH, -(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O-(C 1 -C 6 alkyl).
  • Ring E is phenyl substituted with one or more -OH.
  • Ring E is phenyl substituted with -(OCH 2 CH 2 )m-OH.
  • Ring E is phenyl substituted with one or more –(OCH 2 CH 2 )m-O-(C 1 -C 6 alkyl).
  • 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. [00153] 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.
  • m is 8 to 9. [00154] 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. [00155] 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. [00156] In some embodiments, m is 1 to 6. In some embodiments, m is 2 to 6.
  • m is 3 to 6. In some embodiments, m is 4 to 6. In some embodiments, m is 5 to 6. [00157] 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. [00158] In some embodiments, Ring E is absent. [00159] In some embodiments, Y is -CH 2 NH- or -NH-. In some embodiments, Y is -CH 2 NH-.
  • Y is -NH-. In some embodiments, Y is -O-.
  • R 17 is hydrogen. In some embodiments, R 17 is C 1 -C 6 alkyl. In some embodiments, R 17 is methyl, ethyl, propyl. In some embodiments, R 17 is methyl. In some embodiments, R 17 is ethyl. In some embodiments, R 17 is propyl. [00161] In some embodiments, R 18 and R 19 are each independently hydrogen, CN, or NO 2 . In some embodiments, R 18 and R 19 are each independently halogen or optionally substituted C 1 -C 6 alkyl.
  • R 18 and R 19 are each independently bromo, chloro, fluoro, methyl, or ethyl. In some embodiments, R 18 and R 19 are each independently fluoro or methyl. [00162] 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. [00163] In some embodiments, R 19a is halogen, an optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 haloalkyl.
  • R 19a is halogen or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 19a is chloro, bromo, fluoro, or methyl. In some embodiments, R 19a is 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. [00164] In some embodiments, R 19b is hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 19b is chloro, bromo, fluoro, or methyl. In some embodiments, R 19b is chloro.
  • 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.
  • R 25 is an optionally substituted C 1-6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 1 -C 6 hydroxyalkyl.
  • R 25 is -NHSO 2 R A , wherein R A is C 1 -C 6 alkyl.
  • R 25 is -NHSO 2 Et. In some embodiments, R 25 is -NHSO 2 Me. In some embodiments, R 25 is -SO 2 R A , wherein R A is C 1 -C 6 alkyl. In some embodiments, R 25 is -SO 2 Et. In some embodiments, R 25 is -SO 2 Me. [00169] In some embodiments, R 25a is an optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 1 -C 6 hydroxyalkyl.
  • the second terminus comprises a compound having the structure of Formula (B-3), or a pharmaceutically acceptable salt thereof: Formula (B-3), wherein, R 17 is hydrogen or C 1 -C 6 alkyl; R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO2, an optionally substituted - C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 hydroxyalkyl; or R 18 is -NR A R B ; R 25 is an optionally substituted 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, - SO2R A ,
  • R 33a , R 33b , and R 33c are each independently hydrogen, halogen, hydroxyl, an optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 heteroalkyl, or optionally substituted (PEG) 1-20 .
  • R 33a , R 33b , and R 33c are each independently hydrogen, halogen, or optionally substituted (PEG) 1-20 .
  • R 33a , R 33b , and R 33c are each hydrogen.
  • R 33a is halogen, hydroxyl, an 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 an optionally substituted (PEG)1-20; and R 33b and R 33c are each hydrogen.
  • the second terminus comprises a compound having the structure of Formula (B-4), or a pharmaceutically acceptable salt thereof: Formula (B-4).
  • the second terminus comprises a compound having the structure of Formula (B-5), or a pharmaceutically acceptable salt thereof: Formula (B-5).
  • the second terminus comprises a compound having the structure of Formula (B-6) or (B-7), or a pharmaceutically acceptable salt thereof: [00178] In some embodiments, the second terminus comprises a compound having the structure of Formula (B-8), or a pharmaceutically acceptable salt thereof: Formula (B-8). [00179] In some embodiments, the second terminus comprises a compound having the structure of Formula (B-9), or a pharmaceutically acceptable salt thereof: Formula (B-9). [00180] In some embodiments, the second terminus comprises a compound having the structure of Formula (B-10) or (B-11), or a pharmaceutically acceptable salt thereof: Formula (B-11).
  • the second terminus comprises a compound having the structure of Formula (B-12), (B-13), or (B-14), or a pharmaceutically acceptable salt thereof: Formula (B-14).
  • the second terminus comprises a compound having the structure of Formula (B-15), or a pharmaceutically acceptable salt thereof: Formula (B-15), wherein, Y is -CH 2 NH-, CH 2 O-, -NH-, or -O-; R 17 is hydrogen or C 1 -C 6 alkyl; R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO2, optionally substituted -C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 hydroxyalkyl; R 25 is an optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 1 -C 6 alkenyl,
  • the second terminus comprises a compound having the structure of Formula (B-16), or a pharmaceutically acceptable salt thereof: Formula (B-16), wherein, Y is -CH 2 NH-, CH 2 O-, -NH-, or -O-; R 17 is hydrogen or C 1 -C 6 alkyl; R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO2, optionally substituted -C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 hydroxyalkyl; R 25 is an optionally substituted 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, - SO2R A , or -NHSO2R A
  • R 34 is hydrogen, halogen, or -OH. In some embodiments, R 34 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 hydroxyalkyl. In some embodiments, R 34 is hydrogen. [00185] In some embodiments, R 35 is optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 haloalkyl. In some embodiments, R 35 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 35 is methyl, ethyl, or iso-propyl.
  • R 35 is an optionally substituted 5-6-membered monocyclic aryl or heteroaryl.
  • the second terminus comprises a compound having the structure of Formula (B-17), or a pharmaceutically acceptable salt thereof: Formula (B-17). [00187] In some embodiments, the second terminus is selected from:
  • the oligomeric backbone contains a linker that connects the first terminus and the second terminus and brings the regulatory molecule in proximity to the target gene to modulate gene expression.
  • the length of the linker depends on the type of regulatory protein and also 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 to 30 Angstroms. [00190] In some embodiments, the linker comprises between 5 and 50 chain atoms.
  • the oligomeric backbone comprises -(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 where the sum of a, b, c, d and e is 1 to 5; T 1 , T 2 , T 3 , T 4 and T 5 are each independently selected from an optionally substituted C 1 -C 1 2 alkylene, optionally substituted alkenylene, optionally substituted alkynylene, (EA)w, (EDA)m, (PEG) n , (modified PEG) n , (AA) p , -(CR 2a OH)h-, optionally substituted C 6 -C 10 arylene, optionally substituted C 3 -C7 cycl
  • the a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 1. In some embodiments, the a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 2. In some embodiments, the a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 3. In some embodiments, the a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 4.
  • a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 5.
  • n is 3-9. In some embodiments, n is 4-8. In some embodiments, n is 5 or 6.
  • T 1 , T 2 , T 3 , and T 4 , and T 5 are each independently selected from (C 1 - C 12 )alkyl, substituted (C 1 -C 1 2)alkyl, (EA)w, (EDA)m, (PEG) n , (modified PEG) n , (AA)p, -(CR 2a OH)h-, phenyl, substituted phenyl, piperidin-4-amino (P4A), para-amino-benzyloxycarbonyl (PABC), meta-amino- benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), meta-amino-benzyloxy (MABO), para- aminobenzyl, an acetal group, a disulfide, a hydrazine, a carbohydrate, a beta-lactam, an ester, (AA)p- MABC-(AA)p,
  • T 1 , T 2 , T 3 , T 4 and T 5 are each independently selected from C 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 substituted C 6 -C 10 arylene, 4-10 membered heterocycloalkene, optionally substituted 5-10 membered heteroarylene.
  • EA has the following structure: and EDA has the following structure:
  • x is 2-3 and q is 1-3 for EA and EDA.
  • R 1a is H or C 1 -C 6 alkyl.
  • T 4 or T 5 is an optionally substituted C 6 -C 10 arylene.
  • T 4 or T 5 is phenylene or substituted phenylene. In some embodiments, T 4 or T 5 is phenylene or phenylene substituted with 1-3 substituents selected from -C 1-6 alkyl, halogen, OH or amine. In some embodiments, T 4 or T 5 is 5-10 membered heteroarylene or substituted heteroarylene. In some embodiments, T 4 or T 5 is 4-10 membered heterocylcene or substituted heterocyclene. In some embodiments, T 4 or T 5 is heteroarylene or heterocyclene optionally substituted with 1-3 substituents selected from C 1 -C 6 alkyl, halogen, OH or amine.
  • T 1 , T 2 , T 3 , T 4 and T 5 and V 1 , V 2 , V 3 , V 4 and V 5 are selected from the following Table 2.
  • the linker comprises or any combinations thereof, wherein r is an integer between 1 and 10, preferably between 3 and 7; and X is O, S, or NR 1a . In some embodiments, X is O or NR 1a . In some embodiments, X is O.
  • X is O. In some embodiments, X is NH. In some embodiments, E 3 is a C 6 -C 10 arylene group optionally substituted with 1-3 substituents selected from C 1 -C 6 alkyl, halogen, OH or amine. [00203] In some embodiments, E 3 is a phenylene or substituted phenylene. [00204] In some embodiments, the linker comprise a [00205] In some embodiments, the linker comprises –X(CH 2 ) m (CH 2 CH 2 O) n –, wherein X is -O-, –NH–, or –S–, wherein m is 0 or greater and n is at least 1.
  • the linker comprises following the second terminus, wherein R c is selected from a bond, -N(R 1a )-, -O-, and -S-; R d is selected from -N(R 1a )-, -O-, and - S-; and R e is independently selected from hydrogen and optionally substituted C 1 -C 6 alkyl; and wherein R 1a is H or C 1 -C 6 alkyl.
  • d is 4-6. In other embodiments, d is between 5-9. [00209]
  • the linker comprises –N(R 1a )(CH 2 )xN(R 1b )(CH 2 )xN–, wherein R 1a and R 1b are each independently selected from hydrogen or optionally substituted C 1 -C 6 alkyl; and each x is independently an integer in the range of 1-6.
  • the linker comprises –(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- to 10-membered heterocycloalkylene or spirocyclene., and each x1, x2, and x3 is independently an integer from 1-15.
  • R 26 is C 1 -C50 alkyl. In some embodiments, R 26 is C 1 -C40 alkyl. In some embodiments, R 26 is C 1 -C 3 0 alkyl. In some embodiments, R 26 is C 1 -C 20 alkyl. In some embodiments, R 26 is C 1 -C 10 alkyl. In some embodiments, R 26 is C 1 -C50 heteroalkyl. In some embodiments, R 26 is C 1 -C40 heteroalkyl. In some embodiments, R 26 is C 1 -C 3 0 heteroalkyl. In some embodiments, R 26 is C 1 -C 20 heteroalkyl.
  • R 26 is C 1 -C 10 heteroalkyl.
  • the heteroalkyl is polyethylene glycol (PEG).
  • the linker is joined with the second terminus with a group selected from optionally substituted 4- to 10-membered heterocycloalkylene.
  • the linker is joined with the second terminus with a moiety comprising a structure of Formula (C-1), or a pharmaceutically acceptable salt thereof: Formula (C-1), wherein, Ring D is absent or an optionally substituted arylene or optionally substituted heterocycloalkylene; L 1 is absent or an optionally substituted alkylene, optionally substituted C 2 -C 10 alkenylene, or optionally substituted C 2 -C 10 alkynylene; each X 3 and X 4 is independently CH or N; p1 and p2 are each independently is 0-3; and ** denotes attachment to the second terminus.
  • Ring D is absent. In some embodiments, Ring D is C4-C7 heterocycloalkylene.
  • X 3 is N. In some embodiments, X 3 is CH.
  • X 4 is N. In some embodiments, X 4 is CH.
  • the linker is joined with the second terminus with a moiety comprising a structure of Formula (C-2), or a pharmaceutically acceptable salt thereof: Formula (C-2), wherein L 1 is absent or an optionally substituted alkylene, optionally substituted C 2 -C 10 alkenylene, or optionally substituted C 2 -C 10 alkynylene; X 4 is independently CH or N; each X 5 and X 6 is independently N or CH; and ** denotes attachment to the second terminus. [00227] In some embodiments, each of X 4 and X 5 is independently N or CH; and X 6 is N. [00228] In some embodiments, L 1 is absent.
  • 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; and each R 1G is hydrogen or C 1 -C 3 alkyl.
  • L 1 is C 1 -C 3 alkylene, C 2 -C 4 alkenylene, or C 2 -C 4 alkynylene.
  • L is CH 2 , CH 2 CH 2 , , or .
  • L 1 is -CH 2 - or -CH 2 CH 2 -.
  • L 1 is [00232]
  • R 27 is C 1 -C 10 alkyl. In some embodiments, R 27 is C 1 -C 50 heteroalkyl. In some embodiments, R 27 is C 1 -C 40 heteroalkyl. In some embodiments, R 27 is C 1 -C 3 0 heteroalkyl. In some embodiments, R 27 is C 1 -C 20 heteroalkyl. In some embodiments, R 27 is C 1 -C 10 heteroalkyl. In some embodiments, the heteroalkyl is polyethylene glycol (PEG). [00235] In some embodiments, each R 1G is independently hydrogen. In some embodiments, R 1G is independently C 1 -C 3 alkyl.
  • the C 1 -C 3 alkyl is methyl, ethyl or propyl.
  • each R 1G is independently methyl.
  • p1 is 0, 1, or 2.
  • p1 is 0.
  • p1 is 1.
  • p1 is 2.
  • r 1 is 1 or 2.
  • r 1 is 1.
  • r 1 is 2.
  • the linker is joined with the second terminus with a group selected from:
  • the compound comprises the moiety having the structure of Formula (D-1), or a pharmaceutically acceptable salt thereof: Formula (D-1), wherein, Ring E is absent or an optionally substituted 5-6-membered monocyclic aryl or heteroaryl or optionally substituted 4-8 membered heterocycle; Y is -CH 2 NH-, CH 2 O-, -NH-, or -O-; L A is an optionally substituted alkylene, optionally substituted heteroalkylene, or optionally substituted PEG; L B is absent or , wherein Ring D is absent or an optionally substituted arylene or optionally substituted heterocycloalkylene; L 1 is absent or an optionally substituted alkylene, optionally substituted C 2 -C 10 alkenylene, or optionally substituted C 2 -C 10 alkynylene; each X 3 and X 4 is independently CH or N; p1 and p2 are each independently is 0-3; and ** denotes the point of connection to
  • L B is absent. [00242] In some embodiments, . [00243] In some embodiments, the compound comprises the moiety having the structure of Formula (D-2), or a pharmaceutically acceptable salt thereof: Formula (D-2), wherein, Ring D is absent or an optionally substituted arylene or optionally substituted heterocycloalkylene; Ring E is absent or an optionally substituted 5-6-membered monocyclic aryl or heteroaryl or optionally substituted 4-8 membered heterocycle; Y is -CH 2 NH-, CH 2 O-, -NH-, or -O-; L A is an optionally substituted alkylene, optionally substituted heteroalkylene, or optionally substituted PEG; L 1 is absent or an optionally substituted alkylene, optionally substituted C 2 -C 10 alkenylene, or optionally substituted C 2 -C 10 alkynylene; each X 3 and X 4 is independently CH or N; R 17 is hydrogen or C 1
  • the compound comprises the moiety having the structure of Formula (D-3), or a pharmaceutically acceptable salt thereof: Formula (D-3), wherein, Ring D is absent or an optionally substituted arylene or optionally substituted heterocycloalkylene; Y is -CH 2 NH-, CH 2 O-, -NH-, or -O-; L A is an optionally substituted alkylene, optionally substituted heteroalkylene, or optionally substituted PEG; L 1 is absent or an optionally substituted alkylene, optionally substituted C 2 -C 10 alkenylene, or optionally substituted C 2 -C 10 alkynylene; each X 3 and X 4 is independently CH or N; R 17 is hydrogen or C 1 -C 6 alkyl; R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO 2 , an optionally substituted - C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hal
  • the compound comprises the moiety having the structure of Formula (D-4), or a pharmaceutically acceptable salt thereof: Formula (D-4), wherein, Y is -CH 2 NH-, CH 2 O-, -NH-, or -O-; L A is an optionally substituted alkylene, optionally substituted heteroalkylene, or optionally substituted PEG; R 17 is hydrogen or C 1 -C 6 alkyl; R 18 and R 19 are each independently hydrogen, deuterium, halogen, -CN, -NO2, an optionally substituted - C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, or optionally substituted C 1 -C 6 hydroxyalkyl; or R 18 is -NR A R B ; R 25 is an optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C
  • L A is , wherein n3 is 7, 8, 9, 10, 11, 12, 13, 14, or 15; * denotes the connection to the first terminus; and ** denotes the connection point to the phenyl.
  • L A is , wherein n 3 is 9, 10, 11, 12, 13, 14, or 15; * denotes the connection to the first terminus; and ** denotes the connection point to the phenyl.
  • n 3 is 7.
  • n 3 is 8.
  • n 3 is 9.
  • n 3 is 10.
  • n 3 is 11.
  • n 3 is 12.
  • the compound comprises the moiety having the structure of Formula (D-5), or a pharmaceutically acceptable salt thereof: Formula (D-5).
  • the compound comprises the moiety having the structure of Formula (D-6), or a pharmaceutically acceptable salt thereof: Formula (D-6), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl) and m is 1 to 20.
  • the compound comprises the moiety having the structure of Formula (D-7), or a pharmaceutically acceptable salt thereof: Formula (D-7), wherein n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D-8), or a pharmaceutically acceptable salt thereof: Formula (D-8), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl); m is 1 to 20; and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D-9), or a pharmaceutically acceptable salt thereof: Formula (D-9), wherein, m is 1-20 and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 10), or a pharmaceutically acceptable salt thereof: Formula (D-10).
  • the compound comprises the moiety having the structure of Formula (D- 11), or a pharmaceutically acceptable salt thereof: Formula (D-11), wherein, R E is -OH, –(OCH 2 CH 2 ) m -OH, or –(OCH 2 CH 2 ) m -O(C 1 -C 6 alkyl) and m is 1 to 20.
  • the compound comprises the moiety having the structure of Formula (D- 12), or a pharmaceutically acceptable salt thereof: Formula (D-12), wherein, n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 13), or a pharmaceutically acceptable salt thereof: Formula (D-13), wherein, R E is -OH, –(OCH 2 CH 2 ) m -OH, or –(OCH 2 CH 2 ) m -O(C 1 -C 6 alkyl); m is 1 to 20; and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 14), or a pharmaceutically acceptable salt thereof: Formula (D-14), wherein, m is 1 to 20 and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 15), or a pharmaceutically acceptable salt thereof: Formula (D-15).
  • the compound comprises the moiety having the structure of Formula (D- 16), or a pharmaceutically acceptable salt thereof: Formula (D-16), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl) and m is 1 to 20.
  • the compound comprises the moiety having the structure of Formula (D- 17), or a pharmaceutically acceptable salt thereof: Formula (D-17), wherein, n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 18), or a pharmaceutically acceptable salt thereof: Formula (D-18), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl); m is 1 to 20; and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 19), or a pharmaceutically acceptable salt thereof: Formula (D-19), wherein, m is 1 to 20 and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 20), or a pharmaceutically acceptable salt thereof: Formula (D-20).
  • the compound comprises the moiety having the structure of Formula (D- 21), or a pharmaceutically acceptable salt thereof: Formula (D-21), wherein, R E is -OH, –(OCH 2 CH 2 ) m -OH, or –(OCH 2 CH 2 ) m -O(C 1 -C 6 alkyl) and m is 1 to 20.
  • the compound comprises the moiety having the structure of Formula (D- 22), or a pharmaceutically acceptable salt thereof: Formula (D-22), wherein, n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 23), or a pharmaceutically acceptable salt thereof: Formula (D-23), wherein, R E is -OH, –(OCH 2 CH 2 ) m -OH, or –(OCH 2 CH 2 ) m -O(C 1 -C 6 alkyl); m is 1 to 20; and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 24), or a pharmaceutically acceptable salt thereof: Formula (D-24), wherein, m is 1 to 20 and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 25), or a pharmaceutically acceptable salt thereof:
  • the compound comprises the moiety having the structure of Formula (D- 26), or a pharmaceutically acceptable salt thereof: Formula (D-26), wherein, R E is -OH, –(OCH 2 CH 2 ) m -OH, or –(OCH 2 CH 2 ) m -O(C 1 -C 6 alkyl) and m is 1 to 20.
  • the compound comprises the moiety having the structure of Formula (D- 27), or a pharmaceutically acceptable salt thereof: Formula (D-27), wherein, n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 28), or a pharmaceutically acceptable salt thereof:
  • the compound comprises the moiety having the structure of Formula (D- 29), or a pharmaceutically acceptable salt thereof: Formula (D-29), wherein, m is 1 to 20 and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 30), or a pharmaceutically acceptable salt thereof: Formula (D-30).
  • the compound comprises the moiety having the structure of Formula (D- 31), or a pharmaceutically acceptable salt thereof: Formula (D-31), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl) and m is 1 to 20.
  • the compound comprises the moiety having the structure of Formula (D- 32), or a pharmaceutically acceptable salt thereof: Formula (D-32), wherein, n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 33), or a pharmaceutically acceptable salt thereof: Formula (D-33), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl); m is 1 to 20; and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 34), or a pharmaceutically acceptable salt thereof: Formula (D-34), wherein, m is 1 to 20 and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 35), or a pharmaceutically acceptable salt thereof: Formula (D-35).
  • the compound comprises the moiety having the structure of Formula (D- 36), or a pharmaceutically acceptable salt thereof: Formula (D-36), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl) and m is 1 to 20.
  • the compound comprises the moiety having the structure of Formula (D- 37), or a pharmaceutically acceptable salt thereof:
  • the compound comprises the moiety having the structure of Formula (D- 38), or a pharmaceutically acceptable salt thereof: Formula (D-38), wherein, R E is -OH, –(OCH 2 CH 2 ) m -OH, or –(OCH 2 CH 2 ) m -O(C 1 -C 6 alkyl); m is 1 to 20; and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 39), or a pharmaceutically acceptable salt thereof: Formula (D-39), wherein, m is 1 to 20 and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 40), or a pharmaceutically acceptable salt thereof: Formula (D-40).
  • the compound comprises the moiety having the structure of Formula (D- 41), or a pharmaceutically acceptable salt thereof: Formula (D-41), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl); and m is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 42), or a pharmaceutically acceptable salt thereof: Formula (D-42), wherein, n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 43), or a pharmaceutically acceptable salt thereof: Formula (D-43), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl); m is 1 to 20; and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 44), or a pharmaceutically acceptable salt thereof: Formula (D-44), wherein, m is 1 to 20 and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 45), or a pharmaceutically acceptable salt thereof: Formula (D-45).
  • the compound comprises the moiety having the structure of Formula (D- 46), or a pharmaceutically acceptable salt thereof: Formula (D-46), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl); and m is 1 to 20.
  • the compound comprises the moiety having the structure of Formula (D- 47), or a pharmaceutically acceptable salt thereof: Formula (D-47), wherein, n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 48), or a pharmaceutically acceptable salt thereof: Formula (D-48), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl); m is 1 to 20; and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 49), or a pharmaceutically acceptable salt thereof: Formula (D-49), wherein, m is 1 to 20 and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 50), or a pharmaceutically acceptable salt thereof: Formula (D-50).
  • the compound comprises the moiety having the structure of Formula (D- 51), or a pharmaceutically acceptable salt thereof: Formula (D-51), wherein, R E is -OH, –(OCH 2 CH 2 ) m -OH, or –(OCH 2 CH 2 ) m -O(C 1 -C 6 alkyl); and m is 1 to 20.
  • the compound comprises the moiety having the structure of Formula (D- 52), or a pharmaceutically acceptable salt thereof: Formula (D-52), wherein, n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 53), or a pharmaceutically acceptable salt thereof: Formula (D-53), wherein, R E is -OH, –(OCH 2 CH 2 )m-OH, or –(OCH 2 CH 2 )m-O(C 1 -C 6 alkyl); m is 1 to 20; and n is 1-20.
  • the compound comprises the moiety having the structure of Formula (D- 54), or a pharmaceutically acceptable salt thereof: Formula (D-54), wherein, m is 1 to 20; and n is 1-20.
  • L A is C 2 -C 20 heteroalkylene.
  • L A is PEG 1-20 ,
  • L A is -NH(CH 2 CH 2 -O) n - or –(CH 2 CH 2 -O) n -, wherein n is 1-20.
  • L A is C 2 -C 20 heteroalkylene.
  • L A is PEG 1-20 , 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 -. [00299] In some embodiments, n is 1-15. In some embodiments, n is 7-15. In some embodiments, n is 8-15. In some embodiments, n is 9-15. In some embodiments, n is 7, 8, 9, 10, 11, 12, 13, 14, or 15. [00300] Also provided are embodiments wherein any embodiment above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • two embodiments are “mutually exclusive” when one is defined to be something which is different than the other.
  • an embodiment wherein two groups combine to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen.
  • an embodiment wherein one group is CH 2 is mutually exclusive with an embodiment wherein the same group is NH.
  • the compound of Formula (I) is a compound selected from Table 3, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound selected from Table 3.
  • non-limiting examples of the compounds described herein are presented in Table 3 (next page).
  • a compound disclosed herein possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • isomers as well as the appropriate mixtures thereof.
  • 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 a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • stereoisomers are obtained by stereoselective synthesis.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but 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 usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, and 125 I.
  • isotopic variant refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance.
  • an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the present disclosure also relates to a method of modulating the transcription of ⁇ xn comprising the step of contacting ⁇ xn with a compound as described herein.
  • the cell phenotype, cell proliferation, transcription of ⁇ xn, production of mRNA from transcription of ⁇ xn, translation of ⁇ xn, change in biochemical output produced by the protein coded by ⁇ xn, or noncovalent binding of the protein coded by ⁇ xn with a natural binding partner may be monitored.
  • Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.
  • the compounds described herein can recruit the regulatory molecule to modulate the expression of the defective ⁇ xn gene and effectively treat and/or and alleviate the symptoms associated with diseases such as Friedreich ataxia.
  • a method of treatment of a disease mediated by transcription of ⁇ xn comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • the present 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 present disclosure or a pharmaceutically acceptable salt thereof.
  • the present 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 present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present 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 present disclosure or a pharmaceutically acceptable salt thereof.
  • the present 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 present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the disease or disorder is associated with transcription of ⁇ xn.
  • the disease is Friedreich’s ataxia.
  • Also provided is the use of a compound as disclosed herein for the treatment of a disease mediated by transcription of ⁇ xn.
  • Also provided herein is a method of modulation of transcription of ⁇ xn comprising contacting ⁇ xn with a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.
  • a method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, to a patient, wherein the effect is chosen from improved neural sensation, improved vision, improved balance, improved gait, reduced sensitivity to glucose, and reduced sensitivity to carbohydrates.
  • the compounds described herein can mediate and/or alleviate one or more of muscular atrophy, ataxia, fasciculation, or dementia.
  • the disease or disorder is muscular atrophy. [00325] In some embodiments, the disease or disorder is ataxia. [00326] In some embodiments, the disease or disorder is fasciculation. [00327] In some embodiments, the disease or disorder is dementia. [00328] Certain compounds of the present disclosure may be effective for treatment of subjects whose genotype has 5 or more repeats of GAA. Certain compounds of the present disclosure may be effective for treatment of subjects whose genotype has 10 or more repeats of GAA. Certain compounds of the present disclosure may be effective for treatment of subjects whose genotype has 20 or more repeats of GAA. Certain compounds of the present disclosure may be effective for treatment of subjects whose genotype has 50 or more repeats of GAA.
  • Certain compounds of the present disclosure may be effective for treatment of subjects whose genotype has 100 or more repeats of GAA. Certain compounds of the present disclosure may be effective for treatment of subjects whose genotype has 200 or more repeats of GAA. Certain compounds of the present disclosure may be effective for treatment of subjects whose genotype has 500 or more repeats of GAA. [00329] Also provided is a method of modulation of a ⁇ xn-mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein. [00330] In certain embodiments, ex vivo methods of treatment are provided. Ex vivo methods typically include cells, organs, and/or tissues removed from the subject.
  • the cells, organs and/or tissues can, for example, be incubated with the 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.
  • the compound is generally in a pharmaceutically acceptable carrier.
  • administration of the pharmaceutical composition modulates expression of ⁇ xn within 6 hours of treatment.
  • administration of the pharmaceutical composition modulates expression of ⁇ xn within 24 hours of treatment.
  • administration of the pharmaceutical composition modulates expression of ⁇ xn within 72 hours of treatment.
  • administration of the pharmaceutical composition causes a 2-fold increase in expression of ⁇ xn.
  • administration of the pharmaceutical composition causes a 5-fold increase in expression of ⁇ xn. In certain embodiments, administration of the pharmaceutical composition causes a 10-fold increase in expression of ⁇ xn. In certain embodiments, administration of the pharmaceutical composition causes a 20-fold increase in expression of ⁇ xn. [00333] In certain embodiments, administration of the pharmaceutical composition causes a 20% decrease in expression of ⁇ xn. In certain embodiments, administration of the pharmaceutical composition causes a 50% decrease in expression of ⁇ xn. In certain embodiments, administration of the pharmaceutical composition causes a 80% decrease in expression of ⁇ xn. In certain embodiments, administration of the pharmaceutical composition causes a 90% decrease in expression of ⁇ xn.
  • administration of the pharmaceutical composition causes a 95% decrease in expression of ⁇ xn. In certain embodiments, administration of the pharmaceutical composition causes a 99% decrease in expression of ⁇ xn. [00334] In some embodiments, administration of the pharmaceutical composition causes expression of ⁇ xn to fall within 25% of the level of expression observed for healthy individuals. In some embodiments, administration of the pharmaceutical composition causes expression of ⁇ xn to fall within 50% of the level of expression observed for healthy individuals. In some embodiments, administration of the pharmaceutical composition causes expression of ⁇ xn to fall within 75% of the level of expression observed for healthy individuals. In some embodiments, administration of the pharmaceutical composition causes expression of ⁇ xn to fall within 90% of the level of expression observed for healthy individuals.
  • compositions and Administration [00335] Also provided is a method of modulation of a ⁇ xn-mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein.
  • a pharmaceutical composition comprising a compound as disclosed herein, together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for intravenous injection or infusion.
  • the oral pharmaceutical composition is chosen from a tablet and a capsule.
  • ex vivo methods of treatment are provided.
  • Ex vivo methods typically include cells, organs, or tissues removed from the subject.
  • the cells, organs or tissues can, for example, be incubated with the 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.
  • the compound is generally in a pharmaceutically acceptable carrier.
  • the compound is effective at a concentration less than about 5 ⁇ M. In certain embodiments, the compound is effective at a concentration less than about 1 ⁇ M. In certain embodiments, the compound is effective at a concentration less than about 400 nM. In certain embodiments, the compound is effective at a concentration less than about 200 nM.
  • the compound is effective at a concentration less than about 100 nM. In certain embodiments, the compound is effective at a concentration less than about 50 nM. In certain embodiments, the compound is effective at a concentration less than about 20 nM. In certain embodiments, the compound is effective at a concentration less than about 10 nM.
  • Combinations and Combinations Treatments [00342] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • Specific, non-limiting examples of possible combination therapies include use of certain compounds of the disclosure with an ACE inhibitor.
  • the multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified 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 given in multiple doses, or both may be given as multiple doses.
  • certain embodiments provide methods for treating ⁇ xn-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder that is known in the art.
  • certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of ⁇ xn-mediated disorders.
  • a substituent identified as alkyl that requires two points of attachment includes di-radicals such as –CH 2 –, –CH 2 CH 2 –, – CH 2 CH(CH3)CH 2 –, and the like.
  • Other radical naming conventions clearly indicate that the radical is a di- radical such as “alkylene,” “alkenylene,” “arylene”, “heteroarylene.”
  • a ring e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring
  • each R group is not otherwise limited by the definition of each R group when taken individually.
  • R 1 and R 2 are 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, it is meant that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure: where ring A is a heteroaryl ring containing the depicted nitrogen.
  • two “adjacent” R groups are said to form a ring “together with the atom to which they are attached,” it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring.
  • R 1 and R 2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the atoms to which they are attached form an aryl or carbocyclyl
  • R 1 and R 2 can be selected from hydrogen or alkyl
  • the substructure has structure: where A is an aryl ring or a carbocyclyl containing the depicted double bond.
  • a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated.
  • the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 ⁇ M (micromolar),” which is intended to include 1 ⁇ M, 3 ⁇ M, and everything in between to any number of significant figures (e.g., 1.255 ⁇ M, 2.1 ⁇ M, 2.9999 ⁇ M, etc.). [00353] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error.
  • polyamide refers to polymers of linkable units chemically bound by amide (i.e., CONH) linkages; optionally, polyamides include chemical probes conjugated therewith.
  • Polyamides may be synthesized by stepwise condensation of carboxylic acids (COOH) with amines (RR’NH) using methods known in the art.
  • polyamides may be formed using enzymatic reactions in vitro, or by employing fermentation with microorganisms.
  • linkable unit refers to methylimidazoles, methylpyrroles, and straight and branched chain aliphatic functionalities (e.g., methylene, ethylene, propylene, butylene, and the like) which optionally contain nitrogen Substituents, and chemical derivatives thereof.
  • the aliphatic functionalities of linkable units can be provided, for example, by condensation of beta-alanine or dimethylaminopropylamine during synthesis of the polyamide by methods well known in the art.
  • linker refers to a chain of at least 10 contiguous atoms. In certain embodiments, the linker contains no more than 20 non-hydrogen atoms. In certain embodiments, the linker contains no more than 40 non-hydrogen atoms. In certain embodiments, the linker contains no more than 60 non-hydrogen atoms. In certain embodiments, the linker contains atoms chosen from C, H, N, O, and S. In certain embodiments, every non-hydrogen atom is chemically bonded either to 2 neighboring atoms in the linker, or one neighboring atom in the linker and a terminus of the linker.
  • 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 comprises –(CH 2 OCH 2 )- units.
  • the term “spacer” refers to a chain of at least 5 contiguous atoms. In certain embodiments, the spacer contains no more than 10 non-hydrogen atoms. In certain embodiments, the spacer contains atoms chosen from C, H, N, O, and S. In certain embodiments, the spacer forms amide bonds with the two other groups to which it is attached.
  • the term “turn component” refers to a chain of about 4 to 10 contiguous atoms. In certain embodiments, the turn component contains atoms chosen from C, H, N, O, and S. In certain embodiments, the turn component forms amide bonds with the two other groups to which it is attached. In certain embodiments, the turn component contains at least one positive charge at physiological pH.
  • nucleic acid and nucleotide refer to ribonucleotide and deoxyribonucleotide, and analogs thereof, well known in the art.
  • oligonucleotide sequence refers to a plurality of nucleic acids having a defined sequence and length (e.g., 2, 3, 4, 5, 6, or even more nucleotides).
  • oligonucleotide repeat sequence refers to a contiguous expansion of oligonucleotide sequences.
  • RNA i.e., ribonucleic acid
  • modulate transcription refers to a change in transcriptional level which can be measured by methods well known in the art, for example, assay of mRNA, the product of transcription. In certain embodiments, modulation is an increase in transcription. In other embodiments, modulation is a decrease in transcription.
  • contacting refers to bringing the compound (e.g. a transcription molecular molecule of the present disclosure) into proximity of the desired target gene. The contacting may result in the binding to or result in a conformational change of the target moiety.
  • acyl refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon.
  • 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.
  • alkenyl refers to a straight-chain or branched- chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms.
  • alkenyl may include “alkenylene” groups.
  • alkoxy refers to an alkyl ether radical, wherein 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.
  • alkyl refers to a straight-chain or branched- chain alkyl radical containing from 1 to 20 carbon atoms.
  • said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 8 carbon atoms.
  • Alkyl groups 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.
  • alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH 2 -). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. [00367]
  • alkylamino refers to an alkyl group attached to the parent molecular moiety through an amino group.
  • alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- ethylmethylamino and the like.
  • alkylidene 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.
  • alkylthio refers to an alkyl thioether (R–S–) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.
  • suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n- butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.
  • alkynyl refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms.
  • alkynylene refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C C-).
  • 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.
  • alkynyl may include “alkynylene” groups.
  • acylamino as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group.
  • Amides may be formed by direct condensation of carboxylic acids with amines, or by using acid chlorides.
  • amino refers to -NRR ’ , wherein R and R ’ are independently chosen 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 heterocycloalkyl, either of which may be optionally substituted.
  • aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.
  • aryl embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
  • arylene embraces aromatic groups such as phenylene, naphthylene, anthracenylene, and phenanthrylene.
  • arylalkenyl or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
  • arylalkoxy or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
  • arylalkyl or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • arylalkynyl or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
  • arylalkanoyl or “aralkanoyl” or “aroyl,” as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4- chlorohydrocinnamoyl, and the like.
  • aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.
  • 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 from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
  • -carbamyl as used herein, alone or in combination, refers to a -OC(O)NRR’, group-with R and R’ as defined herein.
  • N-carbamyl refers to a ROC(O)NR’- group, with R and R’ as defined herein.
  • An “O-carboxy” group refers to a RC(O)O- group, where R is as defined herein.
  • cycloalkyl groups examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H- indenyl, adamantyl and the like.
  • “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • 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.
  • heteroalkyl refers to a stable straight or branched chain, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms chosen from N, O, and S, and wherein the N and S atoms may optionally be oxidized and the N heteroatom may optionally be quaternized.
  • the heteroatom(s) may be placed at any interior position of the heteroalkyl group.
  • heteroaryl refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from N, O, and S.
  • said heteroaryl will comprise from 1 to 4 heteroatoms as ring members.
  • said heteroaryl will comprise from 1 to 2 heteroatoms as ring members.
  • said heteroaryl will comprise from 5 to 7 atoms.
  • heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.
  • 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,
  • heterocyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • said heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said heterocycloalkyl will comprise from 5 to 6 ring members in each ring.
  • Heterocycloalkyl and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
  • heterocycle groups include tetrhydroisoquinoline, aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4- dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.
  • heterocycle groups may be optionally substituted unless specifically prohibited.
  • hydrazinyl as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.
  • hydroxy refers to -OH.
  • hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
  • the phrase “in the main chain” refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds or molecules of any one of the formulas disclosed herein.
  • the term “isocyanato” refers to a -NCO group.
  • the term “isothiocyanato” refers to a -NCS group.
  • linear chain of atoms refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
  • lower means containing from 1 to and including 6 carbon atoms (i.e., C 1 -C 6 alkyl).
  • lower aryl means phenyl or naphthyl, either of which may be optionally substituted as provided.
  • lower heteroaryl means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms chosen from N, O, and S, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms chosen from N, O, and S.
  • lower cycloalkyl means a monocyclic cycloalkyl having between three and six ring members (i.e., C 3 -C 6 cycloalkyl). Lower cycloalkyls may be unsaturated.
  • lower cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • lower heterocycloalkyl means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms chosen from N, O, and S (i.e., C 3 -C 6 heterocycloalkyl).
  • lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl.
  • Lower heterocycloalkyls may be unsaturated.
  • the term “lower amino,” as used herein, alone or in combination, refers to -NRR ’ , wherein R and R ’ are independently chosen from hydrogen and lower alkyl, either of which may be optionally substituted.
  • the term “mercaptyl” as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.
  • the terms “oxy” or “oxa,” as used herein, alone or in combination, refer to –O–.
  • perhaloalkoxy refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
  • perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • sulfonate refers the –SO3H group and its anion as the sulfonic acid is used in salt formation.
  • thia and thio refer to a –S– group or an ether wherein the oxygen is replaced with sulfur.
  • the oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
  • thiol as used herein, alone or in combination, refers to an —SH group.
  • thiocarbonyl when alone includes thioformyl –C(S)H and in combination is a –C(S)– group.
  • N-thiocarbamyl refers to an ROC(S)NR’ group, with R and R’ as defined herein.
  • O-thiocarbamyl refers to a OC(S)NRR’, group with R and R’ as defined herein.
  • thiocyanato refers to a CNS group.
  • trimethanesulfonamido refers to a X 3 CS(O) 2 NR group with X is a halogen and R as defined herein.
  • trimihalomethanesulfonyl refers to a X 3 CS(O) 2 group where X is a halogen.
  • trimihalomethoxy refers to a X 3 CO group where X is a halogen.
  • trimsubstituted silyl as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino.
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • the term “optionally substituted” means the anteceding group may be substituted or unsubstituted.
  • the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of 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
  • two substituents may be joined together to form a fused five-, six-, or seven- membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
  • An optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in- between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ).
  • substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with”. [00437] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group.
  • a group is deemed to be “substituted,” it is meant that the group is substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), C 3 -C7-carbocyclyl-C 1 -C 6 -alkyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkyl, and C 1 -C 6 haloalkoxy), 3-10 membered heterocyclyl (optionally substituted with halo, C 1
  • R or the term R’ appearing by itself and without a number designation, unless otherwise defined, refers to a moiety chosen from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted.
  • stereoisomers of compounds or molecules can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds or molecules of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds or molecules disclosed herein may exist as geometric isomers.
  • the present disclosure includes all cis, trans, syn, anti,
  • E
  • Z
  • compounds or molecules may exist as tautomers; all tautomeric isomers are provided by this disclosure.
  • the compounds or molecules disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
  • the term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • a bond may be single, double, or triple unless otherwise specified.
  • a dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
  • the term "combination therapy” means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. [00443] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.
  • treatment refers to those compounds or molecules (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • treatment As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment may also be preemptive in nature, i.e., it may include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression.
  • prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease.
  • patient is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.
  • prodrug refers to a compound or molecule that is made 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 compound that readily undergo chemical changes under physiological conditions to provide the compound.
  • prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug.
  • prodrug may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • a wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • the compounds or molecules disclosed herein can exist as therapeutically acceptable salts.
  • the present disclosure includes 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 will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound or molecule in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).
  • Basic addition salts can be prepared during the final isolation and purification of the compounds or molecules by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic 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.
  • nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, e
  • compositions of the 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 containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • the formulations described above may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the amount of active ingredient that may 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.
  • the compounds or molecules can be administered in various modes, e.g. orally, topically, or by injection.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, dmg combination, the precise disorder being treated, and the severity of the indication or condition being treated.
  • the route of administration may vary depending on the condition and its severity. The above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • DCM dichloromethane
  • DEAD diethyl azodicarboxylate
  • DIBAL-H di-iso-butyl aluminium hydride
  • DMAP 4-dimethylaminopyridine
  • DMF N,N- dimethylformamide
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • DPPA diphenylphosphoryl azide
  • Et 2 O diethyl ether
  • EtOAc ethyl acetate
  • EtOH ethanol
  • h hour
  • HATU 2-(1H-7- azabenzotriazol-l-yl)- 1,1,3,3 -tetramethyl uranium hex
  • T3P Propylphosphonic Anhydride
  • TEA trifluoroacetic acid
  • TFAA trifluoroacetic anhydride
  • THE tetrahydrofuran
  • Tol toluene
  • TsCl tosyl chloride
  • XPhos 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyL
  • Example 1 Synthesis of 3-([1-methyl-4-[3-([1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1- methylimidazole-2-amido)pyrrol-2-yl]formamidolpropanamido)imidazole-2-amido]pyrrol-2- yl]formamido)propanamidolimidazol-2-yl]formamido)propanoic acid (PA01-OH)
  • Step 1 Synthesis of ethyl 4-amino-1-methylimidazole-2-carboxylate
  • Step 2 Synthesis of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2- carboxylate
  • Step 4 Synthesis of methyl 4-(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1- methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate
  • Step 5 Synthesis of methyl 4-[4-(3-aminopropanamido)-1-methylimidazole-2-amido]-1- methylpyrrole-2-carboxylate hydrochloride
  • Step 6 Synthesis of methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1- methylimidazol-2-yl)formamido]propanoate
  • Step 7 Synthesis of methyl 3-[[4-(3-aminopropanamido)-1-methylimidazol-2-yl] formamido]propanoate hydrochloride
  • Step 8 Synthesis of methyl 1-methyl-4-(l-methylimidazole-2-amido)pyrrole-2-carboxylate
  • Step 9 Synthesis of 1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2-carboxylic acid
  • Step 10 Synthesis of methyl 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazole-2- amido)pyrrol-2-yl]formamido]propanamido)imidazole-2-amido]pyrrole-2-carboxylate
  • HATU 20.68 g, 54.38 mmol, 1.50 equiv
  • DIEA 14.06 g, 108.77 mmol, 3.00 equiv
  • methyl 4-[4-(3-aminopropanamido)-1- methylimidazole-2-amido]-1-methylpyrrole-2-carboxylate 13.89 g, 39.87
  • Step 11 Synthesis of 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazole-2- amido)pyrrol-2-yl]formamido]propanamido)imidazole-2-affordamido] pyrrole-2-carboxylic acid
  • Step 12 Synthesis of methyl 3-([1-methyl-4-[3-([1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1- methylimidazole-2-amido)pyrrol-2-yl]formamido] propanamido)imidazole-2-amido]pyrrol-2- yl]formamido)propanamido]imidazol-2-yl]formamido)propanoate [00484] To a stirred solution of 1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1-methylimidazole-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) was added HATU (12.12 g, 31.88 m
  • the resulting mixture was stirred for 2.0 h at room temperature.
  • the reaction was poured into water/ice (300 mL) at 0 °C.
  • the precipitated solids were collected by filtration and washed with H 2 O (3x30 mL), dried under vacuum.
  • Step 13 Synthesis of 3-([1-methyl-4-[3-([1-methyl-4-[1-methyl-4-(3-[[1-methyl-4-(1- methylimidazole-2-amido)pyrrol-2-yl]formamido]propanamido)imidazole-2-amido]pyrrol-2- yl]formamido)propanamido]imidazol-2-yl]formamido)propanoic acid
  • Step 1 Synthesis of ethyl 4-[4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole- 2-amido]-1- methylimidazole-2-carboxylate
  • 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
  • DMAP 14.62 g, 119.66 mmol, 2.50 equiv
  • Step 2 Synthesis of 4-[4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-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-methylpyrrole-2- amido]-1- methylimidazole-2-carboxylate was used, 638.00 mg of 4-[4-[(tert-butoxycarbonyl) amino]-1- methylpyrrole-2-amido]-1-methylimidazole-2-carboxylic acid was obtained as yellow solid (64.36% yield).
  • Step 3 Synthesis of methyl 4-(4- ⁇ 4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido ⁇ -1- methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate
  • 4- ⁇ 4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-amido ⁇ -1-methylimidazole-2-carboxylic acid (6.00 g, 16.51 mmol, 1.00 equiv) was dissolved in DMF (60.00 mL).
  • Step 4 Synthesis of methyl 4-[4-(4-amino-1-methylpyrrole- 2-amido)-1-methylimidazole-2- amido]-1-methylpyrrole-2-carboxylate
  • 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
  • DCM 2.50 mL
  • TFA 0.50 mL
  • Step 5 Synthesis of methyl 1-methyl-4-(1-methyl-4- ⁇ 1- methyl-4-[1-methyl-4-(1- methylimidazole-2-amido)pyrrole-2-amido]pyrrole-2-amido ⁇ imidazole-2-amido)pyrrole-2-carboxylate
  • PyBOP 361.16 mg, 0.69 mmol, 1.00 equiv
  • methyl 4-[4-(4-amino-1-methylpyrrole-2-amido)-1-methylimidazole-2-amido]-1-methylpyrrole-2- carboxylate 280.00 mg, 0.70 mmol, 1.00 equiv
  • DIEA 453.02 mg
  • Step 6 Synthesis of 1-methyl-4-(1-methyl-4- ⁇ 1-methyl-4-[1-methyl-4-(1-methylimidazole-2- amido)pyrrole-2-amido]pyrrole-2-amido ⁇ imidazole-2-amido)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).240.00 mg of methyl 1-methyl-4-(1-methyl-4- ⁇ 1- methyl-4-[1-methyl-4-(1-methylimidazole-2-amido)pyrrole-2-amido]pyrrole-2-amido ⁇ imidazole-2- amido)pyrrole-2-carboxylate was used,
  • 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.2.00g of ethyl 4-[3-[(tert-butoxycarbonyl)amino]propanamido]-1-methylimidazole-2-carboxylate was used, 2.00 g crude of ethyl 4-(3-aminopropanamido)-1-methyl-1H- imidazole-2-carboxylate was obtained as off-white solid.
  • LC/MS mass calcd.
  • Step 2 Synthesis of ethyl 1-methyl-4-[3-( ⁇ 1-methyl-4-[1-methyl-4-(3- ⁇ [1- [00506] methyl-4-(1-methylimidazole-2-amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazole-2- amido]pyrrol-2-yl ⁇ formamido)propanamido]imidazole-2-carboxylate [00507] The procedure was the same as methyl 4-(4- ⁇ 4-[(tert-butoxycarbonyl)amino]-1- methylpyrrole-2- amido ⁇ -1-methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate (Example 2 step 3).270.00 mg of 1- methyl-4-[1-methyl-4-(3- ⁇ [1-methyl-4-
  • Step 3 Synthesis of 1-methyl-4-[3-( ⁇ 1-methyl-4-[1-methyl-4-(3- ⁇ [1-methyl-4- (1- methylimidazole-2-amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazole-2-amido]pyrrol-2- yl ⁇ formamido)propanamido]imidazole-2-carboxylic acid [00509] The procedure was the same as 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-methyl)
  • Step 1 Synthesis of ethyl 4-amino-1H-pyrrole-2-carboxylate
  • the procedure was the same as 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, 4.00 g of ethyl 4-amino-1H-pyrrole-2-carboxylate was obtained as brown solid (95.56% yield).
  • Step 2 Synthesis of ethyl 4-amino-1H-pyrrole-2-carboxylate
  • 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 mins
  • PyBOP (4.39 g, 8.43 mmol, 1.30 equiv) was added, the reaction was stirred at room temperature for 1.0 h.
  • Step 3 Synthesis of 4-(1-methylimidazole-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, 2.00 g crude of 4-(1-methylimidazole-2-amido)-1H-pyrrole-2-carboxylic acid was obtained as brown solid.
  • Step 4 Synthesis of ethyl 1-methyl-4-(3- ⁇ [4-(1-methylimidazole-2-amido)-1H- pyrrol-2- yl]formamido ⁇ propanamido)imidazole-2-carboxylate [00519] The procedure was the same as ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4 step 2).1.60 g of 4-(1-methylimidazole-2-amido)- 1H-pyrrole-2-carboxylic acid was used, 1.10 g of ethyl 1-methyl-4- (3- ⁇ [4-(1-methylimidazole-2-amido)-1H-pyrrol-2-yl]formamido ⁇ propanamido)imidazole-2-carboxylate
  • Step 5 Synthesis of 1-methyl-4-(3- ⁇ [4-(1-methylimidazole-2-amido)-1H-pyrrol- 2- yl]formamido ⁇ propanamido)imidazole-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 time was 1.0 h and the reaction solvent was MeOH/THF(1:1).1.10 g of ethyl 1-methyl-4-(3- ⁇ [4-(1-methylimidazole-2-amido)-1H-pyrrol-2- yl]formamido ⁇ propanamido)imidazole-2-carbox
  • Step 6 Synthesis of ethyl 4-[1-methyl-4-(3- ⁇ [4-(1-methylimidazole-2-amido)- 1H-pyrrol-2- yl]formamido ⁇ propanamido)imidazole-2-amido]-1H-pyrrole-2-carboxylate [00523] The procedure was the same as methyl 4-(4- ⁇ 4-[(tert-butoxycarbonyl)amino]- 1-methylpyrrole-2- amido ⁇ -1-methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate (Example 3 step 2).760.00 mg of 1- methyl-4-(3- ⁇ [4-(1-methylimidazole- 2-amido)-1H-pyrrol-2-yl]formamido ⁇ propanamid
  • Step 7 Synthesis of 4-[1-methyl-4-(3- ⁇ [4-(1-methylimidazole-2-amido)-1H- pyrrol-2- yl]formamido ⁇ propanamido)imidazole-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 3), but the reaction temperature was 40 degrees C and the reaction time was 1.0 h.1.00 g of ethyl 4-[1-methyl-4-(3- ⁇ [4-(1-methylimidazole-2-amido)-1H-pyrrol-2- yl]formamido ⁇ prop
  • Step 8 Synthesis of ethyl 1-methyl-4-[3-( ⁇ 4-[1-methyl-4-(3- ⁇ [4-(1- methylimidazole-2-amido)- 1H-pyrrol-2-yl]formamido ⁇ propanamido)imidazole-2-amido]-1H-pyrrol-2- yl ⁇ formamido)propanamido]imidazole-2-carboxylate [00527] Into a 100 mL flask was added 4-[1-methyl-4-(3- ⁇ [4-(1-methylimidazole-2- amido)-1H-pyrrol-2- yl]formamido ⁇ propanamido)imidazole-2-amido]-1H-pyrrole-2-carboxylic acid (650.00 mg, 1.
  • the reaction was poured into ice water (30 mL), The precipitated solids were collected by filtration and washed with water (3x10 mL), dried under vacuum, the crude product was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), 10% to 50% gradient in 50 min; detector, UV 254 nm. The fractions were combined and concentrated.
  • Step 9 Synthesis of 1-methyl-4-[3-( ⁇ 4-[1-methyl-4-(3- ⁇ [4-(1-methylimidazole- 2-amido)-1H- pyrrol-2-yl]formamido ⁇ propanamido)imidazole-2-amido]-1H-pyrrol-2- yl ⁇ formamido)propanamido]imidazole-2-carboxylic acid (PA-048-Des) [00529] 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.310.00 mg of ethyl 1-methyl-4-[3-( ⁇ 4-[1-methyl-4-(3- ⁇ [4-(1-methylimidazole-2-amido)-1H- pyrrol-2-yl]formamido ⁇ propana
  • Step 1 Synthesis of ethyl 1-methyl-4-[(1r,3r)-3-[(tert-butoxycarbonyl)amino] cyclobutaneamido]imidazole-2-carboxylate
  • the procedure was the same as methyl 3-[(4-[3-[(tert-butoxycarbonyl)amino] propanamido]-1- methylimidazol-2-yl)formamido]propanoate.200.00 mg of (1r,3r)-3-[(tert- butoxycarbonyl)amino]cyclobutane-1-carboxylic acid was used, 330.00 mg of ethyl 1-methyl-4-[(1r,3r)-3- [(tert-butoxycarbonyl)amino] cyclobutaneamido]imidazole-2-carboxylate was obtained as orange solid (96.93% yield).
  • Step 2 Synthesis of ethyl 1-methyl-4-[(1r,3r)-3-aminocyclobutaneamido] imidazole-2- carboxylate
  • the procedure was the same as 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]cyclobutaneamido]imidazole-2-carboxylate was used, 145.00 mg crude of ethyl 1-methyl-4-[(1r,3r)-3-aminocyclobutaneamido
  • Step 3 Synthesis 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]formamido ⁇ propanamido)imidazole-2-amido]pyrrole-2- amido ⁇ cyclobutaneamido]imidazole-2-carboxylate [00537] The procedure was the same as methyl 4-(4- ⁇ 4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2- amido ⁇ -1-methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate (Example 2 Step 3).105.00 mg of ethyl 1-methyl-4-[(1r,3r)-3- ⁇ 1-methyl-4-[1-methyl-4-(3- ⁇ [1- methyl-4-(1- methylimidazole-2-a
  • Step 4 Synthesis of 1-methyl-4-[(1r,3r)-3- ⁇ 1-methyl-4-[1-methyl-4-(3- ⁇ [1- methyl-4-(1- methylimidazole-2-amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazole-2-amido]pyrrole-2- amido ⁇ cyclobutaneamido]imidazole-2-carboxylic acid (PA-048-P6CB) [00539] The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino] propanamido]-1- methylimidazole-2-carboxylic acid (Example 1 Step 3).250.00 mg of ethyl 1-methyl-4-[(1r,3r)-3- ⁇ 1- methyl
  • Step 1 Synthesis of 4-bromo-7-methoxy-1-(4-methylbenzenesulfonyl)pyrrolo [2,3-c]pyridine
  • Step 1 Synthesis of 4-bromo-7-methoxy-1-(4-methylbenzenesulfonyl)pyrrolo [2,3-c]pyridine
  • Step 2 Synthesis of ethyl 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine- 2-carboxylate
  • 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) was added LDA (2M in THF, 12.50 mL, 24.87 mmol, 1.50 equiv) dropwise at -78 °C and the mixture stirred at -78 °C to -50 °C for 1.0 h, followed by dropwise addition of ClCOOEt (2.69 g, 24.87 mmol, 1.50 equiv).
  • Step 3 Synthesis of ethyl 4-bromo-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c] pyridine-2- carboxylate [00551] To 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 CH 3 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 portions at room temperature under N2 atmosphere.
  • Step 4 Synthesis of ethyl 4-bromo-6-methyl-1-(4-methylbenzenesulfonyl)-7- oxopyrrolo[2,3- c]pyridine-2-carboxylate [00553] 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), MeI (1.67 g, 11.78 mmol, 1.20 equiv) was added dropwise into this reaction.
  • 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
  • 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) was added 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
  • Step 8 Synthesis of methyl 3-hromo-4-(4-fluoro-2,6-dlmethylphenoxy)henzoate
  • Step 9 Synthesis of 2-[3-hromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl]propan- 2-ol
  • 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 [00565] 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 di
  • the resulting mixture was stirred for 1.0 h at 75 °C under N 2 atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3x20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • 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 [00567] 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) were added KOH (2M, 3.71 mL, 7.42 mmol, 8.00 equiv) at room temperature.
  • 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 [00571] 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) was added sodium ethoxide (894.40 mg, 13.14 mmol, 2.50 equiv) at room temperature.
  • 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 ethyl 1-(5-bromopentyl)-4-[(tert-butoxycarbonyl)amino]pyrrole-2- carboxylate, but the reaction time was 2.0 h.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 was used, 500.00 mg of ethyl 1-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)
  • 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 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
  • Step 1 Synthesis of ethyl 4-bromo-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate [00579] 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).
  • 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
  • the final reaction mixture was irradiated with microwave radiation for 1.0 h at 120 °C. The reaction was proceeded on 1.0 g scale and 13 times were repeated. Then the reaction mixtures were combined and worked up together. 150 mL H 2 O was added, the resulting mixture was extracted with EA (3x150 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 3 Synthesis of 5-fluoro-2-(4-methanesulfonyl-2-nitrophenoxy)-1,3-dimethylbenzene
  • the procedure was the same as methyl 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzoate, but the reaction temperature was 120 °C and the reaction time was 1.0 h. 2.00 g of 4-fluoro-2,6-dimethylphenol was used, 4.60 g of desired product was obtained as off-white solid (94.05% yield).
  • Step 5 Synthesis of 5- fluoro-2-(2-iodo-4-methanesulfonylphenoxy)-1,3-dimethylbenzene
  • 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
  • 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 [00591] 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) was added caustic soda (74.91 mg, 1.87 mmol, 4.00 equiv) at room temperature.
  • Step 1 Synthesis of 2-bromo-4-(ethanesulfonyl)-1-fluorobenzene
  • fluoresone (1.00 g, 5.31 mmol, 1.00 equiv) in H 2 SO 4 (6.00 mL)
  • 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).
  • Step 2 Synthesis of 2-[2-bromo-4-(ethanesulfonyl)phenoxy]-5-fluoro-1,3- dimethylbenzene
  • the procedure was the same as 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 for next step without purification.870.00 mg of 1,3-Dibromo-5-(ethanesulfonyl)- 2- fluorobenzene was used, 950.00 mg of 2-[2-bromo-4-(ethanesulfonyl) phenoxy]-5-fluoro-1,3- dimethylbenzene was obtained as yellow solid (97.56% yield).
  • Step 3 Synthesis of 2-[2-bromo-4-(ethanesulfonyl)phenoxy]-5- fluoro-1,3-dimethylbenzene
  • the procedure was the same as 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.950.00 mg of 2-[2-bromo-4- (ethanesulfonyl)phenoxy]-5-fluoro- 1,3-dimethylbenzene was used, 870.00 mg of ethyl
  • 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 [00601] The procedure was the same as 4-[3-[(tert-butoxycarbonyl)amino] propanamido]-1- methylimidazole-2-carboxylic acid.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 was used, 590.00 mg of 4-[5-(ethanesulfonyl)-2-(4-fluoro-2,6- dimethylphenoxy)phenyl]-6- methyl-7-oxo-1H
  • Step 1 Synthesis of 1-(2,4-difluorophenoxy)-4-methanesulfonyl-2-nitrobenzene
  • DMSO dimethyl sulfoxide
  • 1-fluoro-4-methanesulfonyl-2-nitrobenzene 3.00 g, 13.682 mmol, 1.00 equiv
  • K 2 CO 3 1.89 g, 13.68 mmol, 1.00 equiv
  • Step 2 Synthesis of 2-(2,4-difluorophenoxy)-5-methanesulfonylaniline
  • Step 3 Synthesis of 1-(2,4-difluorophenoxy)-2-iodo-4-methanesulfonylbenzene
  • Step 4 Synthesis of ethyl 4-[2-(2,4-dlfluorophenoxy)-5-methanesulfonylphenyl]- 6-methyl-7- oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
  • Step 5 Synthesis of 4-[2-(2,4-dlfluorophenoxy)-5-methanesulfonylphenyl]- 6-methyl-7-oxo-1H- pyrrolo[2,3-c]pyridine-2-carboxylic acid
  • Step 1 Synthesis of benzyl N-(4- ⁇ [26-( ⁇ 1-methyl-4-[3-( ⁇ 1-methyl-4-[1-methyl-4-(3- ⁇ [1-methyl-4- (1-methylimidazole-2-amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazole-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 [00621] The procedure was the same as methyl 1-methyl-4-(1-methyl-4- ⁇ 1-methyl-4-[1-methyl-4-(1- methylimidazole-2-amido)pyrrole-2-amido]pyrrole-2-amido ⁇ imidazole-2-amido)pyrrole-2-amido
  • 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-methylimidazole-2-amido)pyrrol-2- yl]formamido ⁇ propanamido)imidazole-2-amido]pyrrol-2-yl ⁇ formamido)propanamido]imidazole-2- carboxamide [00623] The procedure was the same as 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 ⁇ e
  • Step 1 Synthesis of benzyl N-(4- ⁇ [26-( ⁇ 1-methyl-4-[3-( ⁇ 4-[1-methyl-4-(3- ⁇ [4-(1- methylimidazole-2-amido)-1H-pyrrol-2-yl]formamido ⁇ propanamido)imidazole-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 [00629] The procedure was the same as methyl 4-(4- ⁇ 4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2- amido ⁇ -1-methylimidazole-2-amido)-1-methylpyrrole-2-carboxylate (Example 2 Step 3).
  • 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-methylimidazole-2-amido)-1H-pyrrol-2- yl]formamido ⁇ propanamido)imidazole-2-amido]-1H-pyrrol-2-yl ⁇ formamido)propanamido]imidazole-2- carboxamide [00631] The procedure was the same as 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]-1- methyl-4-[3-( ⁇ 4
  • Step 1 Synthesis of 2-(benzyloxy)-5-nitrophenol
  • 4-nitrocatechol (1.00 g, 6.45 mmol, 1.00 equiv) in DMF (10.00 mL)
  • NaH 60%, 0.15 g, 6.45 mmol, 1.00 equiv
  • the resulting mixture was stirred for 1.0 h at room temperature.
  • 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 for additional 17.0 h at room temperature.
  • Step 2 Synthesis of 19-[2-(benzyloxy)-5-nitrophenoxy]-2,5,8,11,14,17- hexaoxanonadecane
  • the procedure was the same as 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.400.00 mg of 2-(benzyloxy)-5-nitrophenol was used, 670.00 mg of 19-[2- (benzyloxy)-5-nitrophenoxy]-2,5,8,11,14,17-hexaoxanonadecane was obtained as light yellow oil (78.45% yield).
  • Step 3 Synthesis of 2-(2,5,8,11,14,17-hexaoxanonadecan-19-yloxy)-4-nitrophenol [00641] 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 for 2.0 h at 70 degrees C.
  • Step 4 Synthesis of tert-butyl N- ⁇ 26-[2-(2,5,8,11,14,17-hexaoxanonadecan-19-yloxy)-4- nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl ⁇ carbamate
  • the procedure was the same as 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.550.00 mg of 2-(2,5,8,11,14,17- hexaoxanonadecan-19-yloxy)-4- nitrophen
  • Step 5 Synthesis of 26-[2-(2,5,8,11,14,17-hexaoxanonadecan-19-yloxy)-4-nitrophenoxy]- 3,6,9,12,15,18,21,24-octaoxahexacosan-1-amine [00645] The procedure was the same as methyl 4-[4-(4-amino-1-methylpyrrole-2-amido)-1- methylimidazole-2-amido]-1-methylpyrrole-2-carboxylate (Example 2 step 3).410.00 mg of tert-butyl N- ⁇ 26-[2-(2,5,8,11,14,17-hexaoxanonadecan-19-yloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24
  • Step 6 Synthesis of N-[5-( ⁇ 2-[(2- ⁇ [2-( ⁇ 26-[2-(2,5,8,11,14,17-hexaoxanonadecan-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- methylimidazole-2-amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazole-2-carbox
  • Step 7 Synthesis of N-[5-( ⁇ 2-[(2- ⁇ [2-( ⁇ 26-[4-amino-2-(2,5,8,11,14,17-hexaoxanonadecan-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- methylimidazole-2-amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazo
  • Step 8 Synthesis of Compound 4 [00651] The procedure was the same as N-(5- ⁇ [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]pyridine-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-(
  • 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
  • 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 2 O (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
  • 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-methylimidazole-2-amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazole-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 [00657] The procedure was the same as methyl 1-methyl-4-(1-methyl-4- ⁇ 1-methyl-4-
  • 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-methylimidazole-2- amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazole-2-carboxamide [00659] The procedure was the same as methyl 4-[
  • Step 1 Synthesis of benzyl N-[(4-hydroxyphenyl)methyl]carbamate
  • 4-(aminomethyl)phenol 500.00 mg, 4.060 mmol, 1.00 equiv
  • THF 8.00 mL
  • H 2 O 8.00 mL
  • 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 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).300.00 mg of benzyl N-[(4- hydroxyphenyl)methyl]carbamate was used, 720.00 mg of benzyl N- ⁇ [4
  • 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 methyl 4-[4-(3-aminopropanamido)-1- methylimidazole-2-amido]- 1-methylpyrrole-2-carboxylate hydrochloride, but the reaction solvent was 4M HCl in dioxane/DCM (1:1) and the reaction time was 1.0 h.690.00 mg of benzyl N- ⁇ [4-( ⁇ 26-[(tert-butoxycarbonyl)amino]- 3,6,9,12,15,18,21,24-octao
  • Step 4 Synthesis of benzyl N- ⁇ [4-( ⁇ 26-[3-( ⁇ 1-methyl-4-[3-( ⁇ 1-methyl-4-[1-methyl-4-(3- ⁇ [1- methyl-4-(1-methylimidazole-2-amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazole-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 [00671] The procedure was the same as methyl 4-(4- ⁇ 4-[(tert-butoxycarbonyl)
  • 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-methylimidazole-2-amido)pyrrol-2- yl]formamido ⁇ propanamido)imidazole-2-carboxamide [00673] The procedure was the same as 9H-fluoren-9-y
  • 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-methylimidazole-2-amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazole-2-amido]pyrrole-2- amido ⁇ cyclobutaneamido]imidazol-2-yl ⁇ formamido)-3,6,9,12,15,18,21,24-octaoxahexacosan-1- yl]oxy ⁇ phenyl)carbamate [00691] The procedure was the same as ethyl 4-amino-1H-pyrrole-2-carboxylate (Example 4 step 2).
  • Step 2 Synthesis of 1-methyl-4-(3- ⁇ [1-methyl-4-(1-methylimidazole- 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 [00693] The procedure was the same as ethyl 4-amino-1-methylimidazole-2- carboxylate (Example 1 step 2), but the reaction time was 2.0 h and solvent was DMF.240.00 mg of benzyl N-(4- ⁇ [26-
  • Example 23 Synthesis of N-(5- ⁇ [2-( ⁇ 2-[(2- ⁇ [26-(4- ⁇ 4-[2-(4-fluoro-2.6-dimethylphenoxy)-5-(2- hydroxynronan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2.3-c]pyridine-2-amido ⁇ -2-hydroxyphenoxy)-
  • Step 2 Synthesis of 2-(benzyloxy)-1-fluoro-4-nitrobenzene
  • 2-(benzyloxy)-1-fluoro-4-nitrobenzene (INT-503-201) was synthesized by using NaH (60%1.00 equiv) in DMF as a solvent 0 °C to room temperature and the reaction time was 2.0 h.100.00 mg of 2- (benzyloxy)-1-fluoro-4-nitrobenzene was used, 290.00 mg of tert-butyl N- ⁇ 26-[2-(benzyloxy)-4- nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-yl ⁇ carbamate was obtained as yellow oil (96.78% yield).
  • Step 3 Synthesis of 26-[2-(benzyloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan- 1-amine [00703] The procedure was the same as 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, 240.00 mg crude of 26- [2-(benzyloxy)-4-nitrophenoxy]-3,6,9,12,15,18,21,24-octaoxahexacosan-1-amine was obtained as yellow oil.
  • 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-methylimidazole-2-amido)pyrrol-2- yl]formamido ⁇ propanamido)imidazole-2-carboxamide [00705] The procedure was the same as Example 2 step 5.240.00 mg of 26-[
  • 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-methylimidazole-2-amido)pyrrol-2- yl]formamido ⁇ propanamido)imidazole-2-carboxamide [00707] The procedure was the same as ethyl 4-amino-1-methyl
  • Step 7 Synthesis of Compound 12 [00711] To a stirred solution of 5- ⁇ 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2- yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-amido ⁇ -2-( ⁇ 26-[3-( ⁇ 1-methyl-4-[3-( ⁇ 1-methyl-4- [1-methyl-4-(3- ⁇ [1-methyl-4-(1-methylimidazole-2-amido)pyrrol-2-yl]formamido ⁇ propanamido)imidazole- 2-amido]pyrrol-2-yl ⁇ formamido)propanamido]imidazol-2-yl ⁇ formamido)prop
  • Step 1 Synthesis of methyl 3-bromo-4-(2,6-dimethyl-4-nitrophenoxy)benzoate
  • Step 2 Synthesis of methyl 4-(4-amino-2,6-dimethylphenoxy)-3-bromobenzoate
  • Step 3 Synthesis of 3-bromo-4-(4-hydroxy-2,6-dimethylphenoxy)benzoate [00726] Methyl 4-(4-amino-2,6-dimethylphenoxy)-3-bromobenzoate (1.30 g, 3.71 mmol, 1.00 equiv) was dissolved in a cooled solution of H 2 O (10.00 mL) and 2 M H 2 SO 4 (5.00 mL) and NaNO 2 (0.26 g, 3.71 mmol, 1.00 equiv) was added.
  • 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 [00728] 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
  • 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 [00730] 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
  • 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 into a mixture of 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 2 CO 3 (149.04 mg, 1.41 mmol, 1.50 equiv) in H 2 O (10.00 mL) and THF
  • 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 [00734] To a stirred solution 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 (680.00 mg, 0.77 mmol, 1.00 equiv) in THF (10.00 mL) was added MeMgBr
  • Step 8 Synthesis of ethyl 4-(2- ⁇ 4-[(26- ⁇ [(benzyloxy)carbonyl]amino ⁇ -3,6,9,12,15,18,21,24- octaoxahexacosan-1-yl)oxy]-2,6-dimethylphenoxy ⁇ -5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-1H- pyrrolo[2,3-c]pyridine-2-carboxylate [00736] To a stirred mixture 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 (450.00 mg, 0.51 mmol, 1.00 equiv), ethyl 6-methyl-7-oxo-4-(
  • Step 9 Synthesis of 4-(2- ⁇ 4-[(26- ⁇ [(benzyloxy)carbonyl]amino ⁇ -3,6,9,12,15,18,21,24- octaoxahexacosan-1-yl)oxy]-2,6-dimethylphenoxy ⁇ -5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-1H- pyrrolo[2,3-c]pyridine-2-carboxylic acid [00738] To a stirred solution of ethyl 4-(2- ⁇ 4-[(26- ⁇ [(benzyloxy)carbonyl]amino ⁇ -3,6,9,12,15,18,21,24- octaoxahexacosan-1-yl)oxy]-2,6-dimethylphenoxy ⁇ -5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-1H- pyrrolo[2,3-c]pyr
  • Step 10 Synthesis of benzyl N-[26-(4- ⁇ 2-[2-(ethylcarbamoyl)-6-methyl-7-oxo-1H-pyrrolo[2,3- c]pyridin-4-yl]-4-(2-hydroxypropan-2-yl)phenoxy ⁇ -3,5-dimethylphenoxy)-3,6,9,12,15,18,21,24- octaoxahexacosan-1-yl]carbamate [00740] To a stirred mixture of 4-(2- ⁇ 4-[(26- ⁇ [(benzyloxy)carbonyl]amino ⁇ -3,6,9,12,15,18,21,24- octaoxahexacosan-1-yl)oxy]-2,6-dimethylphenoxy ⁇
  • Step 11 Synthesis of 4-(2- ⁇ 4-[2-(2-aminoethoxy)ethoxy]-2,6-dimethylphenoxy ⁇ -5-(2- hydroxypropan-2-yl)phenyl)-N-ethyl-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
  • Example 27 General synthesis and purification of the compounds of the disclosure
  • Method A Instrument: Waters Acquity I Class UPLC with Xevo G2-XSQ Tof HRMS; Column: ACQUITY UPLC BEH-C18, 2.1 x 50 mm, 2.7 pm; mobile phase A: H 2 O (0.1% HCOOH), mobile B, CAN (0.1% HCOOH); Flow rate:0.4mL/min; Gradient: 10% B to 95% B in 1.5 min, hold 95% for another 0.5 min, then down to 10% B in 0.3 min, hold 10% B for another 0.7 min; detector: 254nm.
  • Method B Instrument: Waters Acquity I Class UPLC with Xevo G2-XS Q Tof HRMS; Column: ACQUITY UPLC BEH-C18, 2.1 x 50 mm, 2.7pm; mobile phase A: H 2 O (0.1% HCOOH), mobile B, CAN (0.1% HCOOH); Flow rate:0.4 mL/min; Gradient: 5% B to 40% B in 2.0min, to 95% in another 1.5 min, hold 95% for 1.5 min, then down to 5% B in 0.3 min, hold 5% B for another 0.7 min; detector: 254nm. [00749] Experimental data for the compounds of the disclosure purified by Method A are provided in Table 4.
  • Example B1 EC50 Assay
  • Cell culture Cells were cultured in RPMI1640 medium + 15% FBS. Cells were maintained at a density between 2 x 10 6 /mL and 1 x 0 6 /mL. Cells were centrifuged, resuspended in fresh medium, counted and plated at 150,000 cells per well in 100 ⁇ L in a non-coated, flat bottom tissue culture plate.
  • Compound treatment 10 mM stock solution of FA GeneTAC was diluted 1:10 in DMSO followed by a 1:100 dilution in growth medium. Working solution was then further diluted to 10X desired final concentration of 150 nM.
  • RNA isolation Total RNA was isolated and purified in 384-well column filter plates using chaotropic salt.
  • qRT-PCR qRT-PCR reactions were assembled using AgPath-ID reagents (Thermo Fisher) using 6uL mastermix and 4 ⁇ L RNA. qRT-PCR TaqMan primer probe sets against human FXN (Assay ID Hs01075496_m1) and human GAPDH (Assay ID Hs00266705_g1) were used to measure the intended targets. qRT-PCR was run on the ThermoFisher QuantStudio 6 PRO instrument using the manufacturer's recommended cycling conditions. [00755] Data analysis: qPCR data was analyzed using Thermo Fisher Design and Analysis software.

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